WO2023030295A1 - Inhibiteur de protéase 1 spécifique de l'ubiquitine - Google Patents

Inhibiteur de protéase 1 spécifique de l'ubiquitine Download PDF

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WO2023030295A1
WO2023030295A1 PCT/CN2022/115739 CN2022115739W WO2023030295A1 WO 2023030295 A1 WO2023030295 A1 WO 2023030295A1 CN 2022115739 W CN2022115739 W CN 2022115739W WO 2023030295 A1 WO2023030295 A1 WO 2023030295A1
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cycloalkyl
group
optionally substituted
compound
alkyl
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PCT/CN2022/115739
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English (en)
Chinese (zh)
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祝伟
刘晓武
邹昊
汪涛
陈祥
祝东星
孙天文
李正涛
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先声再明医药有限公司
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Priority to CN202280057195.6A priority Critical patent/CN117980294A/zh
Publication of WO2023030295A1 publication Critical patent/WO2023030295A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the disclosure belongs to the field of medical technology, and relates to USP1 inhibitor compounds or their optical isomers, pharmaceutically acceptable salts, pharmaceutical compositions containing them and their use as USP1 inhibitors in the prevention or treatment of related diseases.
  • Ubiquitination is a reversible process involving a series of deubiquitinating enzymes (DUBs) that regulate diverse cellular processes by deubiquitinating substrates.
  • DUBs are encoded by about 100 human genes and are divided into six families, the largest of which is the ubiquitin-specific proteases (USPs) with more than 50 members.
  • USPs ubiquitin-specific proteases
  • DUBs and their substrate proteins are frequently dysregulated in cancer, supporting the idea that targeting specific DUB enzymes may participate in tumor growth, survival, differentiation, and maintenance of the tumor microenvironment by enhancing the ubiquitination and degradation of oncogenic substrates and regulating their involvement.
  • USP1 is a cysteine isopeptidase of the USP subfamily in DUBs.
  • the full-length human USP1 consists of 785 amino acids and includes a catalytic triad consisting of Cys90, His593 and Asp751 (Nijman, S.M.B., et al. "The deubiquitinating enzyme USPl regulates the fanconi anemia pathway. Mal. Cell 17, 331-339 (2005)).
  • USP1 plays a role in DNA damage repair. USP1 itself is relatively inactive, and only the complex required for deubiquitinase activity can be obtained by combining with the cofactor UAF1.
  • the USP1/UAF1 complex goes to Ubiquitinated mononuclear ubiquitinated PCNA (proliferating cell nuclear antigen) and monoubiquitinated FANCD2 (Fanconi anemia group complementary group D2), these two proteins are in translation synthesis (TLS) and Fanconi anemia (FA) respectively
  • TLS translation synthesis
  • FA Fanconi anemia
  • the USP1/UAF1 complex also deubiquitinates FANCI (Fanconi anemia Complementation group I).
  • the importance of these findings was further confirmed experimentally that mice lacking USP1 were highly sensitive to DNA damage.
  • the expression of USP1 was significantly increased in many cancers. Blocking USP1 to inhibit DNA repair, can Induction of apoptosis in multiple myeloma cells also enhanced sensitization of lung cancer cells to cisplatin, suggesting that USP1 is a promising target for chemotherapy in certain cancers.
  • the disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • X 1 is selected from N or CR 1a ;
  • Ring A is selected from aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group or C 3 -C 10 cycloalkyl;
  • Ring B is selected from arylene, 5-10 membered heteroarylene, 4-10 membered heterocyclylene or C 3 -C 10 cycloalkylene;
  • Ring C is selected from aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group;
  • R 1 and R 2 are independently selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-8 membered heterocyclic group, the OH, NH 2.
  • C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-8 membered heterocyclyl are optionally substituted by R d ;
  • R 3 is selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocyclyl, alkenyl, alkynyl, said OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocyclyl, alkenyl, alkynyl are optionally substituted by R d ;
  • R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b are independently selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, alkenes OH, NH 2 , C 1 -C 6 alkyl , alkenyl , C 3 -C 10 cycloalkyl or 4-10 membered Heterocyclyl is optionally substituted by R;
  • R a , R b , R c are independently selected from halogen, CN, OH, NH 2 , SH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-8 membered heterocyclyl, said OH, NH 2 , SH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-8 membered heterocyclyl are optionally substituted by R d ;
  • X 2 and X 3 , X 3 and X 4 can be selected to form a double bond
  • Each R d is independently selected from halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-8 membered heterocyclyl, the OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-8 membered heterocyclyl are optionally substituted by R e ;
  • R e is selected from halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocyclic group, the OH, NH 2 , C 1 -C 6 Alkyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocyclyl are optionally substituted by R f ;
  • R f is selected from halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocyclyl;
  • n, p are independently selected from 0, 1, 2, 3, 4, 5 or 6.
