WO2023030295A1 - Ubiquitin specific protease 1 (usp1) inhibitor - Google Patents

Ubiquitin specific protease 1 (usp1) inhibitor 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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French (fr)
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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    • 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.

Abstract

A compound having a USP1 inhibitory activity or function and a pharmaceutically acceptable salt thereof. The compound has the structure of formula (I), and have substituents and structural features described in the present invention. Also described is a pharmaceutical composition comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, and a use thereof as a USP1 inhibitor in the prevention or treatment of related diseases.

Description

泛素特异性蛋白酶1(USP1)抑制剂Ubiquitin-specific protease 1 (USP1) inhibitors
相关申请的交叉引用Cross References to Related Applications
本申请要求以下中国发明专利申请的权益和优先权，在此将它们的全部内容以援引的方式整体并入本文中：This application claims the benefit and priority of the following Chinese invention patent applications, the entire contents of which are hereby incorporated by reference in their entirety:
2021年9月1日向中国国家知识产权局提交的第202111019014.4号，发明名称为：泛素特异性蛋白酶1(USP1)抑制剂的专利申请。No. 202111019014.4 submitted to the State Intellectual Property Office of China on September 1, 2021, and the title of the invention is: a patent application for an inhibitor of ubiquitin-specific protease 1 (USP1).
技术领域technical field
本公开属于医药技术领域，涉及USP1抑制剂化合物或其光学异构体、药学上可接受的盐，含有它们的药物组合物以及作为USP1抑制剂在预防或治疗相关疾病中的用途。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.
背景技术Background technique
泛素化是一个可逆的过程，它涉及一系列去泛素化酶(DUBs)，通过将底物去泛素化来调控多种细胞过程。DUBs由大约100个人类基因编码，分为6个家族，其中最大的家族是拥有50多个成员的泛素特异性蛋白酶(USPs)。DUBs和它们的底物蛋白在癌症中经常失调，这个现象支持了靶向特定DUB酶可以通过提高致癌底物的泛素化和降解及调控参与肿瘤的生长、生存、分化和肿瘤微环境维护的其他关键蛋白质的活性这一假说(Hussain,S.,et.al.,"DUBs and cancer:The role of deubiquitinatingenzymes as oncogenes,non-oncogenes and tumor suppressors."Cell Cycle 8,1688-1697(2009))。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. 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. The hypothesis of the activity of other key proteins (Hussain, S., et.al., "DUBs and cancer: The role of deubiquitinating enzymes as oncogenes, non-oncogenes and tumor suppressors." Cell Cycle 8, 1688-1697 (2009)) .
USP1是DUBs中USP亚家族的半胱氨酸异肽酶。全长的人类USP1由785个氨基酸组成，包括一个由Cys90,His593和Asp751组成的催化三元组(Nijman,S.M.B.,et al."The deubiquitinating enzyme USPl regulates the fanconi anemia pathway.Mal.Cell 17,331-339(2005))。USP1在DNA损伤修复中发挥作用。USP1自身相对不活跃，只有与辅助因子UAF1结合形成去泛素酶活性所需的复合体才能获得完整的酶活性。USP1/UAFl复合物去泛素化单核泛素化PCNA(proliferating cell nuclear antigen)和单泛素化的FANCD2(Fanconi anemia group complementary group D2)，这两种蛋白分别在转译合成(TLS)和范科尼贫血(FA)通路中发挥重要作用。这两种途径是修复DNA交联剂如顺铂和丝裂霉素C(MMC)引起的DNA损伤所必需的。USPl/UAFl复合物也去泛素化FANCI(Fanconi anemia complementation group I)。这些发现的重要性进一步通过实验证实，即缺乏USP1的小鼠对DNA损伤高度敏感。有趣的是，USP1的表达在许多癌症被显著增加。阻断USP1以抑制DNA修复，可以在多发性骨髓瘤细胞中诱导细胞凋亡，也可以增强肺癌细胞对顺铂的敏感性。这些表明，USP1是某些癌症的化学疗法的有希望的靶标。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 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. Interestingly, 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.
综上所述，靶向抑制USP1蛋白是一种潜在的治疗癌症和其他疾病的方法。因此，开发USP1的小分子抑制剂是必要的。Taken together, targeted inhibition of the USP1 protein is a potential treatment for cancer and other diseases. Therefore, the development of small molecule inhibitors of USP1 is necessary.
发明内容Contents of the invention
一方面，本公开涉及式(I)化合物或其药学上可接受的盐，In one aspect, the disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022115739-appb-000001
Figure PCTCN2022115739-appb-000001
其中，in,
X 1选自N或CR 1a； X 1 is selected from N or CR 1a ;
X 2选自O、NR 2a、CR 2aR 2b、C＝CR 2aR 2b、S、S(＝O)R 2a、C(＝O)、S(＝O) 2或C(＝NR 2a)； X 2 is selected from O, NR 2a , CR 2a R 2b , C=CR 2a R 2b , S, S(=O)R 2a , C(=O), S(=O) 2 or C(=NR 2a ) ;
X 3选自CR 3aR 3b、CR 3a、NR 3a、N、C(＝O)、O或C(＝NR 3a)； X 3 is selected from CR 3a R 3b , CR 3a , NR 3a , N, C(=O), O or C(=NR 3a );
X 4选自CR 4aR 4b、CR 4a或C(＝O)； X 4 is selected from CR 4a R 4b , CR 4a or C(=O);
X 5选自CR 5aR 5b、C(＝O)或S(＝O) 2； X 5 is selected from CR 5a R 5b , C(=O) or S(=O) 2 ;
环A选自芳基、5-10元杂芳基、4-10元杂环基或C 3-C 10环烷基； Ring A is selected from aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group or C 3 -C 10 cycloalkyl;
环B选自亚芳基、5-10元亚杂芳基、4-10元亚杂环基或C 3-C 10亚环烷基； Ring B is selected from arylene, 5-10 membered heteroarylene, 4-10 membered heterocyclylene or C 3 -C 10 cycloalkylene;
环C选自芳基、5-10元杂芳基或4-10元杂环基；Ring C is selected from aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group;
R 1、R 2独立地选自H、卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基任选被R d取代； 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 ;
或者R 1、R 2以及它们所连接的原子共同形成C 3-C 10环烷基或4-8元杂环基，所述C 3-C 10环烷基或4-8元杂环基任选被R d取代； Or R 1 , R 2 and the atoms they connect together form a C 3 -C 10 cycloalkyl group or a 4-8 membered heterocyclic group, and the C 3 -C 10 cycloalkyl group or a 4-8 membered heterocyclic group is any selected to be replaced by R d ;
R 3选自H、卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基、4-8元杂环基、烯基、炔基，所述OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基、4-8元杂环基、烯基、炔基任选被R d取代； 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独立地选自H、卤素、CN、OH、NH 2、C 1-C 6烷基、烯基、C 3-C 10环烷基或4-10元杂环基，所述OH、NH 2、C 1-C 6烷基、烯基、C 3-C 10环烷基或4-10元杂环基任选被R d取代； 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独立地选自卤素、CN、OH、NH 2、SH、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基，所述OH、NH 2、SH、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基任选被R d取代； 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 ;
或R 1a、R a与其连接的原子共同形成C 3-C 10环烷基、4-10元杂环基或C 3-C 10环烯基，所述C 3-C 10环烷基、4-10元杂环基或C 3-C 10环烯基任选被R d取代。 Or R 1a , R a and the atoms they connect together form a C 3 -C 10 cycloalkyl group, a 4-10 membered heterocyclyl group or a C 3 -C 10 cycloalkenyl group, and the C 3 -C 10 cycloalkyl group, 4 -10-membered heterocyclyl or C 3 -C 10 cycloalkenyl is optionally substituted by R d .
或R b、R c与其连接的原子共同形成C 3-C 10环烷基、4-10元杂环基或C 3-C 10环烯基，所述C 3-C 10环烷基、4-10元杂环基或C 3-C 10环烯基任选被R d取代； Or R b , R c and the atoms they connect together form a C 3 -C 10 cycloalkyl group, a 4-10 membered heterocyclic group or a C 3 -C 10 cycloalkenyl group, and the C 3 -C 10 cycloalkyl group, 4 -10-membered heterocyclyl or C 3 -C 10 cycloalkenyl is optionally substituted by R d ;
或R 2a、R 2b与其连接的原子共同形成C 3-C 10环烷基或4-10元杂环基，所述C 3-C 10环烷基或4-10元杂环基任选被R d取代； Or R 2a , R 2b and the atoms they connect together form a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group, and the C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group is optionally replaced by Rd replaces;
或R 2a、R 3a与其连接的原子共同形成5-10元杂芳基、C 3-C 10环烷基或4-10元杂环基，所述5-10元杂芳基、C 3-C 10环烷基或4-10元杂环基任选被R d取代； Or R 2a , R 3a and the atoms they connect together form a 5-10 membered heteroaryl group, a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group, and the 5-10 membered heteroaryl group, C 3 - C 10 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R ;
或R 3a、R 4a与其连接的原子共同形成C 3-C 10环烷基、4-10元杂环基或5-10元杂芳基，所述C 3-C 10环烷基、4-10元杂环基或5-10元杂芳基任选被R d取代； Or R 3a , R 4a and the atoms they connect together form a C 3 -C 10 cycloalkyl group, a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group, the C 3 -C 10 cycloalkyl group, 4- A 10-membered heterocyclic group or a 5-10-membered heteroaryl group is optionally substituted by R d ;
或R 3a、R 5a与其连接的原子共同形成C 3-C 10环烷基、4-10元杂环基或5-10元杂芳基，所述C 3-C 10环烷基、4-10元杂环基或5-10元杂芳基任选被R d取代； Or R 3a , R 5a and the atoms they connect together form a C 3 -C 10 cycloalkyl group, a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group, the C 3 -C 10 cycloalkyl group, 4- A 10-membered heterocyclic group or a 5-10-membered heteroaryl group is optionally substituted by R d ;
或R 4a、R 4b与其连接的原子共同形成C 3-C 10环烷基或4-10元杂环基，所述C 3-C 10环烷基或4-10元杂环基任选被R d取代； Or R 4a , R 4b and the atoms they connect together form a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group, and the C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group is optionally replaced by Rd replaces;
或R 4a、R 5a与其连接的原子共同形成C 3-C 10环烷基或4-10元杂环基；所述C 3-C 10环烷基或4-10元杂环基任选被R d取代； Or R 4a , R 5a and the atoms they connect together form a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group; the C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group is optionally Rd replaces;
或R 5a、R 5b与其连接的原子共同形成C 3-C 10环烷基或4-10元杂环基；所述C 3-C 10环烷基或4-10元杂环基任选被R d取代； Or R 5a , R 5b and the atoms they connect together form a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group; the C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group is optionally replaced by Rd replaces;
或R 2a、R 4a与其连接的原子共同形成5-10元杂芳基、C 3-C 10环烷基或4-10元杂环基，所述5-10元杂芳基、C 3-C 10环烷基或4-10元杂环基任选被R d取代； Or R 2a , R 4a and the atoms they connect together form a 5-10 membered heteroaryl group, a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group, and the 5-10 membered heteroaryl group, C 3 - C 10 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R ;
或R 2a、R 5a与其连接的原子共同形成5-10元杂芳基、C 3-C 10环烷基或4-10元杂环基，所述5-10元杂芳基、C 3-C 10环烷基或4-10元杂环基任选被R d取代； Or R 2a , R 5a and the atoms they connect together form a 5-10 membered heteroaryl group, a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group, and the 5-10 membered heteroaryl group, C 3 - C 10 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R ;
或X 2与X 3，X 3与X 4之间可选其一形成双键； Or one of X 2 and X 3 , X 3 and X 4 can be selected to form a double bond;
每一个R d独立地选自卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基任选被R e取代； 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选自卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-8元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-8元杂环基任选被R f取代； 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选自卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-8元杂环基； 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;
m、n、p独立地选自0、1、2、3、4、5或6。m, n, p are independently selected from 0, 1, 2, 3, 4, 5 or 6.
在一些实施方案中，X 1选自N。 In some embodiments, X is selected from N.
在一些实施方案中，X 1选自CR 1a。 In some embodiments, X 1 is selected from CR 1a .
在一些实施方案中，X 2选自O、NR 2a、CR 2aR 2b、C＝CR 2aR 2b、S、S(＝O)R 2a、C(＝O)或S(＝O) 2。 In some embodiments, X 2 is selected from O, NR 2a , CR 2a R 2b , C=CR 2a R 2b , S, S(=O)R 2a , C(=O), or S(=O) 2 .
在一些实施方案中，X 2选自O、NR 2a、CR 2aR 2b或C(＝O)。 In some embodiments, X 2 is selected from O, NR 2a , CR 2a R 2b , or C(=O).
