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WO2025040156A1 - Composé macrocyclique, sa préparation et son utilisation - Google Patents

Composé macrocyclique, sa préparation et son utilisation Download PDF

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Publication number
WO2025040156A1
WO2025040156A1 PCT/CN2024/114006 CN2024114006W WO2025040156A1 WO 2025040156 A1 WO2025040156 A1 WO 2025040156A1 CN 2024114006 W CN2024114006 W CN 2024114006W WO 2025040156 A1 WO2025040156 A1 WO 2025040156A1
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alkyl
group
halogenated
cycloalkyl
alkoxy
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Chinese (zh)
Inventor
牛成山
陈明涛
李元杰
郑茂林
窦雨歌
姬凯歌
李美华
梁阿朋
陈少清
李钧
吴豫生
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TYK Medicines Inc
TYK Medicines Zhengzhou Inc
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TYK Medicines Inc
TYK Medicines Zhengzhou Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
    • 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
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the present invention relates to the field of medical technology, and in particular to a class of macrocyclic compounds used as CDK2 kinase inhibitors.
  • Cyclin-dependent kinases are a family of serine/threonine kinases, important cellular enzymes that perform essential functions in regulating cell division and proliferation.
  • CDKs and regulatory subunits cyclins
  • Uncontrolled proliferation is a characteristic of cancer cells.
  • Abnormal regulation of CDK activity is associated with abnormal regulation of the cell cycle and can be detected in almost all forms of human cancer (Sherr, c.j., Science, 1996, 274(5293): 1672-7).
  • CDK2 plays a crucial role in G1/S transition and S phase progression.
  • CDK2 and cyclin E (CCNE) complex phosphorylates retinoblastoma pocket protein family members (p107, p130, pRb), releases E2F transcription factor, and promotes the transition from G1 phase to S phase (Henley, S.A. and F.A. Dick, Cell Div, 2012, 7(1):10).
  • CDK2/cyclin A is then activated to phosphorylate endogenous substrates, thereby allowing DNA synthesis, replication, and centrosome duplication (Ekholm, S.V. and S.I. Reed, Curr Opin Cell Biol, 2000, 12(6):67684). It is reported that the CDK2 pathway mainly affects tumorigenesis through the amplification and/or overexpression of CCNE1 and the mutational inactivation of CDK2 endogenous inhibitors (such as p27).
  • CCNE1 copy number gain and overexpression have been demonstrated in ovarian, gastric, endometrial, breast, and other tumors and are associated with poor prognosis in these tumors (Keyomarsi, K., et al., N Engl J Med., 2002, 347(20):1566-75; Nakayama, N., et al., Cancer, 2010, 116(11):2621-34; Au-Yeung, G., et al., Clin Cancer Res, 2017, 23(7):1862-1874; Rosen, D.G., et al., Cancer, 2006, 106(9):1925-32).
  • CCNE1 Amplification and/or overexpression of CCNE1 have also been reported to lead to trastuzumab resistance in HER2+ breast cancer and resistance to CDK4/6 inhibitors in estrogen receptor-positive breast cancer. Inhibitors targeting CDK2 have been shown to induce apoptosis and inhibit tumor proliferation.
  • CDK2 kinase inhibitors have broad application prospects.
  • One object of the present invention is to provide a macrocyclic compound as a CDK2 kinase inhibitor and its use.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer or deuterated product thereof,
  • Ring A is selected from the following group: C 4-6 cycloalkyl, saturated or partially saturated 5-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6 membered heteroaryl or phenyl-5-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl-5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, wherein the group is optionally substituted by 0, 1, 2, 3 or 4 R 1 ;
  • Ring B is selected from the group consisting of:
  • R is selected from the following group: H, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S;
  • Ra is independently selected from the group consisting of hydrogen, C1-4 alkyl, halogenated C1-4 alkyl, deuterated C1-4 alkyl, C3-6 cycloalkyl, and 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S;
  • the compound has a structure selected from the following group:
  • Ring A, X 1 , X 2 , L 1 , and R are as defined herein;
  • ring A has a structure selected from the following group:
  • Y 1 is selected from the following group: N, CH;
  • Y 2 is selected from the following group: N, CH;
  • Y 3 is selected from the following group: NH, NR 1 , O, CH 2 ;
  • ring A is
  • ring A is
  • ring A is
  • ring A is
  • ring A is selected from the following group:
  • X1 is a bond or a C1-3 alkylene group; wherein the C1-3 alkylene group is optionally substituted by 0, 1 or 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, C1-3 alkyl and halogenated C1-3 alkyl.
