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WO2022135442A1 - Cdk2抑制剂及其制备方法 - Google Patents

Cdk2抑制剂及其制备方法 Download PDF

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Publication number
WO2022135442A1
WO2022135442A1 PCT/CN2021/140312 CN2021140312W WO2022135442A1 WO 2022135442 A1 WO2022135442 A1 WO 2022135442A1 CN 2021140312 W CN2021140312 W CN 2021140312W WO 2022135442 A1 WO2022135442 A1 WO 2022135442A1
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compound
pharmaceutically acceptable
tautomer
acceptable salt
ring
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PCT/CN2021/140312
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English (en)
French (fr)
Inventor
邹昊
刘浩淼
李云飞
龚红龙
张超
庞夏明
张芳
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上海拓界生物医药科技有限公司
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Publication of WO2022135442A1 publication Critical patent/WO2022135442A1/zh

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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
    • A61K31/41—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
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a CDK2 inhibitor.
  • Cyclin-dependent kinases are members of the serine/threonine kinase subfamily, and each CDK/cyclin complex is responsible for the transition or progression of a specific phase within the cell cycle, which is involved in the regulation of eukaryotic cell division and play an important role in proliferation. Cyclin-dependent kinase catalytic units are activated by regulatory subunits called cyclins. At least 16 mammalian cyclins have been identified (Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312).
  • Cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6 and possibly other heterodynes are important regulators of cell cycle progression.
  • Other functions of cyclin/CDK heterodynes include transcriptional regulation, DNA repair, differentiation and apoptosis (Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).
  • CDK2 Overexpression of CDK2 is associated with dysregulation of the cell cycle.
  • the cyclin E/CDK2 complex plays an important role in regulating G1/S transition, histone biosynthesis, and centrosome duplication. Progressive phosphorylation of Rb by cyclin D/Cdk4/6 and cyclin E/Cdk2 releases the G1 transcription factor E2F and promotes S-phase entry. Activation of cyclin A/CDK2 during early S phase promotes phosphorylation of endogenous substrates that allow DNA replication and inactivation of E2F to complete S phase (Nat. Rev. Drug. Discov. 2015; 14( 2): 130-146).
  • Cyclin E is overexpressed in various cancers, especially breast cancer, lung cancer, leukemia, and lymphoma (Guo Cuiping et al. Regulation of Cyclin E and Malignant Tumors. International Journal of Oncology, 2012, 39(005): 337 -340), amplification or overexpression of cyclin E has also been associated with poor prognosis in ovarian, gastric, endometrial and other cancers.
  • CDK2 cyclin A/E binds to CDK2 and triggers phosphorylation to activate CDK2.
  • CDK2 also binds cyclin A for the entire progression of S phase and is involved in DNA repair.
  • major companies have identified and discovered a series of inhibitors that selectively inhibit CDK 2 for the treatment of cancer and other diseases, such as Seliciclib, Dinaciclib, etc.
  • CDK2 inhibitors that selectively inhibit CDK 2 for the treatment of cancer and other diseases, such as Seliciclib, Dinaciclib, etc.
  • the market demand still needs to develop a new generation of selective CDK2 inhibitors with high efficiency and low toxicity.
  • -L 1 -, -L 2 - are each independently selected from a bond, a C 1 -C 6 alkylene group, -O- and -NH-, and the C 1-6 alkylene group is optionally replaced by one or more substituted with a substituent selected from the group consisting of hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, amino and nitro;
  • R is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more Z;
  • R 2 , R 3 are each independently selected from hydrogen, deuterium, halogen, alkyl, cyano, hydroxy, nitro, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally selected from one or more groups selected from halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxy Substituent substitution of alkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;
  • R 2 and R 3 together form a 3-8 membered ring optionally substituted with one or more Z;
  • R 4 is selected from monocyclic and polycyclic rings, optionally substituted with one or more Z
  • R 5 is selected from hydrogen, deuterium, alkyl, and halo, wherein said alkyl is optionally substituted by one or Substituted with multiple substituents selected from halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,
  • R4 is selected from monocyclic ring
  • R4 is selected from and R 1 is selected from
  • R is selected from hydrogen, deuterium, halogen and alkyl ;
  • R 4 , R 5 and the N atom to which they are attached together form a polycyclic ring, optionally substituted with one or more Z;
  • Each R' or R" is independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, the alkyl, alkoxy, cycloalkane radical, heterocyclyl, aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano;
  • Compound 1 is:
  • Compound IIa includes:
  • Compound IIb includes:
  • R' or R" is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl and phenyl;
  • X is selected from -CH and N;
  • Y is selected from -CH2- , -CH( CH3 )-, -NH-, -N( CH3 )- and -O-.
  • Compound 1 is:
  • ring A is selected from C 3-7 cycloalkyl, 5-8-membered aryl and 5-8-membered heterocyclic group, the C 3-7 cycloalkyl, 5-8-membered aryl, 5-8-membered aryl Heterocyclyl is optionally substituted with one or more Z.
  • Compound IIc comprises:
  • the compound IId includes:
  • Ring A is selected from 5-8 membered heterocyclyl optionally selected from halogen, hydroxy, oxo, nitro, alkyl, and alkoxy substituted with one or more substituents.
  • Ring A is selected from wherein Y is selected from -CH2- , -CH( CH3 )-, -NH-, -N( CH3 )- and -O-.
  • Ring A is selected from
  • R 6 is selected from hydrogen, deuterium, halogen, and C 1-6 alkyl, such as hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, and isopropyl.
  • R 6 is selected from methyl.
  • R1 when R4 is selected from polycyclic, R1 is selected from C6 - C12 aryl and 5-10 membered heteroaryl, wherein said C6 - C12 aryl or 5-10 membered Heteroaryl is optionally substituted with one or more Z.
  • C 6 -C 12 aryl or 5-10 membered heteroaryl is selected from pyrazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyridyl, pyrazinyl, indazolyl, benzimidazolyl and phenyl, preferably from isoxazolyl, wherein said C6 - C12aryl or 5- The 10-membered heteroaryl is optionally substituted with one or more Z.
  • Compound 1 is:
  • Compound III includes
  • R' or R" is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl and phenyl;
  • X is selected from -CH and N;
  • Y is selected from -CH2- , -CH( CH3 )-, -NH-, -N( CH3 )- and -O-.
  • Z is selected from methyl.
  • Compound III is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R4 is selected from spiro, fused and bridged rings, and optionally substituted with one or more Z, which are attached to by any carbon or nitrogen atom. in the structure of formula I.
  • the spiro ring includes spirocycloalkyl or spiroheterocyclyl selected from [3.3], [3.4], [3.5], [3.6], [4.4], [4.5], [4.6], [5.5 ], [5.6] and [6.7] Spiro.
  • the spiro ring is selected from The spiro ring is attached to the structure of Formula I through any of the attachment sites indicated by *, and is optionally further substituted with one or more Z.
  • the spiro ring is selected from The spiro ring is attached to the structure of formula I through the attachment site indicated by *.
  • fused rings include fused cycloalkyl or fused heterocyclyl, selected from bicyclic and tricyclic, optionally further substituted with one or more Z.
  • the fused ring is selected from The fused ring is attached to the structure of formula I through any of the attachment sites represented by *, optionally further substituted with one or more Z.
  • the fused ring is selected from Linked into the structure of formula I through the attachment site indicated by *.
  • the bridged ring includes a bridged cycloalkyl or bridged heterocyclyl group selected from bicyclic and tricyclic rings, each bridge having 0-3 carbon atoms, optionally substituted with one or more Z.
  • the bridged ring is selected from The attachment to the structure of Formula I is through any of the attachment sites indicated by *, optionally further substituted with one or more Z.
  • the bridged ring is selected from Linked into the structure of formula I through the attachment site indicated by *.
  • R 5 is selected from hydrogen, deuterium, halogen and C 1-6 alkyl.
  • R5 is selected from the group consisting of hydrogen, deuterium, fluoro, chloro, bromo, methyl, ethyl, propyl, and isopropyl.
  • R5 is selected from hydrogen
  • ring C is selected from optionally substituted with one or more Z.
  • Compound IV compounds include
  • R 1 is selected from C 6 -C 12 aryl and 5-10 membered heteroaryl, wherein the C 6 -C 12 aryl or 5-10 membered heteroaryl is optionally surrounded by one or more A Z is replaced.
  • R 1 is selected from pyrazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyridyl , pyrazinyl, indazolyl, benzimidazolyl and phenyl, optionally substituted with one or more Z.
  • Compound IV is:
  • Compound IVa compounds include:
  • R' or R" is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl and phenyl;
  • X is selected from -CH and N;
  • Y is selected from -CH2- , -CH( CH3 )-, -NH-, -N( CH3 )- and -O-.
  • Z is selected from methyl.
  • -L2- is selected from bond, -CH2- , -CH( CH3 )-, -CH2 - CH2-, -O-, and -NH-.
  • -L2- is selected from -CH2- and -CH( CH3 ) -.
  • R2, R3 are each independently selected from hydrogen , deuterium, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, phenyl, cyano, hydroxy, and oxo.
  • R 2 , R 3 are each independently selected from hydrogen, deuterium, fluorine, chlorine, and methyl.
  • R 2 , R 3 are each independently selected from hydrogen.
  • R 2 and R 3 together form a 3-8 membered ring, and the 3-8 membered ring is selected from C 3-7 cycloalkyl, 3-8 membered heterocyclic group, and 5-8 membered aryl group and 5-8 membered heteroaryl, the 3-8 membered ring is optionally substituted with one or more Z.
  • the 3-8 membered ring formed by R 2 and R 3 is selected from cyclopropyl, cyclobutyl, and cyclopentyl, and the 3-8 membered ring is optionally surrounded by one or more Z Substituted, wherein Z is selected from fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, phenyl, cyano, hydroxy, and oxo.
  • the 3-8 membered ring formed by R 2 and R 3 is selected from cyclopropyl, cyclobutyl, and cyclopentyl substituted with one Z, wherein Z is selected from fluorine, chlorine and methyl.
  • R 2 and R 3 together constitute cyclopropyl, cyclobutyl or cyclopentyl.
  • R 2 and R 3 together form a cyclopropyl group.
  • -L 1 - is selected from bond, -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -, -O-, and -NH-.
  • -L 1 - is selected from -CH 2 - and -O-.
  • the present disclosure also provides a series of compounds selected from:
  • the present disclosure also provides a series of compounds selected from:
  • the present disclosure also provides a method for preparing the compound described in the first or second aspect, or a pharmaceutically acceptable salt or tautomer thereof.
  • the reagent of alkaline conditions is selected from organic bases or inorganic bases, and the organic bases are selected from triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, bistrimethylamine Lithium silylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide; the inorganic base is selected from sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, Potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide;
  • LG 3 is selected from phenoxy, 4-nitrophenoxy.
  • the compound represented by the formula I-4 and the compound represented by the formula I-6 are subjected to carbamate reaction in the presence of an acylating reagent, and then the protective group LG 1 is removed to obtain the compound represented by the formula I;
  • the acylating reagent is selected from triphosgene, 1,1'-carbonyldiimidazole;
  • formula I-4 is obtained by reducing the compound represented by formula I-3:
  • the compound represented by the formula I-3 is obtained by the acylation reaction of the compound represented by the formula I-1 and the compound represented by the formula I-2 in the presence of a condensing agent or under basic conditions:
  • LG 2 is selected from hydroxyl, alkoxy, and halogen.
  • the condensing agent is selected from dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, HATU, HBTU, TBTU, HCTU, TSTU, TNTU, PyBOP, 1-propylphosphoric anhydride.
  • the reagents for the alkaline condition test include organic bases and inorganic bases
  • the organic bases are selected from triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropyl Lithium amide, lithium bistrimethylsilylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide
  • the inorganic base is selected from sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide , sodium tert-butoxide, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in the first or second aspect or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient .
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the compound or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.
  • the present disclosure also provides a method of preventing and/or treating a patient suffering from a protein-dependent kinase-related disease by administering to the patient a therapeutically effective amount of a compound of the present disclosure or a medicament thereof The salt used or the aforementioned pharmaceutical composition.
  • the present disclosure also provides a method of preventing and/or treating a patient suffering from a cyclin-related disease by administering to the patient a therapeutically effective amount of a compound described in the present disclosure or pharmaceutically acceptable thereof The salt or the aforementioned pharmaceutical composition.
  • the protein-dependent kinase-related disease or the cyclin-related disease is a cell proliferative disease, cancer, or an immune disease.
  • the protein-dependent kinase-related disease or cyclin-related disease is selected from the group consisting of breast cancer, ovarian 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), kidney cancer (including RCC), skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, bone 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 , cholangiocarcinoma, choriocarcinoma, or pediatric tumors.
  • the cancer is selected from cyclin E1 and/or cyclin E2 amplified cancers.
  • the present disclosure also provides a method of preventing and/or treating a patient suffering from cancer by administering to the patient a therapeutically effective amount of a compound described in the present disclosure, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, wherein the
  • the cancer is selected from breast cancer, ovarian 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), kidney cancer (including RCC), skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer , head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureter
  • the present disclosure provides the use of a therapeutically effective amount of a compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating a protein-dependent kinase-related disease,
  • the protein-dependent kinase is selected from CDK2, and the disease associated with the protein-dependent kinase is selected from cell proliferative diseases, cancer or immune diseases.
  • the present disclosure provides the use of a therapeutically effective amount of a compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the manufacture of a medicament for preventing and/or treating cyclin-related diseases .
  • the cyclin is selected from cyclin E, eg, cyclin El, cyclin E2.
  • the cyclin-related diseases are selected from cell proliferative diseases, cancer or immune diseases.
  • the present disclosure provides the use of a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing, in the manufacture of a medicament for the treatment of cancer.
  • the cancer is selected from the group consisting of breast cancer, ovarian 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), kidney cancer (including RCC), skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, 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, bile duct cancer, chorioepithelial cancer or Pediatric Oncology.
  • the cancer is selected from cyclin E1 and/or cyclin E2 amplified cancers.
  • the pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts, and the compounds described in the present disclosure can react with acidic or basic substances to form corresponding salts.
  • the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms.
  • This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of this disclosure.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.
  • tautomer or tautomeric form refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton tautomers
  • proton transfer such as keto-enol and imine-enamine, lactam-lactam isomerizations , Pyrazolyl isomerization.
  • the compounds of the present disclosure may be asymmetric, eg, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, such as enantiomers and diastereomers.
  • Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the present disclosure also includes certain isotopically-labeled compounds of the present disclosure which are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic weight or mass number different from that normally found in nature.
  • isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 13 , respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and the like.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (ie, at least 1000 times greater than the natural abundance of deuterium (which is 0.015%)) % of deuterium incorporated).
  • Exemplary compounds having natural abundance greater than deuterium may be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 4000 times more abundant 5000 times more abundant deuterium, at least 6000 times more abundant deuterium or more abundant deuterium.
  • the present disclosure also includes compounds of Formula I in various deuterated forms.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art can synthesize compounds of formula I in deuterated form with reference to the relevant literature.
  • Commercially available deuterated starting materials can be used in preparing deuterated forms of the compounds of formula I, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane Tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • C 1-6 alkyl optionally substituted by halogen or cyano means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano substitution.
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or or both and Two configurations.
  • the bond no configuration is specified, i.e. the bond The configuration can be E or Z, or both E and Z configurations.
  • pharmaceutical composition means a mixture comprising one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiologically acceptable carrier and excipient.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvant, carrier, excipient that has been approved by the U.S. Food and Drug Administration and is acceptable for use in humans or livestock animals. Excipients, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifier.