在一些实施方案中，X 3选自CR 3aR 3b、CR 3a、NR 3a、N、C(＝O)或C(＝NR 3a)。 In some embodiments, X 3 is selected from CR 3a R 3b , CR 3a , NR 3a , N, C(=O), or C(=NR 3a ).
在一些实施方案中，X 3选自CR 3aR 3b、NR 3a或C(＝O)。 In some embodiments, X 3 is selected from CR 3a R 3b , NR 3a or C(=O).
在一些实施方案中，X 4选自CR 4aR 4b或C(＝O)。在一些实施方案中，X 4选自CR 4aR 4b。 In some embodiments, X 4 is selected from CR 4a R 4b or C(=O). In some embodiments, X 4 is selected from CR 4a R 4b .
在一些实施方案中，X 4选自CR 4a。 In some embodiments, X 4 is selected from CR 4a .
在一些实施方案中，X 5选自CR 5aR 5b或C(＝O)。 In some embodiments, X 5 is selected from CR 5a R 5b or C(=O).
在一些实施方案中，环A选自芳基或5-10元杂芳基。In some embodiments, ring A is selected from aryl or 5-10 membered heteroaryl.
在一些实施方案中，环A选自
Figure PCTCN2022115739-appb-000002
In some embodiments, Ring A is selected from
Figure PCTCN2022115739-appb-000002
在一些实施方案中，环B选自亚芳基、4-8元亚杂环基或亚C 3-C 6环烷基。 In some embodiments, ring B is selected from arylene, 4-8 membered heterocyclylene, or C 3 -C 6 cycloalkylene.
在一些实施方案中，环B选自亚芳基或4-8元亚杂环基。In some embodiments, ring B is selected from arylene or 4-8 membered heterocyclylene.
在一些实施方案中，环B选自
Figure PCTCN2022115739-appb-000003
In some embodiments, Ring B is selected from
Figure PCTCN2022115739-appb-000003
在一些实施方案中，环C选自5-10元杂芳基。In some embodiments, Ring C is selected from 5-10 membered heteroaryls.
在一些实施方案中，环C选自
Figure PCTCN2022115739-appb-000004
In some embodiments, ring C is selected from
Figure PCTCN2022115739-appb-000004
在一些实施方案中，环C选自
Figure PCTCN2022115739-appb-000005
In some embodiments, ring C is selected from
Figure PCTCN2022115739-appb-000005
在一些实施方案中，R 1、R 2独立地选自H、卤素或C 1-C 6烷基，所述C 1-C 6烷基任选被R d取代。 In some embodiments, R 1 , R 2 are independently selected from H, halogen, or C 1 -C 6 alkyl optionally substituted with R d .
在一些实施方案中，R 1、R 2独立地选自H或C 1-C 6烷基，所述C 1-C 6烷基任选被R d取代。在一些实施方案中，R 1、R 2独立地选自H。 In some embodiments, 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.
在一些实施方案中，R 1、R 2以及它们所连接的原子共同形成C 3-C 6环烷基，所述C 3-C 6环烷基任选被R d取代。 In some embodiments, 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 .
在一些实施方案中，R 1、R 2以及它们所连接的原子共同形成环丙基，所述环丙基任选被R d取代。 In some embodiments, R 1 , R 2 and the atoms to which they are attached together form cyclopropyl optionally substituted with R d .
在一些实施方案中，R 3选自H、卤素、CN、OH、C 1-C 6烷基、C 3-C 6环烷基、4-8元杂环基、烯基或炔基，所述OH、C 1-C 6烷基、C 3-C 6环烷基、4-8元杂环基、烯基或炔基任选被R d取代。 In some embodiments, 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 .
在一些实施方案中，R 3选自H、卤素、CN、OH、C 1-C 6烷基或C 3-C 6环烷基，所述OH、C 1-C 6烷基或C 3-C 6环烷基任选被R d取代。 In some embodiments, 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 .
在一些实施方案中，R 3选自H、卤素、OH或C 1-C 6烷基，所述OH或C 1-C 6烷基任选被R d取代。 In some embodiments, R 3 is selected from H, halogen, OH, or C 1 -C 6 alkyl optionally substituted with R d .
在一些实施方案中，R 3选自H。 In some embodiments, R is selected from H.
在一些实施方案中，R 1a、R 2a、R 2b、R 3a、R 3b、R 4a、R 4b、R 5a、R 5b独立地选自H、卤素、CN、OH、NH 2、C 1-C 6烷基、烯基、C 3-C 6环烷基或4-8元杂环基，所述OH、NH 2、C 1-C 6烷基、烯基、C 3-C 6环烷基或4-8元杂环基任选被R d取代。 In some embodiments, 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 .
在一些实施方案中，R 1a、R 2a、R 2b、R 3a、R 3b、R 4a、R 4b、R 5a、R 5b独立地选自H、卤素、OH、NH 2、C 1-C 6烷基、烯基或C 3-C 6环烷基，所述OH、NH 2、C 1-C 6烷基、烯基或C 3-C 6环烷基任选被R d取代。 In some embodiments, 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 .
在一些实施方案中，R a、R b、R c独立地选自卤素、OH、NH 2、SH、C 1-C 6烷基、C 3-C 6环烷基或4-8元杂环基，所述OH、NH 2、SH、C 1-C 6烷基、C 3-C 6环烷基或4-8元杂环基任选被R d取代。 In some embodiments, 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 .
在一些实施方案中，R a独立地选自OH、C 1-C 6烷基或C 3-C 6环烷基，所述OH、C 1-C 6烷基或C 3-C 6环烷基任选被R d取代。 In some embodiments, 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 .
在一些实施方案中，R a独立地选自-O-CH 3、-O-CHF 2、甲基、乙基、异丙基或环丙基。 In some embodiments, R a is independently selected from -O-CH 3 , -O-CHF 2 , methyl, ethyl, isopropyl, or cyclopropyl.
在一些实施方案中，R a独立地选自-O-CH 3、甲基、乙基、异丙基或环丙基。 In some embodiments, Ra is independently selected from -O- CH3 , methyl, ethyl, isopropyl, or cyclopropyl.
在一些实施方案中，R a独立地选自-O-CH 3、-O-CHF 2或环丙基。 In some embodiments, R a is independently selected from -O-CH 3 , -O-CHF 2 , or cyclopropyl.
在一些实施方案中，R b独立地选自卤素、OH或C 1-C 6烷基，所述OH或C 1-C 6烷基任选被R d取代。 In some embodiments, R b is independently selected from halogen, OH, or C 1 -C 6 alkyl optionally substituted with R d .
在一些实施方案中，R b独立地选自H。 In some embodiments, Rb is independently selected from H.
在一些实施方案中，R c独立地选自卤素、OH、C 1-C 6烷基或C 3-C 6环烷基，所述OH、C 1-C 6烷基或C 3-C 6环烷基任选被R d取代。 In some embodiments, 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 .
在一些实施方案中，R c独立地选自OH、C 1-C 6烷基或C 3-C 6环烷基，所述OH、C 1-C 6烷基或C 3-C 6环烷基任选被R d取代。 In some embodiments, 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 .
在一些实施方案中，R c独立地选自OH、甲基、乙基、异丙基或环丙基，所述OH、甲基、乙基、异丙基或环丙基任选被R d取代。 In some embodiments, R c is independently selected from OH, methyl, ethyl, isopropyl or cyclopropyl optionally replaced by R replace.
在一些实施方案中，R c独立地选自OCH 3、CF 3、CH 2CF 3、CH 3、CH 2CH 3、异丙基、环丙基或
Figure PCTCN2022115739-appb-000006
In some embodiments, R c is independently selected from OCH 3 , CF 3 , CH 2 CF 3 , CH 3 , CH 2 CH 3 , isopropyl, cyclopropyl, or
Figure PCTCN2022115739-appb-000006
在一些实施方案中，R c独立地选自CF 3或CH 3。 In some embodiments, Rc is independently selected from CF3 or CH3 .
在一些实施方案中，R 1a、R a与其连接的原子共同形成C 3-C 10环烷基或4-10元杂环基，所述C 3-C 10环烷基或4-10元杂环基任选被R d取代。 In some embodiments, R 1a , R a and the atoms they are connected to together form a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group, and the C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group Cyclic is optionally substituted with Rd .
在一些实施方案中，R 1a、R a与其连接的原子共同形成4-8元杂环基，所述4-8元杂环基任选被R d取代。 In some embodiments, R 1a , R a and the atoms to which they are attached together form a 4-8 membered heterocyclyl optionally substituted by R d .
在一些实施方案中，R b、R c与其连接的原子共同形成C 3-C 10环烷基或4-10元杂环基，所述C 3-C 10环烷基或4-10元杂环基任选被R d取代。 In some embodiments, R b , R c and the atoms they are connected to together form a C 3 -C 10 cycloalkyl or a 4-10 membered heterocyclyl, and the C 3 -C 10 cycloalkyl or 4-10 membered heterocyclyl Cyclic is optionally substituted with Rd .
在一些实施方案中，R b、R c与其连接的原子共同形成4-8元杂环基，所述4-8元杂环基任选被R d取代。 In some embodiments, R b , R c and the atoms to which they are attached together form a 4-8 membered heterocyclyl optionally substituted by R d .
在一些实施方案中，R 2a、R 2b与其连接的原子共同形成C 3-C 6环烷基或4-7元杂环基，所述C 3-C 6环烷基或4-7元杂环基任选被R d取代。 In some embodiments, R 2a , R 2b and the atoms they are connected to together form a C 3 -C 6 cycloalkyl group or a 4-7 membered heterocyclic group, and the C 3 -C 6 cycloalkyl group or a 4-7 membered heterocyclic group Cyclic is optionally substituted with Rd .
在一些实施方案中，R 2a、R 2b与其连接的原子共同形成C 3-C 10环烷基，所述C 3-C 10环烷基任选被R d取代。 In some embodiments, R 2a , R 2b and the atoms they are connected to together form a C 3 -C 10 cycloalkyl group, the C 3 -C 10 cycloalkyl group is optionally substituted by R d .
在一些实施方案中，R 2a、R 2b与其连接的原子共同形成环丁基，所述环丁基任选被R d取代。 In some embodiments, R 2a , R 2b and the atoms to which they are attached together form a cyclobutyl group, which is optionally substituted with R d .
在一些实施方案中，R 2a、R 3a与其连接的原子共同形成5-10元杂芳基，所述5-10元杂芳基任选被R d取代。 In some embodiments, R 2a , R 3a and the atoms they are connected to together form a 5-10 membered heteroaryl, which is optionally substituted by R d .
在一些实施方案中，R 2a、R 3a与其连接的原子共同形成
Figure PCTCN2022115739-appb-000007
所述
Figure PCTCN2022115739-appb-000008
任 选被R d取代。 In some embodiments, R 2a , R 3a and the atoms to which they are attached together form
Figure PCTCN2022115739-appb-000007
said
Figure PCTCN2022115739-appb-000008
is optionally substituted by Rd .
在一些实施方案中，R 3a、R 4a与其连接的原子共同形成C 3-C 10环烷基或4-8元杂环基，所述C 3-C 10环烷基或4-8元杂环基任选被R d取代。 In some embodiments, R 3a , R 4a and the atoms they are connected to together form a C 3 -C 10 cycloalkyl or a 4-8 membered heterocyclyl, and the C 3 -C 10 cycloalkyl or 4-8 membered heterocyclyl Cyclic is optionally substituted with Rd .
在一些实施方案中，R 3a、R 4a与其连接的原子共同形成环丙基、
Figure PCTCN2022115739-appb-000009
所述环丙基、
Figure PCTCN2022115739-appb-000010
任选被R d取代。 In some embodiments, R 3a , R 4a and the atoms they are connected to together form cyclopropyl,
Figure PCTCN2022115739-appb-000009
The cyclopropyl,
Figure PCTCN2022115739-appb-000010
is optionally substituted by Rd .
在一些实施方案中，R 3a、R 5a与其连接的原子共同形成C 3-C 10环烷基或4-8元杂环基，所述C 3-C 10环烷基或4-8元杂环基任选被R d取代。 In some embodiments, R 3a , R 5a and the atoms they are connected to together form a C 3 -C 10 cycloalkyl or a 4-8 membered heterocyclyl, and the C 3 -C 10 cycloalkyl or 4-8 membered heterocyclyl Cyclic is optionally substituted with Rd .
在一些实施方案中，R 3a、R 5a与其连接的原子共同形成
Figure PCTCN2022115739-appb-000011
所述
Figure PCTCN2022115739-appb-000012
Figure PCTCN2022115739-appb-000013
任选被R d取代。 In some embodiments, R 3a , R 5a and the atoms to which they are attached together form
Figure PCTCN2022115739-appb-000011
said
Figure PCTCN2022115739-appb-000012
Figure PCTCN2022115739-appb-000013
is optionally substituted by Rd .