  • L 1 is O or S; preferably L 1 is O.
  • X2 is a bond, a C1-6 alkylene group, or a C3-6 cycloalkyl group; wherein the C1-6 alkylene group or the C3-6 cycloalkyl group is optionally substituted by 0, 1 or 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, C1-3 alkyl and halogenated C1-3 alkyl.
  • X3 is a bond, -NR-, a C3-6 cycloalkyl, or a 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, wherein the C3-6 cycloalkyl, or the 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S is optionally substituted by 0, 1 or 2, 3 or 4 substituents selected from the following groups: deuterium, halogen, C1-3 alkyl and halogenated C1-3 alkyl; R is selected from the following groups: H, C1-4 alkyl, halogenated C1-4 alkyl, deuterated C1-4 alkyl or C3-4 cycloalkyl.
  • X2 has a structure selected from the following group:
  • ring C has a structure selected from the following group:
  • R 1 is independently selected from the group consisting of C 1-3 alkyl, halogenated C 1-3 alkyl and C 3-6 cycloalkyl; more preferably methyl, ethyl, isopropyl, CF 2 CH 2 —, CF 3 CH 2 —, and cyclopropyl.
  • the present invention provides a compound of formula Ia, or a pharmaceutically acceptable salt, stereoisomer or deuterated product thereof,
  • X1 and L1 are each independently a bond, -O-, -S-, -NRa- , substituted or unsubstituted C1-6 alkylene, substituted or unsubstituted C2-10 alkenylene, substituted or unsubstituted C2-10 alkynylene, substituted or unsubstituted C3-6 cycloalkylene, substituted or unsubstituted 3-6 membered heterocycloalkylene containing 1-2 heteroatoms independently selected from N, O or S, -( CH2 )0-4O-, -(CH2) 0-4S- , -( CH2 ) 0-4NRa- , -C(O) - , -NRaC(O)-, -C(O) NRa- , wherein the substitution refers to that one or more hydrogen atoms (e.g., 1, 2, 3 or 4 ) on the group are replaced by a substituent selected from the group consisting of deuterium
  • Ring A is selected from the following group: a substituted or unsubstituted saturated or partially saturated 5-6 membered heterocyclic group containing 1-4 heteroatoms independently selected from N, O or S, a substituted or unsubstituted oxo 9-10 membered ring, wherein the substitution refers to one or more hydrogen atoms (e.g., 1, 2, 3, 4, 5 or 6) on the group being replaced by R1 ,
  • Ra is independently selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C3-6 cycloalkyl, and 3-6 membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N, O or S;
  • X1 and L1 are each independently a bond, -O-, -S-, -NRa- , substituted or unsubstituted C1-6 alkylene, substituted or unsubstituted C2-6 alkenylene, substituted or unsubstituted C2-6 alkynylene, substituted or unsubstituted C3-6 cycloalkylene, substituted or unsubstituted 3-6 membered heterocycloalkylene containing 1-2 heteroatoms independently selected from N, O or S, -(CH2)0-2O-, -( CH2 ) 0-2S- , -( CH2 ) 0-2NRa- , -C(O)-, -NRaC(O) - , -C(O) NRa- , wherein the substitution refers to that one or more hydrogen atoms (e.g., 1, 2, 3 or 4) on the group are replaced by a substituent selected from the group consisting of de
  • Ring A is selected from the following group: a substituted or unsubstituted saturated or partially saturated 5-6 membered heterocyclic group containing 1-4 heteroatoms independently selected from N, O or S, a substituted or unsubstituted oxo 9-10 membered ring, wherein the substitution refers to one or more hydrogen atoms (e.g., 1, 2, 3, 4, 5 or 6) on the group being replaced by R1 ,
  • Ra is independently selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C3-6 cycloalkyl, and 3-6 membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N, O or S;
  • R b and R c are each independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N, O or S, -(CH 2 ) 0-2 (C 3-6 cycloalkyl), -(CH 2 ) 0-2 (3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N, O or S), wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxy, halogen, cyano, oxo ( ⁇ O), C 1-6 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkyl, halogenated C
  • Rb and Rc together with the N to which they are attached form a 3-6 membered heteroatom containing 1, 2 or 3 heteroatoms selected from N, O or S.