  • X is selected from N.
  • X 1 is selected from CR 1a .
  • X 4 is selected from CR 4a .
  • ring A is selected from aryl or 5-10 membered heteroaryl.
  • Ring A is selected from
  • ring B is selected from arylene, 4-8 membered heterocyclylene, or C 3 -C 6 cycloalkylene.
  • ring B is selected from arylene or 4-8 membered heterocyclylene.
  • Ring B is selected from
  • Ring C is selected from 5-10 membered heteroaryls.
  • ring C is selected from
  • ring C is selected from
  • R 1 , R 2 are independently selected from H, halogen, or C 1 -C 6 alkyl optionally substituted with R d .
  • R 1 , R 2 are independently selected from H or C 1 -C 6 alkyl optionally substituted by R d . In some embodiments, R 1 , R 2 are independently selected from H.
  • R 1 , R 2 and the atoms to which they are attached together form a C 3 -C 6 cycloalkyl optionally substituted with R d .
  • R 1 , R 2 and the atoms to which they are attached together form cyclopropyl optionally substituted with R d .
  • R is selected from H, halogen, CN, OH, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocyclyl, alkenyl or alkynyl, so The OH, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocyclyl, alkenyl or alkynyl are optionally substituted by R d .
  • R 3 is selected from H, halogen, CN, OH, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, said OH, C 1 -C 6 alkyl or C 3 - C6 cycloalkyl is optionally substituted by Rd .
  • R 3 is selected from H, halogen, OH, or C 1 -C 6 alkyl optionally substituted with R d .
  • R is selected from H.
  • R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b are independently selected from H, halogen, CN, OH, NH 2 , C 1 - C 6 alkyl, alkenyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocyclic group, the OH, NH 2 , C 1 -C 6 alkyl, alkenyl, C 3 -C 6 cycloalkane A group or a 4-8 membered heterocyclyl group is optionally substituted by Rd .
  • R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b are independently selected from H, halogen, OH, NH 2 , C 1 -C 6 Alkyl, alkenyl or C 3 -C 6 cycloalkyl, said OH, NH 2 , C 1 -C 6 alkyl, alkenyl or C 3 -C 6 cycloalkyl is optionally substituted by R d .
  • R a , R b , and R c are independently selected from halogen, OH, NH 2 , SH, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-8 membered heterocycles
  • the OH, NH 2 , SH, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by R d .
  • R a is independently selected from OH, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, said OH, C 1 -C 6 alkyl or C 3 -C 6 cycloalkane The group is optionally substituted by Rd .
  • R a is independently selected from -O-CH 3 , -O-CHF 2 , methyl, ethyl, isopropyl, or cyclopropyl.
  • Ra is independently selected from -O- CH3 , methyl, ethyl, isopropyl, or cyclopropyl.
  • R a is independently selected from -O-CH 3 , -O-CHF 2 , or cyclopropyl.
  • R b is independently selected from halogen, OH, or C 1 -C 6 alkyl optionally substituted with R d .
  • Rb is independently selected from H.
  • R c is independently selected from halogen, OH, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, the OH, C 1 -C 6 alkyl or C 3 -C 6 Cycloalkyl is optionally substituted with Rd .
  • R c is independently selected from OH, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, said OH, C 1 -C 6 alkyl or C 3 -C 6 cycloalkane The group is optionally substituted by Rd .
  • R c is independently selected from OH, methyl, ethyl, isopropyl or cyclopropyl optionally replaced by R replace.
  • R c is independently selected from OCH 3 , CF 3 , CH 2 CF 3 , CH 3 , CH 2 CH 3 , isopropyl, cyclopropyl, or
  • Rc is independently selected from CF3 or CH3 .
  • R 1a , R a and the atoms to which they are attached together form a 4-8 membered heterocyclyl optionally substituted by R d .
  • R b , R c and the atoms to which they are attached together form a 4-8 membered heterocyclyl optionally substituted by R d .