在一些实施方案中，R 4a、R 4b与其连接的原子共同形成C 3-C 6环烷基或4-8元杂环基，所述C 3-C 6环烷基或4-8元杂环基任选被R d取代。 In some embodiments, R 4a , R 4b and the atoms they are connected to together form a C 3 -C 6 cycloalkyl group or a 4-8 membered heterocyclic group, and the C 3 -C 6 cycloalkyl group or a 4-8 membered heterocyclic group Cyclic is optionally substituted with Rd .
在一些实施方案中，R 4a、R 4b与其连接的原子共同形成环丙基、环丁基或
Figure PCTCN2022115739-appb-000014
所述环丙基、环丁基或
Figure PCTCN2022115739-appb-000015
任选被R d取代。 In some embodiments, R 4a , R 4b and the atoms they are connected to together form cyclopropyl, cyclobutyl or
Figure PCTCN2022115739-appb-000014
The cyclopropyl, cyclobutyl or
Figure PCTCN2022115739-appb-000015
is optionally substituted by Rd .
在一些实施方案中，R 4a、R 5a与其连接的原子共同形成C 3-C 6环烷基或4-8元杂环基；所述C 3-C 6环烷基或4-8元杂环基任选被R d取代。在一些实施方案中，R 4a、R 5a与其连接的原子共同形成环丙基或环丁基；所述环丙基或环丁基任选被R d取代。 In some embodiments, R 4a , R 5a and the atoms they are connected to together form a C 3 -C 6 cycloalkyl group or a 4-8 membered heterocyclic group; the C 3 -C 6 cycloalkyl group or a 4-8 membered heterocyclic group Cyclic is optionally substituted with Rd . In some embodiments, 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 .
在一些实施方案中，R 5a、R 5b与其连接的原子共同形成C 3-C 6环烷基或4-8元杂环基；所述C 3-C 6环烷基或4-8元杂环基任选被R d取代。 In some embodiments, R 5a , R 5b and the atoms they are connected to together form a C 3 -C 6 cycloalkyl group or a 4-8 membered heterocyclic group; the C 3 -C 6 cycloalkyl group or a 4-8 membered heterocyclic group Cyclic is optionally substituted with Rd .
在一些实施方案中，R 5a、R 5b与其连接的原子共同形成C 3-C 6环烷基，所述C 3-C 6环烷基任选被R d取代。 In some embodiments, R 5a , R 5b and the atoms they are connected to together form a C 3 -C 6 cycloalkyl group, and the C 3 -C 6 cycloalkyl group is optionally substituted by R d .
在一些实施方案中，R 5a、R 5b与其连接的原子共同形成环丙基或环丁基；所述环丙基或环丁基任选被R d取代。 In some embodiments, 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 .
在一些实施方案中，R 2a、R 4a与其连接的原子共同形成C 3-C 10环烷基或4-8元杂环基，所述C 3-C 10环烷基或4-8元杂环基任选被R d取代。 In some embodiments, R 2a , R 4a and the atoms they are connected to together form a C 3 -C 10 cycloalkyl or a 4-8 membered heterocyclic group, and the C 3 -C 10 cycloalkyl or 4-8 membered heterocyclic group Cyclic is optionally substituted with Rd .
在一些实施方案中，R 2a、R 5a与其连接的原子共同形成C 3-C 10环烷基或4-8元杂环基，所述C 3-C 10环烷基或4-8元杂环基任选被R d取代。 In some embodiments, R 2a , R 5a and the atoms they are connected to together form a C 3 -C 10 cycloalkyl or a 4-8 membered heterocyclyl, and the C 3 -C 10 cycloalkyl or 4-8 membered heterocyclyl Cyclic is optionally substituted with Rd .
在一些实施方案中，X 2与X 3之间形成双键。 In some embodiments, a double bond is formed between X2 and X3 .
在一些实施方案中，X 3与X 4之间形成双键。 In some embodiments, a double bond is formed between X3 and X4 .
在一些实施方案中，每一个R d独立地选自卤素、OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基任选被R e取代。 In some embodiments, 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 .
在一些实施方案中，每一个R d独立地选自卤素、OH、NH 2、C 1-C 6烷基或C 3-C 10环烷基，所述OH、NH 2、C 1-C 6烷基或C 3-C 10环烷基任选被R e取代。 In some embodiments, 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 .
在一些实施方案中，R e选自卤素、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-8元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-8元杂环基任选被R f取代。 In some embodiments, 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 .
在一些实施方案中，R f选自卤素、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-8元杂环基。 In some embodiments, R f is selected from halogen, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-8 membered heterocyclyl.
在一些实施方案中，m选自1、2、3。In some embodiments, m is selected from 1,2,3.
在一些实施方案中，m选自1或2。In some embodiments, m is selected from 1 or 2.
在一些实施方案中，n选自0、1、2。In some embodiments, n is selected from 0, 1, 2.
在一些实施方案中，n选自0或1。In some embodiments, n is selected from 0 or 1.
在一些实施方案中，p选自1、2、3。In some embodiments, p is selected from 1, 2, 3.
在一些实施方案中，p选自1或2。In some embodiments, p is selected from 1 or 2.
在一些实施方案中，本公开的式(I)化合物或其药学上可接受的盐选自式(II)化合物或其药学上可接受的盐，In some embodiments, 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,
Figure PCTCN2022115739-appb-000016
Figure PCTCN2022115739-appb-000016
其中，in,
X 1选自N或CR 1a； X 1 is selected from N or CR 1a ;
X 2选自O、NR 2a、CR 2aR 2b、C＝CR 2aR 2b、S、C(＝O)、S(＝O) 2或C(＝NR 2a)； X 2 is selected from O, NR 2a , CR 2a R 2b , C=CR 2a R 2b , S, C(=O), S(=O) 2 or C(=NR 2a );
X 3选自CR 3aR 3b、NR 3a、C(＝O)、O或C(＝NR 3a)； X 3 is selected from CR 3a R 3b , NR 3a , C(=O), O or C(=NR 3a );
X 4选自CR 4aR 4b或C(＝O)； X 4 is selected from CR 4a R 4b or C(=O);
X 5选自CR 5aR 5b、C(＝O)或S(＝O) 2； X 5 is selected from CR 5a R 5b , C(=O) or S(=O) 2 ;
环A、环B、环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和R 5b如上文所定义。 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.
在一些实施方式中，式(II)化合物或其药学上可接受的盐中X 4为CR 4aR 4b。 In some embodiments, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, X 4 is CR 4a R 4b .
应理解，在涉及式(II)的权利要求中，当前述权利要求x时，所述式(II)中的环A、环B、环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和R 5b如权利要求x定义。例如，当权利要求27引用前述权利要求1时，所述式(II)中的环A、环B、环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和R 5b如权利要求1定义；当权利要求27引用前述权利要求7时，所述式(II)中的环A、环B、环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和R 5b如权利要求7定义，以此类推。 It should be understood that in the claims related to formula (II), when the preceding claim x, 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 x. For example, when claim 27 refers to the preceding 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 1; when claim 27 refers to the preceding claim 7, the formula 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.
在一些实施方案中，本公开的式(I)化合物或其药学上可接受的盐选自式(III)化合物或其药学上可接受的盐，In some embodiments, 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,
Figure PCTCN2022115739-appb-000017
Figure PCTCN2022115739-appb-000017
其中，in,
X 1选自N或CR 1a； X 1 is selected from N or CR 1a ;
X 2选自O、NR 2a、CR 2aR 2b、C＝CR 2aR 2b、S、C(＝O)、S(＝O) 2或C(＝NR 2a)； X 2 is selected from O, NR 2a , CR 2a R 2b , C=CR 2a R 2b , S, C(=O), S(=O) 2 or C(=NR 2a );
X 3选自CR 3aR 3b、NR 3a、C(＝O)、O或C(＝NR 3a)； X 3 is selected from CR 3a R 3b , NR 3a , C(=O), O or C(=NR 3a );
X 4选自CR 4aR 4b或C(＝O)； X 4 is selected from CR 4a R 4b or C(=O);
X 5选自CR 5aR 5b、C(＝O)或S(＝O) 2； X 5 is selected from CR 5a R 5b , C(=O) or S(=O) 2 ;
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和R 5b如上文定义。 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 as defined above.
应理解，在涉及式(III)的权利要求中，当前述权利要求x时，所述式(III)中的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和R 5b如权利要求x定义。例如，当权利要求28引用前述权利要求1时，所述式(III)中的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和R 5b如权利要求1定义；当权利要求28引用前述权利要求10时，所述式(III)中的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和R 5b如权利要求10定义，以此类推。 It should be understood that in claims related to formula (III), when the preceding claim x, R 1 , R 2 , R 3 , R a , R b , R c , m, n in said formula (III) , 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 x. For example, when claim 28 refers to the preceding claim 1, 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; when claim 28 refers to the preceding claim 10, 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.
在不冲突的情况下，应理解上述实施方案可以任意组合，形成包括所组合的实施方案的特征的技术方案。 这样的组合的技术方案在本发明的范围内。In the case of no conflict, it should be understood that the above-mentioned embodiments can be combined arbitrarily to form a technical solution including the features of the combined embodiments. Such combined technical solutions are within the scope of the present invention.
在一些实施方案中，式(I)化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐，In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022115739-appb-000018
Figure PCTCN2022115739-appb-000018
Figure PCTCN2022115739-appb-000019
Figure PCTCN2022115739-appb-000019
Figure PCTCN2022115739-appb-000020
Figure PCTCN2022115739-appb-000020
Figure PCTCN2022115739-appb-000021
Figure PCTCN2022115739-appb-000021
Figure PCTCN2022115739-appb-000022
Figure PCTCN2022115739-appb-000022
Figure PCTCN2022115739-appb-000023
Figure PCTCN2022115739-appb-000023
Figure PCTCN2022115739-appb-000024
Figure PCTCN2022115739-appb-000024
Figure PCTCN2022115739-appb-000025
Figure PCTCN2022115739-appb-000025
Figure PCTCN2022115739-appb-000026
Figure PCTCN2022115739-appb-000026
另一方面，本公开提供药物组合物，其包含本公开的式(I)化合物或其药学上可接受的盐和药学上可接受的辅料。In another aspect, 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.
另一方面，本公开提供治疗哺乳动物由USP1介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式(I)化合物或其药学上可接受的盐、或其药物组合物。In another aspect, 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.
另一方面，本公开提供式(Ⅰ)化合物或其药学上可接受的盐、或其药物组合物在制备预防或者治疗USP1介导的疾病的药物中的用途。In another aspect, 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.
另一方面，本公开提供式(Ⅰ)化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗USP1介导的疾病中的用途。In another aspect, 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.
另一方面，本公开提供预防或者治疗USP1介导的疾病的式(Ⅰ)化合物或其药学上可接受的盐、或其药物组合物。In another aspect, 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.
在一些实施方案中，USP1介导的疾病为肿瘤。例如为实体瘤。In some embodiments, the USP1 -mediated disease is a tumor. For example, solid tumors.
术语定义和说明Definitions and Explanations of Terms
除非另有说明，本公开中所用的下列术语具有下列含义，本公开中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms used in this disclosure have the following meanings, definitions of groups and terms recorded in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, implementations The definitions of the specific compounds in the examples, etc., can be combined and combined arbitrarily with each other. A specific term should not be regarded as indeterminate or unclear if there is no special definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
本文中
Figure PCTCN2022115739-appb-000027
表示连接位点。 In this article
Figure PCTCN2022115739-appb-000027
Indicates the junction site.
本文中，合成路线中的多箭头
Figure PCTCN2022115739-appb-000028
表示多步反应。 In this paper, the multiple arrows in the synthetic route
Figure PCTCN2022115739-appb-000028
Indicates a multi-step reaction.
本文中，由实线和虚线描绘的键
Figure PCTCN2022115739-appb-000029
是单双键。例如，组成部分
Figure PCTCN2022115739-appb-000030
涵盖以下两者：
Figure PCTCN2022115739-appb-000031
Figure PCTCN2022115739-appb-000032
In this paper, the bonds depicted by solid and dashed lines
Figure PCTCN2022115739-appb-000029
is a single double bond. For example, the component
Figure PCTCN2022115739-appb-000030
Covers both:
Figure PCTCN2022115739-appb-000031
Figure PCTCN2022115739-appb-000032
本公开的化合物可以具有不对称原子如碳原子、硫原子、氮原子、磷原子或不对称双键，因此本公开的化合物可以存在特定的几何或立体异构体形式。特定的几何或立体异构体形式可以是顺式和反式异构体、E型和Z型几何异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，以及其外消旋混合物或其它混合物，例如对映异构体或非对映体富集的混合物，以上所有这些异构体以及它们的混合物都属于本公开化合物的定义范围之内。烷基等取代基中可存在另外的不对称碳原子、不对称硫原子、不对称氮原子或不对称磷原子，所有取代基中涉及到的这些异构体以及它们的混合物，也均包括在本公开化合物的定义范围之内。本公开的含有不对称原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来，光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。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. 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 .