  • an effective amount includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms.
  • 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-methylp
  • alkyl groups containing 1 to 6 carbon atoms 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-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • alkylene refers to the remainder of the alkane molecule after removal of 2 hydrogen atoms, including straight and branched chain subgroups of 1 to 20 carbon atoms.
  • An alkylene group containing 1 to 6 carbon atoms non-limiting examples including methylene ( -CH2- ), ethylene (eg -CH2CH2- or -CH( CH3 ) -), methylene Propyl (eg -CH2CH2CH2- or -CH ( CH2CH3 ) - ) , butylene ( eg -CH2CH2CH2CH2- ) .
  • an alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from deuterium , aryl, heteroaryl, halogen substituted.
  • cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms.
  • monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro Ring, fused and bridged cycloalkyl groups.
  • Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxy, Oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 Alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl
  • the substituents may be substituted at any available point of attachment,
  • the cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzo rings Heptyl, etc.
  • Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy , C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 Alkynoxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl,
  • heterocycloalkyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which are selected from nitrogen, Oxygen or heteroatoms of S(O) m (where m is an integer from 0 to 2), excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 7 ring atoms.
  • Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piper pyridyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.
  • Polycyclic heterocycloalkyl groups include spiro, fused and bridged ring heterocycloalkyl groups.
  • Non-limiting examples of "heterocycloalkyl" include:
  • heterocycloalkyl ring can be fused to an aryl or heteroaryl ring, wherein the ring linked to the parent structure is a heterocycloalkyl, non-limiting examples of which include:
  • Heterocycloalkyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano base, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy base, C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2- 6 -alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl optionally replaced by one or more Substituted from halogen, deuter
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 12 membered, such as benzene base and naphthyl.
  • the aryl ring can be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C1 -6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3 -8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy , C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl optionally by one or more selected from halogen, Deuterium, hydroxyl, oxo, nitro
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 6- to 12-membered, more preferably 5- or 6-membered.
  • Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl , thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, Wait.
  • the heteroaryl ring can be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy , C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 Alkynoxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl
  • spirocycle refers to a compound in which two rings share one atom.
  • spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated ⁇ electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
  • Spirocarbocycle refers to the ring system in a spirocycloalkyl.
  • Non-limiting examples of spirocycloalkyl include:
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
  • Spiroheterocycle refers to the ring system in a spiroheterocyclyl group.
  • Non-limiting examples of spiroheterocyclyl include:
  • fused ring refers to a compound in which two or more rings are fused by sharing two adjacent atoms.
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. "Fused carbocycle” refers to the ring system in a fused cycloalkyl. Non-limiting examples of fused cycloalkyl groups include:
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more Double bonds, but none of the rings have a fully conjugated pi-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), the remaining rings Atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocycle refers to a ring system in a fused heterocyclyl.
  • fused heterocyclyl groups include:
  • fused heteroaryl may be an unsaturated heteroaryl group containing 5-14 ring atoms (including at least one heteroatom) formed by two or more cyclic structures that share two adjacent atoms connected to each other.
  • Aromatic condensed ring structure, including carbon atom, nitrogen atom and sulfur atom can be oxo, preferably "5-12-membered condensed heteroaryl", “7-12-membered condensed heteroaryl”, “9-12-membered heteroaryl” fused heteroaryl” etc., such as benzofuranyl, benzoisofuranyl, benzothienyl, indolyl, isoindole, benzoxazolyl, benzimidazolyl, indazolyl, benzotri azolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridine, phenanthridine, benzopyridaziny
  • the fused heteroaryl group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkanethio group, heterocycloalkylthio group, carboxyl group or carboxylate group.
  • bridged ring refers to a structure formed by two or more ring structures sharing two non-adjacent ring atoms with each other.
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings have complete Conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclyl group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings have a complete common A pi-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
  • m is an integer from 0 to 2
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl groups include:
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy , C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 Alkynoxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl,
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group substituted with halogen, wherein alkyl is as defined above.
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • a carbon atom is linked to an oxygen atom by a double bond, in which a ketone or aldehyde group is formed.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • aldehyde group refers to -CHO.
  • substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort.
  • Substituted with one or more means that it may be substituted with single or multiple substituents. When substituted by a plurality of substituents, it may be a plurality of the same substituents, or a combination of one or a plurality of different substituents.
  • experimental methods without specific conditions are generally based on conventional conditions or conditions suggested by raw material or commodity manufacturers.
  • Reagents with no specific source indicated are conventional reagents purchased in the market.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS was measured with a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer.
  • HPLC uses Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200 LC high pressure liquid chromatograph (Ultimate XB-C18 3.0*150mm chromatographic column or Xtimate C18 2.1*30mm chromatographic column).
  • Chiral HPLC analysis and determination using Chiralpak IC-3 100 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 150 ⁇ 4.6mm I.D.,3um, Chiralpak AS-3 100 ⁇ 4.6mm I.D.,3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm I.D.,3um, Chiralcel OD-3 100 ⁇ 4.6mm I.D.,3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm I.D., 5um, Chiralcel OJ-3 150 ⁇ 4.6mm I.D., 3um chromatographic column;
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • the chiral preparative column uses DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
  • the CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).
  • the average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: petroleum ether/ethyl acetate/methanol, the volume ratio of the solvent depends on the polarity of the compound For adjustment, a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • compound 1d (0.90 g, 4.1 mmol), 2-(3-methylisothiazol-5-yl)acetic acid (0.69 g, 4.9 mmol), N,N-diisopropylethylamine ( 1.5 g, 11 mmol) was dissolved in 16 mL of dichloromethane.
  • a solution of 1-propylphosphoric anhydride (50% wt, 6.5 g, 10 mmol) was added at room temperature and stirred at room temperature for 2 hours. The reaction was quenched by the addition of 100 mL of saturated sodium bicarbonate solution.
  • compound 1f (760 mg, 2.2 mmol) was dissolved in 16 mL of tetrahydrofuran. The temperature was lowered to -60°C, lithium triethylborohydride (1 mol/L, 4.4 mL, 4.4 mmol) was added dropwise to the reaction, and the reaction was carried out at -60°C for 2 hours. The reaction was quenched by the addition of 80 mL of saturated sodium bicarbonate solution.
  • Example 2 For the synthesis steps of Example 2, refer to Example 1, wherein the compound spiro[3.3]heptane-2-amine hydrochloride was replaced with bicyclo[1.1.1]pentane-1-amine hydrochloride to obtain Example 2.
  • Example 3 For the synthesis steps of Example 3, refer to Example 1, wherein the compound spiro[2.3]hexane-4-amine hydrochloride was used to replace bicyclo[1.1.1]pentane-1-amine hydrochloride to obtain Example 3.
  • compound 4a 500 mg, 2.0 mmol
  • dimethylphosphine oxide 240.8 mg, 3.1 mmol
  • Xantphos 238.0 mg, 0.41 mmol
  • K 3 PO 4 654.89 mg, 3.1 mmol
  • Pd ( OAc) 2 46.2 mg, 0.2 mmol
  • compound 4b (200 mg, 0.94 mmol), cis-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl(1-methyl) cyclopropyl) carbamate 4c (302mg, 0.94mmol, prepared by the method disclosed in patent application "WO 2020/157652A2"), N,N-diisopropylethylamine (0.31mL, 1.89mmol) Dissolve in 5 mL of dichloromethane. A solution of 1-propyl phosphoric anhydride (50% wt, 600 mg, 1.89 mmol) was added at room temperature, followed by stirring at room temperature for 2 hours.
  • compound 4d (50 mg, 0.1 mmol) was sequentially dissolved in 1 mL of formic acid. The reaction was carried out at 75°C for 4 hours. The solvent was spin-dried, 20 mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure, and purified by C-18 reverse phase chromatography to give the title compound 4e (20 mg, yield: 42%).
  • the retention time is 2.653min (analysis method: Column: Chiralpak IG-3 (50mm*4.6mm, 3 ⁇ m) Gradient: 40% EtOH (0.05% DEA) in CO 2 ; FlowRate: 4ml/min; ABPR: 1500psi;
  • the retention time is 4.489min (Analysis method: Column: Chiralpak IG-3 (50mm*4.6mm, 3 ⁇ m) Gradient: 40% EtOH (0.05% DEA) in CO 2 ; FlowRate: 4ml/min; ABPR: 1500psi;
  • Example 5 For the synthesis procedure of Example 5, see Example 4, wherein compound 4a was replaced by compound ethyl 2-(4-iodophenyl)acetate to obtain Example 5.
  • Chiral separation conditions Column: Phenomenex-Cellulose-2 (250mm*30mm, 10 ⁇ m) Condition: 45% EtOH in CO2; FlowRate: 80ml/min. The retention time is 6.249min (Analysis method: Column: Cellulose 2 (150mm* 4.6 mm, 5 ⁇ m) Gradient: Isomers of 40% EtOH (0.05% DEA) in CO 2 ; FlowRate: 2.5 ml/min; ABPR: 1500 psi; Temperature: 35° C.):
  • the retention time is 8.351min (analysis method: Column: Cellulose 2 (150mm*4.6mm, 5 ⁇ m) Gradient: 40% EtOH (0.05% DEA) in CO 2 ; FlowRate: 2.5ml/min; ABPR: 1500psi;
  • compound INT-1 (2.5 g, 13.81 mmol) was dissolved in 25 mL of anhydrous tetrahydrofuran at room temperature, carbonyldiimidazole (3.3 g, 20.72 mmol) was added, and the reaction was heated at 60 ° C for 10 hours, and the reaction solution was cooled to After concentration under reduced pressure at room temperature, the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate system) to obtain the title compound INT-2 (2.5 g, yield: 87.7%).
  • compound INT-2 (2.5 g, 12.07 mmol) was dissolved in 20 mL of anhydrous N,N-dimethylformamide at room temperature, potassium carbonate (2.5 g, 18.11 mmol) was added, and stirring was continued for 20 minutes, followed by The temperature was lowered to 0° C. and iodomethane (2.1 g, 14.48 mmol) was added dropwise. After the dropping was completed, the temperature was raised to room temperature and stirring was continued for 5 hours.
  • reaction solution was quenched with saturated sodium chloride solution, extracted with ethyl acetate (15 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and the filtrate was reduced under reduced pressure. After concentration, the residue was subjected to silica gel column chromatography (n-heptane/ethyl acetate system) to obtain the title compound INT-3 (2.3 g, yield: 86.5%).
  • compound INT-3 (300 mg, 1.36 mmol) was suspended in 20 mL of 6N aqueous hydrochloric acid at room temperature, heated for 3 hours at 100 °C, the reaction solution was cooled to room temperature, and filtered to obtain compound INT-4 (200 mg, yield : 71.4%).
  • reaction solution was poured into 200 mL of water, extracted with ethyl acetate (80 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. It was concentrated under pressure, and the residue was purified by silica gel chromatography eluting with petroleum ether, ethyl acetate to give the title compound 8c (2.50 g, yield: 93.3%).
  • reaction solution was stirred under the protection of an argon balloon for 2 hours. After the reaction, the reaction solution was diluted with dichloromethane (40 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain the title compound 8e (130 mg, yield rate: 82.8%).
  • compound INT-5 (1.5 g, 9.03 mmol) was dissolved in 12 mL of petroleum ether at room temperature, cooled to about 0 °C, and HNO 3 (0.9 mL)/AC 2 O (9 mL) solution was added dropwise, and stirring was continued for 20 minutes. .
  • compound INT-7 (0.7 g, 3.86 mmol) was used as raw material to obtain compound INT-8 (0.65 g, yield: 81.2%).
  • compound INT-8 (0.5 g, 2.41 mmol) was used as raw material to obtain compound INT-9 (0.5 g, yield: 78.5%).
  • compound INT-9 (0.3 g, 1.36 mmol) was used as raw material to obtain compound INT-10 (0.2 g, yield: 72%).
  • reaction was stirred under an argon balloon for 2 hours. After the reaction, the reaction solution was diluted with dichloromethane (40 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain the title compound 9a (110 mg, yield rate: 87.6%).
  • compound 10F (3.2 g, 15.1 mmol) was dissolved in dichloromethane (32 mL), triethylamine (3.1 mL, 22.5 mmol) was added, and 4-chlorobutyryl chloride (3.7 mL) was added dropwise at 0°C , 32.9mmol), reacted at room temperature for 3h. Quenched with water (30 mL), extracted with dichloromethane (100 mL ⁇ 3). Washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give compound 10G (4.6 g, yield: 96%).
  • compound 10H (520 mg, 1.8 mmol) was suspended in 20 mL of 6N aqueous hydrochloric acid at room temperature, heated for 3 hours at 100 °C, the reaction solution was cooled to room temperature, and filtered to obtain compound 10I (460 mg, yield: 92%) .
  • compound 11C (17 g, 51.5 mmol) was used as raw material to obtain compound 11D (8.5 g, yield: 71%).
  • compound 11D (5 g, 21.8 mmol) was used as the raw material to obtain compound 11E (4.8 g, yield: 90%).
  • compound 11E (4.8 g, 19.7 mmol) was used as raw material to obtain compound 11F (4.2 g, yield: 99%).
  • compound 11G (2.9 g, yield: 97%) was obtained from compound 11F (2 g, 9.4 mmol) as raw material.
  • compound 11G (2.9 g, 9.1 mmol) was used as raw material to obtain compound 11H (1.6 g, yield: 62%).
  • compound 11H (760 mg, 2.6 mmol) was used as raw material to obtain compound 11I (650 mg, yield: 90%).
  • compound 11I (89 mg, 0.33 mmol) was used as the starting material to obtain compound 11J (140 mg, yield: 88%).
  • compound 11 (70 mg, yield: 55%) was obtained from compound 11J (140 mg, 0.25 mmol) as a pair of isomers.
  • Mobile phase 40% of iso-propanol (0.05% DEA) in CO 2 ;
  • the compounds of the present disclosure are assayed for cyclin-dependent kinase activity.
  • Compound dilutions were transferred to each well of an assay plate using an Echo 550 (784075, Greiner). Seal assay plate, centrifuge plate at 1000g for 1 min; prepare 2x enzyme in 1x kinase buffer (prepared from 1 volume 5X kinase buffer and 4 volumes distilled water and 50uM DTT), add 2.5 ⁇ l 2x enzyme to 384 wells Plates were assayed, centrifuged at 1000 g for 30 s and left at room temperature for 10 minutes. Prepare a 2x substrate and ATP mix in 1x kinase buffer and add 2.5 ⁇ l of the 2x substrate and ATP mix to start the reaction.
  • Echo 550 784075, Greiner
  • the plate was centrifuged at 1000 g for 30 seconds, the assay plate was sealed, and the reaction was carried out at room temperature for 1 hour. Add 4 ⁇ l of ADP-Glo reagent and incubate at room temperature for 40 minutes, then add 8 ⁇ l of kinase detection reagent and incubate at room temperature for 40 minutes.
  • the luminescence signal from each well was read on an Envision 2104 plate reader.
  • the percent inhibition was calculated as follows:
  • Inhibition percentage 100-(cmpd signal-Ave_PC signal)/(Ave_VC signal-Ave_PC signal) ⁇ 100.
  • IC50s were calculated using GraphPad 8.0 by fitting the percent inhibition values and the logarithm of compound concentration to a nonlinear regression (dose response - variable slope).
  • X log of inhibitor concentration
  • Y % inhibition.