  • the compound has a structure shown in Formula II-a or Formula III-a:
  • ring A, X 1 , X 2 and L 1 are as defined in the first aspect of the present invention.
  • ring A is selected from the following group: substituted or unsubstituted oxo 5-membered heterocyclic 6-membered heteroaryl, substituted or unsubstituted oxo 5-6-membered heteroaryl.
  • ring A is selected from the following group: substituted or unsubstituted oxo 9-10 membered ring.
  • ring A is a structure selected from the following group:
  • Y 1 is selected from the group consisting of N, CH;
  • Y2 is selected from the group consisting of N, CH;
  • Y 3 is selected from the group consisting of NH, NR 1 , O, S, CH 2 ;
  • -6-membered heterocycloalkyl 5-6-membered heteroaryl containing 1 or 2 heteroatoms each independently selected from N, O or S , -SO2Rb , -C(O) ORb , -SO2NRbRc , -OC (O) NRbRc , -C ( O) NRbRc , -NRbSO2Rc , -NRbC ( O ) ORc ;
  • n is selected from the following group: 0, 1, 2, 3, 4, 5, 6;
  • ring A is wherein, Y 1 , Y 2 , Y 3 and R 1 are as shown in the second aspect of the present invention.
  • ring A is wherein, Y 1 , Y 2 , Y 3 and R 1 are as shown in the second aspect of the present invention.
  • ring A is wherein, Y 1 , Y 2 , Y 3 and R 1 are as shown in the second aspect of the present invention.
  • ring A is wherein, Y 1 , Y 2 , Y 3 , m, and R 1 are as shown in the second aspect of the present invention.
  • X 2 is selected from the following group: a bond, a substituted or unsubstituted C 1-6 alkylene group, a substituted or unsubstituted C 2-6 alkenylene group, a substituted or unsubstituted C 2-6 alkynylene group, a substituted or unsubstituted C 3-6 cycloalkylene group, -(CH 2 ) 0-4 (C 3-6 cycloalkyl group);
  • X2 is selected from the following group:
  • ring A is selected from the following group:
  • X 1 is selected from the group consisting of a bond, -O-, a substituted or unsubstituted C 1-6 alkylene group;
  • L 1 is selected from the group consisting of a bond, -O-, -S-, a substituted or unsubstituted C 1-6 alkylene group;
  • X2 is selected from the following group:
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds described in the first or second aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, and a pharmaceutically acceptable carrier.
  • the compound in the composition, accounts for 0.001-99.999wt% of the total weight of the composition; preferably 0.01-99.99wt%; more preferably 0.1-90wt%.
  • the pharmaceutical composition is in the form of an injection, tablet, capsule, pill, suspension or emulsion.
  • the compound described in the first or second aspect of the present invention or the pharmaceutical composition described in the second aspect of the present invention for preparing a drug or preparation, wherein the drug or preparation is used for (a) regulating CDK kinase activity, and/or (b) preventing and/or treating CDK-related diseases.
  • the CDK kinase is CDK2 kinase.
  • the CDK-related disease is cancer.
  • the cell cycle protein-related disease is cancer.
  • the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, prostate cancer, melanoma Pigmented tumor, brain tumor, esophageal cancer, gastric cancer, liver cancer (including HCC), pancreatic cancer, colorectal cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), kidney cancer (including RCC), skin cancer, glioblastoma, glioblastoma, mantle cell lymphoma (MCL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), neuroblastoma, sarcoma, liposarcoma, chondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureteral tumor, bladder tumor, gallblad
  • the fourth aspect of the present invention there is provided a use of the compound described in the first or second aspect of the present invention or the pharmaceutical composition described in the third aspect of the present invention for preparing a drug or preparation, wherein the drug or preparation is used to prevent and/or treat cell cycle protein-related diseases.
  • the cell cycle protein is cyclin E.
  • the cyclin E is selected from the following group: cyclin E1 and cyclin E2.
  • the cell cycle protein-related disease is cancer.
  • the cancer is selected from the following group: breast cancer, ovarian cancer, bladder cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer (including HCC), pancreatic cancer, colorectal cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), renal cancer (including RCC), skin cancer, glioblastoma, glioblastoma, mantle cell lymphoma (MCL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), neuroblastoma, sarcoma, liposarcoma, chondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureteral tumor, bladder tumor, gallbladder cancer,
  • the present invention provides use of the compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or deuterated product thereof, in the preparation of a CDK kinase inhibitor.