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。The term "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. When a substituent is oxo (ie, =0), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，是指乙基可以是未被取代的(CH 2CH 3)、单取代的(CH 2CH 2F、CH 2CH 2Cl等)、多取代的(CHFCH 2F、CH 2CHF 2、CHFCH 2Cl、CH 2CHCl 2等)或完全被取代的(CF 2CF 3、CF 2CCl 3、CCl 2CCl 3等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。 The term "optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that description includes that said event or circumstance occurs and that it does not. For example, 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.
当任何变量(例如R a、R b)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。例如，如果一个基团被2个R b所取代，则每个R b都有独立的选项。 When any variable (eg R a , R b ) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. For example, if a group is substituted by 2 R b , each R b has independent options.
当本文中涉及到的连接基团若没有指明其连接方向，则其连接方向是任意的。例如当结构单元
Figure PCTCN2022115739-appb-000033
中的L 1选自“C 1-C 3亚烷基-O”时，此时L 1既可以按照与从左到右的读取顺序相同的方向连接环Q和R 1构成“环Q-C 1-C 3亚烷基-O-R 1”，也可以按照从左到右的读取顺序相反的方向连接环Q和R 1构成“环Q-O-C 1-C 3亚烷基-R 1”。 When the linking group mentioned herein does not indicate its linking direction, its linking direction is arbitrary. For example when the structural unit
Figure PCTCN2022115739-appb-000033
When L 1 in is selected from "C 1 -C 3 alkylene-O", at this time 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 ".
当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元
Figure PCTCN2022115739-appb-000034
表示R 5可在苯环上的任意一个位置发生取代。 When a bond of a substituent cross-links two atoms in a ring, the substituent may be bonded to any atom on the ring. For example, the structural unit
Figure PCTCN2022115739-appb-000034
Indicates that R 5 can be substituted at any position on the benzene ring.
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
本文中的C m-C n，是指具有m-n范围中的整数个碳原子。例如“C 1-C 10”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。 C m -C n herein means having an integer number of carbon atoms in the range of mn. For example, "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.
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1-C 10烷基”应理解为表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1，2-二甲基丙基、新戊基、1，1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、2，3-二甲基丁基、1，3-二甲基丁基或1，2-二甲基丁基等；术语“C 1- 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基和二烷基氨基的烷基部分(即烷基)具有上述相同定义。 The term "alkyl" refers to a hydrocarbon group of the general formula CnH2n +1 . The alkyl group may be linear or branched. For example, the term "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 as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methyl butyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (ie the alkyl group) of alkoxy, alkylamino and dialkylamino has the same definition as above.
本文所述“C 1-C 10烷基”可以包含“C 1-C 6烷基”或“C 1-C 3烷基”，所述“C 1-C 6烷基”可以进一步包含“C 1-C 3烷基”。 The "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".
术语“烯基”是指由碳原子和氢原子组成的直链或支链的且具有至少一个双键的不饱和脂肪族烃基。术语“C 2-C 10烯基”可理解为表示直链或支链的不饱和烃基，其包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子，“C 2-C 10烯基”优选“C 2-C 6烯基”，进一步优选“C 2-C 4烯基”，更进一步优选C 2或C 3烯基。可理 解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或共轭。所述烯基的具体实例包括但不限于乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基或(Z)-1-甲基丙-1-烯基等。 The term "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. The term "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. Specific examples of the alkenyl group 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.
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基。术语“C 2-C 10炔基”可理解为表示直链或支链的不饱和烃基，其包含一个或多个三键并且具有2、3、4、5、6、7、8、9或10个碳原子。“C 2-C 10炔基”的实例包括但不限于乙炔基(-C≡CH)、丙炔基(-C≡CCH 3、-CH 2C≡CH)、丁-1-炔基、丁-2-炔基或丁-3-炔基。“C 2-C 10炔基”可以包含“C 2-C 3炔基”，“C 2-C 3炔基”实例包括乙炔基(-C≡CH)、丙-1-炔基(-C≡CCH 3)、丙-2-炔基(-CH 2C≡CH)。 The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond. The term "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).
术语“环烷基”是指完全饱和的且以单环、并环、桥环或螺环等形式存在的碳环。除非另有指示，该碳环通常为3至10元环。术语“C 3-C 10环烷基”可理解为表示饱和的单环、并环、螺环或桥环，其具有3、4、5、6、7、8、9或10个碳原子。所述环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基，降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、螺[4.5]癸烷基等。术语“C 3-C 10环烷基”可以包含“C 3-C 6环烷基”，术语“C 3-C 6环烷基”可理解为表示饱和的单环或双环烃环，其具有3-6个碳原子，具体实例包括但不限于环丙基、环丁基、环戊基或环己基等。 The term "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. The term "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. Specific examples of said cycloalkyl 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. The term "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.
术语“杂环基”是指完全饱和的或部分饱和的(整体上不是具有芳香性的杂芳族)单环、并环、螺环或桥环基团，其环原子中含有1-5个杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O) 2-、-S(＝O)-、-P(＝O) 2-、-P(＝O)-、-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-或-NHC(＝O)NH-等。术语“4-10元杂环基”是指环原子数目为4、5、6、7、8、9或10的杂环基，且其环原子中含有1-5个独立选自上文所述的杂原子或杂原子团。“4-10元杂环基”包括“4-7元杂环基”，其中，4元杂环基的具体实例包括但不限于氮杂环丁烷基或氧杂环丁烷基；5元杂环基的具体实例包括但不限于四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、4,5-二氢噁唑基或2,5-二氢-1H-吡咯基；6元杂环基的具体实例包括但不限于四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、三噻烷基、四氢吡啶基或4H-[1,3,4]噻二嗪基；7元杂环基的具体实例包括但不限于二氮杂环庚烷基。所述杂环基还可以是双环基，其中，5,5元双环基的具体实例包括但不限于六氢环戊并[c]吡咯-2(1H)-基；5,6元双环基的具体实例包括但不限于六氢吡咯并[1,2-a]吡嗪-2(1H)-基、5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡嗪基或5,6,7,8-四氢咪唑并[1,5-a]吡嗪基。任选地，所述杂环基可以是上述4-7元杂环基的苯并稠合环基，具体实例包括但不限于二氢异喹啉基等。“4-10元杂环基”可以包含“5-10元杂环基”、“4-7元杂环基”、“5-6元杂环基”、“6-8元杂环基”、“4-10元杂环烷基”、“5-10元杂环烷基”、“4-7元杂环烷基”、“5-6元杂环烷基”、“6-8元杂环烷基”等范围，“4-7元杂环基”进一步可以包含“4-6元杂环基”、“5-6元杂环基”、“4-7元杂环烷基”、“4-6元杂环烷基”、“5-6元杂环烷基”等范围。本公开中尽管有些双环类杂环基部分地含有一个苯环或一个杂芳环，但所述杂环基整体上仍是无芳香性的。 The term "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 Heteroatoms or heteroatom groups (ie, atomic groups containing heteroatoms), the "heteroatoms or heteroatom groups" include but are not limited to nitrogen atoms (N), oxygen atoms (O), sulfur atoms (S), phosphorus atoms (P) , boron atom (B), -S(=O) 2 -, -S(=O)-, -P(=O) 2 -, -P(=O)-, -NH-, -S(=O )(=NH)-, -C(=O)NH- or -NHC(=O)NH-, etc. The term "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. "4-10 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 heterocyclyl include, but are not limited to, diazepanyl. 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. Optionally, 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 heterocycloalkyl" and other ranges. Although some bicyclic heterocyclic groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic groups as a whole are non-aromatic.
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。术语“C 6-C 20芳基”可理解为具有6～20个碳原子的芳基。特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或者具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基；或者具有13个碳原子的环(“C 13芳基”)，例如芴基；或者是具有14个碳原子的环(“C 14芳基”)，例如蒽基。术语“C 6-C 10芳基”可理解为具有6～10个碳原子的芳基。特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或者具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基。 The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. The aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms. The term "C 6 -C 20 aryl" is understood to mean an aryl group having 6 to 20 carbon atoms. Especially 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. The term "C 6 -C 10 aryl" is understood to mean an aryl group having 6 to 10 carbon atoms. Especially 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 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
术语“杂芳基”是指具有芳香性的单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C的芳香环基。术语“5-10元杂芳基”可理解为包括这样的单环或双环芳族环系：其具有5、6、7、8、9或10个环原子，特别是5或6或9或10个环原子，且其包含1-5个，优选1-3个独立选自N、O和S的杂原子。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基或噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并***基、吲唑基、吲哚基或异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基等以及它们的苯并衍生物，例如喹啉基、喹唑啉基或异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基或吩噁嗪基等。术语“5-6元杂芳基”指具有5或6个环原子的芳族环系，且其包含1-3个，优选1-2个独立选自N、O和S的杂原子。The term "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. The term "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. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiazolyl Diazolyl, etc. and their 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. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthalene Pyridyl, pteridyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, etc. The term "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.
术语“治疗有效量”意指(i)治疗特定疾病、病况或病症，(ii)减轻、改善或消除特定疾病、病况或病症的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本公开化合物的用量。构成“治疗有效量”的本公开化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "therapeutically 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.
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "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.
术语“药学上可接受的盐”是指药学上可接受的酸或碱的盐，包括化合物与无机酸或有机酸形成的盐，以及化合物与无机碱或有机碱形成的盐。The term "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.
术语“药物组合物”是指一种或多种本公开的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本公开的化合物。The term "pharmaceutical 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.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "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.
哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。Examples of 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. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising可理解为开放的、非排他性的意义，即“包括但不限于”。The word "comprise" or "comprise" and its English variants such as comprises or comprising can be interpreted in an open and non-exclusive sense, ie "including but not limited to".
本公开还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。 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. Examples of 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.
某些同位素标记的本公开化合物(例如用 3H及 14C标记)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本公开化合物。 Certain isotopically labeled compounds of the disclosure (eg, with3H and14C ) 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.
本公开的药物组合物可通过将本公开的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。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.
给予本公开化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。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.
本公开的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、乳化法、冷冻干燥法等。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.
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本公开的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in oral form. For oral administration, 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.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂或矫味剂等。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.
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。The pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
具体实施方式Detailed ways
下面结合具体实施例来进一步描述本公开，本公开的优点和特点将会随着描述而更为清楚。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。The present disclosure will be further described below in conjunction with specific embodiments, and the advantages and characteristics of the present disclosure will become clearer along with the description. Those who do not indicate the specific conditions in the examples are carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be purchased from the market.
本公开实施例仅是范例性的，并不对本公开的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本公开的精神和范围下可以对本公开技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本公开的保护范围内。The embodiments of the present disclosure are exemplary only, and do not constitute any limitation to the scope of the present disclosure. Those skilled in the art should understand that without departing from the spirit and scope of the present disclosure, the details and forms of the technical solution of the present disclosure can be modified or replaced, but these modifications and replacements all fall within the protection scope of the present disclosure.
除非另作说明，混合溶剂表示的比例是体积混合比例。Unless otherwise specified, the ratios indicated for mixed solvents are volume mixing ratios.
化合物经手工或
Figure PCTCN2022115739-appb-000035
软件命名，市售化合物采用供应商目录名称。 compound by hand or
Figure PCTCN2022115739-appb-000035
The software is named, and the commercially available compounds adopt the supplier catalog name.
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10-6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)；“IC 50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。 Compound structures were determined by nuclear magnetic resonance (NMR) and/or mass spectroscopy (MS). The unit of NMR shift is 10-6 (ppm). The solvents measured by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); concentration.