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Abstract

本公开提供了CDK2抑制剂及其制备方法。具体而言，本公开提供一种式I所示化合物或其可药用的盐、互变异构体，其中各基团如本公开定义。所述式I所示化合物可作为细胞周期蛋白-依赖性激酶抑制剂，用于预防和/或治疗与蛋白依赖性激酶或细胞周期蛋白相关的疾病，例如细胞增殖性疾病，癌症或免疫性疾病。

Description

CDK2抑制剂及其制备方法 技术领域
本公开属于医药领域，涉及一种CDK2抑制剂。
背景技术
细胞周期蛋白-依赖性激酶(CDK)是丝氨酸/苏氨酸激酶亚家族的成员，每个CDK/细胞周期蛋白复合物负责细胞周期内特定期的转换或进展，其在调节真核细胞分裂和增殖中发挥重要作用。细胞周期蛋白-依赖性激酶催化单元被称为细胞周期蛋白的调节亚基激活。已经鉴定出至少16种哺乳动物细胞周期蛋白(Annu.Rev.Pharmacol.Toxicol.(1999)39:295-312)。细胞周期蛋白B/CDK1、细胞周期蛋白A/CDK2、细胞周期蛋白E/CDK2、细胞周期蛋白D/CDK4、细胞周期蛋白D/CDK6和可能的其他heterodynes是细胞周期进展的重要调节因子。细胞周期蛋白/CDK heterodynes的其他功能包括转录调节、DNA修复、分化和凋亡(Annu.Rev.Cell.Dev.Biol.(1997)13:261-291)。
近年来，乳腺癌治疗领域最大的进展无疑是CDK4/6单用或联合内分泌治疗在激素受体阳性晚期乳腺癌，如帕博西尼(palbociclib)、瑞博西尼(ribociclib)和玻玛西尼(abemaciclib)已被批准与芳香酶抑制剂组合用于治疗绝经后妇女的激素受体(HR)-阳性、人类表皮生长因子受体2(HER2)-阴性晚期或转移性乳腺癌，并且帕博西尼和玻玛西尼(abemaciclib)已被批准与氟维司群组合用于在内分泌疗法后疾病进展后治疗绝经后妇女的激素受体(HR)-阳性、人类表皮生长因子受体2(HER2)-阴性晚期或转移性乳腺癌(Nature Reviews(2016)13:417-430、J Clin Oncol 2017,35,2875-2884)。尽管CDK4/6抑制剂在雌激素受体ER阳性转移性乳腺癌中显示出显著的临床功效，但与其他激酶一样，它们的作用可能随着时间的推移被原发性或获得性抗性的发展限制。
CDK2的过表达与细胞周期的异常调节有关。细胞周期蛋白E/CDK2复合物在调节G1/S转换、组蛋白生物合成和中心体复制中起重要作用。细胞周期蛋白D/Cdk4/6和细胞周期蛋白E/Cdk2对Rb的进行性磷酸化释放G1转录因子E2F，并促进S期进入。在早期S期期间细胞周期蛋白A/CDK2的激活促进内源性底物的磷酸化，其允许DNA复制和E2F的失活，以完成S期(Nat.Rev.Drug.Discov.2015；14(2):130-146)。细胞周期蛋白E在多种癌症中过度表达，特别是乳腺癌、肺癌、白血病、淋巴瘤(郭翠萍等，细胞周期蛋白E的调控与恶性肿瘤.国际肿瘤学杂志,2012,39(005):337-340)，细胞周期蛋白E的扩增或过表达也与卵巢癌、胃癌、子宫内膜癌和其他癌症的不良预后有关。
研究表明，抑制CDK2激酶会诱导肿瘤细胞调亡，但对于正常细胞只会造成较小的损伤。CDK激酶的单体形式是无活性的，而细胞周期蛋白A/E与CDK2结合并促发磷酸化的结合激活CDK2。CDK2还可结合细胞周期蛋白A用于S期的整个进展并参与DNA修复。近几年各大公司分别鉴定发现了一系列选择性抑制CDK 2的抑制剂，用于治疗癌症等疾病，如Seliciclib、Dinaciclib等，但是为了达到更好的癌症治疗效果的目的，更好的满足市场需求，仍需要开发出新一代的高效低毒的选择性CDK2抑制剂。
发明内容
本公开提供式I化合物或其可药用盐、互变异构体：
Figure PCTCN2021140312-appb-000001
其中，-L 1-、-L 2-各自独立选自键、C 1-C 6亚烷基、-O-和-NH-，所述C 1-6亚烷基任选地被一个或多个选自羟基、烷基、烷氧基、卤代烷基、卤代烷氧基、卤素、羟基、氰基、氨基和硝基的取代基取代；
R 1选自环烷基、杂环基、芳基和杂芳基，其中所述环烷基、杂环基、芳基或杂芳基任选地被一个或多个Z取代；
一些实施方案中，R 2、R 3各自独立选自氢、氘、卤素、烷基、氰基、羟基、硝基、氧代基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、烷基、烷氧基、氰基、氨基、硝基、羟基、羟烷基、羧基、环烷基、杂环基、芳基和杂芳基的取代基取代；
一些实施方案中，R 2、R 3共同构成3-8元环，所述3-8元环任选地被一个或多个Z取代；
一些实施方案中，R 4选自单环和多环，任选地被一个或多个Z取代，且R 5选自氢、氘、烷基和卤素，其中所述烷基任选被一个或多个选自卤素、烷基、烷氧基、氰基、氨基、硝基、羟基、羟烷基、羧基、环烷基、杂环基、芳基和杂芳基的取代基取代，
条件是，当R 4选自单环时，R 4选自
Figure PCTCN2021140312-appb-000002
且R 1选自
Figure PCTCN2021140312-appb-000003
Figure PCTCN2021140312-appb-000004
R 6选自氢、氘、卤素和烷基；
R 7相同或不同，且R 7各自独立选自氢、氘、卤素、羟基、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、SR'、SOR'、SO 2R'、SO 2NR'(R”)、NR'(R”)、COOR'、CONR'(R”)和-(P＝O)R'(R”)，所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氧代、硝基、氰基、SR'、SOR'、SO 2R'、SO 2NR'(R”)、NR'(R”)、COR'、COOR'、CONR'(R”)或-(P＝O)R'(R”)的取代基取代；或任意两个相邻R 7共同构成3-8元环，所述3-8元环任选地被一个或多个Z取代；
一些实施方案中，R 4、R 5与它们所连接的N原子共同构成多环，任选地被一个或多个Z取代；
Z选自卤素、氰基、羟基、硝基、氧代基、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、SR'、SOR'、SO 2R'、SO 2NR'(R”)、NR'(R”)、COR'、COOR'、CONR'(R”)和-(P＝O)R'(R”)；
每个R'或R”独立地选自氢、氘、羟基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氧代、硝基和氰基的取代基取代；
本公开中，式I所示的化合物不是
Figure PCTCN2021140312-appb-000005
Figure PCTCN2021140312-appb-000006
一些实施方案中，化合物I为：
Figure PCTCN2021140312-appb-000007
其中，R 7相同或不同，且R 7各自独立选自氢、氘、卤素、C 1-6烷基、C 3-7环烷基、3-7元杂环基、5-12元芳基、5-12元杂芳基和-(P＝O)R'(R”)，所述C 3-7环烷基、3-7元杂环基、5-12元芳基、5-12元杂芳基任选被一个或多个选自卤素、羟基、氧代、硝基、烷基和烷氧基的取代基取代。
一些实施方案中，化合物IIa包括：
Figure PCTCN2021140312-appb-000008
化合物IIb包括：
Figure PCTCN2021140312-appb-000009
Figure PCTCN2021140312-appb-000010
一些实施方案中，R 7相同或不同，且R 7各自独立选自氢、氘、氟、氯、溴、甲基、乙基、丙基、异丙基、-(P＝O)R'(R”)、
Figure PCTCN2021140312-appb-000011
其中，
R'或R”独立地选自氢、氘、甲基、乙基、丙基、异丙基和苯基；
X选自-CH和N；
Y选自-CH 2-、-CH(CH 3)-、-NH-、-N(CH 3)-和-O-。
一些具体的实施方案中R 7相同或不同，且R 7各自独立选自氢、氘、甲基、-(P＝O)(CH 3) 2、
Figure PCTCN2021140312-appb-000012
一些实施方案中，化合物I为：
Figure PCTCN2021140312-appb-000013
其中，环A选自C 3-7环烷基、5-8元芳基和5-8元杂环基，所述C 3-7环烷基、5-8元芳基、5-8元杂环基任选地被一个或多个Z取代。
一些实施方案中，化合物IIc包括：
Figure PCTCN2021140312-appb-000014
Figure PCTCN2021140312-appb-000015
所述化合物IId包括：
Figure PCTCN2021140312-appb-000016
一些实施方案中，环A选自5-8元杂环基，所述5-8元杂环基任选地被选自卤素、羟基、氧代、硝基、烷基和烷氧基中的一个或多个取代基所取代。
一些实施方案中，环A选自
Figure PCTCN2021140312-appb-000017
其中，Y选自-CH 2-、-CH(CH 3)-、-NH-、-N(CH 3)-和-O-。
一些具体的实施方案中，环A选自
Figure PCTCN2021140312-appb-000018
一些实施方案中，R 6选自氢、氘、卤素和C 1-6烷基，例如氢、氘、氟、氯、溴、甲基、乙基、丙基和异丙基。
一些具体的实施方案中，R 6选自甲基。
另一些实施方案中，当R 4选自多环时，R 1选自C 6-C 12芳基和5-10元杂芳基，其中所述C 6-C 12芳基或5-10元杂芳基任选地被一个或多个Z取代。
一些具体的实施方案中，C 6-C 12芳基或5-10元杂芳基选自吡唑基、三唑基、异噁唑基(isoxazolyl)、噁唑基(oxazolyl)、噻唑基、噻二唑基(thiadiazolyl)、咪唑基、吡啶基、吡嗪基、吲唑基、苯并咪唑基和苯基，优选自异噁唑基，其中所述 C 6-C 12芳基或5-10元杂芳基任选地被一个或多个Z取代。
一些实施方案中，化合物I为：
Figure PCTCN2021140312-appb-000019
一些实施方案中，化合物III包括
Figure PCTCN2021140312-appb-000020
一些实施方案中Z选自氟、氯、溴、甲基、乙基、丙基、异丙基、氰基、羟基、卤代烷基、-(P＝O)R'(R”)、
Figure PCTCN2021140312-appb-000021
的取代基取代；其中，
R'或R”独立地选自氢、氘、甲基、乙基、丙基、异丙基和苯基；
X选自-CH和N；
Y选自-CH 2-、-CH(CH 3)-、-NH-、-N(CH 3)-和-O-。
一些具体的实施方案中，Z选自甲基、-(P＝O)(CH 3) 2、
Figure PCTCN2021140312-appb-000022
的取代基取代。
一些具体的实施方案中，Z选自甲基。
一些实施方案中，化合物III为
Figure PCTCN2021140312-appb-000023
一些实施方案中，R 4选自螺环、稠环和桥环，并任选地被一个或多个Z取代，所述螺环、稠环或桥环由任一个的碳或氮原子连接到式I结构中。
一些实施方案中，螺环包括螺环烷基或螺杂环基，选自[3.3]、[3.4]、[3.5]、[3.6]、[4.4]、[4.5]、[4.6]、[5.5]、[5.6]和[6.7]螺环。
一些具体的实施方案中，螺环选自
Figure PCTCN2021140312-appb-000024
Figure PCTCN2021140312-appb-000025
螺环通过任一*表示的连接位点连接到式I结构，并任选地进一步被一个或多个Z取代。
一些具体的实施方案中，螺环选自
Figure PCTCN2021140312-appb-000026
所述螺环通过*表示的连接位点连接到式I结构中。
一些实施方案中，稠环包括稠环烷基或稠杂环基，选自二环和三环，任选地进一步被一个或多个Z取代。
一些具体的实施方案中，稠环选自
Figure PCTCN2021140312-appb-000027
Figure PCTCN2021140312-appb-000028
稠环通过任一*表示的连接位点连接到式I结构中，任选地进一步被一个或多个Z取代。
一些具体的实施方案中，稠环选自
Figure PCTCN2021140312-appb-000029
通过*表示的连接位点连接到式I结构中。
一些实施方案中，桥环包括桥环烷基或桥杂环基，选自二环和三环，每条桥上碳原子数为0-3个，任选地被一个或多个Z取代。
一些具体的实施方案中，桥环选自
Figure PCTCN2021140312-appb-000030
Figure PCTCN2021140312-appb-000031
通过任一*表示的连接位点连接到式I结构中，任选地进一步被一个或多个Z取代。
一些具体的实施方案中，桥环选自
Figure PCTCN2021140312-appb-000032
通过*表示的连接位点连接到式I结构中。
一些实施方案中，R 5选自氢、氘、卤素和C 1-6烷基。
一些实施方案中，R 5选自氢、氘、氟、氯、溴、甲基、乙基、丙基和异丙基。
一些具体的实施方案中，R 5选自氢。
另一些实施方案中，当R 4、R 5与它们所连接的N原子共同构成的多环时，所述化合物I为
Figure PCTCN2021140312-appb-000033
其中环C选自
Figure PCTCN2021140312-appb-000034
Figure PCTCN2021140312-appb-000035
Figure PCTCN2021140312-appb-000036
任选地被一个或多个Z取代。
一些实施方案中，化合物IV化合物包括
Figure PCTCN2021140312-appb-000037
Figure PCTCN2021140312-appb-000038
一些实施方案中，R 1选自C 6-C 12芳基和5-10元杂芳基，其中所述C 6-C 12芳基或5-10元杂芳基任选地被一个或多个Z取代。
一些具体的实施方案中，R 1选自吡唑基、三唑基、异噁唑基(isoxazolyl)、噁唑基(oxazolyl)、噻唑基、噻二唑基(thiadiazolyl)、咪唑基、吡啶基、吡嗪基、吲唑基、苯并咪唑基和苯基，任选地被一个或多个Z取代。
一些实施方案中，化合物IV为：
Figure PCTCN2021140312-appb-000039
一些实施方案中，化合物IVa化合物包括：
Figure PCTCN2021140312-appb-000040
一些实施方案中Z选自氟、氯、溴、甲基、乙基、丙基、异丙基、氰基、羟基、卤代烷基、-(P＝O)R'(R”)、
Figure PCTCN2021140312-appb-000041
的取代基取代；其中，
R'或R”独立地选自氢、氘、甲基、乙基、丙基、异丙基和苯基；
X选自-CH和N；
Y选自-CH 2-、-CH(CH 3)-、-NH-、-N(CH 3)-和-O-。
一些具体的实施方案中，Z选自甲基、-(P＝O)(CH 3) 2、
Figure PCTCN2021140312-appb-000042
的取代基取代。
一些具体的实施方案中，Z选自甲基。
一些实施方案中，-L 2-选自键、-CH 2-、-CH(CH 3)-、-CH 2-CH 2-、-O-和-NH-。
一些具体的实施方案中，-L 2-选自-CH 2-和-CH(CH 3)-。
一些实施方案中，R 2、R 3各自独立选自氢、氘、氟、氯、溴、甲基、乙基、丙基、异丙基、苯基、氰基、羟基和氧代基。
一些具体的实施方案中，R 2、R 3各自独立选自氢、氘、氟、氯和甲基。
一些具体的实施方案中，R 2、R 3各自独立选自氢。
另一些实施方案中，R 2、R 3共同构成3-8元环，所述3-8元环选自C 3-7环烷基、3-8元杂环基、5-8元芳基和5-8元杂芳基，所述3-8元环任选地被一个或多个Z取代。
一些具体的实施方案中，R 2、R 3共同构成的3-8元环选自环丙基、环丁基、环戊基，所述3-8元环任选地被一个或多个Z取代，其中Z选自氟、氯、溴、甲基、乙基、丙基、异丙基、苯基、氰基、羟基和氧代基。
一些具体的实施方案中，R 2、R 3共同构成的3-8元环选自被一个Z取代的环丙基、环丁基、环戊基，其中Z选自氟、氯和甲基。
一些具体的实施方案中，R 2、R 3共同构成环丙基、环丁基或环戊基。
一些具体的实施方案中，R 2、R 3共同构成环丙基。
一些实施方案中，-L 1-选自键、-CH 2-、-CH(CH 3)-、-CH 2-CH 2-、-O-和-NH-。
一些具体的实施方案中，-L 1-选自-CH 2-和-O-。
第二方面，本公开还提供一系列化合物，选自：
Figure PCTCN2021140312-appb-000043
Figure PCTCN2021140312-appb-000044
Figure PCTCN2021140312-appb-000045
Figure PCTCN2021140312-appb-000046
或其可药用盐、互变异构体。一些具体的实施方案中，本公开还提供一系列化合物，选自：
Figure PCTCN2021140312-appb-000047
Figure PCTCN2021140312-appb-000048
Figure PCTCN2021140312-appb-000049
Figure PCTCN2021140312-appb-000050
Figure PCTCN2021140312-appb-000051
Figure PCTCN2021140312-appb-000052
Figure PCTCN2021140312-appb-000053
Figure PCTCN2021140312-appb-000054
Figure PCTCN2021140312-appb-000055
或其可药用盐、互变异构体。
第三方面，本公开还提供第一或第二方面所述化合物或其可药用盐、互变异构体的制备方法。
一些实施方案中，包括如下步骤：
Figure PCTCN2021140312-appb-000056
其中，
式I-5所示化合物与式I-6所示化合物在碱性条件下，经取代反应，然后脱去保护基团LG 1，得到式I所示化合物；
碱性条件的试剂选自有机碱或无机碱，所述的有机碱选自三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、叔丁醇钠和叔丁醇钾；所述的无机碱选自氢化钠、磷酸钾、碳酸钠、碳酸钾、甲醇钠、乙醇钠、叔丁醇钠、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂；
LG 1选自保护基 tBu,S(＝O) tBu,Cbz,Boc,Bn,PMB,SEM,THP；
LG 3选自苯氧基、4-硝基苯氧基。
一些具体的实施方案中，当式I中-L 1-选自-O-时，包括如下步骤：
Figure PCTCN2021140312-appb-000057
另一些实施方案中，当式I中-L 1-选自-O-时，包括如下步骤：
Figure PCTCN2021140312-appb-000058
其中：
式I-4所示化合物与式I-6所示化合物在酰化试剂存在条件下，经氨基甲酸酯化反应，然后脱去保护基团LG 1，得到式I所示化合物；
所述酰化试剂选自三光气、1,1'-羰基二咪唑；
LG 1选自保护基 tBu,S(＝O) tBu,Cbz,Boc,Bn,PMB,SEM,THP。
一些实施方案中，式I-4由式I-3所示化合物经还原反应得到：
Figure PCTCN2021140312-appb-000059
一些实施方案中，式I-3所示化合物由式I-1所示的化合物与式I-2所示化合物在缩合剂存在条件下，或者在碱性条件下，经酰化反应得到：
Figure PCTCN2021140312-appb-000060
其中，LG 2选自羟基、烷氧基、卤素。