  • R 2a , R 2b and the atoms to which they are attached together form a cyclobutyl group, which is optionally substituted with R d .
  • R 2a , R 3a and the atoms to which they are attached together form said is optionally substituted by Rd .
  • R 3a , R 5a and the atoms to which they are attached together form said is optionally substituted by Rd .
  • R 4a , R 5a and the atoms to which they are attached together form cyclopropyl or cyclobutyl; said cyclopropyl or cyclobutyl is optionally substituted by R d .
  • R 5a , R 5b and the atoms to which they are attached together form cyclopropyl or cyclobutyl; said cyclopropyl or cyclobutyl is optionally substituted by R d .
  • a double bond is formed between X2 and X3 .
  • a double bond is formed between X3 and X4 .
  • each R d is independently selected from halogen, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or 4-8 membered heterocyclyl, said OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-8 membered heterocyclyl is optionally substituted by R e .
  • each R d is independently selected from halogen, OH, NH 2 , C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl, wherein OH, NH 2 , C 1 -C 6 Alkyl or C 3 -C 10 cycloalkyl is optionally substituted by Re .
  • R e is selected from halogen, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocyclyl, said OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocyclyl is optionally substituted by R f .
  • R f is selected from halogen, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-8 membered heterocyclyl.
  • m is selected from 1,2,3.
  • m is selected from 1 or 2.
  • n is selected from 0, 1, 2.
  • n is selected from 0 or 1.
  • p is selected from 1, 2, 3.
  • p is selected from 1 or 2.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from a compound of formula (II) or a pharmaceutically acceptable salt thereof,
  • X 1 is selected from N or CR 1a ;
  • Ring A, Ring B, Ring C, R 1 , R 2 , R 3 , R a , R b , R c , m, n, p, R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a and R 5b are as defined above.
  • X 4 is CR 4a R 4b .
  • Ring A, ring B, ring C, R 1 , R 2 , R 3 , R a , R b , R c , m, n, p, R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a and R 5b are as defined in claim 1;
  • Ring A, ring B, ring C, R 1 , R 2 , R 3 , R a , R b , R c , m, n, p, R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a and R 5b are as defined in claim 7, and so on.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from a compound of formula (III) or a pharmaceutically acceptable salt thereof,
  • X 1 is selected from N or CR 1a ;
  • R 1 , R 2 , R 3 , R a , R b , R c , m, n, p, R 1a , R 2a in the formula (III) , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a and R 5b are as defined in claim 1;
  • R 1 , R in the formula (III) 2 , R 3 , R a , R b , R c , m, n, p, R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a and R 5b as claimed in claim 10 definition, and so on.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,
  • the present disclosure provides a pharmaceutical composition, which comprises the compound of formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.
  • the present disclosure provides a method for treating a disease mediated by USP1 in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, to a mammal in need of the treatment, preferably a human, or its pharmaceutical composition.
  • the present disclosure provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating USP1-mediated diseases.
  • the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating diseases mediated by USP1.
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating USP1-mediated diseases.
  • the USP1 -mediated disease is a tumor.
  • a tumor for example, solid tumors.
  • the compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms.
  • Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S )-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as enantiomers or diastereomers Enriched mixtures, all of the above isomers and mixtures thereof are within the definition of the disclosed compounds.
  • asymmetric carbon atoms there may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups, and these isomers and their mixtures involved in all substituents are also included in Compounds of the disclosure are within the definition.
  • Compounds of the present disclosure containing asymmetric 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 .
  • substituted means that any one or more hydrogen atoms on the specified atom are replaced by a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • ethyl is “optionally” substituted with halogen , meaning that the ethyl group can be unsubstituted ( CH2CH3 ), monosubstituted ( CH2CH2F , CH2CH2Cl , etc.), polysubstituted ( CHFCH2F , CH2CHF2 , CHFCH2Cl , CH2CHCl2 , etc. ) or fully substituted ( CF2CF3 , CF2CCl3 , CCl2CCl3 , etc.) . It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
  • any variable eg R a , R b
  • its definition is independent at each occurrence. For example, if a group is substituted by 2 R b , each R b has independent options.
  • linking group mentioned herein does not indicate its linking direction
  • its linking direction is arbitrary.
  • L 1 in is selected from “C 1 -C 3 alkylene-O”
  • L 1 can connect ring Q and R 1 in the same direction as the reading order from left to right to form “ring QC 1 -C 3 alkylene-OR 1 "
  • ring Q and R 1 can also be connected in the opposite direction according to the reading order from left to right to form “ring QOC 1 -C 3 alkylene-R 1 ".