实施例1：2-(4-环丙基-6-甲氧基嘧啶-5-基)-9-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-6,7,8,9-四氢嘧啶并[5,4-b][1,4]氧杂氮杂卓(化合物1)Example 1: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2 -yl)benzyl)-6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepine (Compound 1)
Figure PCTCN2022115739-appb-000036
Figure PCTCN2022115739-appb-000036
步骤1：4-(5-(三氟甲基)-1H-咪唑-2-基)苯腈(1C)Step 1: 4-(5-(Trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (1C)
室温下，将3,3-二溴-1,1,1-三氟丙酮(9.9g,37mmol,1.2eq)和乙酸钠(3.0g,37mmol,1.2eq)加入水中，所得混合物在100℃搅拌加热反应1h。将反应液冷却至室温，缓慢滴加到溶有4-氰基苯甲醛(4.0g,30mmol,1.0eq)的甲醇(100mL)溶液中，然后于反应液中加入氨水(35mL)，并在室温下搅拌反应16小时。所得混合物减压蒸馏除去溶剂后，将所得残留物加入到水中(100mL)，用乙酸乙酯萃取(100mL*3)。所得有机相合并后用饱和食盐水洗涤(50mL)，减压蒸馏除去溶剂。将所得残留物用硅胶柱纯化(石油醚:乙酸乙酯＝5:1-1:1)得固体标题化合物1C(4.4g，收率61％)。m/z(ESI):238[M+H] +。 At room temperature, 3,3-dibromo-1,1,1-trifluoroacetone (9.9g, 37mmol, 1.2eq) and sodium acetate (3.0g, 37mmol, 1.2eq) were added to water, and the resulting mixture was stirred at 100°C The reaction was heated for 1h. The reaction solution was cooled to room temperature, slowly added dropwise to a methanol (100mL) solution in which 4-cyanobenzaldehyde (4.0g, 30mmol, 1.0eq) was dissolved, then ammonia water (35mL) was added to the reaction solution, and at room temperature The reaction was stirred for 16 hours. After the solvent was distilled off from the resulting mixture under reduced pressure, the resulting residue was added to water (100 mL), and extracted with ethyl acetate (100 mL*3). The obtained organic phases were combined and washed with saturated brine (50 mL), and the solvent was distilled off under reduced pressure. The resulting residue was purified with a silica gel column (petroleum ether: ethyl acetate = 5:1-1:1) to obtain the title compound 1C as a solid (4.4 g, yield 61%). m/z(ESI):238[M+H] + .
步骤2：4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯腈(1D)Step 2: 4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (1D)
将化合物1C(3.0g，13mmol)溶解于四氢呋喃中(30mL)，在0℃分批加入氢化钠(含量60％，0.67g，17mmol，1.3eq)。反应液在0℃下搅拌0.5小时后加入碘甲烷(3.2g,22mmol，1.7eq)，缓慢恢复到室温反应2小时。将反应液加入到冰水中(30mL)，并用乙酸乙酯萃取(20mL*3)。有机相合并后用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥后，减压蒸馏除去溶剂得固体标题化合物1D(3.0g，收率91％)。LC-MS:m/z(ESI):252[M+H] +。 Compound 1C (3.0 g, 13 mmol) was dissolved in tetrahydrofuran (30 mL), and sodium hydride (content 60%, 0.67 g, 17 mmol, 1.3 eq) was added in portions at 0°C. The reaction solution was stirred at 0° C. for 0.5 hours, then methyl iodide (3.2 g, 22 mmol, 1.7 eq) was added, and the mixture was slowly returned to room temperature for 2 hours. The reaction solution was added to ice water (30 mL), and extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound 1D as a solid (3.0 g, yield 91%). LC-MS: m/z (ESI): 252 [M+H] + .
步骤3：4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄胺(1E)Step 3: 4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzylamine (1E)
将化合物1D(3.0g，12mmol)加入到四氢呋喃中(60mL)，在0℃分批加入四氢铝锂(1.4g,36mmol,3.0eq)。所得混合物在0℃下搅拌反应1小时，然后缓慢恢复到室温反应1小时。在0℃下于反应液中依次加入1.3mL水，1.3mL 15％NaOH水溶液，3.8mL水。所得混合物在室温搅拌1小时后经硅藻土过滤，滤饼用二氯甲烷淋洗，所得滤液合并后经减压蒸馏除去溶剂，得油状标题化合物1E(3.0g，收率98％)。m/z(ESI):256[M+H] +。 Compound 1D (3.0 g, 12 mmol) was added into tetrahydrofuran (60 mL), and lithium aluminum hydride (1.4 g, 36 mmol, 3.0 eq) was added in portions at 0°C. The resulting mixture was stirred at 0°C for 1 hour, and then slowly returned to room temperature for 1 hour. At 0°C, 1.3 mL of water, 1.3 mL of 15% NaOH aqueous solution, and 3.8 mL of water were successively added to the reaction liquid. The resulting mixture was stirred at room temperature for 1 hour and then filtered through celite. The filter cake was rinsed with dichloromethane. The combined filtrates were evaporated under reduced pressure to remove the solvent to give the title compound 1E (3.0 g, yield 98%) as an oil. m/z(ESI):256[M+H] + .
步骤4：2-氯-4-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲胺基)-5-甲氧基嘧啶(1G)Step 4: 2-Chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzylamino)-5-methoxypyrimidine (1G)
室温下，将2,4-二氯-5-甲氧基嘧啶(0.86g,3.9mmol)和N,N-二异丙基乙基胺(1.0g，7.8mmol，2.0eq)溶解于到四氢呋喃中(20mL)，冷却至0℃后，于反应液中加入1E(0.93g,3.7mmol,1.0eq)。所得混合物在室温搅拌反应2小时后加热至50℃反应16小时。然后将反应液加入到冰水中(50mL)，用乙酸乙酯萃取(50mL*3)。有机相合并后饱和食盐水反洗一次(50mL)，减压蒸馏除去溶剂后，将所得残留物用硅胶柱纯化(石油醚:乙酸乙酯＝5:1-3:1)得固体1G(0.90g，收率58％)。m/z(ESI):398[M+H] +。 At room temperature, 2,4-dichloro-5-methoxypyrimidine (0.86g, 3.9mmol) and N,N-diisopropylethylamine (1.0g, 7.8mmol, 2.0eq) were dissolved in THF (20mL), after cooling to 0°C, 1E (0.93g, 3.7mmol, 1.0eq) was added to the reaction solution. The resulting mixture was stirred at room temperature for 2 hours and then heated to 50° C. for 16 hours. Then the reaction solution was added to ice water (50 mL), and extracted with ethyl acetate (50 mL*3). After the organic phases were combined, they were backwashed once with saturated brine (50 mL). After the solvent was distilled off under reduced pressure, the resulting residue was purified with a silica gel column (petroleum ether: ethyl acetate = 5:1-3:1) to obtain a solid 1G (0.90 g, yield 58%). m/z(ESI):398[M+H] + .
步骤5：2-氯-4-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲胺基)-5-羟基嘧啶(1H)Step 5: 2-Chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzylamino)-5-hydroxypyrimidine (1H)
将1G(0.90g,2.3mmol)溶解于到二氯甲烷(20mL)中，在0℃加入三溴化硼(12mL,23mmol,10eq)。所得混合物在40℃加热反应16小时。在0℃下加入甲醇(20mL)淬灭后，将所得反应液减压蒸馏除去溶剂。所得残余物经硅胶柱纯化(石油醚:乙酸乙酯＝3:1-1:2)得白色固体标题化合物1H(0.60g,收率67％)。m/z(ESI):384[M+H] +。 1G (0.90g, 2.3mmol) was dissolved in dichloromethane (20mL), and boron tribromide (12mL, 23mmol, 10eq) was added at 0°C. The resulting mixture was heated at 40°C for 16 hours. After quenching by adding methanol (20 mL) at 0°C, the resulting reaction solution was evaporated under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column (petroleum ether:ethyl acetate=3:1-1:2) to obtain the title compound 1H (0.60 g, yield 67%) as a white solid. m/z(ESI):384[M+H] + .
步骤6：2-氯-9-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-6,7,8,9-四氢嘧啶并[5,4-b][1,4]氧杂氮杂卓(1J)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)
室温下，将1H(50mg，0.13mmol),1,3-二溴丙烷(52mg，0.26mmol,2.0eq),碳酸钾(36mg，0.26mmol,2.0eq)，加入到N,N-二甲基甲酰胺(2mL)中。所得混合物在氮气保护下50℃反应3小时后体系加热到100℃， 反应2小时，冷却至室温，反应液反相柱纯化得1J(27mg,收率49％)。m/z(ESI):424[M+H] +。 At room temperature, 1H (50mg, 0.13mmol), 1,3-dibromopropane (52mg, 0.26mmol, 2.0eq), potassium carbonate (36mg, 0.26mmol, 2.0eq), was added to N,N-dimethyl formamide (2 mL). The resulting mixture was reacted at 50°C for 3 hours under the protection of nitrogen, then the system was heated to 100°C, reacted for 2 hours, cooled to room temperature, and the reaction solution was purified by reverse-phase column to obtain 1J (27 mg, yield 49%). m/z(ESI):424[M+H] + .
步骤7：2-(4-环丙基-6-甲氧基嘧啶-5-基)-9-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-6,7,8,9-四氢嘧啶并[5,4-b][1,4]氧杂氮杂卓(化合物1)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)
室温下，将1J(27.00mg，0.064mmol),1K(18.62mg，0.096mmol,1.5eq),碳酸钾(17.69mg，0.128mmol,2.0eq),Pd(dppf)Cl 2-CH 2Cl 2(0.9mg，1.28μmol，0.20eq)加入到二氧六环(2mL)和水(0.5mL)的混合溶液中。所得混合物在氮气保护下100℃微波反应1小时。反应液冷却后经硅藻土过滤，滤饼用乙酸乙酯淋洗，所得滤液合并后减压蒸馏除去溶剂得粗品化合物，经制备色谱(Waters AutoP，Xbridge-C18，19*150mm，20-75％乙腈的水溶液梯度洗脱，15mL/min)纯化后得固体标题化合物1(4mg,收率12％)。m/z(ESI):538[M+H] +。 1H NMR(400MHz,DMSO)δ8.57(s,1H),8.03(s,1H),7.90(s,1H),7.66(d,J＝8.2Hz,2H),7.42(d,J＝8.2Hz,2H),4.85(s,2H),4.26(t,J＝6.6Hz,2H),3.83(s,3H),3.76(s,3H),3.69–3.61(m,2H),2.11(dd,J＝11.8,6.2Hz,2H),1.84–1.72(m,1H),1.02–0.91(m,2H),0.81(dd,J＝8.0,3.2Hz,2H). At room temperature, 1J (27.00mg, 0.064mmol), 1K (18.62mg, 0.096mmol, 1.5eq), potassium carbonate (17.69mg, 0.128mmol, 2.0eq), Pd(dppf)Cl 2 -CH 2 Cl 2 ( 0.9mg, 1.28μmol, 0.20eq) was added to a mixed solution of dioxane (2mL) and water (0.5mL). The resulting mixture was subjected to microwave reaction at 100° C. for 1 hour under the protection of nitrogen. After the reaction solution was cooled, it was filtered through diatomaceous earth, and the filter cake was rinsed with ethyl acetate. After the combined filtrates were combined, the solvent was distilled off under reduced pressure to obtain the crude compound. % acetonitrile (gradient elution in aqueous solution, 15 mL/min) to obtain the solid title compound 1 (4 mg, yield 12%) after purification. m/z (ESI): 538[M+H] + . 1 H NMR (400MHz, DMSO) δ8.57(s, 1H), 8.03(s, 1H), 7.90(s, 1H), 7.66(d, J=8.2Hz, 2H), 7.42(d, J=8.2 Hz, 2H), 4.85(s, 2H), 4.26(t, J=6.6Hz, 2H), 3.83(s, 3H), 3.76(s, 3H), 3.69–3.61(m, 2H), 2.11(dd ,J=11.8,6.2Hz,2H),1.84–1.72(m,1H),1.02–0.91(m,2H),0.81(dd,J=8.0,3.2Hz,2H).
实施例2：2-(4-环丙基-6-甲氧基嘧啶-5-基)-5-甲基-9-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-5,7,8,9-四氢-6H-嘧啶并[4,5-b][1,4]重氮基庚英-6-酮(化合物2)Example 2: 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)
Figure PCTCN2022115739-appb-000037
Figure PCTCN2022115739-appb-000037
步骤1：2-氯-N-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-5-硝基嘧啶-4-胺(2B)Step 1: 2-Chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-nitropyrimidin-4-amine ( 2B)
室温下，将2,4-二氯-5-硝基嘧啶(708mg,3.65mmol)溶解于四氢呋喃中(20mL)，后加入二异丙基乙基胺(1.01g，7.84mmol，2.0eq),0℃搅拌下加入化合物1E(932mg,3.65mmol,1.0eq)。所得混合物在0℃反应0.5小时后缓慢恢复到室温，继续搅拌反应2小时。将反应液加入到冰水中(50mL)，用乙酸乙酯萃取(50mL*3)。所得有机相合并后用饱和食盐水洗涤(50mL)，减压蒸馏除去溶剂。将所得残留物用硅胶柱纯化(PE:EA＝5:1-3:1)制得化合物2B(900mg，收率59.7％)。m/z(ESI):413[M+H] +。 At room temperature, 2,4-dichloro-5-nitropyrimidine (708mg, 3.65mmol) was dissolved in tetrahydrofuran (20mL), and then diisopropylethylamine (1.01g, 7.84mmol, 2.0eq) was added, Compound 1E (932mg, 3.65mmol, 1.0eq) was added under stirring at 0°C. The obtained mixture was reacted at 0° C. for 0.5 hour and then slowly returned to room temperature, and the stirring reaction was continued for 2 hours. The reaction solution was added to ice water (50 mL), and extracted with ethyl acetate (50 mL*3). The obtained organic phases were combined and washed with saturated brine (50 mL), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column (PE:EA=5:1-3:1) to obtain compound 2B (900 mg, yield 59.7%). m/z (ESI): 413[M+H] + .