一些实施方案中，所述缩合剂选自二环己基碳二亚胺，二异丙基碳二亚胺，1-(3-二甲胺基丙基)-3-乙基碳二亚胺，HATU，HBTU，TBTU，HCTU，TSTU，TNTU，PyBOP，1-丙基磷酸酐。
一些实施方案中，碱性条件试的试剂包括有机碱和无机碱类，所述的有机碱选自三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基 锂、醋酸钾、叔丁醇钠和叔丁醇钾，所述的无机碱选自氢化钠、磷酸钾、碳酸钠、碳酸钾、甲醇钠、乙醇钠、叔丁醇钠、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂。
第四方面，本公开还提供一种药物组合物，其包含第一或第二方面所述的化合物或其可药用盐，和至少一种药学上可接受的载体、稀释剂或者赋形剂。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有1％-99％的化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有2％-98％的化合物或其可药用的盐。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。
第五方面，本公开还提供一种预防和/或治疗患有与蛋白依赖性激酶相关疾病的患者的方法，其通过向所述患者施用治疗有效量的本公开所述的化合物或其可药用的盐或前述药物组合物。
另一方面，本公开还提供一种预防和/或治疗患有与细胞周期蛋白相关疾病的患者的方法，其通过向所述患者施用治疗有效量的本公开所述的化合物或其可药用的盐或前述药物组合物。
在一些实施方案中，所述与蛋白依赖性激酶相关疾病或与细胞周期蛋白相关疾病选细胞增殖性疾病，癌症或免疫性疾病。
在一些实施方案中，所述与蛋白依赖性激酶相关疾病或与细胞周期蛋白相关疾病选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食道癌、胃癌、肝癌(包括HCC)、胰腺癌、结直肠癌、肺癌(包括NSCLC、SCLC、鳞状细胞癌或腺癌)、肾癌(包括RCC)、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈癌、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺癌、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤。
一些具体的实施方案中，所述的癌症选自细胞周期蛋白E1和/或细胞周期蛋白E2扩增的癌症。
本公开还提供一种预防和/或治疗患有癌症的患者的方法，其通过向所述患者施用治疗有效量的本公开所述的化合物或其可药用的盐或前述药物组合物，所述 的癌症选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食道癌、胃癌、肝癌(包括HCC)、胰腺癌、结直肠癌、肺癌(包括NSCLC、SCLC、鳞状细胞癌或腺癌)、肾癌(包括RCC)、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈癌、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺癌、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤。
本公开提供了治疗有效量的本公开所述的化合物或其可药用的盐或前述药物组合物在制备用于预防和/或治疗与蛋白依赖性激酶相关疾病的药物中的用途，
一些具体的实施方案中，蛋白依赖性激酶选自CDK2，与蛋白依赖性激酶相关疾病选自细胞增殖性疾病，癌症或免疫性疾病。
另一方面，本公开提供了治疗有效量的本公开所述的化合物或其可药用的盐或前述药物组合物在制备用于预防和/或治疗与细胞周期蛋白相关疾病的药物中的用途。
一些具体的实施方案中，细胞周期蛋白选自细胞周期蛋白E，例如细胞周期蛋白E1、细胞周期蛋白E2。与细胞周期蛋白相关疾病选自细胞增殖性疾病，癌症或免疫性疾病。
在一些实施方案中，本公开提供了治疗有效量的本公开所述的化合物或其可药用的盐或前述药物组合物在制备治疗癌症的药物中的用途。
一些具体的实施方案中，所述的癌症选自选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食道癌、胃癌、肝癌(包括HCC)、胰腺癌、结直肠癌、肺癌(包括NSCLC、SCLC、鳞状细胞癌或腺癌)、肾癌(包括RCC)、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈癌、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺癌、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤。
一些具体的实施方案中，所述的癌症选自细胞周期蛋白E1和/或细胞周期蛋白E2扩增的癌症。
本公开中所述化合物可药用盐选自无机盐或有机盐，本公开所述化合物可与酸性或碱性物质反应成相应盐。
另一方面，本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。
另外，本公开的化合物和中间体还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于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化、吡唑基异构化。
吡唑基平衡实例是在如下所示的E和F之间：
Figure PCTCN2021140312-appb-000061
本发明中的所有化合物可以被画成E型或F型，例如：
Figure PCTCN2021140312-appb-000062
所有的互变异构形式在本发明的范围内。化合物的命名不排除任何互变异构体。
本公开化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本公开某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。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，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本公开还包括一些与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、 硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。本公开还包括各种氘化形式的式I化合物。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。本领域技术人员能够参考相关文献合成氘化形式的式I化合物。在制备氘代形式的式I化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取代的C 1-6烷基”是指卤素或者氰基可以但不必须存在，该说明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。
本发明所述化合物的化学结构中，键
Figure PCTCN2021140312-appb-000063
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2021140312-appb-000064
可以为
Figure PCTCN2021140312-appb-000065
或
Figure PCTCN2021140312-appb-000066
或者同时包含
Figure PCTCN2021140312-appb-000067
和
Figure PCTCN2021140312-appb-000068
两种构型。虽然为简便起见将全部上述结构式画成某些异构体形式，但是本发明可以包括所有的异构体，如互变异构体、旋转异构体、几何异构体、非对映异构体、外消旋体和对映异构体。本公开所述化合物的化学结构中，键
Figure PCTCN2021140312-appb-000069
并未指定构型，即键
Figure PCTCN2021140312-appb-000070
的构型可以为E型或Z型，或者同时包含E和Z两种构型。
术语解释：
术语“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。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。
术语“可药用赋形剂”或“药学上可接受的赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
术语“有效量”或“有效治疗量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者 的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基。非限制性实例包括甲基、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。更优选的是含有1至6个碳原子的烷基，非限制性实施例包括甲基、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、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“亚烷基”表示烷烃分子中去除2个氢原子后余下的部分，包括1至20个碳原子的直链和支链亚基团。含有1至6个碳原子的亚烷基，非限制性实施例包括亚甲基(-CH 2-)、亚乙基(如-CH 2CH 2-或-CH(CH 3)-)、亚丙基(如-CH 2CH 2CH 2-或-CH(CH 2CH 3)-)、亚丁基(如-CH 2CH 2CH 2CH 2-)。如无特殊说明，亚烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自氘、芳基、杂芳基、卤素所取代。
术语“环烷基”或“碳环”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至7个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等；多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多 个以下基团，独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
所述环烷基环可以稠合于芳基或杂芳基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
术语“杂环烷基”或“杂环”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至7个环原子。单环杂环烷基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环烷基包括螺环、稠环和桥环的杂环烷基。“杂环烷基”非限制性实例包括：
Figure PCTCN2021140312-appb-000071
Figure PCTCN2021140312-appb-000072
等等。
所述杂环烷基环可以稠合于芳基或杂芳基环上，其中与母体结构连接在一起 的环为杂环烷基，其非限制性实例包括：
Figure PCTCN2021140312-appb-000073
等。
杂环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至12元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2021140312-appb-000074
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为6至12元，更优选为5元或6元。例如。其非限制性实例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基(oxazolyl)、异噁唑基(isoxazolyl)、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基、三唑基、吲唑基、苯并咪唑基、
Figure PCTCN2021140312-appb-000075
等。
所述杂芳基环可以稠合于芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2021140312-appb-000076
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
术语“螺环”指两环共用一个原子的化合物。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。“螺碳环”指的是螺环烷基中的环系。螺环烷基的非限制性实例包括：
Figure PCTCN2021140312-appb-000077
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环”指的是螺杂环基中的环系。螺杂环基的非限制性实例包括：
Figure PCTCN2021140312-appb-000078
术语“稠环”指两个或两个以上环通过共用两个相邻的原子稠合而成的化合物。
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。“稠碳环”指的是稠环烷基中的环系。稠环烷基的非限制性实例包括：
Figure PCTCN2021140312-appb-000079
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。“稠杂环”指的是稠杂环基中的环系。稠杂环基的非限制性实例包括：
Figure PCTCN2021140312-appb-000080
术语“稠杂芳基”可以是含有5-14个环原子(其中至少含有一个杂原子)由两个或两个以上环状结构彼此共用两个相邻的原子连接起来形成的不饱和的具有芳香性的稠环结构，同时包括碳原子、氮原子和硫原子可以被氧代，优选"5-12元稠杂芳基"、"7-12元稠杂芳基"、"9-12元稠杂芳基"等，例如苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、异吲哚、苯并噁唑基、苯并咪唑基、吲唑基、苯并三唑基、喹啉基、2-喹啉酮、4-喹啉酮、1-异喹啉酮、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、酚嗪基、喋啶基、嘌呤基、萘啶基、吩嗪、吩噻嗪等。“稠杂芳环”指的是稠杂芳基中的环系。
稠杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“桥环”指两个或两个以上环状结构彼此共用两个非相邻的环原子所形成的结构。
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2021140312-appb-000081
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2021140312-appb-000082
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯 氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。同理，“炔氧基”、“烯氧基”、“环烷氧基”、“杂环烷氧基”、“环烯氧基”的定义如上述“烷氧基”定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“卤代烷基”指被卤素取代的烷基，其中烷基如上所定义。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代”指＝O基团。例如，碳原子与氧原子通过双键连接，其中形成酮或醛基。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“羧基”指-C(O)OH。
术语“醛基”指-CHO。
术语“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。
“被一个或多个……取代”是指可以被单个或多个取代基取代。当被多个取代基取代时，可以是复数个相同取代基，也可以是一个或复数个不同取代基的组合。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。
本公开实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
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-400核磁仪，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)。
MS的测定用Shimadzu 2010 Mass Spectrometer或Agilent 6110A MSD质谱仪。
HPLC的测定使用Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200 LC高压液相色谱仪(Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.,3um、Chiralpak AD-3 150×4.6mm I.D.,3um、Chiralpak AD-3 50×4.6mm I.D.,3um、Chiralpak AS-3 150×4.6mm I.D.,3um、Chiralpak AS-3 100×4.6mm I.D.,3μm、ChiralCel OD-3 150×4.6mm I.D.,3um、Chiralcel OD-3 100×4.6mm I.D.,3μm、ChiralCel OJ-H 150×4.6mm I.D.,5um、Chiralcel OJ-3 150×4.6mm I.D.,3um色谱柱；
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。
柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体。
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。
CombiFlash快速制备仪使用Combiflash Rf150(TELEDYNE ISCO)。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
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。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
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。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
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。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
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，D：石油醚/乙酸乙酯/甲醇，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。