  • a method for preventing and/or treating CDK-related diseases comprising the steps of administering the compound as described in the first or second aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof to a subject in need, thereby preventing and/or treating the disease.
  • the subject is a human or a non-human mammal, such as a monkey, a rat and a mouse.
  • the inventors After extensive and in-depth research, the inventors have provided a macrocyclic compound with excellent CDK kinase inhibitory activity for the first time. Specifically, through structural optimization, the inventors have obtained a class of compounds with excellent CDK2 selective inhibitory activity. Based on this, the inventors have completed the present invention.
  • substituents When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left.
  • -CH2O- includes -OCH2- .
  • the term "plurality” refers to two or more, such as 2, 3, 4, 5 or 6.
  • halogen or halogen atom refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "Halogenated” means substituted with an atom selected from F, Cl, Br, and I.
  • C 1-6 alkyl refers to a straight or branched alkyl group including 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like.
  • C 1-3 alkyl or "C 1-4 alkyl” has a similar meaning.
  • C2-6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.
  • C2-6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.
  • C 1-6 alkoxy refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc.
  • C 1-4 alkoxy has a similar meaning.
  • C 2-10 alkenylene refers to a straight or branched chain alkenylene group having 2 to 10 carbon atoms and containing one double bond, including but not limited to: wait.
  • C 1-6 alkoxy refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is a C1-C4 alkoxy group.
  • C 1-6 alkylene refers to a straight or branched alkylene structure comprising 1 to 6 carbon atoms, including but not limited to: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - , -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - , -CH 2 CH 2 CH 2 CH 2 - , -CH(CH 3 )CH 2 -, -CH(CH 3 ) CH 2 CH 2 -, -CH(CH 3 )CH(CH 3 )-, and the like.
  • cycloalkyl refers to an alkyl group containing 3 to 12 carbon atoms in a ring, including monocyclic alkyl groups and condensed cyclic alkyl groups. Condensed cyclic alkyl groups include cycloalkyl groups, bridged cycloalkyl groups, and spirocyclic alkyl groups.
  • C 3-6 cycloalkyl refers to a cyclic alkyl group having 3 to 6 carbon atoms in the ring, and the ring includes C 3-6 monocyclic alkyl groups, C 5-6 bicyclic alkyl groups, C 5-6 bridged cyclic groups, and C 5-6 spirocyclic groups, including but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • the cycloalkyl group may be a "saturated or partially saturated cycloalkyl group" with or without a double bond in the ring.
  • the ring includes: C 5-7 monocycloalkyl, C 6-12 bicycloalkyl, C 5-12 bridged ring group, C 5-12 spirocyclic group, including but not limited to: cyclopentyl, cyclohexyl, cycloheptyl,
  • heterocycloalkyl refers to a cycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O, and S, including monocyclic heterocycloalkyl groups and fused-ring heterocycloalkyl groups.
  • the fused-ring heterocycloalkyl groups include cyclic heterocycloalkyl groups, bridged-ring heterocycloalkyl groups, and spirocyclic heterocycloalkyl groups.
  • the “3-6 membered heterocycloalkyl” refers to a C 3-6 cycloalkyl in which an optional CH 2 or CH group is replaced by an N or NH or O or S atom, including but not limited to:
  • saturated or partially saturated 5-6 membered heterocycloalkyl refers to a C5-10 cycloalkyl group with or without a double bond in the ring, wherein the optional CH2 or CH group is replaced by N or NH or O or S atom, and the ring connected to the parent is a non-aromatic ring structure, including but not limited to:
  • saturated or partially saturated heterocycloalkyl refers to a cycloalkyl group with or without double bonds in the ring, wherein the optional CH2 or CH group is replaced by N or NH or O or S atom, and the ring connected to the parent is a non-aromatic ring structure, including but not limited to:
  • a 5-6-membered cycloalkyl or a 5-6-membered heterocycloalkyl and a 5-6-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S refers to a ring structure containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, the ring structure having a 5-6-membered cycloalkyl and a 5-6-membered heteroaryl or a 5-6-membered heterocycloalkyl and a heteroaryl structure, and the ring connected to the parent is a non-aromatic ring structure, including but not limited to:
  • a 5-6 membered heteroaryl or a phenyl 5-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S refers to a ring structure containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, and the ring structure has a 5-6 membered heteroaryl 5-6 membered heterocycloalkyl or a phenyl 5-6 membered heterocycloalkyl structure, including but not limited to:
  • aromatic heterocycle or “heteroaryl” has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms.