步骤2：2-氯-N4-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)嘧啶-4,5-二胺(2C)Step 2: 2-Chloro-N4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidine-4,5-diamine (2C)
室温下，将还原铁粉(676.5mg，12.11mmol,10eq)加入到水(5mL)和乙醇(5mL)中，后加入氯化铵(648mg,12.11mmol,10eq)，在100℃下搅拌反应1小时后加入化合物2B(500mg，1.211mmol)。所得混合物在80℃下继续搅拌反应1小时。于反应液中加入25mL乙酸乙酯稀释后趁热过滤，滤饼用乙酸乙酯淋洗。所得有机相用饱和食盐水洗涤(20mL)，减压蒸馏除去溶剂。将所得残留物用硅胶柱纯化(PE:EA＝1:1)制得化合物2C(0.35g，收率75.5％)。m/z(ESI):383[M+H] +。 At room temperature, reduced iron powder (676.5mg, 12.11mmol, 10eq) was added to water (5mL) and ethanol (5mL), then ammonium chloride (648mg, 12.11mmol, 10eq) was added, and the reaction was stirred at 100°C 1 Compound 2B (500 mg, 1.211 mmol) was added after 2 hours. The resulting mixture was stirred and reacted at 80° C. for 1 hour. Add 25 mL of ethyl acetate to the reaction solution for dilution, then filter while hot, and rinse the filter cake with ethyl acetate. The obtained organic phase was washed with saturated brine (20 mL), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column (PE:EA=1:1) to obtain compound 2C (0.35 g, yield 75.5%). m/z(ESI):383[M+H] + .
步骤3：3-氯-N-(2-氯-4-((4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)氨基)嘧啶-5-基)丙酰胺(2E)Step 3: 3-Chloro-N-(2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidine -5-yl)propionamide (2E)
室温下，将2C(500.0mg,1.3mmol)和碳酸钾(361.1mg,2.6mmol)加入到N-甲基吡咯烷酮(5mL)中，在0℃下搅拌加入2-氯丙酰氯(199.0mg,1.6mmol,149.6μL)。0℃下搅拌反应1小时后，将反应液加入到水中(20mL)中,并用乙酸乙酯萃取三次(10mL*3)。所得有机相合并后用饱和食盐水洗涤(50mL)，减压蒸馏除去溶剂。将所得残留物用硅胶柱纯化(PE:EA＝2:1-1:1)2E粗品500mg。m/z(ESI):473.0[M+H] +。 At room temperature, 2C (500.0 mg, 1.3 mmol) and potassium carbonate (361.1 mg, 2.6 mmol) were added to N-methylpyrrolidone (5 mL), and 2-chloropropionyl chloride (199.0 mg, 1.6 mmol, 149.6 μL). After stirring and reacting at 0°C for 1 hour, the reaction solution was added into water (20 mL), and extracted three times with ethyl acetate (10 mL*3). The obtained organic phases were combined and washed with saturated brine (50 mL), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column (PE:EA=2:1-1:1) 500 mg of crude 2E. m/z (ESI): 473.0 [M+H] + .
步骤4：2-氯-9-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-5,7,8,9-四氢-6H-嘧啶并[4,5-b][1,4]重氮基庚英-6-酮(2F)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)
室温下，将2E(500.0mg,粗品，约1.1mmol)加入到N,N-二甲基甲酰胺(40mL)中，后加入碳酸钾(292.0mg,2.1mmol)。所得混合物在60℃下搅拌反应2小时后，于反应液中加入100mL水，并用乙酸乙酯萃取三次(40mL*3)，所得有机相合并后用饱和食盐水洗涤(50mL)，减压蒸馏除去溶剂。将所得残留物用反相C18硅胶柱(乙腈:水＝1:3-3:1梯度洗脱)纯化得2F(127mg,收率28％)。m/z(ESI):437.1[M+H] +。 At room temperature, 2E (500.0 mg, crude product, about 1.1 mmol) was added to N,N-dimethylformamide (40 mL), followed by potassium carbonate (292.0 mg, 2.1 mmol). After the resulting mixture was stirred and reacted at 60°C for 2 hours, 100 mL of water was added to the reaction solution, and extracted three times with ethyl acetate (40 mL*3). The obtained organic phases were combined and washed with saturated brine (50 mL), and evaporated under reduced pressure. solvent. The obtained residue was purified by a reverse phase C18 silica gel column (acetonitrile:water=1:3-3:1 gradient elution) to obtain 2F (127 mg, yield 28%). m/z (ESI): 437.1 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ8.19(s,1H),7.92–7.88(m,1H),7.64(d,J＝8.3Hz,2H),7.35(d,J＝8.3Hz,2H),6.24(t,J＝3.1Hz,1H),5.18(s,2H),3.76(s,3H),3.72–3.65(m,2H),2.77–2.70(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.19(s, 1H), 7.92–7.88(m, 1H), 7.64(d, J=8.3Hz, 2H), 7.35(d, J=8.3Hz, 2H),6.24(t,J＝3.1Hz,1H),5.18(s,2H),3.76(s,3H),3.72–3.65(m,2H),2.77–2.70(m,2H).
步骤5：2-(4-环丙基-6-甲氧基嘧啶-5-基)-9-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-5,7,8,9-四氢-6H-嘧啶 并[4,5-b][1,4]重氮基庚英-6-酮(2G)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)
室温下，将1K(39.5mg,183.1μmol),2F(50.0mg,114.5μmol),氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(18.0mg,22.9μmol),磷酸钾(72.9mg,343.4μmol)加入到二氧六环(1mL)和水(0.01mL)的混合溶剂中，氮气保护下100℃搅拌反应4小时。所得混合物经C18反相硅胶柱(乙腈:水＝1:3-3:1梯度洗脱)纯化得2G(29mg,收率46％)。m/z(ESI):551.1[M+H] +。 At room temperature, 1K (39.5mg, 183.1μmol), 2F (50.0mg, 114.5μmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (18.0mg, 22.9μmol), potassium phosphate (72.9mg, 343.4μmol) was added to dioxane (1 mL) and water (0.01 mL) in a mixed solvent, stirred and reacted at 100° C. for 4 hours under nitrogen protection. The resulting mixture was purified by a C18 reverse-phase silica gel column (acetonitrile:water=1:3-3:1 gradient elution) to obtain 2G (29 mg, yield 46%). m/z (ESI): 551.1 [M+H] + .
步骤6：2-(4-环丙基-6-甲氧基嘧啶-5-基)-5-甲基-9-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-5,7,8,9-四氢-6H-嘧啶并[4,5-b][1,4]重氮基庚英-6-酮(化合物2)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)
将2G(8.0mg,14.5μmol)加入N,N-二甲基甲酰胺(1mL)中，0℃下加入氢化钠(697.5μg,17.4μmol,含量60％)，搅拌反应10min后再加入碘甲烷(2.1mg,14.5μmol,7.16μL)，继续反应20min。所得混合溶液经prep HPLC制备(Waters AutoP，Xbridge-C18，19*150mm，20-75％乙腈的水溶液梯度洗脱，15mL/min)得化合物2(3.0mg,收率37％)。m/z(ESI):565.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.63(s,1H),8.61(s,1H),7.90(s,1H),7.60(d,J＝8.3Hz,2H),7.34(d,J＝8.3Hz,2H),5.21(s,2H),3.81(s,3H),3.74(s,3H),3.65(t,J＝6.2Hz,2H),2.94(s,3H),2.69(t,J＝6.2Hz,2H),1.67(m,1H),1.00(m,2H),0.80(m,2H). Add 2G (8.0mg, 14.5μmol) into N,N-dimethylformamide (1mL), add sodium hydride (697.5μg, 17.4μmol, content 60%) at 0°C, stir for 10min and then add iodomethane (2.1mg, 14.5μmol, 7.16μL), continue to react for 20min. The resulting mixed solution was prepared by prep HPLC (Waters AutoP, Xbridge-C18, 19*150mm, gradient elution of 20-75% acetonitrile in water, 15mL/min) to obtain compound 2 (3.0 mg, yield 37%). m/z (ESI): 565.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.63(s, 1H), 8.61(s, 1H), 7.90(s, 1H), 7.60(d, J=8.3Hz, 2H), 7.34(d, J＝8.3Hz, 2H), 5.21(s, 2H), 3.81(s, 3H), 3.74(s, 3H), 3.65(t, J＝6.2Hz, 2H), 2.94(s, 3H), 2.69( t,J＝6.2Hz,2H),1.67(m,1H),1.00(m,2H),0.80(m,2H).
实施例3：2-(4-环丙基-6-甲氧基嘧啶-5-基)-11-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-7,8,9,9a-四氢-5H-嘧啶并[4,5-e]吡咯并[1,2-a][1,4]二氮杂卓-5,10(11H)-二酮(化合物3)Example 3: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-11-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2 -yl)benzyl)-7,8,9,9a-tetrahydro-5H-pyrimido[4,5-e]pyrrolo[1,2-a][1,4]diazepine-5 ,10(11H)-Diketone (Compound 3)
Figure PCTCN2022115739-appb-000038
Figure PCTCN2022115739-appb-000038
步骤1：2-氯-4-((4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)氨基)嘧啶-5-羧酸乙酯(3C)Step 1: Ethyl 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidine-5-carboxylate (3C)
将化合物3A(500mg,2.48mmol)加入N,N-二甲基甲酰胺(10mL)中，在0℃下分批加入NaH(119.04mg,2.98mmol,含量60％)后，再加入化合物3B(791.43mg,2.48mmol)。所得混合物在室温下搅拌反应2h。于反应液中加入10mL饱和氯化铵溶液淬灭反应，并用乙酸乙酯萃取(10mL×3)。所得有机相合并后用饱和食盐水洗涤(20mL)，减压蒸馏除去溶剂。将所得残留物用硅胶柱纯化(PE:EA＝5:1-1:1)过柱纯化制得化合物3C(400mg，收率36.7％)。m/z(ESI):440.0[M+H] +。 1H NMR(400MHz,Chloroform-d)δ8.77(br.s,1H),8.71(s,1H),7.63(d,J＝8.3Hz,2H),7.45(d,J＝8.3Hz,2H),7.32(s,1H),4.81(d,J＝5.8Hz,2H),4.36(q,J＝7.1Hz,2H),3.77(s,3H),1.39(t,J＝7.1Hz,3H). Compound 3A (500mg, 2.48mmol) was added to N,N-dimethylformamide (10mL), NaH (119.04mg, 2.98mmol, content 60%) was added in batches at 0°C, and then compound 3B ( 791.43 mg, 2.48 mmol). The resulting mixture was stirred at room temperature for 2 h. Add 10 mL of saturated ammonium chloride solution to the reaction solution to quench the reaction, and extract 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. The obtained residue was purified by silica gel column (PE:EA=5:1-1:1) to obtain compound 3C (400 mg, yield 36.7%). m/z (ESI): 440.0 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ8.77(br.s, 1H), 8.71(s, 1H), 7.63(d, J=8.3Hz, 2H), 7.45(d, J=8.3Hz, 2H ),7.32(s,1H),4.81(d,J=5.8Hz,2H),4.36(q,J=7.1Hz,2H),3.77(s,3H),1.39(t,J=7.1Hz,3H ).
步骤2：4'-环丙基-6'-甲氧基-4-((4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)氨基)-[2,5'-联嘧啶]-5-羧酸乙酯(3D)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)
室温下，将1K(135.85mg,700.29μmol)，3C(280mg,636.63μmol)，K 3PO 4(405.40mg,1.91mmol)，XPhos Pd G2(100.18mg,127.33μmol)加入到二氧六环(4mL)和H 2O(1mL)的混合溶剂中。所得混合物在氮气保护100℃下搅拌反应4h。减压蒸馏除去溶剂，将所得残留物用硅胶柱纯化(PE:EA＝5:1-1:2)过柱纯化制得化合物3D(270mg，收率76.6％)。m/z(ESI):554.2[M+H] +。 At room temperature, 1K (135.85 mg, 700.29 μmol), 3C (280 mg, 636.63 μmol), K 3 PO 4 (405.40 mg, 1.91 mmol), XPhos Pd G2 (100.18 mg, 127.33 μmol) were added to dioxane ( 4 mL) and H 2 O (1 mL) in a mixed solvent. The resulting mixture was stirred and reacted at 100° C. for 4 h under nitrogen protection. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column (PE:EA=5:1-1:2) to obtain compound 3D (270 mg, yield 76.6%). m/z (ESI): 554.2 [M+H] + .