实施例1
顺式-3-(5-(2-(3-甲基异噻唑-5-基)乙酰氨基)-1H-吡唑-3-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯异构体
Figure PCTCN2021140312-appb-000083
第一步
甲基3,3-二甲氧基环戊烷-1-羧酸酯1b
将化合物1a(15g,0.12mol)溶于200mL甲醇中，在室温下加入原甲酸三甲酯(76.8mL,0.70mol)和对甲苯磺酸(0.4g,2.3mmol)，并在室温下搅拌20小时。反应完毕后，加入饱和碳酸氢钠水溶液(20mL)，用乙酸乙酯萃取(80mL×3)，合并有机相，用水洗涤(150mL)，饱和氯化钠溶液洗涤(150mL)，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩得到标题化合物1b(23g,产率：84％)。
第二步
3-羰基-3-(3-羰基环戊基)丙腈1c
在-65℃和氮气氛下，依次将n-BuLi(98mL,0.24mmol)和乙腈(13mL,0.24mol)滴入100mL THF中，反应1h后，将化合物1b(23g,0.12mol)的THF溶液(100mL)缓慢滴入反应液中，待反应完毕后，加入饱和氯化铵溶液淬灭反应，随后加入3M HCl至pH为2，充分搅拌后，用乙酸乙酯萃取(80mL×3)，合并有机相，用水洗涤(150mL)，饱和氯化钠溶液洗涤(150mL)，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩得到标题化合物1c(30g,产率：87％)。
第三步
3-(5-氨基-1-(叔-丁基)-1H-吡唑-3-基)环戊烷-1-酮1d
室温下，将氢氧化钠(0.5g,13mmol)加入到叔丁基肼(1.6g,13mmol)的乙醇(10mL)溶液中，搅拌1h后，将化合物1c(3.0g,20mmol)的乙醇溶液(10mL)加入到上述反应液中，在75℃下，搅拌15h至反应完全，反应液减压浓缩，残余物用硅胶色谱法层析石油醚和乙酸乙酯洗脱纯化，减压浓缩得到标题化合物1d(3.0g,产率：68％)。
MS(ESI)m/z 222.3[M+H] +
第四步
N-(1-(叔-丁基)-3-(3-羰基环戊基)-1H-吡唑-5-基)-2-(3-甲基异噻唑-5-基)乙酰胺1f
氮气氛下，依次将化合物1d(0.90g，4.1mmol)、2-(3-甲基异噻唑-5-基)乙酸(0.69g，4.9mmol)、N,N-二异丙基乙胺(1.5g,11mmol)溶于16mL二氯甲烷中。在室温下加入1-丙基磷酸酐溶液(50％wt，6.5g,10mmol)并在室温下搅拌2小时。加入100mL饱和碳酸氢钠溶液淬灭反应。用100mL二氯甲烷萃取，有机相用饱和氯化钠溶液洗涤(100mL)，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩，残余物用C-18反相色谱法水和乙腈洗脱纯化得到标题化合物1f(760mg，产率：54％)。
MS(ESI)m/z 345.4[M+H] +
第五步
N-(1-(叔-丁基)-3-(3-羟基环戊基)-1H-吡唑-5-基)-2-(3-甲基异噻唑-5-基)乙酰胺1g
氮气氛下，将化合物1f(760mg，2.2mmol)溶于16mL四氢呋喃中。降温至-60℃，将三乙基硼氢化锂(1mol/L，4.4mL，4.4mmol)滴加到反应中，并在-60℃条件下反应2小时。加入80mL饱和碳酸氢钠溶液淬灭反应。用乙酸乙酯萃取(80mL×3)，合并有机相，用饱和氯化铵溶液洗涤(150mL)，用饱和氯化钠溶液洗涤(150mL)，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩得到标题化合物1g(836mg，产率：100％)。
MS(ESI)m/z 347.5[M+H] +
第六步
3-(1-(叔-丁基)-5-(2-(3-甲基异噻唑-5-基)乙酰氨基)-1H-吡唑-3-基)环戊基(4-硝基苯基)碳酸酯1h
氮气氛下，依次将化合物1g(836mg，2.4mmol)、吡啶(570mg，7.2mmol)、4-二甲氨基吡啶(29mg,0.24mmol)、氯化酯4-硝基苯基(677mg,3.4mmol)溶于16mL二氯甲烷中。在室温下搅拌3小时。将溶剂旋干，加入100mL乙酸乙酯，用饱和氯化铵溶液洗涤(100mL)，用饱和氯化钠溶液洗涤(100mL)，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩，残余物用C-18反相色谱法水和乙腈洗脱纯化得到标题化合物1h(900mg，产率：72％)。
MS(ESI)m/z 512.5[M+H] +
第七步
3-(1-(叔-丁基)-5-(2-(3-甲基异噻唑-5-基)乙酰氨基)-1H-吡唑-3-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯1i
氮气氛下，依次将化合物1h(45mg，0.09mmol)、N,N-二异丙基乙胺(46mg,0.35mmol)、二环[1.1.1]戊烷-1-胺盐酸盐(9.5mg,0.11mmol)溶于5mL四氢呋喃中。在60℃条件下反应3小时。将溶剂旋干，加入20mL饱和碳酸氢钠溶液，用 乙酸乙酯萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL)，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩得到标题化合物1i(42mg，产率：100％)。
MS(ESI)m/z 456.5[M+H] +
第八步
3-(5-(2-(3-甲基异噻唑-5-基)乙酰氨基)-1H-吡唑-3-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯1
氮气氛下，依次将化合物1i(42mg，0.09mmol)溶于1mL甲酸中。在75℃条件下反应4小时。将溶剂旋干，加入20mL饱和碳酸氢钠溶液，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL)，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩，残余物用Waters Xbridge C-18(
Figure PCTCN2021140312-appb-000084
19*150mm,Eluent of 50～70％乙腈/水(0.05％FA)gradient@15mL/min)反相色谱法纯化得到，第一个流出物(t R＝6.91min)冻干得到11.8mg，产率：32％)；第二个流出物(t R＝7.35min)冻干得到3.5mg，产率：9.5％)
保留时间为6.91min的异构体:
MS(ESI)m/z 400.4[M+H] +
1H NMR(400MHz,DMSO-d 6)δ＝12.09(br s,1H),10.67(br s,1H),7.77(br s,1H),6.28(s,1H),6.22(s,1H),4.98(br s,1H),3.83(s,2H),3.04(br t,J＝8.0Hz,1H),2.49-2.41(m,1H),2.34(br s,1H),2.20(s,3H),2.05-1.96(m,1H),1.89(br s,7H),1.76-1.51(m,3H)
保留时间为7.35min的异构体:
MS(ESI)m/z 400.4[M+H] +
1H NMR(400MHz,DMSO-d 6)δ＝10.68(br s,1H),7.79(br s,1H),6.28(s,1H),6.22(s,1H),5.05(br s,1H),3.83(s,2H),2.36(s,1H),2.20(s,3H),2.16-1.97(m,3H),1.91(s,7H),1.82(ddd,J＝6.0,10.5,13.6Hz,1H),1.59(br d,J＝8.8Hz,3H)
实施例2
顺式-3-(5-(2-(3-甲基异噻唑-5-基)乙酰氨基)-1H-吡唑-3-基)环戊基螺[3.3]庚烷-2-基氨基甲酸酯异构体
Figure PCTCN2021140312-appb-000085
实施例2的合成步骤参见实施例1，其中以化合物螺[3.3]庚烷-2-胺盐酸盐替换二环[1.1.1]戊烷-1-胺盐酸盐制备获得实施例2。
分离方法：Waters Xbridge C-18(
Figure PCTCN2021140312-appb-000086
30*150mm,Eluent of 40～55％乙腈/水(0.1％NH 4OH)gradient@30mL/min)反相色谱法纯化，第一个流出物(t R＝7.48min)2a(10.2mg，产率：24％)；第二个流出物(t R＝8.15min)2b(2.2mg，产率： 5.2％)。
保留时间为7.48min的异构体:
MS(ESI)m/z 428.5[M+H] +
1H NMR(400MHz,DMSO-d6)δ＝12.11(s,1H),10.63(s,1H),7.28(br d,J＝7.8Hz,1H),6.28(s,1H),6.22(s,1H),4.96(br s,1H),3.82(s,2H),3.80-3.73(m,1H),3.11-2.94(m,1H),2.46-2.37(m,1H),2.20(s,3H),2.17(br s,1H),2.05-1.92(m,3H),1.91-1.61(m,10H),1.61-1.49(m,1H)
保留时间为8.15min的异构体:
MS(ESI)m/z 428.5[M+H] +
1H NMR(400MHz,DMSO-d6)δ＝12.14(s,1H),10.63(s,1H),7.27-7.27(m,1H),7.30(br d,J＝8.0Hz,1H),6.28(s,1H),6.21(s,1H),5.02(br s,1H),3.82(s,2H),3.80-3.75(m,1H),3.23-3.14(m,1H),2.19(s,3H),2.14-2.04(m,2H),2.03-1.93(m,1H),1.97(br t,J＝7.2Hz,3H),1.88-1.73(m,8H),1.66-1.52(m,2H)
实施例3
顺式-3-(5-(2-(3-甲基异噻唑-5-基)乙酰氨基)-1H-吡唑-3-基)环戊基螺[2.3]己烷-4-基氨基甲酸酯异构体
Figure PCTCN2021140312-appb-000087
实施例3的合成步骤参见实施例1，其中以化合物螺[2.3]己烷-4-胺盐酸盐替换二环[1.1.1]戊烷-1-胺盐酸盐制备获得实施例3。
分离方法：Waters Xbridge C-18(
Figure PCTCN2021140312-appb-000088
30*150mm,Eluent of 30～95％乙腈/水(0.1％FA)gradient@30mL/min)反相色谱法纯化，第一个流出物(t R＝7.50min)(5.8mg，产率：16％)；第二个流出物(t R＝7.89min)2b(2.0mg，产率：5.5％)。保留时间为7.50min的异构体:
MS(ESI)m/z 414.4[M+H] +
1H NMR(400MHz,DMSO-d6)δ＝12.11(s,1H),10.64(s,1H),7.23(d,J＝8.3Hz,1H),6.28(s,1H),6.22(s,1H),4.93(d,J＝6.9Hz,1H),4.20–4.06(m,1H),3.83(s,2H),3.11–2.96(m,1H),2.46–2.37(m,1H),2.20(s,4H),2.06–1.80(m,4H),1.68(q,J＝7.6,7.1Hz,3H),0.53(dt,J＝10.2,5.0Hz,1H),0.36(tq,J＝10.0,4.8Hz,2H),0.29–0.18(m,1H).
实施例4
顺式-3-(3-(2-(3-(二甲基磷基)苯基)乙酰氨基)-1H-吡唑-5-基)环戊基(1-甲基环丙基)氨基甲酸酯异构体
Figure PCTCN2021140312-appb-000089
Figure PCTCN2021140312-appb-000090
第一步
2-(3-(二甲基磷基)苯基)乙酸4b
氮气氛围下，将化合物4a(500mg,2.0mmol)，二甲基氧化膦(240.8mg,3.1mmol)，Xantphos(238.0mg,0.41mmol)，K 3PO 4(654.89mg,3.1mmol)和Pd(OAc) 2(46.2mg,0.2mmol)溶于5mL DMF中，在135℃下微波反应1.5h。反应完毕后，加入水洗涤(10mL×3)，用乙酸乙酯萃取(15mL×3)，合并有机相，用水洗涤(20mL)，饱和氯化钠溶液洗涤(20mL)，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩得到粗品(520mg)。将该粗品溶解于THF(3mL)和水(1mL)中，将3M NaOH(2mL)加入到上述溶液中，室温搅拌6h。反应完毕后，加入2N HCl调pH至酸性，用C-18反相色谱法纯化得到标题化合物4b(200mg，产率：45％)。
MS(ESI)m/z 213.2[M+H] +
第二步
顺式-3-(1-(叔-丁基)-3-(2-(3-(二甲基磷基)苯基)乙酰氨基)-1H-吡唑-5-基)环戊基(1-methylcyclopropyl)氨基甲酸酯4d
氮气氛下，依次将化合物4b(200mg,0.94mmol)、顺式-3-(3-氨基-1-(叔-丁基)-1H-吡唑-5-基)环戊基(1-甲基环丙基)氨基甲酸酯4c(302mg,0.94mmol,采用专利申请“WO 2020/157652A2”公开的方法制备而得),N,N-二异丙基乙胺(0.31mL,1.89mmol)溶于5mL二氯甲烷中。在室温下加入1-丙基磷酸酐溶液(50％wt，600mg,1.89mmol)，在室温下搅拌2小时。加入100mL饱和碳酸氢钠溶液淬灭反应。用100mL二氯甲烷萃取，有机相用饱和氯化钠溶液洗涤(100mL)，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩，残余物用C-18反相色谱法纯化得到标题化合物1f(102mg，产率：21％)。
MS(ESI)m/z 515.3[M+H] +
第三步
顺式-3-(3-(2-(3-(二甲基磷基)苯基)乙酰氨基)-1H-吡唑-5-基)环戊基(1-甲基环丙基)氨基甲酸酯4e
氮气氛下，依次将化合物4d(50mg，0.1mmol)溶于1mL甲酸中。在75℃条 件下反应4小时。将溶剂旋干，加入20mL饱和碳酸氢钠溶液，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL)，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩，用C-18反相色谱法纯化得到标题化合物4e(20mg，产率：42％)。
MS(ESI)m/z 459.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ＝12.07(s,1H),10.59(s,1H),7.74(dd,J＝11.9,1.7Hz,1H),7.61(ddt,J＝11.3,7.0,1.6Hz,1H),7.53–7.40(m,2H),7.34(s,1H),6.26(s,1H),4.96(s,1H),4.13(d,J＝5.6Hz,1H),3.65(s,2H),3.01(d,J＝9.4Hz,1H),2.42(dd,J＝14.2,7.1Hz,1H),1.96(d,J＝9.4Hz,1H),1.68(s,1H),1.65(s,3H),1.62(s,3H),1.21(s,3H),0.57(s,2H),0.49–0.41(m,2H)
第四步
顺式-3-(3-(2-(3-(二甲基磷基)苯基)乙酰氨基)-1H-吡唑-5-基)环戊基(1-甲基环丙基)氨基甲酸酯异构体
化合物4e(12mg，0.027mmol)通过手性拆分(Column:DAICEL CHIRALPAK IG(250mm*30mm,10μm)Condition:60％EtOH(0.1％NH 3·H 2O)in CO2；FlowRate:80ml/min.)得到实施例4异构体。
保留时间为2.653min(分析方法：Column:Chiralpak IG-3(50mm*4.6mm,3μm)Gradient:40％EtOH(0.05％DEA)in CO 2；FlowRate:4ml/min；ABPR:1500psi；
Temperature:35℃)的异构体(2.1mg，产率：17％)。
MS(ESI)m/z 459.2[M+H] +
保留时间为4.489min(分析方法：Column:Chiralpak IG-3(50mm*4.6mm,3μm)Gradient:40％EtOH(0.05％DEA)in CO 2；FlowRate:4ml/min；ABPR:1500psi；
Temperature:35℃)的异构体(2.0mg，产率：16％)。
MS(ESI)m/z 459.3[M+H] +
实施例5
顺式-3-(3-(2-(4-(二甲基磷基)苯基)乙酰氨基)-1H-吡唑-5-基)环戊基(1-甲基环丙基)氨基甲酸酯异构体
Figure PCTCN2021140312-appb-000091
实施例5的合成步骤参见实施例4，其中以化合物乙基2-(4-碘苯基)乙酸酯替换化合物4a制备获得实施例5。手性拆分条件：Column:Phenomenex-Cellulose-2(250mm*30mm,10μm)Condition:45％EtOH in CO2；FlowRate:80ml/min.保留时间为6.249min(分析方法：Column:Cellulose 2(150mm*4.6mm,5μm)Gradient:40％EtOH(0.05％DEA)in CO 2；FlowRate:2.5ml/min；ABPR:1500psi；Temperature:35℃)的异构体：
MS(ESI)m/z 459.2[M+H] +
保留时间为8.351min(分析方法：Column:Cellulose 2(150mm*4.6mm,5μm)Gradient:40％EtOH(0.05％DEA)in CO 2；FlowRate:2.5ml/min；ABPR:1500psi；
Temperature:35℃)的异构体：
MS(ESI)m/z 459.2[M+H] +
实施例6
顺式-3-(3-(2-(4-(2-羰基噁唑烷-3-基)苯基)乙酰氨基)-1H-吡唑-5-基)环戊基(1-甲基环丙基)氨基甲酸酯
Figure PCTCN2021140312-appb-000092
第一步
顺式-3-(1-(叔-丁基)-5-(2-(4-(2-羰基噁唑烷-3-基)苯基)乙酰氨基)-1H-吡唑-3-基)环戊基(1-甲基环丙基)氨基甲酸酯6b
氮气氛下，将2-(4-(2-羰基噁唑烷-3-基)苯基)乙酸(参照专利WO20110037780合成，50mg，0.2mmol)、(顺式-3-(5-氨基-1-(叔-丁基)-1H-吡唑-3-基)环戊基(1-甲基环丙基)氨基甲酸酯(参照专利US2020247784合成，80mg，0.2mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(129mg，0.3mmol)、三乙胺(69mg，0.7mmol)溶于2mL N,N-二甲基甲酰胺中。在20℃条件下反应1小时，加入10mL水，用乙酸乙酯萃取，合并有机相，将有机相洗涤，干燥，反应液减压浓缩后残余物用硅胶正相色谱法纯化得到标题化合物6b(80mg，产率：68％)。
MS(ESI)m/z 524.4[M+H] +
第二步
顺式-3-(3-(2-(4-(2-羰基噁唑烷-3-基)苯基)乙酰氨基)-1H-吡唑-5-基)环戊基(1-甲基环丙基)氨基甲酸酯6