  • heteroaromatic group containing one to multiple heteroatoms.
  • 5-6 membered heteroaryl refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen and 1 to 5 carbon atoms.
  • Non-limiting examples include: furanyl, thienyl, pyridyl, pyrazolyl, thiazolyl, isothiazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, tetrazolyl, etc.
  • the heteroaryl group may be optionally substituted or unsubstituted.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituent is the substituent described above, or the substituent appearing in the embodiments.
  • a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those that are stable or chemically feasible.
  • the term 1-4 means 1, 2, 3 or 4. Other similar terms have similar meanings.
  • the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or conformational isomers) are all within the scope of the present invention.
  • the compounds of the present application can be prepared by a variety of synthesis methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining specific embodiments with other chemical synthesis methods, and equivalent substitution methods known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.
  • the invention provides a macrocyclic compound with CDK kinase inhibitory activity, which is used for inducing cell apoptosis and inhibiting tumor proliferation.
  • Ring A, Ring B, X 1 , X 2 , X 3 and L 1 are as defined above.
  • the term "pharmaceutically acceptable salt” refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts is a salt formed by a compound of the present invention and an acid.
  • Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid
  • the compounds of the present invention can be prepared by the process described in the examples, wherein the raw materials and reagents used can be purchased from commercial sources unless otherwise specified.
  • compositions and methods of administration are provided.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound of the present invention or, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof.
  • the compounds of the present invention have excellent anti-tumor activity
  • the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.
  • the pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.
  • safe and effective amount means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • the pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.
  • compositions of the present invention include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for
  • Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottons
  • composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).
  • the treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.
  • the main advantages of the present invention include:
  • the compound has excellent CDK2 inhibitory activity.
  • the compound can be used to induce cell apoptosis and inhibit tumor proliferation.
  • the compound has excellent selectivity in inhibiting CDK subtypes.
  • the compounds of the present invention have excellent pharmacokinetic and pharmacodynamic properties and good drugability.
  • the absolute stereochemistry of all chiral atoms is defined as follows.
  • the compound marked with the "&” symbol in the structural formula indicates that the compound is a cis racemate; the compound marked with the "or1” symbol indicates that the compound is a single-configuration compound, but the absolute configuration is unknown; the compound marked with the “or2” symbol indicates that the compound is a single-configuration compound, which is an enantiomer of the "or1" structure, but the absolute configuration is unknown; the compound marked with the “abs” symbol indicates that the absolute configuration of the compound is the structure shown; the compound marked with the "rac” symbol indicates that the compound is a racemate; the compound marked with the "S” or “R” symbol indicates that the chirality of the carbon at that position of the compound is the known configuration marked. ()
  • Int1-5 (19.12 g, 41.0 mmol) was dissolved in 160 mL of acetonitrile, and benzyl chloroformate (11.7 mL, 82.0 mmol) was added dropwise under ice-water cooling. After the addition was complete, the mixture was heated to room temperature and stirred for 2 h. Then, NaHCO 3 (11.02 g, 130.0 mmol) was added and stirred for 16 h at room temperature. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with ethyl acetate several times.
  • Int1-6 (21.0 g, 35.0 mmol) was dissolved in 150 mL of anhydrous tetrahydrofuran under stirring at room temperature, and glacial acetic acid (4.2 mL, 70.0 mmol) and tetrabutylammonium fluoride (35.0 mL, 1 M in tetrahydrofuran) were added in sequence. The mixture was heated to 40 °C and stirred for 23 hours under a nitrogen atmosphere.
  • reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 4.41 g. Ms[M+H] + :358.2.
  • Int1-8 (1.07 g, 2.42 mmol) was dissolved in a mixed solvent of 10 mL methanol and 10 mL ethyl acetate, and then Pd/C (214 mg, 20 mol%) was added and stirred at room temperature for 5 h under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified to obtain int1 (640 mg).
  • Int2-3 500 mg
  • Pd/C 200 mg
  • methanol 10 ml
  • N,N-dimethylformamide (20 mL) to a 100 mL flask, add NaH (2.25 g) at 0°C, add dimethyl malonate (9 g) at room temperature, react at 40°C for 40 min, then add C91-1 and heat to 100°C to continue reacting for 16 h.