步骤3：4'-环丙基-6'-甲氧基-4-((4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)氨基)-[2,5'-联嘧啶]-5-羧酸(3E)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)
室温下，将3D(100mg,180.66μmol)，氢氧化锂(12.98mg,541.97μmol)加入到甲醇(3mL)和0.5mL水中。所得溶液在60℃下搅拌反应2h。将反应液pH用盐酸调整到4，减压蒸馏除去溶剂，所得混合物经乙酸乙酯打浆并用水洗涤得白色固体3E(50mg,95.15μmol,收率52.67％)。m/z(ESI):526.1[M+H] +。 3D (100 mg, 180.66 μmol), lithium hydroxide (12.98 mg, 541.97 μmol) were added to methanol (3 mL) and 0.5 mL of water at room temperature. The resulting solution was stirred and reacted at 60 °C for 2 h. The pH of the reaction solution was adjusted to 4 with hydrochloric acid, and the solvent was distilled off under reduced pressure. The resulting mixture was slurried with ethyl acetate and washed with water to obtain a white solid 3E (50 mg, 95.15 μmol, yield 52.67%). m/z (ESI): 526.1 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ9.13(br.s,1H),8.85(s,1H),8.63(s,1H),7.92(s,1H),7.65(d,J＝8.3Hz,2H),7.44(d,J＝8.3Hz,2H),4.78(d,J＝6.1Hz,2H),3.83(s,3H),3.76(s,3H),1.77–1.67(m,1H),1.03–0.92(m,2H),0.83–0.76(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ9.13(br.s,1H),8.85(s,1H),8.63(s,1H),7.92(s,1H),7.65(d,J=8.3 Hz, 2H), 7.44(d, J=8.3Hz, 2H), 4.78(d, J=6.1Hz, 2H), 3.83(s, 3H), 3.76(s, 3H), 1.77–1.67(m, 1H ),1.03–0.92(m,2H),0.83–0.76(m,2H).
步骤4：(4'-环丙基-6'-甲氧基-4-((4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)氨基)-[2,5'-联嘧啶]-5-羰基)脯氨酸甲酯(3G)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)
将3E(80.0mg,152.2μmol)，N,N-二异丙基乙胺(78.7mg,608.9μmol,106.1μL)，2-(7-氮杂苯并三氮 唑)-N,N,N',N'-四甲基脲六氟磷酸酯(68.9mg,182.7μmol)加入到二氯甲烷(2mL)中，然后加入3F(30.3mg,182.7μmol)。所的混合物在室温下搅拌反应2小时。减压蒸馏除去溶剂，将所得残留物用硅胶柱纯化(PE:EA＝5:1-1:2)过柱纯化制得化合物3G(90mg,收率93％)。m/z(ESI):637.2[M+H] +。 3E (80.0mg, 152.2μmol), N,N-diisopropylethylamine (78.7mg, 608.9μmol, 106.1μL), 2-(7-azabenzotriazole)-N,N,N ',N'-Tetramethylurea hexafluorophosphate (68.9 mg, 182.7 μmol) was added to dichloromethane (2 mL), followed by 3F (30.3 mg, 182.7 μmol). The resulting mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column (PE:EA=5:1-1:2) to obtain compound 3G (90 mg, yield 93%). m/z (ESI): 637.2[M+H] + .
步骤5：(4'-环丙基-6'-甲氧基-4-((4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)氨基)-[2,5'-联嘧啶]-5-羰基)脯氨酸(3H)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)
将3G(130.0mg,204.2μmol)，氢氧化锂(13.0mg,543μmol)，加入到甲醇(3mL)和水(0.2mL)中。所得溶液在室温下反应2小时，将反应液pH用盐酸调整到4，减压蒸馏除去溶剂，所得残余物用反相C18硅胶柱(乙腈:水＝1:9-2:1梯度洗脱)纯化得化合物3H(45mg,收率35％)。m/z(ESI):623.1[M+H] +。 3G (130.0 mg, 204.2 μmol), lithium hydroxide (13.0 mg, 543 μmol), were added to methanol (3 mL) and water (0.2 mL). The resulting solution was reacted at room temperature for 2 hours, the pH of the reaction solution was adjusted to 4 with hydrochloric acid, the solvent was distilled off under reduced pressure, and the obtained residue was eluted with a reverse-phase C18 silica gel column (acetonitrile:water=1:9-2:1 gradient elution) Compound 3H (45 mg, yield 35%) was purified. m/z (ESI): 623.1 [M+H] + .
步骤6：2-(4-环丙基-6-甲氧基嘧啶-5-基)-11-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-7,8,9,9a-四氢-5H-嘧啶并[4,5-e]吡咯并[1,2-a][1,4]二氮杂卓-5,10(11H)-二酮(化合物3)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)
将3H(40.0mg,64.3μmol)，N,N-二异丙基乙胺(33.2mg,257.0μmol,44.8μL)，HATU(29.1mg,77.1μmol)加入到二氯甲烷(2mL)中。所得混合物经减压蒸馏，残余物经prep HPLC制备(Waters AutoP，Xbridge-C18，19*150mm，20-75％乙腈的水溶液梯度洗脱，15mL/min)得化合物3(15mg,收率39％)。m/z(ESI):605.2[M+H] +。 3H (40.0 mg, 64.3 μmol), N,N-diisopropylethylamine (33.2 mg, 257.0 μmol, 44.8 μL), HATU (29.1 mg, 77.1 μmol) were added to dichloromethane (2 mL). The resulting mixture was distilled under reduced pressure, and the residue was prepared by prep HPLC (Waters AutoP, Xbridge-C18, 19*150mm, gradient elution of 20-75% acetonitrile in water, 15mL/min) to obtain compound 3 (15mg, yield 39% ). m/z(ESI):605.2[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ9.22(s,1H),8.68(s,1H),7.91(s,1H),7.61(d,J＝8.2Hz,2H),7.35(d,J＝8.2Hz,2H),5.39(d,J＝15.7Hz,1H),5.26(d,J＝15.6Hz,1H),4.71(dd,J＝7.7,2.1Hz,1H),3.84(s,3H),3.74(s,3H),3.67(m,1H),3.55(m,1H),2.13–1.86(m,4H),1.80(m,1H),1.07–1.01(m,2H),0.88–0.83(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ9.22(s, 1H), 8.68(s, 1H), 7.91(s, 1H), 7.61(d, J=8.2Hz, 2H), 7.35(d, J＝8.2Hz, 2H), 5.39(d, J＝15.7Hz, 1H), 5.26(d, J＝15.6Hz, 1H), 4.71(dd, J＝7.7, 2.1Hz, 1H), 3.84(s, 3H),3.74(s,3H),3.67(m,1H),3.55(m,1H),2.13–1.86(m,4H),1.80(m,1H),1.07–1.01(m,2H),0.88 –0.83(m,2H).
实施例4：2'-(4-环丙基-6-甲氧基嘧啶-5-基)-6'-甲基-9'-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)螺[环丙烷-1,7'-嘧啶并[4,5-e][1,4]二氮杂卓]-5',8'(6'H,9'H)-二酮(化合物4)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)
Figure PCTCN2022115739-appb-000039
Figure PCTCN2022115739-appb-000039
采用化合物3的类似的合成步骤和操作，将步骤4中的3F替换为4A，可制得化合物4。m/z(ESI):605.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.10(s,1H),8.61(s,1H),7.85(d,J＝1.3Hz,1H),7.56(d,J＝8.3Hz,2H),7.20(d,J＝8.1Hz,2H),5.28–5.13(m,2H),3.78(s,3H),3.68(s,3H),3.02(s,3H),1.66(tt,J＝8.1,4.6Hz,1H),1.44(dt,J＝10.7,6.8Hz,1H),1.32(dt,J＝10.2,6.9Hz,1H),1.19–1.05(m,1H),0.96(s,2H),0.81(dd,J＝7.9,3.4Hz,2H). Using the similar synthesis steps and operations of compound 3, replacing 3F in step 4 with 4A, compound 4 can be prepared. m/z(ESI):605.2[M+H] + . 1 H NMR (400MHz,DMSO-d 6 )δ9.10(s,1H),8.61(s,1H),7.85(d,J=1.3Hz,1H),7.56(d,J=8.3Hz,2H) ,7.20(d,J=8.1Hz,2H),5.28–5.13(m,2H),3.78(s,3H),3.68(s,3H),3.02(s,3H),1.66(tt,J=8.1 ,4.6Hz,1H),1.44(dt,J＝10.7,6.8Hz,1H),1.32(dt,J＝10.2,6.9Hz,1H),1.19–1.05(m,1H),0.96(s,2H) ,0.81(dd,J=7.9,3.4Hz,2H).
Figure PCTCN2022115739-appb-000040
Figure PCTCN2022115739-appb-000040
实施例5：2'-(4-环丙基-6-甲氧基嘧啶-5-基)-9'-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-5',9'-二氢螺[环丙烷-1,7'-嘧啶并[4,5-b][1,4]二氮杂
Figure PCTCN2022115739-appb-000041
]-8'(6'H)-酮(化合物5) Example 5: 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]diazepine
Figure PCTCN2022115739-appb-000041
]-8'(6'H)-one (compound 5)
Figure PCTCN2022115739-appb-000042
Figure PCTCN2022115739-appb-000042
步骤1：N-(5-氨基-2-氯嘧啶-4-基)-1-(氯甲基)-N-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)环丙烷-1-甲酰胺(5B)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)
将化合物5A(200.0mg,1.7mmol)加入氯化亚砜(2mL)中，加热至80℃反应2h。所得溶液经过减压蒸馏后，残留物用二氯甲烷(1mL)溶解后，在-20℃下缓慢滴加到加入了N,N-二异丙基乙胺(445.2mg,3.4mmol)和 2C(659.3mg,1.7mmol)的二氯甲烷(5mL)溶液中。所的混合物保持-20℃继续反应1h，减压蒸馏除去溶剂，将所得残留物用硅胶柱纯化(PE:EA＝5:1-1:1)制得5B粗品190mg。Compound 5A (200.0 mg, 1.7 mmol) was added into thionyl chloride (2 mL), heated to 80° C. for 2 h. After the resulting solution was distilled under reduced pressure, the residue was dissolved in dichloromethane (1 mL), and slowly added dropwise at -20°C to N,N-diisopropylethylamine (445.2 mg, 3.4 mmol) and 2C (659.3mg, 1.7mmol) in dichloromethane (5mL) solution. The resulting mixture was kept at -20°C to continue the reaction for 1 h, the solvent was distilled off under reduced pressure, and the resulting residue was purified by a silica gel column (PE:EA=5:1-1:1) to obtain 190 mg of crude product 5B.
步骤2：2'-氯-9'-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-5',9'-二氢螺[环丙烷-1,7'-嘧啶并[4,5-b][1,4]重氮基庚英]-8'(6'H)-酮(5C)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)
室温下，将5B(180.0mg,360.5μmol)，碳酸钾(99.6mg,721.0μmol)加入N,N-二甲基甲酰胺(10mL)中，反应液在50℃下搅拌反应2h。将反应液加入到水中(30mL)，用乙酸乙酯萃取(20mL×3)。所得有机相合并后用饱和食盐水洗涤(20mL)，减压蒸馏除去溶剂得5C粗品180mg。m/z(ESI):463.0[M+H] +。 At room temperature, 5B (180.0 mg, 360.5 μmol) and potassium carbonate (99.6 mg, 721.0 μmol) were added to N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 50° C. for 2 h. The reaction solution was added to water (30 mL), and extracted with ethyl acetate (20 mL×3). The obtained organic phases were combined and washed with saturated brine (20 mL), and the solvent was distilled off under reduced pressure to obtain 180 mg of crude 5C. m/z (ESI): 463.0 [M+H] + .