氮气氛下，将化合物顺式-3-(1-(叔-丁基)-5-(2-(4-(2-羰基噁唑烷-3-基)苯基)乙酰氨基)-1H-吡唑-3-基)环戊基(1-甲基环丙基)氨基甲酸酯(30mg，0.06mmol)溶于1.5mL甲酸中。在80℃条件下微波反应1.5小时。将溶剂旋干，加入20mL饱和碳酸氢钠溶液，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL)，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩，残余物用C-18反相色谱法纯化得到标题化合物6(14mg，产率：52％)，其为一对对映异构体。
MS(ESI)m/z 468.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ＝12.05(br s,1H),10.48(br s,1H),7.49(d,J＝8.5Hz,2H),7.39-7.26(m,3H),6.26(br s,1H),4.96(br s,1H),4.42(t,J＝8.0Hz,2H),4.03(t, J＝7.9Hz,2H),3.55(s,2H),3.01(br d,J＝8.3Hz,1H),2.43(br d,J＝6.8Hz,1H),1.96(br d,J＝8.6Hz,1H),1.90-1.81(m,1H),1.73-1.60(m,2H),1.52(br s,1H),1.22(br s,3H),0.57(br s,2H),0.51-0.38(m,2H)
实施例7
顺式-3-(3-(2-(4-(2-羰基吡咯烷-1-基)苯基)乙酰氨基)-1H-吡唑-5-基)环戊基(1-甲基环丙基)氨基甲酸酯
Figure PCTCN2021140312-appb-000093
参照实施例6合成，其中化合物2-(4-(2-羰基吡咯烷-1-基)苯基)乙酸7a参照专利WO2015145371合成，得到的7是一对对映异构体。
MS(ESI)m/z 466.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ＝12.04(br s,1H),10.47(s,1H),7.57(d,J＝8.6Hz,2H),7.34(br s,1H),7.29(d,J＝8.8Hz,2H),6.26(br s,1H),4.96(br s,1H),3.80(t,J＝7.1Hz,2H),3.54(s,2H),2.12-1.98(m,4H),1.96-1.79(m,2H),1.77-1.41(m,4H),1.27-1.17(m,4H),0.57(br s,2H),0.49-0.42(m,2H)
实施例8
(1R,3S)-3-(3-(2-(3-甲基-2-羰基-2,3-二氢苯并[d]噁唑-5-基)乙酰氨基)-1H-吡唑-5-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯
Figure PCTCN2021140312-appb-000094
第一步
2-(2-氧代-2,3-二氢苯并[d]恶唑-5-基)乙酸甲酯INT-2
氮气氛下，常温将化合物INT-1(2.5g,13.81mmol)溶于25mL无水四氢呋喃中， 加入羰基二咪唑(3.3g,20.72mmol),60℃条件下加热反应10小时，反应液冷却至室温，减压浓缩后残余物用硅胶柱层析(石油醚/乙酸乙酯体系)得到题化合物INT-2(2.5g，产率：87.7％)。
MS(ESI)m/z 208.1[M+H] +
第二步
2-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-5-基)乙酸甲酯INT-3
氮气氛下，常温将化合物INT-2(2.5g,12.07mmol)溶于20mL无水N,N-二甲基甲酰胺中，加入碳酸钾(2.5g,18.11mmol),继续搅拌20分钟，接着降温到0℃并滴加碘甲烷(2.1g,14.48mmol)，滴毕后升温至室温并继续搅拌5小时。反应液用饱和氯化钠溶液淬灭，用乙酸乙酯萃取(15mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL)，无水硫酸钠干燥，过滤，收集滤液，减压浓缩后残余物用硅胶柱层析(正庚烷/乙酸乙酯体系)得到标题化合物INT-3(2.3g，产率：86.5％)。
MS(ESI)m/z 222.1[M+H] +
第三步
2-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-5-基)乙酸INT-4
氮气氛下，常温将化合物INT-3(300mg,1.36mmol)悬浮于20mL 6N盐酸水溶液中，100℃条件下加热反应3小时，反应液冷却至室温，过滤得到化合物INT-4(200mg，产率：71.4％)。
MS(ESI)m/z 206.1[M-H] -
第四步
(1R,3S)-3-(5-(((苄氧基)羰基)氨基)-1-(叔-丁基)-1H-吡唑-3-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯
在室温下，将苯甲基(1-(叔-丁基)-3-((1S,3R)-3-(((4-硝基苯氧基)羰基)氧)环戊基)-1氢-吡唑-5-基)氨基甲酸酯8a(3.00g,5.74mmol)溶于30mL N,N-二甲基甲酰胺中，加入二环[1.1.1]戊烷-1-胺盐酸8b(686mg，5.74mmol)和N,N-二异丙基乙胺(2226mg,17.22mmol)，将反应液升温至60℃氩气下搅拌反应16小时。反应结束后将反应液倒入200mL水中，用乙酸乙酯萃取(80mL×3)，合并有机相，用饱和氯化钠溶液洗涤(100mL)，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩，残留物用硅胶色谱法以石油醚、乙酸乙酯洗脱纯化，得到标题化合物8c(2.50g，产率：93.3％)。
MS(ESI)m/z 467.5[M+H] +
第五步
(1R,3S)-3-(5-氨基-1-(叔-丁基)-1H-吡唑-3-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯
在室温下，将(1R,3S)-3-(5-(((苄氧基)羰基)氨基)-1-(叔-丁基)-1H-吡唑-3-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯8c(2.50g,5.36mmol)溶于20mL二氯甲烷和 16mL甲醇中，加入湿钯/碳(500mg)，将反应液氢气球下搅拌反应16小时。反应结束后将反应液过滤，收集滤液，滤液减压浓缩，得到标题化合物8d(1.50g，产率：74.4％)。
MS(ESI)m/z 377.5[M+H] +
第六步
(1R,3S)-3-(1-(叔-丁基)-5-(2-(3-甲基-2-羰基-2,3-二氢苯并[d]噁唑-5-基)乙酰氨基)-1H-吡唑-3-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯
在室温下，将(1R,3S)-3-(5-氨基-1-(叔-丁基)-1H-吡唑-3-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯8d(100mg,0.301mmol)和2-(3-甲基-2-羰基-2,3-二氢苯并[d]噁唑-5-基)乙酸INT-4(62.4mg，0.301mmol)溶于2mL二氯甲烷中，加入N,N-二异丙基乙胺(116.6mg，0.902mmol)和丙基磷酸三环酸酐溶液(574mg,0.902mmol，50％质量含量)，将反应液在氩气球保护下搅拌反应2小时。反应结束后将反应液使用二氯甲烷(40mL)稀释，用饱和氯化钠溶液洗涤(20mL)，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩，得到标题化合物8e(130mg，产率：82.8％)。
MS(ESI)m/z 521.6[M+H] +
第七步
(1R,3S)-3-(3-(2-(3-甲基-2-羰基-2,3-二氢苯并[d]噁唑-5-基)乙酰氨基)-1H-吡唑-5-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯
在室温下，将(1R,3S)-3-(1-(叔-丁基)-5-(2-(3-甲基-2-羰基-2,3-二氢苯并[d]噁唑-5-基)乙酰氨基)-1H-吡唑-3-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯8e(130mg,0.249mmol)溶于2mL甲酸中，将反应液在85℃下氩气球保护下搅拌反应16小时。反应8h结束后将反应液减压浓缩，使用C18反相柱得到标题化合物8(85mg，产率：73.3％)。
MS(ESI)m/z 466.6[M+H]
1H NMR(400MHz,DMSO-d 6)δ＝10.70(s,1H),7.73(s,1H),7.25(dd,J＝7.7,1.5Hz,1H),7.15–7.05(m,2H),6.26(s,1H),4.96(s,1H),3.94(s,2H),3.58(s,3H),3.04(d,J＝10.0Hz,1H),2.48–2.39(m,1H),2.37–2.24(m,1H),1.98(d,J＝9.8Hz,1H),1.92–1.80(m,7H),1.62(d,J＝52.7Hz,3H).
实施例9
(1R,3S)-3-(3-(2-(3-甲基-2-羰基-2,3-二氢苯并[d]噁唑-7-基)乙酰氨基)-1H-吡唑-5-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯
Figure PCTCN2021140312-appb-000095
Figure PCTCN2021140312-appb-000096
第一步
2-(2-羟基-3-硝基苯基)乙酸甲酯INT-6
氮气氛下，常温将化合物INT-5(1.5g,9.03mmol)溶于12mL石油醚中，降温到0℃左右滴加HNO 3(0.9mL)/AC 2O(9mL)溶液,继续搅拌20分钟。用冰水淬灭反应，用乙酸乙酯萃取(25mL×3)，合并有机相，用饱和氯化钠溶液洗涤(30mL)，无水硫酸钠干燥，过滤，收集滤液，减压浓缩后残余物用硅胶柱层析(正庚烷/乙酸乙酯体系)得到标题化合物INT-6(0.95g，产率：49.8％)。
第二步
2-(3-氨基-2-羟基苯基)乙酸甲酯INT-7
常温将化合物INT-6(0.8g,3.79mmol)溶于20mL甲醇中，加入0.2g 10％Pd/C,氢气置换三次，继续搅拌12小时。过滤，滤饼用甲醇(20mL×3)洗涤，收集滤液，减压浓缩后得到标题化合物INT-7(0.66g，产率：96％)。
MS(ESI)m/z 182.1[M+H] +
第三步
2-(2-氧代-2,3-二氢苯并[d]恶唑-7-基)乙酸甲酯INT-8
参照化合物INT-2的合成方法,以化合物INT-7(0.7g,3.86mmol)为原料得到化合物INT-8(0.65g，产率：81.2％)。
MS(ESI)m/z 208.1[M+H] +
第四步
2-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-7-基)乙酸甲酯INT-9
参照化合物INT-3的合成方法,以化合物INT-8(0.5g,2.41mmol)为原料得到化合物INT-9(0.5g，产率：78.5％)。
MS(ESI)m/z 222.1[M+H] +
第五步
2-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-7-基)乙酸INT-10
参照化合物INT-4的合成方法,以化合物INT-9(0.3g,1.36mmol)为原料得到化合物INT-10(0.2g，产率：72％)。
MS(ESI)m/z 206.1[M-H] -
第六步
(1R,3S)-3-(1-(叔-丁基)-5-(2-(3-甲基-2-羰基-2,3-二氢苯并[d]噁唑-7-基)乙酰氨基)-1H-吡唑-3-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯
在室温下，将(1R,3S)-3-(5-氨基-1-(叔-丁基)-1H-吡唑-3-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯8d(80mg,0.241mmol)和2-(3-甲基-2-羰基-2,3-二氢苯并[d]噁唑-7-基)乙酸INT-10(50.0mg，0.241mmol)溶于2mL二氯甲烷中，加入N,N-二异丙基乙胺(93.3mg，0.772mmol)和丙基磷酸三环酸酐溶液(459mg,0.722mmol，50％质量含量)，将反应在氩气球下搅拌反应2小时。反应结束后将反应液使用二氯甲烷(40mL)稀释，用饱和氯化钠溶液洗涤(20mL)，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩，得到标题化合物9a(110mg，产率：87.6％)。
MS(ESI)m/z 521.6[M+H] +
第七步
(1R,3S)-3-(3-(2-(3-甲基-2-羰基-2,3-二氢苯并[d]噁唑-7-基)乙酰氨基)-1H-吡唑-5-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯
在室温下，将(1R,3S)-3-(1-(叔-丁基)-5-(2-(3-甲基-2-羰基-2,3-二氢苯并[d]噁唑-7-基)乙酰氨基)-1H-吡唑-3-基)环戊基二环[1.1.1]戊烷-1-基氨基甲酸酯9a(110mg,0.211mmol)溶于2mL甲酸中，将反应液在85℃氩气球下搅拌反应16小时。反应结束后将反应液减压浓缩，使用C18反相柱得到标题化合物9(85mg，产率：86.6％)。MS(ESI)m/z 466.6[M+H] +
实施例10
(1R,3S)-3-(5-(2-(2-氯-4-(2-氧吡咯烷-1-基)苯基)丙胺基)-1H-吡唑-3-基)环戊基(1-甲基环丙基)氨基甲酸酯
Figure PCTCN2021140312-appb-000097
Figure PCTCN2021140312-appb-000098
第一步
2-(2-氯-4-硝基苯基)-2-甲基丙二酸二乙酯10C
氮气氛下，在0℃，60％NaH(3.1g,77.9mmol)加到DMF(100mL)，保持0℃逐滴加入化合物10B(11.8mL,68.4mmol)，滴毕0℃搅拌0.5小时。加入化合物10A(10g,56.9mmol)，将混合物加热至70℃并搅拌3小时。将反应混合物倒入饱和NH 4Cl溶液中。用二氯甲烷萃取，用无水硫酸钠干燥，过滤，滤液浓缩得到化合物10C(17g，产率：99％)。
LCMS(ESI)m/z 330.2[M+H] +。
第二步
2-(2-氯-4-硝基苯基)丙酸10D
将化合物10C(11g,33.3mmol)加入水(27mL)，乙酸(37mL)和硫酸(10mL)的混合溶液中回流反应24小时。反应液减压浓缩，DCM萃取，有机层用饱和Na 2CO 3水溶液洗涤，用1N HCl酸化水层后用DCM萃取,干燥浓缩得化合物10D(6.6g,产率：86％)。
1H NMR(400MHz,Chloroform-d)δ8.33(d,J＝2.4Hz,1H),8.18(dd,J＝8.6,2.4Hz,1H),7.60(d,J＝8.6Hz,1H),4.38(q,J＝7.2Hz,1H),1.63(d,J＝7.2Hz,3H)。
第三步
2-(2-氯-4-硝基苯基)丙酸甲酯10E
将化合物10D(6.6g,28.8mmol)溶于甲醇(100mL)，在浓硫酸(0.1g，1.1mmol)催化下回流3h。冷却至室温后，减压浓缩反应液。MTBE(100×3mL)萃取，用饱和NaHCO 3水溶液和盐水洗涤。用无水硫酸钠干燥，浓缩得化合物10E(7.0g，产率：100％)。
第四步
2-(2-氯-4-氨基苯基)丙酸甲酯10F
氮气氛下，将化合物10E(7g,28.6mmol)溶于甲醇(35mL)和水(28mL)的混合液中，加入NH 4Cl(1.2mL,34.3mmol)和铁粉(4.8g,85.9mmol)。将混合物加热至68℃，继续搅拌2小时。将反应物冷却至室温并过滤，滤饼用甲醇(50mL×3)洗涤。浓缩滤液除MeOH，水相用乙酸乙酯(50mL×3)萃取，用盐水(40mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩得化合物10F(5.8g，产率：94％)。
LCMS(ESI)m/z 214.2[M+H] +。
第五步
2-(2-氯-4-(4-氯丁胺基)苯基)丙酸甲酯10G
氮气氛下，将化合物10F(3.2g,15.1mmol)溶于二氯甲烷(32mL)，加入三乙胺(3.1mL，22.5mmol)，在0℃下逐滴加入4-氯丁酰氯(3.7mL，32.9mmol)，在室温反应3h。用水(30mL)淬灭，二氯甲烷萃取(100mL×3).盐水(100mL)洗涤，无水硫酸钠干燥，浓缩得化合物10G(4.6g，产率：96％)。
LCMS(ESI)m/z 318.2[M+H] +。
第六步
2-(2-氯-4-(2-氧吡咯烷-1-基)苯基)丙酸甲酯10H
氮气氛下，将化合物10G(4.6g,14.5mmol)溶于DMF(20mL)，在室温下滴加DBU(1.5mL，10mmol)。反应在100℃下加热搅拌过夜。用水(50mL)淬灭反应，并用二氯甲烷萃取(50mL×3)，用盐水(50mL)洗涤，在无水硫酸钠干燥，浓缩得化合物10H(3.80g，产率：99％)。
LCMS(ESI)m/z 282.3[M+H] +。
第七步
2-(2-氯-4-(2-氧吡咯烷-1-基)苯基)丙酸10I
氮气氛下，常温将化合物10H(520mg,1.8mmol)悬浮于20mL 6N盐酸水溶液中，100℃条件下加热反应3小时，反应液冷却至室温，过滤得到化合物10I(460mg，产率：92％)。
LCMS(ESI)m/z 268.4[M+H] +。
第八步
(1R,3S)-3-(1-(叔丁基)-5-(2-(2-氯-4-(2-氧吡咯烷-1-基)苯基)丙胺基)-1H-吡唑-3-基)环戊基(1-甲基环丙基)氨基甲酸酯10J
氮气氛下，将化合物10I(100mg,0.37mmol))和(1R,3S)-3-(3-氨基-1-(叔-丁基)-1H-吡唑-5-基)(46mg，采用专利申请“WO 2020/157652 A2”公开的方法制备而得)溶于DMF(20mL)，加入三乙胺(0.52mL，3.6mmol)，然后分批滴加T 3P(50％in EA，952mg)。在80℃搅拌16小时。用Na 2CO 3水溶液(5ml)淬灭，EA萃取(15mL×3)，盐水(10mL)洗涤，无水硫酸钠干燥，浓缩柱层析得化合物10J(125mg，产率：71％)。
LCMS(ESI)m/z 570.5[M+H] +。
第九步
(1R,3S)-3-(5-(2-(2-氯-4-(2-氧吡咯烷-1-基)苯基)丙胺基)-1H-吡唑-3-基)环戊基(1-甲基环丙基)氨基甲酸酯10
氮气氛下，将化合物10J(125mg,0.21mmol)溶于4mL甲酸中，75℃条件下加热反应20小时，反应液冷却至室温，减压浓缩后残余物用饱和碳酸氢钠溶液调至pH＝7，用乙酸乙酯萃取(15mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL)，无水硫酸钠干燥，过滤，收集滤液，减压浓缩后残余物用硅胶柱层析得到题化合物10(54mg，产率：47.9％)，为一对异构体。
LCMS(ESI)m/z 514.5[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),7.91(d,J＝2.2Hz,1H),7.60–7.41(m,2H),7.36(s,1H),6.31(s,1H),5.00(s,1H),4.21(d,J＝7.1Hz,1H),3.85(t,J＝7.1Hz,2H),3.05(d,J＝9.4Hz,1H),2.08(p,J＝7.6Hz,3H),1.90(dt,J＝9.0,4.8Hz,1H),1.71(s,2H),1.42(d,J＝7.0Hz,3H),1.25(s,3H),0.61(s,2H),0.49(q,J＝4.5Hz,2H).