  • concentrate to remove N,N-dimethylformamide add water (20 mL), extract with ethyl acetate (4*20 mL) to remove impurities, retain the aqueous phase, add concentrated H 2 SO 4 to adjust the pH until a large amount of solid precipitates, collect the solid, wash with water several times, and finally dry to obtain 2.5 g of crude product, which is directly used in the next step.
  • Int3-3 (1.5 g) was added to a 50 mL flask, dissolved in anhydrous dichloromethane (20 mL) and stirred for 3-5 min, Zn(OTf) 2 (0.6 g) and DBU (2.5 g) were added in sequence at room temperature, and finally diphenyl (vinyl) sulfonium trifluoromethanesulfonate (1.1 g) was added, and the reaction was carried out at room temperature for 15 min.
  • Int3-4 (100 mg) was added to a 50 mL flask, dissolved in anhydrous N, N-dimethylformamide (5 mL), and NaH (40 mg) was added at 0°C. The mixture was reacted at 0°C for 0.5 h, and then CH 3 I (100 mg) was added and the reaction was continued for 1.5 h. After the reaction was completed, water was added to the reaction solution, and then extracted with ethyl acetate three times. The organic phases were combined, washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain 110 mg of the product.
  • Int5-4 (2.2 g, 1.0 eq) was dissolved in methanol (25 mL), and Pd/C (500 mg) and di-tert-butyl dicarbonate (2.58 g, 1.2 eq) were added at room temperature, and the mixture was reacted for 3 h under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure. Purification by column chromatography gave 1.4 g of the product.
  • Int6-3 (300 mg, 1.0 eq) was dissolved in triethylamine trihydrofluoride (4 mL) and reacted at 105°C for 16 h under nitrogen protection. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, and water was added. The mixture was extracted twice with ethyl acetate, and the organic phases were combined, dried, filtered, concentrated under reduced pressure, and separated by a thin layer preparation plate to obtain 71 mg of the product.
  • Int8-3 (5.58 g, 1.0 eq) was dissolved in methanol (60 mL), and then Pd/C (600 mg) was added and reacted at 60° C. for 16 h under a hydrogen atmosphere. After the reaction of the raw materials was complete, the product was filtered and concentrated to obtain 1.6 g.
  • Dissolve int9-2 (15 g, 1.0 eq) in ultra-dry dichloromethane (150 mL), protect with nitrogen, and add 1N diisobutylaluminum hydride (50.5 mL, 1.2 eq) dropwise at -70 ° C. After the addition, keep warm for 2 h. Add aqueous ammonium chloride to the reaction solution to quench, filter, add dichloromethane to the filtrate to extract twice, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by silica gel column to obtain 14.9 g of the product.
  • Dissolve int9-4 (8 g, 1.0 eq) in ultra-dry tetrahydrofuran (80 mL), protect with nitrogen, slowly add 3N methylmagnesium bromide (12.4 mL, 2.0 eq) at -40 ° C, and react at room temperature for 2 h. Add aqueous ammonium chloride to the reaction solution to quench, then add ethyl acetate to extract twice, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 3.5 g of the product.
  • Int13-2 (10.38 g, 1.0 eq) was dissolved in acetic acid (110 mL), and reduced iron powder (7.94 g, 5.0 eq) was added, and the reaction solution was stirred at room temperature for 1-2 h. Filtered with diatomaceous earth, the filter cake was washed with ethyl acetate several times, concentrated, and purified by silica gel column chromatography to obtain 5.45 g of the product.
  • reaction was quenched by adding saturated aqueous ammonium chloride solution, the aqueous phase was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 4.35 g of the product.
  • Dissolve compound C19-4 (100 mg, crude) in acetonitrile (3 mL), cool to 0°C, slowly add triethylamine (164 mg, 12.00 eq), and stir at room temperature for 30 min. Dilute the reaction solution with ethyl acetate, and wash the organic phase with 1N sodium hydroxide aqueous solution. Dry and concentrate the organic phase. Purify by preparative chromatography to obtain 3 mg of the product.