  • the substituent When a bond of a substituent cross-links two atoms in a ring, the substituent may be bonded to any atom on the ring.
  • the structural unit Indicates that R 5 can be substituted at any position on the benzene ring.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • C m -C n herein means having an integer number of carbon atoms in the range of mn.
  • C 1 -C 10 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 .
  • the alkyl group may be linear or branched.
  • C 1 -C 10 alkyl is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; term "C 1 - 6 alkyl” refers to an alkyl group containing 1 to 6 carbon atoms (such
  • C 1 -C 10 alkyl described herein may include “C 1 -C 6 alkyl” or “C 1 -C 3 alkyl", and the “C 1 -C 6 alkyl” may further include “C 1 -C 3 alkyl”.
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond.
  • C 2 -C 10 alkenyl is understood to mean a linear or branched unsaturated hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms
  • C 2 -C 10 alkenyl is preferably "C 2 -C 6 alkenyl", more preferably "C 2 -C 4 alkenyl", even more preferably C 2 or C 3 alkenyl. It will be appreciated that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated.
  • alkenyl group examples include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl , (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1 -Methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl wait.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond.
  • C 2 -C 10 alkynyl is understood to mean a linear or branched unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • Examples of “C 2 -C 10 alkynyl” include, but are not limited to, ethynyl (-C ⁇ CH), propynyl (-C ⁇ CCH 3 , -CH 2 C ⁇ CH), but-1-ynyl, but -2-ynyl or but-3-ynyl.
  • C 2 -C 10 alkynyl may include “C 2 -C 3 alkynyl", examples of “C 2 -C 3 alkynyl” include ethynyl (-C ⁇ CH), prop-1-ynyl (-C ⁇ CCH 3 ), prop-2-ynyl (—CH 2 C ⁇ CH).
  • cycloalkyl refers to a fully saturated carbocyclic ring in the form of a monocyclic ring, a double ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring.
  • C 3 -C 10 cycloalkyl is understood to mean a saturated monocyclic, fused, spiro or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2 .1] heptyl), bicyclo [2.2.2] octyl, adamantyl, spiro [4.5] decanyl, etc.
  • C 3 -C 10 cycloalkyl may include “C 3 -C 6 cycloalkyl”, and the term “C 3 -C 6 cycloalkyl” can be understood as representing a saturated monocyclic or bicyclic hydrocarbon ring, which has 3-6 carbon atoms, specific examples include but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.
  • heterocyclic group refers to a fully saturated or partially saturated (heteroaromatic that is not aromatic as a whole) monocyclic, cyclic, spiro or bridged ring group containing 1-5 ring atoms
  • 4-10 membered heterocyclic group refers to a heterocyclic group with 4, 5, 6, 7, 8, 9 or 10 ring atoms, and its ring atoms contain 1-5 ring atoms independently selected from the above-mentioned heteroatoms or heteroatom groups.
  • 4-membered heterocyclic group includes “4-7 membered heterocyclic group", wherein, specific examples of 4-membered heterocyclic group include but are not limited to azetidinyl or oxetanyl; 5-membered Specific examples of heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl, or 2, 5-dihydro-1H-pyrrolyl; Specific examples of 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl , trithianyl, tetrahydropyridyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered
  • the heterocyclic group can also be a bicyclic group, wherein, specific examples of the 5,5-membered bicyclic group include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; 5,6-membered bicyclic group Specific examples include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl.
  • the heterocyclic group may be a benzofused cyclic group of the above-mentioned 4-7 membered heterocyclic group, specific examples include but not limited to dihydroisoquinolyl and the like.
  • “4-10 membered heterocyclic group” may include “5-10 membered heterocyclic group”, “4-7 membered heterocyclic group”, “5-6 membered heterocyclic group”, “6-8 membered heterocyclic group” , “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered "Heterocycloalkyl” and other ranges, "4-7 membered heterocyclyl” may further include "4-6 membered heterocyclyl", “5-6 membered heterocyclyl”, “4-7 membered heterocyclyl” , “4-6 membered heterocycloalkyl", "5-6 membered
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • the aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms.
  • C 6 -C 20 aryl is understood to mean an aryl group having 6 to 20 carbon atoms.