实施例11
(1R,3S)-3-(5-(2-(3-氯-4-(2-氧吡咯烷-1-基)苯基)丙胺基)-1H-吡唑-3-基)环戊基(1-甲基环丙基)氨基甲酸酯
Figure PCTCN2021140312-appb-000099
第一步
2-(3-氯-4-硝基苯基)-2-甲基丙二酸二乙酯11C
25℃，NaOH(2.4g，59.8mmol),10B(10.3mL，59.8mmol)和11A(10g,96mmol),加到N,N-二甲基甲酰胺(65mL)，混合物室温搅拌14小时。将反应混合 物用甲基叔丁基醚稀释，用稀盐酸调pH＝7,萃取，用盐水洗涤，用无水硫酸钠干燥，过滤，滤液浓缩得到化合物11C(17g，产率：90％)。
LCMS(ESI)m/z 330.4[M+H] +。
第二步
2-(3-氯-4-硝基苯基)丙酸11D
参照化合物10D的合成方法,以化合物11C(17g,51.5mmol)为原料得到化合物11D(8.5g，产率：71％)。
LCMS(ESI)m/z 228.0[M-H] +。
第三步
2-(3-氯-4-硝基苯基)丙酸甲酯11E
参照化合物10E的合成方法,以化合物11D(5g,21.8mmol)为原料得到化合物11E(4.8g，产率：90％)。
1H NMR(400MHz,Chloroform-d)δ7.90(d,J＝8Hz,1H),7.53(s,1H),7.39(d,J＝8Hz,1H),3.82(q,J＝8Hz,16Hz,1H),3.74(s,3H),1.57(d,J＝8Hz,3H)。
第四步
2-(4-氨基-3-氯苯基)丙酸甲酯11F
参照化合物10F的合成方法,以化合物11E(4.8g,19.7mmol)为原料得到化合物11F(4.2g,产率：99％)。
第五步
2-(3-氯-4-(4-氯丁胺基)苯基)丙酸甲酯11G
参照化合物10G的合成方法,以化合物11F(2g,9.4mmol)为原料得到化合物11G(2.9g，产率：97％)。
LCMS(ESI)m/z 318.2[M+H] +。
第六步
2-(3-氯-4-(2-氧吡咯烷-1-基)苯基)丙酸甲酯11H
参照化合物10H的合成方法,以化合物11G(2.9g，9.1mmol)为原料得到化合物11H(1.6g,产率：62％)。
LCMS(ESI)m/z 282.3[M+H] +。
第七步
2-(3-氯-4-(2-氧吡咯烷-1-基)苯基)丙酸11I
参照化合物10I的合成方法,以化合物11H(760mg,2.6mmol)为原料得到化合物11I(650mg,产率：90％)。
1H NMR(400MHz,DMSO-d 6)δ12.51(s,1H),7.50(s,1H),7.39-7.33(m,2H),3.81-3.75(m,1H),3.70(t,J＝8Hz,2H),2.44(t,J＝4Hz,2H),2.20–2.12(m,2H),1.40(d,J＝4Hz,3H)。
第八步
(1R,3S)-3-(1-(叔丁基)-5-(2-(3-氯-4-(2-氧吡咯烷-1-基)苯基)丙胺基)-1H-吡唑-3-基)环戊基(1-甲基环丙基)氨基甲酸酯11J
参照化合物10J的合成方法,以化合物11I(89mg，0.33mmol)为原料得到化合物11J(140mg，产率：88％)。
LCMS(ESI)m/z 570.6[M+H] +。
第九步
(1R,3S)-3-(5-(2-(3-氯-4-(2-氧吡咯烷-1-基)苯基)丙胺基)-1H-吡唑-3-基)环戊基(1-甲基环丙基)氨基甲酸酯11
参照化合物10的合成方法,以化合物11J(140mg,0.25mmol)为原料得到化合物11(70mg,产率：55％)，为一对异构体。
MS(ESI)m/z 514.6[M+H] +。
1H NMR(400MHz,Chloroform-d)δ8.36(s,1H),7.47(s,1H),7.29-7.26(m,2H),6.51(s,1H),5.23-5.20(m,1H),3.80(t,J＝8Hz,2H),3.72-3.67(m,1H),3.17(s,1H),2.62(t,J＝8Hz,2H),2.48(s,1H),2.32-2.25(m,2H),2.17-2.06(m,1H),1.99-1.79(m,4H),1.57(d,J＝8Hz,3H),1.34-1.24(m,3H),0.78(s,2H),0.64(s,2H)。
实施例12
(1R,3S)-3-(3-((S)-2-(2-氯-4-(2-氧代吡咯烷-1-基)苯基)丙酰胺)-1H-吡唑-5-基)环戊(1-甲基环丙基)氨基甲酸酯异构体1
(1R,3S)-3-(3-((R)-2-(2-氯-4-(2-氧代吡咯烷-1-基)苯基)丙酰胺)-1H-吡唑-5-基)环戊(1-甲基环丙基)氨基甲酸酯异构体2
Figure PCTCN2021140312-appb-000100
通过实施例10的方法制备得到(1R,3S)-3-(5-(2-(2-氯-4-(2-氧吡咯烷-1-基)苯基)丙胺基)-1H-吡唑-3-基)环戊基(1-甲基环丙基)氨基甲酸酯10 100mg，通过手性拆分[Column:DAICEL CHIRALPAK AD(250mm*30mm,10um),Condition:0.1％氨水IPA,Begin B:45％；End B:45％；FlowRate(ml/min):80)]得到标题化合物异构体1(40mg，产率：40％)和标题化合物异构体2(40mg，产率：40％)。
分析方法：
Column：DAICEL CHIRALCEL AD-3(100mm*4.6mm,3μm)；
Mobile phase：40％of iso-propanol(0.05％DEA)in CO 2；
FlowRate:2.5mL/min；
ABPR:1500psi；
Temperature:35℃.
将保留时间为3.829min的化合物定义为异构体1；
MS(ESI)m/z 514.2[M+H] +
1H NMR(400MHz,Chloroform-d)δ8.05(br s,1H),7.77(d,J＝2.4Hz,1H),7.54-7.48(m,1H),7.46-7.40(m,1H),6.51(br s,1H),5.17(br s,2H),4.18(q,J＝7.2Hz,1H),3.83(t,J＝7.2Hz,2H),3.13(br s,1H),2.62(t,J＝8.4Hz,2H),2.45(br s,1H),2.18(quin,J＝7.6Hz,2H),2.09(br s,1H),1.93-1.78(m,4H),1.65(br s,1H),1.55(d,J＝7.2Hz,3H),1.34(br s,3H),0.74(br s,2H),0.60(br s,2H).
将保留时间为5.777min的化合物定义为异构体2；
MS(ESI)m/z 514.2[M+H] +
1H NMR(400MHz,Chloroform-d)δ8.01(br s,1H),7.77(d,J＝2.4Hz,1H),7.55-7.49(m,1H),7.45-7.40(m,1H),6.51(br s,1H),5.16(br s,2H),4.18(q,J＝7.2Hz,1H),3.83(t,J＝7.2Hz,2H),3.13(br s,1H),2.62(t,J＝8.4Hz,2H),2.45(br s,1H),2.18(quin,J＝7.6Hz,2H),2.09(br d,J＝7.6Hz,1H),1.98-1.76(m,5H),1.55(d,J＝7.2Hz,3H),1.34(br s,3H),0.74(br s,2H),0.60(br s,2H).
生物学评价
以下结合测试例进一步描述解释本公开，但这些实施例并非意味着限制本公开的范围。
本公开化合物对细胞周期蛋白-依赖性激酶活性检测。
1.实验材料及仪器
Figure PCTCN2021140312-appb-000101
Figure PCTCN2021140312-appb-000102
2.实验步骤
使用Echo 550将化合物稀释液转移到测定板的每个孔中(784075，Greiner)。密封测定板，以1000g离心测定板1分钟；在1x激酶缓冲液(由1体积的5X激酶缓冲液和4体积的蒸馏水及50uM DTT制备得到)中准备2x酶，将2.5μl 2x酶加入384孔测定板，将板在1000g下离心30s，在室温放置10分钟。在1x激酶缓冲液中制备2x底物和ATP混合物，加入2.5μl 2x底物和ATP混合物开始反应。将板以1000g离心30秒，密封测定板，室温反应1小时。加入4μl ADP-Glo试剂，在室温下孵育40分钟，再加入8μl激酶检测试剂，在室温下孵育40分钟。
在Envision 2104读板器上读取每个孔发光信号。
抑制百分率计算如下：
抑制百分率＝100-(cmpd信号-Ave_PC信号)/(Ave_VC信号-Ave_PC信号)×100。
使用GraphPad 8.0通过将抑制百分率值和化合物浓度的对数拟合为非线性回归(剂量响应–可变斜率)来计算IC50。
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X：抑制剂浓度的对数；Y：％抑制。
测得的IC 50值见表1。
表1.本公开化合物对CDK1/B、CDK2/Cyclin E、CDK2/CycA2的IC 50
Figure PCTCN2021140312-appb-000103
Figure PCTCN2021140312-appb-000104
表1中NA表示未测。

Claims (37)

  1. 如式I所示的化合物或其可药用盐、互变异构体，
    Figure PCTCN2021140312-appb-100001
    其中，-L 1-、-L 2-各自独立选自键、C 1-C 6亚烷基、-O-和-NH-，所述C 1-6亚烷基任选被一个或多个选自羟基、烷基、烷氧基、卤代烷基、卤代烷氧基、卤素、羟基、氰基、氨基和硝基的取代基取代；
    R 1选自环烷基、杂环基、芳基和杂芳基，其中所述环烷基、杂环基、芳基或杂芳基各自独立任选被一个或多个Z取代；
    R 2、R 3各自独立选自氢、氘、卤素、烷基、氰基、羟基、硝基、氧代基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、烷基、烷氧基、氰基、氨基、硝基、羟基、羟烷基、羧基、环烷基、杂环基、芳基和杂芳基的取代基取代；或R 2、R 3共同构成3-8元环，所述3-8元环任选地被一个或多个Z取代；
    R 4选自单环、多环，任选地被一个或多个Z取代，且R 5选自氢、氘、烷基和卤素，其中所述烷基任选被一个或多个选自卤素、烷基、烷氧基、氰基、氨基、硝基、羟基、羟烷基、羧基、环烷基、杂环基、芳基和杂芳基的取代基取代，条件是，当R 4选自单环时，R 4选自
    Figure PCTCN2021140312-appb-100002
    且R 1选自
    Figure PCTCN2021140312-appb-100003
    R 6选自氢、氘、卤素、烷基；
    R 7各自独立选自氢、氘、卤素、羟基、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、SR'、SOR'、SO 2R'、SO 2NR'(R”)、NR'(R”)、COOR'、CONR'(R”)和-(P＝O)R'(R”)，所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氧代、硝基、氰基、SR'、SOR'、SO 2R'、SO 2NR'(R”)、NR'(R”)、COR'、COOR'、CONR'(R”)和-(P＝O)R'(R”)的取代基取代；或任意两个相邻R 7共同构成3-8元环，所述3-8元环任选地被一个或多个Z取代；
    或R 4、R 5与它们所连接的N原子共同构成多环，并任选地被一个或多个Z取代；
    Z选自卤素、氰基、羟基、硝基、氧代基、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、SR'、SOR'、SO 2R'、SO 2NR'(R”)、NR'(R”)、COR'、COOR'、CONR'(R”)和-(P＝O)R'(R”)；
    每个R'或R”独立地选自氢、氘、羟基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氧代、硝基、氰基的取代基取代；
    条件是，式I所示的化合物不是
    Figure PCTCN2021140312-appb-100004
    Figure PCTCN2021140312-appb-100005
  2. 如权利要求1所述的化合物或其可药用的盐、互变异构体，当R 4选自单环时，所述化合物I为，
    Figure PCTCN2021140312-appb-100006
    其中，
    R 7各自独立选自氢、氘、卤素、C 1-6烷基、C 3-7环烷基、3-7元杂环基、5-12元芳基、5-12元杂芳基和-(P＝O)R'(R”)，所述C 3-7环烷基、3-7元杂环基、5-12元芳基、5-12元杂芳基任选被一个或多个选自卤素、羟基、氧代、硝基、烷基和烷氧基的取代基取代；
    -L 1-、-L 2-、R 2、R 3、R 5、R 6、R'或R”如权利要求1中所定义。
  3. 如权利要求2所述的化合物或其可药用的盐、互变异构体，所述化合物IIa选自，
    Figure PCTCN2021140312-appb-100007
    所述化合物IIb选自：
    Figure PCTCN2021140312-appb-100008
    -L 1-、-L 2-、R 2、R 3、R 5、R 6、R 7、R'或R”如权利要求2中所定义。
  4. 如权利要求2或3所述的化合物或其可药用的盐、互变异构体，所述R 7选自氢、氘、氟、氯、溴、甲基、乙基、丙基、异丙基、-(P＝O)R'(R”)、
    Figure PCTCN2021140312-appb-100009
    Figure PCTCN2021140312-appb-100010
    其中，
    R'或R”独立地选自氢、氘、甲基、乙基、丙基、异丙基和苯基；
    X选自-CH和N；
    Y选自-CH 2-、-CH(CH 3)-、-NH-、-N(CH 3)-和-O-；优选地，所述R 7选自氢、氘、甲基、-(P＝O)(CH 3) 2、
    Figure PCTCN2021140312-appb-100011
  5. 如权利要求1所述的化合物或其可药用的盐、互变异构体，所述化合物I为：
    Figure PCTCN2021140312-appb-100012
    其中，环A选自C 3-7环烷基、5-8元芳基和5-8元杂环基，所述C 3-7环烷基、5-8芳基、5-8杂芳基任选地被一个或多个Z取代；
    -L 1-、-L 2-、R 2、R 3、R 5、R 6、Z如权利要求1中所定义。
  6. 如权利要求5所述的化合物或其可药用的盐、互变异构体，
    所述化合物IIc选自：
    Figure PCTCN2021140312-appb-100013