  • Dissolve compound C20-6 (600 mg, crude) in acetonitrile (20 mL), cool to 0°C, slowly add triethylamine (717 mg, 12.00 eq), and stir at room temperature for 30 min. The reaction is complete. Dilute the reaction solution with ethyl acetate, and wash the organic phase with 1N sodium hydroxide aqueous solution. Dry and concentrate the organic phase. Purify on a thin layer chromatography plate to obtain 70 mg of the product.
  • the peak time of the front peak C20 was 13.0min. After concentration and freeze-drying, 19mg of the product was obtained.
  • the peak time of the latter peak C21 was 23.4 min. After concentration and freeze-drying, 17 mg of the product was obtained.
  • Dissolve C37-2 (636 mg, 1.0 eq) in acetonitrile (10 mL), then add lithium bromide (1.13 g, 8.0 eq), protect with nitrogen, and react at 35 ° C for 16 h. Add water to the reaction solution, extract twice with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. After purification on a silica gel column, 284 mg of the product was obtained.
  • Triethylamine (2 mL) was added to the reaction solution of C37-8 and stirred at room temperature for 3 h. Liquid quality monitoring showed that the raw material reacted completely. Water was added to the reaction solution and extracted twice with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After purification on a thin layer chromatography preparative plate, products C38 (1.12 mg) and C37 (3.2 mg) were obtained.
  • the untreated solution was cooled to 0°C and triethylamine (2 mL) was added dropwise. After the addition was completed, the temperature was naturally raised to room temperature and reacted for 4 h. Saturated sodium bicarbonate and dichloromethane were added to the reaction solution, and the liquids were separated. The aqueous phase was extracted once with dichloromethane, and the organic phases were combined, dried, filtered, concentrated, and purified by TLC preparative plate to obtain 42 mg of the product.
  • the survival rate (%Cell Survival) is calculated using the following formula:
  • %Cell Survival 100% ⁇ (OD_Sample-OD_LCave)/(OD_HC-OD_LCave)
  • the cell proliferation activity values in the table are represented by A, B, C, and D, wherein A ⁇ 500nM, 500nM ⁇ B ⁇ 1000nM, 1000nM ⁇ C ⁇ 3000nM, and 3000nM ⁇ D.
  • the positive control (PC) was treated with DMSO
  • the negative control (NC) was without enzyme.
  • % inhibition rate 100-100*((CR PC -CR sample )/(CR PC -CR NC ))
  • the present invention provides a series of compounds with excellent CDK2 kinase activity and selectivity.
  • the series of compounds have good inhibitory effects on excessive cell proliferation caused by abnormal expression or amplification of CyclineE and have broad application prospects.

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Abstract

La présente invention concerne un composé macrocyclique, son procédé de préparation et son utilisation. Plus particulièrement, le composé macrocyclique selon la présente invention a une structure représentée par la formule (I), les définitions des groupes et des substituants étant telles que décrites dans la description. La présente invention concerne en outre un procédé de préparation du composé, et une utilisation du composé dans la régulation de l'activité de CDK2 et/ou la prévention et/ou le traitement de maladies associées à CDK2.
PCT/CN2024/114006 2023-08-24 2024-08-22 Composé macrocyclique, sa préparation et son utilisation Pending WO2025040156A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112661745A (zh) * 2020-07-24 2021-04-16 浙江同源康医药股份有限公司 用作cdk7激酶抑制剂的化合物及其应用
WO2022206888A1 (fr) * 2021-03-31 2022-10-06 Qilu Regor Therapeutics Inc. Inhibiteurs de cdk2 et leur utilisation
WO2023274397A1 (fr) * 2021-07-01 2023-01-05 上海拓界生物医药科技有限公司 Inhibiteur de cdk2, son procédé de préparation et son utilisation
CN116456987A (zh) * 2021-06-09 2023-07-18 郑州同源康医药有限公司 用作cdk激酶抑制剂的化合物及其应用

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CN112661745A (zh) * 2020-07-24 2021-04-16 浙江同源康医药股份有限公司 用作cdk7激酶抑制剂的化合物及其应用
WO2022206888A1 (fr) * 2021-03-31 2022-10-06 Qilu Regor Therapeutics Inc. Inhibiteurs de cdk2 et leur utilisation
CN116456987A (zh) * 2021-06-09 2023-07-18 郑州同源康医药有限公司 用作cdk激酶抑制剂的化合物及其应用
WO2023274397A1 (fr) * 2021-07-01 2023-01-05 上海拓界生物医药科技有限公司 Inhibiteur de cdk2, son procédé de préparation et son utilisation

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