  • C aryl rings with 6 carbon atoms
  • C aryl such as phenyl; or rings with 9 carbon atoms (“C aryl”), such as indanyl or indenyl; or rings with 10 a ring of 3 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl; or a ring of 13 carbon atoms (“C 13 aryl”), such as fluorenyl; or is a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6 -C 10 aryl is understood to mean an aryl group having 6 to 10 carbon atoms.
  • C aryl rings with 6 carbon atoms
  • C aryl such as phenyl
  • C aryl rings with 9 carbon atoms
  • C aryl such as indanyl or indenyl
  • C 10 aryl rings with 10 carbon atoms
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C.
  • 5-10 membered heteroaryl is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S.
  • heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiazolyl Diazolyl, etc.
  • benzo derivatives such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazole Linyl or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc.
  • 5-6 membered heteroaryl refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1-3, preferably 1-2, heteroatoms independently selected from N, O and S.
  • terapéuticaally effective amount means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying the The amount of a compound of the disclosure required for the onset of one or more symptoms of a particular disease, condition or disorder.
  • the amount of a compound of the present disclosure that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art according to its own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of pharmaceutically acceptable acids or bases, including salts formed between compounds and inorganic or organic acids, and salts formed between compounds and inorganic or organic bases.
  • composition refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (such as chimpanzees and other apes and monkeys); livestock such as cattle, horses, sheep, goats, pigs; domesticated animals , such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs.
  • non-human mammals include, but are not limited to, birds, fish, and the like.
  • the mammal is a human.
  • the disclosure also includes isotopically labeled compounds of the disclosure that are identical to those described herein, but with one or more atoms replaced by an atom of an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotopically labeled compounds of the disclosure are useful in compound and/or substrate tissue distribution assays. Tritiated (ie3H ) and carbon-14 ( ie14C ) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the disclosure can generally be prepared by following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the pharmaceutical composition of the present disclosure can be prepared by combining the compound of the present disclosure with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present disclosure can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, emulsifying methods, freeze-drying methods and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to patients.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating.
  • Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • the pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
  • ratios indicated for mixed solvents are volume mixing ratios.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • Step 6 2-Chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro Pyrimido[5,4-b][1,4]oxazepine (1J)
  • Step 7 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- Base) benzyl) -6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepine (compound 1)
  • Step 4 2-Chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,7,8,9-tetrahydro -6H-pyrimido[4,5-b][1,4]diazoheptin-6-one (2F)
  • Step 5 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- Base) benzyl)-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazoheptin-6-one (2G)
  • Step 6 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-5-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H -imidazol-2-yl)benzyl)-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazoheptin-6-one (compound 2)
  • Step 1 Ethyl 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidine-5-carboxylate (3C)
  • Step 2 4'-Cyclopropyl-6'-methoxy-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) Amino)-[2,5'-bipyrimidine]-5-carboxylic acid ethyl ester (3D)
  • Step 3 4'-Cyclopropyl-6'-methoxy-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) Amino)-[2,5'-bipyrimidine]-5-carboxylic acid (3E)
  • Step 4 (4'-Cyclopropyl-6'-methoxy-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl )amino)-[2,5'-bipyrimidine]-5-carbonyl)proline methyl ester (3G)
  • Step 5 (4'-Cyclopropyl-6'-methoxy-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl )amino)-[2,5'-bipyrimidine]-5-carbonyl)proline (3H)
  • Step 6 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-11-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- Base) benzyl)-7,8,9,9a-tetrahydro-5H-pyrimido[4,5-e]pyrrolo[1,2-a][1,4]diazepine-5, 10(11H)-Diketone (Compound 3)