    所述化合物IId选自：
    Figure PCTCN2021140312-appb-100014
    其中，环A、-L 1-、-L 2-、R 2、R 3、R 5、R 6、Z如权利要求5中所定义。
  7. 如权利要求5或6所述的化合物或其可药用的盐、互变异构体，所述环A选自5-8元杂环基，所述5-8元杂环基任选地被一个或多个选自卤素、羟基、氧代、硝基、烷基和烷氧基的取代基取代。
  8. 如权利要求7所述的化合物或其可药用的盐、互变异构体，所述环A选自
    Figure PCTCN2021140312-appb-100015
    其中，
    Y选自-CH 2-、-CH(CH 3)-、-NH-、-N(CH 3)-和-O-；优选地，所述环A选自
    Figure PCTCN2021140312-appb-100016
    Figure PCTCN2021140312-appb-100017
  9. 如权利要求1-8任一项所述的化合物或其可药用的盐、互变异构体，R 6选自氢、氘、卤素和C 1-6烷基；优选自氢、氘、氟、氯、溴、甲基、乙基、丙基和异丙基，更优选自甲基。
  10. 如权利要求1或2所述的化合物或其可药用的盐、互变异构体，当R 4选自多环时，R 1选自C 6-C 12芳基和5-10元杂芳基，其中所述C 6-C 12芳基或5-10 元杂芳基任选地被一个或多个Z取代；
    Z如权利要求1中所定义；优选地，所述C 6-C 12芳基或5-10元杂芳基选自吡唑基、三唑基、异噁唑基(isoxazolyl)、噁唑基(oxazolyl)、噻唑基、噻二唑基(thiadiazolyl)、咪唑基、吡啶基、吡嗪基、吲唑基、苯并咪唑基和苯基，最优选自异噁唑基，其中所述C 6-C 12芳基或5-10元杂芳基任选地被一个或多个Z取代；
    Z如权利要求1中所定义。
  11. 如权利要求10所述的化合物或其可药用的盐、互变异构体，所述化合物I为：
    Figure PCTCN2021140312-appb-100018
    -L 1-、-L 2-、R 2、R 3、R 4、R 5、Z如权利要求1中所定义。
  12. 如权利要求11所述的化合物或其可药用的盐、互变异构体，所述化合物III选自
    Figure PCTCN2021140312-appb-100019
    -L 1-、-L 2-、R 2、R 3、R 4、R 5、Z如权利要求11中所定义。
  13. 如权利要求10-12任一项所述的化合物或其可药用的盐、互变异构体，所述Z选自氟、氯、溴、甲基、乙基、丙基、异丙基、氰基、羟基、卤代烷基、 -(P＝O)R'(R”)、
    Figure PCTCN2021140312-appb-100020
    的取代基取代；其中，
    R'或R”独立地选自氢、氘、甲基、乙基、丙基、异丙基和苯基；
    X选自-CH和N；
    Y选自-CH 2-、-CH(CH 3)-、-NH-、-N(CH 3)-和-O-；优选地，所述Z选自甲基、-(P＝O)(CH 3) 2、
    Figure PCTCN2021140312-appb-100021
    的取代基取代，最优选甲基。
  14. 如权利要求11-13任一项所述的化合物或其可药用的盐、互变异构体，所述化合物III为
    Figure PCTCN2021140312-appb-100022
    -L 1-、-L 2-、R 2、R 3、R 4、R 5如权利要求11中所定义。
  15. 如权利要求1、10-14任一项所述的化合物或其可药用的盐、互变异构体，当R 4选自多环时，R 4选自螺环、稠环和桥环，并任选地被一个或多个Z取代；
    所述螺环选自螺环烷基和螺杂环基，选自[3.3]、[3.4]、[3.5]、[3.6]、[4.4]、[4.5]、[4.6]、[5.5]、[5.6]和[6.7]螺环；
    所述稠环选自稠环烷基、稠杂环基和稠杂芳基，选自二环和三环；
    所述桥环选自桥环烷基和桥杂环基，选自二环和三环，每条桥上碳原子数为0-3个；
    所述螺环、稠环或桥环由任一个的碳或氮原子连接到式I结构中；
    Z如权利要求1中所定义。
  16. 如权利要求15所述的化合物或其可药用的盐、互变异构体，
    所述螺环选自
    Figure PCTCN2021140312-appb-100023
    Figure PCTCN2021140312-appb-100024
    任选地进一步被一个或多个Z取代；
    所述螺环通过任一*表示的连接位点连接到式I结构中；
    Z如权利要求1中所定义；优选地，所述螺环选自
    Figure PCTCN2021140312-appb-100025
    所述螺环通过*表示的连接位点连接到式I结构中。
  17. 如权利要求15所述的化合物或其可药用的盐、互变异构体，所述稠环选自
    Figure PCTCN2021140312-appb-100026
    任选地进一步被一个或多个Z取代；
    所述稠环通过任一*表示的连接位点连接到式I结构中；
    Z如权利要求1中所定义；优选地，所述稠环选自
    Figure PCTCN2021140312-appb-100027
    通过*表示的连接位点连接到式I结构中。
  18. 如权利要求15所述的化合物或其可药用的盐、互变异构体，所述桥环选自
    Figure PCTCN2021140312-appb-100028
    任选地进一步被一个或多个Z取代；
    所述桥环通过任一*表示的连接位点连接到式I结构中；
    Z如权利要求1中所定义；优选地，所述桥环选自
    Figure PCTCN2021140312-appb-100029
    通过*表示的连接位点连接到式I结构中。
  19. 如权利要求1-18任一项所述的化合物或其可药用的盐、互变异构体，R 5选自氢、氘、卤素和C 1-6烷基；优选自氢、氘、氟、氯、溴、甲基、乙基、丙基和异丙基，更优选自氢。
  20. 如权利要求1所述的化合物或其可药用的盐、互变异构体，当R 4、R 5与它们所连接的N原子共同构成的多环时，所述化合物I为
    Figure PCTCN2021140312-appb-100030
    其中环C选自
    Figure PCTCN2021140312-appb-100031
    Figure PCTCN2021140312-appb-100032
    Figure PCTCN2021140312-appb-100033
    任选地被一个或多个Z取代；
    -L 1-、-L 2-、R 1、R 2、R 3如权利要求1中所定义。
  21. 如权利要求20所述的化合物或其可药用的盐、互变异构体，所述化合物IV化合物选自
    Figure PCTCN2021140312-appb-100034
    Figure PCTCN2021140312-appb-100035
    -L 1-、-L 2-、R 1、R 2、R 3、环C如权利要求20中所定义。
  22. 如权利要求20或21所述的化合物或其可药用的盐、互变异构体，所述R 1选自C 6-C 12芳基和5-10元杂芳基，其中所述C 6-C 12芳基或5-10元杂芳基任选地被一个或多个Z取代；
    Z如权利要求1中所定义；优选地，所述C 6-C 12芳基或5-10元杂芳基选自吡唑基、三唑基、异噁唑基(isoxazolyl)、噁唑基(oxazolyl)、噻唑基、噻二唑基(thiadiazolyl)、咪唑基、吡啶基、吡嗪基、吲唑基、苯并咪唑基和苯基，优选自异噁唑基，其中所述C 6-C 12芳基或5-10元杂芳基任选地被一个或多个Z取代；
    Z如权利要求1中所定义。
  23. 如权利要求20-22任一项所述的化合物或其可药用的盐、互变异构体，所述化合物IV为：
    Figure PCTCN2021140312-appb-100036
    -L 1-、-L 2-、R 2、R 3、R 4、R 5、Z如权利要求1中所定义，环C如权利要求20中所定义。
  24. 如权利要求23所述的化合物或其可药用的盐、互变异构体，所述化合物IVa化合物选自：
    Figure PCTCN2021140312-appb-100037
    Figure PCTCN2021140312-appb-100038
    -L 1-、-L 2-、R 2、R 3、R 4、R 5、Z、环C如权利要求23中所定义。
  25. 如权利要求20-24任一项所述的化合物或其可药用的盐、互变异构体，所述Z选自氟、氯、溴、甲基、乙基、丙基、异丙基、氰基、羟基、卤代烷基、-(P＝O)R'(R”)、
    Figure PCTCN2021140312-appb-100039
    的取代基取代；其中，
    R'或R”独立地选自氢、氘、甲基、乙基、丙基、异丙基和苯基；
    X选自-CH和N；
    Y选自-CH 2-、-CH(CH 3)-、-NH-、-N(CH 3)-和-O-；优选地，所述Z选自甲基、-(P＝O)(CH 3) 2、
    Figure PCTCN2021140312-appb-100040
    的取代基取代，优选甲基。
  26. 如权利要求1-25任一项所述的化合物或其可药用的盐、互变异构体，所述-L 2-选自键、-CH 2-、-CH(CH 3)-、-CH 2-CH 2-、-O-和-NH-，优选自-CH 2-和-CH(CH 3)-。
  27. 如权利要求1-26任一项所述的化合物或其可药用的盐、互变异构体，所述R 2、R 3各自独立选自氢、氘、氟、氯、溴、甲基、乙基、丙基、异丙基、苯基、氰基、羟基和氧代基，优选自氢、氘、氟、氯和甲基，更优选自氢。
  28. 如权利要求1-27任一项所述的化合物或其可药用的盐、互变异构体，所述R 2、R 3共同构成3-8元环，所述3-8元环选自C 3-7环烷基、3-8元杂环基、5-8元芳基和5-8元杂芳基，所述3-8元环任选地被一个或多个Z取代；
    Z如权利要求1中所定义；优选地，所述3-8元环选自环丙基、环丁基和环戊基，所述3-8元环任选地被一个或多个Z取代，所述Z选自氟、氯、溴、甲基、乙基、丙基、异丙基、苯基、氰基、羟基和氧代基，优选自氟、氯和甲基。
  29. 如权利要求1-28任一项所述的化合物或其可药用的盐、互变异构体，所述-L 1-选自键、-CH 2-、-CH(CH 3)-、-CH 2-CH 2-、-O-和-NH-，优选自-CH 2-和-O-，更优选-O-。
  30. 如权利要求1所述的化合物，选自：
    Figure PCTCN2021140312-appb-100041
    Figure PCTCN2021140312-appb-100042
    Figure PCTCN2021140312-appb-100043
    Figure PCTCN2021140312-appb-100044
    Figure PCTCN2021140312-appb-100045
    Figure PCTCN2021140312-appb-100046
    Figure PCTCN2021140312-appb-100047
    Figure PCTCN2021140312-appb-100048
    Figure PCTCN2021140312-appb-100049
    Figure PCTCN2021140312-appb-100050
    Figure PCTCN2021140312-appb-100051
    或其可药用盐、互变异构体。
  31. 一种根据权利要求1-30任一项所述的化合物的同位素取代物，优选地，所述的同位素取代物为氘原子取代。
  32. 一种药物组合物，包括至少一种治疗有效量的如权利要求1-30任一项所述的化合物或其可药用的盐、互变异构体或根据权利要求31所述的同位素取代物以及药学上可接受的赋形剂。
  33. 权利要求1-30任一项所述的化合物或其可药用的盐、互变异构体或根据权利要求31所述的同位素取代物或权利要求32所述的药物组合物在制备用于预防和/或治疗与蛋白依赖性激酶相关疾病的药物中的用途，所述蛋白依赖性激酶优选CDK2，所述与蛋白依赖性激酶相关疾病优选细胞增殖性疾病，癌症或免疫性疾病。
  34. 权利要求1-30任一项所述的化合物或其可药用的盐、互变异构体或根据权利要求31所述的同位素取代物或权利要求32所述的药物组合物在制备用于预防和/或治疗与细胞周期蛋白相关疾病的药物中的用途，所述细胞周期蛋白优选细胞周期蛋白E，更优选细胞周期蛋白E1、细胞周期蛋白E2，所述与细胞周期 蛋白相关疾病优选细胞增殖性疾病，癌症或免疫性疾病。
  35. 权利要求1-30任一项所述的化合物或其可药用的盐、互变异构体或根据权利要求31所述的同位素取代物或权利要求32所述的药物组合物在制备用于预防和/或治疗癌症的药物中的用途，所述的癌症选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食道癌、胃癌、肝癌(包括HCC)、胰腺癌、结直肠癌、肺癌(包括NSCLC、SCLC、鳞状细胞癌或腺癌)、肾癌(包括RCC)、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈癌、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺癌、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤。
  36. 制备如权利要求1所述式I化合物或其可药用的盐、互变异构体的方法，包括如下步骤：
    Figure PCTCN2021140312-appb-100052
    其中，
    式I-5所示化合物与式I-6所示化合物在碱性条件下，经取代反应，然后脱去保护基团LG 1，得到式I所示化合物；
    LG 1选自保护基 tBu,S(＝O) tBu,Cbz,Boc,Bn,PMB,SEM,THP；
    LG 3选自苯氧基、4-硝基苯氧基；
    R 1、R 2、R 3、R 4、R 5、L 1、L 2如权利要求1中定义。
  37. 制备如权利要求1所述式I化合物或其可药用的盐、互变异构体的方法，当-L 1-选自-O-时，包括如下步骤：
    Figure PCTCN2021140312-appb-100053
    其中：
    式I-4所示化合物与式I-6所示化合物在酰化试剂存在条件下，经氨基甲酸酯化反应，然后脱去保护基团LG 1，得到式I所示化合物；
    所述酰化试剂选自三光气、1,1'-羰基二咪唑；
    LG 1选自保护基 tBu,S(＝O) tBu,Cbz,Boc,Bn,PMB,SEM,THP；
    R 1、R 2、R 3、R 4、R 5、L 2如权利要求1中定义。
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