WO2022135442A1 - Inhibiteur de cdk2 et son procédé de préparation - Google Patents

Inhibiteur de cdk2 et son procédé de préparation Download PDF

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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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Chinese (zh)
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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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    • 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

La présente invention concerne un inhibiteur de CDK2 et son procédé de préparation. Plus particulièrement, la présente invention concerne un composé tel que représenté par la formule I ou un sel pharmaceutiquement acceptable de celui-ci. Les groupes sont tels que définis dans la présente invention. Le composé représenté par la formule I peut être utilisé en tant qu'inhibiteur de kinase dépendant de la cycline, et est utilisé pour prévenir et/ou traiter une kinase dépendante de la protéine ou une maladie liée à la cycline, telle qu'une maladie de prolifération cellulaire, un cancer ou une maladie immunitaire.
PCT/CN2021/140312 2020-12-22 2021-12-22 Inhibiteur de cdk2 et son procédé de préparation WO2022135442A1 (fr)

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WO2023141852A1 (fr) * 2022-01-27 2023-08-03 益方生物科技(上海)股份有限公司 Inhibiteurs de la cdk2, leur procédé de préparation et leur utilisation
WO2024066981A1 (fr) * 2022-09-30 2024-04-04 楚浦创制（武汉）医药科技有限公司 Dérivés de pyrazole deutérés, composition pharmaceutique, utilisation et procédé de préparation

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CN1518543A (zh) * 2000-08-31 2004-08-04 �Ʒ� 吡唑衍生物和它们作为蛋白激酶抑制剂的用途
WO2005051919A1 (fr) * 2003-11-26 2005-06-09 Pfizer Products Inc. Derives d'aminopyrazole en tant qu'inhibiteurs de la gsk-3
WO2020157652A2 (fr) * 2019-01-31 2020-08-06 Pfizer Inc. Inhibiteurs de cdk2

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Publication number Priority date Publication date Assignee Title
CN1290164A (zh) * 1997-12-22 2001-04-04 拜尔有限公司 用取代杂环脲抑制raf激酶
CN1373662A (zh) * 1999-08-12 2002-10-09 法玛西雅意大利公司 3(5)－氨基－吡唑衍生物、其制备方法及其用作抗肿瘤剂的用途
CN1379668A (zh) * 1999-08-12 2002-11-13 法玛西雅厄普约翰公司 3(5)－脲基－吡唑衍生物、其制备方法及其作为抗肿瘤剂的用途
CN1518543A (zh) * 2000-08-31 2004-08-04 �Ʒ� 吡唑衍生物和它们作为蛋白激酶抑制剂的用途
WO2005051919A1 (fr) * 2003-11-26 2005-06-09 Pfizer Products Inc. Derives d'aminopyrazole en tant qu'inhibiteurs de la gsk-3
WO2020157652A2 (fr) * 2019-01-31 2020-08-06 Pfizer Inc. Inhibiteurs de cdk2

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023141852A1 (fr) * 2022-01-27 2023-08-03 益方生物科技(上海)股份有限公司 Inhibiteurs de la cdk2, leur procédé de préparation et leur utilisation
WO2024066981A1 (fr) * 2022-09-30 2024-04-04 楚浦创制（武汉）医药科技有限公司 Dérivés de pyrazole deutérés, composition pharmaceutique, utilisation et procédé de préparation

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