  • Example 4 2'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6'-methyl-9'-(4-(1-methyl-4-(trifluoroform Base)-1H-imidazol-2-yl)benzyl)spiro[cyclopropane-1,7'-pyrimido[4,5-e][1,4]diazepine]-5',8' (6'H,9'H)-Diketone (Compound 4)
  • Step 1 N-(5-amino-2-chloropyrimidin-4-yl)-1-(chloromethyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)cyclopropane-1-carboxamide (5B)
  • Step 2 2'-Chloro-9'-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5',9'-dihydro Spiro[cyclopropane-1,7'-pyrimido[4,5-b][1,4]diazoheptin]-8'(6'H)-one (5C)
  • Step 3 2'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-9'-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole- 2-yl)benzyl)-5',9'-dihydrospiro[cyclopropane-1,7'-pyrimido[4,5-b][1,4]diazoheptin]-8' (6'H)-Kone (Compound 5)
  • Example 6 2'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5'-methyl-9'-(4-(1-methyl-4-(trifluoroform Base)-1H-imidazol-2-yl)benzyl)-5',9'-dihydrospiro[cyclopropane-1,7'-pyrimido[4,5-b][1,4]diazepine ]-8'(6'H)-one (Compound 6)
  • Example 7 2'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5'-methyl-9'-(4-(1-methyl-4-(trifluoroform Base)-1H-imidazol-2-yl)benzyl)-8',9'-dihydrospiro[cyclopropane-1,7'-pyrimido[4,5-b][1,4]diazepine ]-6'(5'H)-one (compound 7)
  • Step 1 Ethyl 1-(((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)methyl)cyclopropane-1-carboxylate Esters (7B)
  • Step 2 1-(((2-Chloro-5-nitropyrimidin-4-yl)(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl Base) amino) methyl) ethyl cyclopropane-1-carboxylate (7C)
  • Step 3 1-(((4'-cyclopropyl-6'-methoxy-5-nitro-[2,5'-bipyrimidinyl]-4-yl)(4-(1-methyl- 4-(Trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)methyl)cyclopropane-1-carboxylic acid ethyl ester (7D)
  • Step 4 2'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-9'-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole- 2-yl)benzyl)-8',9'-dihydrospiro[cyclopropane-1,7'-pyrimido[4,5-b][1,4]diazoheptin]-6' (5'H)-keto (7E)
  • Iron powder (34.2 mg, 612.9 ⁇ mol) was added to acetic acid (3 mL) at room temperature, followed by 7D (80.0 mg, 122.6 ⁇ mol). The resulting mixture was reacted at 90 °C for 2 h. Excess acetic acid was removed by rotary evaporation under reduced pressure, and the pH was adjusted to 5-6 with aqueous sodium bicarbonate solution, and extracted with ethyl acetate (10 mL ⁇ 3). The obtained organic phases were combined and washed with saturated brine (20 mL), and the solvent was distilled off under reduced pressure.
  • Step 5 2'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-5'-methyl-9'-(4-(1-methyl-4-(trifluoromethyl )-1H-imidazol-2-yl)benzyl)-8',9'-dihydrospiro[cyclopropane-1,7'-pyrimido[4,5-b][1,4]diazepine ]-6'(5'H)-one (7)
  • reaction solution was quenched with saturated aqueous sodium chloride solution (6mL), and extracted with ethyl acetate (6mL ⁇ 3), the organic phases were combined, and the crude product obtained by rotary evaporation under reduced pressure was prepared by prep HPLC (Waters AutoP, Xbridge-C18, 19*150mm , 20-75% acetonitrile in water gradient elution, 15 mL/min) to obtain compound 7 (18 mg, yield 29%).
  • Example 8 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7,7-difluoro-5-methyl-9-(4-(1-methyl-4- (Trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,7,8,9-tetrahydro-6H-pyrimidine[4,5-b][1,4]diazepine-6 - Ketone (compound 8)
  • Step 1 Ethyl 2,2-difluoro-3-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)propanoate ( 8C)
  • Compound 8D can be synthesized by referring to the method and operation similar to steps 2-4 in the synthesis of compound 7. m/z (ESI): 587.2.
  • Example 10 2'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9'-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole -2-yl)benzyl)-8',9'-dihydrospiro[cyclobutane-1,5'-pyrimido[4,5-e][1,4]diazepine ]-7'(6'H)-one (Compound 10)
  • Step 6 (1-(2-Chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidine-5- Base) cyclobutyl) tert-butyl carbamate (10I)
  • Step 7 5-(1-Aminocyclobutyl)-2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) Pyrimidin-4-amine (10J)
  • Step 8 2-Chloro-N-(1-(2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) Amino)pyrimidin-5-yl)cyclobutyl)acetamide (10L)
  • Step 9 2-Chloro-9'-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-8',9'-dihydrospiro [Cyclobutane-1,5'-pyrimido[4,5-e][1,4]diazoheptin]-7'(6'H)-one (10M)
  • Step 10 2'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9'-(4-(1-methyl Base-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-8',9'-dihydrospiro[cyclobutane-1,5'-pyrimido[4,5-e ][1,4]Dinitrogen ]-7'(6'H)-one (Compound 10)
  • Example 11 2'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6'-methyl-9'-(4-(1-methyl-4-(trifluoroform Base)-1H-imidazol-2-yl)benzyl)-8',9'-dihydrospiro[cyclobutane-1,5'-pyrimido[4,5-e][1,4]diaze Zhuo]-7'(6'H)-one (compound 11)
  • Example 12 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5,5-dimethyl-9-(4-(1-methyl-4-(trifluoroform Base)-1H-imidazol-2-yl)benzyl)-5,6,8,9-tetrahydro-7H-pyrimidin[4,5-e][1,4]diazepine-7-one (compound 12)
  • compound 12 can be prepared by substituting acetone for cyclobutanone in step 1.
  • Example 13 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5,5-dimethyl-9-(4-(1-methyl-4-(trifluoroform Base)-1H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepine (compound 13)
  • Example 14 2-(4-cyclopropyl-6-difluoromethoxypyrimidin-5-yl)-5,5-dimethyl-9-(4-(1-methyl-4-(tri Fluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,8,9-tetrahydro-7H-pyrimidin[4,5-e][1,4]diazepine-7-one (compound 14)
  • compound 14 can be prepared by substituting acetone for cyclobutanone in step 1 and substituting compound 14A for 1K in step 10.
  • Example 15 6-cyclopropyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5,5-dimethyl-9-(4-(1-methyl-4 -(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,8,9-tetrahydro-7H-pyrimidine[4,5-e][1,4]diazepine- 7-keto (compound 14)
  • compound 15 can be prepared by substituting compound 12 for compound 8D.
  • Test Example 1 In vitro activity detection experiment of USP1 enzyme
  • the USP1 enzyme (Recombinant Human His6-USP1/His6-UAF1 Complex Protein, CF) used in the experiment was purchased from R&D Systems, Cat. No. E-568-050.
  • the USP1 with 6 HIS-tags at the N-terminal and the UAF1 enzyme complex with 6 HIS-tags at the N-terminal are expressed by the eukaryotic baculovirus expression system. Purified by affinity chromatography based on nickel column, the purity is above 80%, the concentration is 1mg/mL, and stored at -80°C after aliquoting.
  • the detection kit (Ub-CHOP2-Reporter Deubiquitination Assay Kit) was purchased from Lifesensors, the article number is PR1101. Store at -80°C after aliquoting.
  • the kit contains a ubiquitinated reporter enzyme, which becomes active when it is deubiquitinated by USP1/UAF1, and after catalyzing the substrate, the substrate is excited by a 485nm laser to generate a 531nm emission light signal.
  • Test compounds were dissolved in DMSO to 10 mM.
  • the compound and pure DMSO were poured into each well of a 384-well plate using a compound dilution and sample loading instrument.
  • the total volume of the compound and DMSO was 50 nL.
  • the instrument obtained the sample concentration of the gradient dilution through different ratios.
  • the enzyme was diluted with freshly prepared reaction solution (20 mM Tris-HCl (pH 8.0), 2 mM CaCl 2 , 2 mM ⁇ -mercaptoethanol, 0.05% CHAPS, ddH 2 O). Add 5 ⁇ L of the diluted enzyme reaction solution to each well, centrifuge to mix the enzyme and compound, then centrifuge and place on ice.
  • x represents the logarithmic form of compound concentration
  • A, B, C and D are four parameters.
  • IC50 values were further calculated with Xlfit as the compound concentration required for 50% inhibition of enzyme activity in the best-fit curve.

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Abstract

L'invention concerne un composé ayant une activité ou une fonction inhibitrice de USP1 et un sel pharmaceutiquement acceptable de celui-ci. Le composé a la structure de formule (I) et a des substituants et des caractéristiques structurales telles que décrites dans la présente invention. L'invention concerne également une composition pharmaceutique comprenant le composé de formule (I) ou le sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique le contenant, et une utilisation de celui-ci en tant qu'inhibiteur de USP1 dans la prévention ou le traitement de maladies associées.
PCT/CN2022/115739 2021-09-01 2022-08-30 Inhibiteur de protéase 1 spécifique de l'ubiquitine WO2023030295A1 (fr)

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CN116768906A (zh) * 2023-05-29 2023-09-19 遵义医科大学珠海校区 一种三并环化合物及其制备方法和应用
WO2024022266A1 (fr) * 2022-07-25 2024-02-01 Guangdong Newopp Biopharmaceuticals Co., Ltd. Composés hétéroaryle utilisés comme inhibiteurs de usp1

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