步骤3：2'-(4-环丙基-6-甲氧基嘧啶-5-基)-9'-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-5',9'-二氢螺[环丙烷-1,7'-嘧啶并[4,5-b][1,4]重氮基庚英]-8'(6'H)-酮(化合物5)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)
室温下，将1K(150.9mg,777.8μmol),5C(180.0mg,388.9μmol),XPhos Pd G2(61.2mg,77.8μmol),磷酸钾(247.6mg,1.2mmol)加入到水(0.1mL)和二氧六环(2mL)的混合溶液中，氮气保护下100℃反应4小时，所得反应液经反相C18硅胶柱(乙腈:水＝1:9-2:1梯度洗脱)纯化得化合物5。(150mg,收率67％)。m/z(ESI):577.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.60(s,1H),8.39(s,1H),7.91(s,1H),7.61(d,J＝8.1Hz,2H),7.30(d,J＝8.0Hz,2H),6.42(t,J＝3.2Hz,1H),5.26(s,2H),3.81(s,3H),3.75(s,3H),3.53(d,J＝3.2Hz,2H),1.62(m,1H),0.97(s,4H),0.79(m,4H). At room temperature, 1K (150.9 mg, 777.8 μmol), 5C (180.0 mg, 388.9 μmol), XPhos Pd G2 (61.2 mg, 77.8 μmol), potassium phosphate (247.6 mg, 1.2 mmol) were added to water (0.1 mL) and In a mixed solution of dioxane (2 mL), react at 100° C. for 4 hours under nitrogen protection, and the resulting reaction solution is purified by a reverse-phase C18 silica gel column (acetonitrile:water=1:9-2:1 gradient elution) to obtain compound 5 . (150mg, yield 67%). m/z (ESI): 577.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.60(s, 1H), 8.39(s, 1H), 7.91(s, 1H), 7.61(d, J=8.1Hz, 2H), 7.30(d, J=8.0Hz, 2H), 6.42(t, J=3.2Hz, 1H), 5.26(s, 2H), 3.81(s, 3H), 3.75(s, 3H), 3.53(d, J=3.2Hz, 2H), 1.62(m, 1H), 0.97(s, 4H), 0.79(m, 4H).
实施例6：2'-(4-环丙基-6-甲氧基嘧啶-5-基)-5'-甲基-9'-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-5',9'-二氢螺[环丙烷-1,7'-嘧啶并[4,5-b][1,4]二氮杂
Figure PCTCN2022115739-appb-000043
]-8'(6'H)-酮(化合物6) 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
Figure PCTCN2022115739-appb-000043
]-8'(6'H)-one (Compound 6)
Figure PCTCN2022115739-appb-000044
Figure PCTCN2022115739-appb-000044
向反应瓶中加入化合物5(58.0mg,100.6μmol)，1,8-二氮杂双环[5.4.0]十一碳-7-烯(30.6mg,201.2μmol,30.0μL)，用N’N-二甲基甲酰胺(2mL)溶解，滴加碘甲烷(14.3mg,100.6μmol,6.3μL)。所得混合物在60℃下反应16h。混合物直接经prep HPLC制备(Waters AutoP，Xbridge-C18，19*150mm，20-75％乙腈的水溶液梯度洗脱，15mL/min)得化合物6(10mg,收率17％)。m/z(ESI):591.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.78(s,1H),8.48(s,1H),7.93(s,1H),7.56(d,J＝8.3Hz,2H),7.24(d,J＝8.2Hz,2H),5.33(d,J＝15.5Hz,1H),5.17(d,J＝15.6Hz,1H),3.87(s,3H),3.86(s,3H),3.73(s,3H),3.67–3.52(m,2H),1.73(m,1H),1.04(s,4H),0.86–0.81(m,4H). Add compound 5 (58.0mg, 100.6μmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (30.6mg, 201.2μmol, 30.0μL) to the reaction flask, and use N'N - Dimethylformamide (2 mL) was dissolved and iodomethane (14.3 mg, 100.6 μmol, 6.3 μL) was added dropwise. The resulting mixture was reacted at 60 °C for 16 h. The mixture was directly prepared by prep HPLC (Waters AutoP, Xbridge-C18, 19*150mm, gradient elution of 20-75% acetonitrile in water, 15mL/min) to obtain compound 6 (10 mg, yield 17%). m/z (ESI): 591.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.78(s, 1H), 8.48(s, 1H), 7.93(s, 1H), 7.56(d, J=8.3Hz, 2H), 7.24(d, J＝8.2Hz, 2H), 5.33(d, J＝15.5Hz, 1H), 5.17(d, J＝15.6Hz, 1H), 3.87(s, 3H), 3.86(s, 3H), 3.73(s, 3H),3.67–3.52(m,2H),1.73(m,1H),1.04(s,4H),0.86–0.81(m,4H).
实施例7：2'-(4-环丙基-6-甲氧基嘧啶-5-基)-5'-甲基-9'-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-8',9'-二氢螺[环丙烷-1,7'-嘧啶并[4,5-b][1,4]二氮杂
Figure PCTCN2022115739-appb-000045
]-6'(5'H)-酮(化合物7) 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
Figure PCTCN2022115739-appb-000045
]-6'(5'H)-one (compound 7)
Figure PCTCN2022115739-appb-000046
Figure PCTCN2022115739-appb-000046
步骤1：1-(((4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)氨基)甲基)环丙烷-1-羧酸乙酯(7B)Step 1: Ethyl 1-(((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)methyl)cyclopropane-1-carboxylate Esters (7B)
将3B(2.2g,7.0mmol)，7A(1.0g,7.0mmol)，N’N-二异丙基乙胺(2.7g,21.0mmol,3.7mL)加入二氧六环(10mL)中。所得混合物在90℃下反应2h。减压旋蒸除去溶剂，所得残留物用硅胶柱纯化(PE:EA＝3:1-1:2)过柱纯化制得7B(1.2g,收率46％)。m/z(ESI):382.1[M+H] +。 3B (2.2 g, 7.0 mmol), 7A (1.0 g, 7.0 mmol), N'N-diisopropylethylamine (2.7 g, 21.0 mmol, 3.7 mL) were added to dioxane (10 mL). The resulting mixture was reacted at 90 °C for 2 h. The solvent was removed by rotary evaporation under reduced pressure, and the obtained residue was purified by silica gel column (PE:EA=3:1-1:2) to obtain 7B (1.2 g, yield 46%). m/z (ESI): 382.1 [M+H] + .
步骤2：1-(((2-氯-5-硝基嘧啶-4-基)(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)氨基)甲基)环丙烷-1-羧酸乙酯(7C)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)
将7B(1.1g,2.9mmol)，N’N-二异丙基乙胺(1.2g,8.9mmol,1.6mL)溶解于二氧六环(20mL)中，在-20℃下加入2A(574.7mg,2.9mmol)。所得混合物在该温度下反应2h。减压旋蒸除去溶剂，所得残留物用硅胶柱纯化(PE:EA＝3:1-1:2)过柱纯化制得7C(1.4g,收率89％)。m/z(ESI):539.1[M+H] +。 7B (1.1g, 2.9mmol), N'N-diisopropylethylamine (1.2g, 8.9mmol, 1.6mL) was dissolved in dioxane (20mL), and 2A (574.7 mg, 2.9mmol). The resulting mixture was reacted at this temperature for 2 h. The solvent was removed by rotary evaporation under reduced pressure, and the obtained residue was purified by silica gel column (PE:EA=3:1-1:2) to obtain 7C (1.4 g, yield 89%). m/z (ESI): 539.1 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ8.94(s,1H),7.94(s 1H),7.68(d,J＝8.3Hz,2H),7.37(d,J＝8.2Hz,2H),4.94(s,2H),3.91(q,J＝7.1Hz,2H),3.77(s,3H),3.65(s,2H),1.13(m,2H),1.00(m,2H),0.93(t,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.94(s, 1H), 7.94(s 1H), 7.68(d, J=8.3Hz, 2H), 7.37(d, J=8.2Hz, 2H), 4.94(s,2H),3.91(q,J=7.1Hz,2H),3.77(s,3H),3.65(s,2H),1.13(m,2H),1.00(m,2H),0.93(t ,J＝7.1Hz,3H).
步骤3：1-(((4'-环丙基-6'-甲氧基-5-硝基-[2,5'-联嘧啶]-4-基)(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)氨基)甲基)环丙烷-1-羧酸乙酯(7D)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)
室温下，将7C(600.0mg,1.1mmol)，1K(432.0mg,2.2mmol)，1,3,5,7-四甲基-8-苯基-2,4,6-三氧杂-8-磷金刚烷(65.2mg,222.7μmol)，三(二亚苄基丙酮)二钯(203.9mg,222.7μmol)，碳酸钾(307.7mg,2.2mmol)加入到水(0.1mL)和二氧六环(2mL)的混合溶剂中。所得混合物在氮气保护下70℃搅拌反应4h。减压旋蒸除去溶剂，所得残留物用硅胶柱纯化(PE:EA＝3:1-0:1)过柱纯化制得7D(207mg,收率57％)。m/z(ESI):653.2[M+H] +。 At room temperature, 7C (600.0mg, 1.1mmol), 1K (432.0mg, 2.2mmol), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8 - Phosphoadamantane (65.2 mg, 222.7 μmol), tris(dibenzylideneacetone) dipalladium (203.9 mg, 222.7 μmol), potassium carbonate (307.7 mg, 2.2 mmol) were added to water (0.1 mL) and dioxane Ring (2mL) in the mixed solvent. The resulting mixture was stirred and reacted at 70° C. for 4 h under the protection of nitrogen. The solvent was removed by rotary evaporation under reduced pressure, and the obtained residue was purified by silica gel column (PE:EA=3:1-0:1) to obtain 7D (207 mg, yield 57%). m/z (ESI): 653.2[M+H] + .
步骤4：2'-(4-环丙基-6-甲氧基嘧啶-5-基)-9'-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-8',9'-二氢螺[环丙烷-1,7'-嘧啶并[4,5-b][1,4]重氮基庚英]-6'(5'H)-酮(7E)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)
室温下，将铁粉(34.2mg,612.9μmol)加入到醋酸(3mL)中，再加入7D(80.0mg,122.6μmol)。所得混合物在90℃下反应2h。减压旋蒸除去过量的乙酸，并用碳酸氢钠水溶液调节pH到5-6，经乙酸乙酯(10mL×3)萃取。所得有机相合并后用饱和食盐水洗涤(20mL)，减压蒸馏除去溶剂。将所得残留物用反相C18硅胶柱(乙腈:水＝1:9-2:1梯度洗脱)纯化制得化合物7E(70mg，粗品)。m/z(ESI):577.2[M+H] +。 Iron powder (34.2 mg, 612.9 μmol) was added to acetic acid (3 mL) at room temperature, followed by 7D (80.0 mg, 122.6 μmol). 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. The obtained residue was purified by a reverse phase C18 silica gel column (acetonitrile:water=1:9-2:1 gradient elution) to obtain compound 7E (70 mg, crude product). m/z (ESI): 577.2 [M+H] + .
步骤5：2'-(4-环丙基-6-甲氧基嘧啶-5-基)-5'-甲基-9'-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-8',9'-二氢螺[环丙烷-1,7'-嘧啶并[4,5-b][1,4]二氮杂
Figure PCTCN2022115739-appb-000047
]-6'(5'H)-酮(7) 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
Figure PCTCN2022115739-appb-000047
]-6'(5'H)-one (7)
室温下，将7E(60.0mg,104.1μmol),氢化钠(5.0mg,124.9μmol,含量60％)加入到N’N-二甲基甲酰胺(2mL)中，加入碘甲烷(14.8mg,104.1μmol,6.5μL)。所的混合物在室温下继续反应1h。反应液加饱和氯化钠水溶液淬灭(6mL)，并用乙酸乙酯(6mL×3)萃取，合并有机相，减压旋蒸所得粗品经prep HPLC制备(Waters AutoP，Xbridge-C18，19*150mm，20-75％乙腈的水溶液梯度洗脱，15mL/min)得化合物7(18mg,收率29％)。m/z(ESI):591.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.61(s,1H),8.36(s,1H),7.93(s,1H),7.67(d,J＝8.3Hz,2H),7.42(d,J＝8.2Hz,2H),4.86(s,2H),3.87(s,3H),3.76(s,3H),3.60(s,2H),3.28(s,3H),1.81(m,1H),1.00(m,4H),0.88(m,2H),0.60–0.53(m,2H). At room temperature, 7E (60.0mg, 104.1μmol), sodium hydride (5.0mg, 124.9μmol, content 60%) was added to N'N-dimethylformamide (2mL), and iodomethane (14.8mg, 104.1 μmol, 6.5μL). The resulting mixture was continued to react at room temperature for 1 h. The 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%). m/z (ESI): 591.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.61(s, 1H), 8.36(s, 1H), 7.93(s, 1H), 7.67(d, J=8.3Hz, 2H), 7.42(d, J＝8.2Hz, 2H), 4.86(s, 2H), 3.87(s, 3H), 3.76(s, 3H), 3.60(s, 2H), 3.28(s, 3H), 1.81(m, 1H), 1.00(m,4H),0.88(m,2H),0.60–0.53(m,2H).
实施例8：2-(4-环丙基-6-甲氧基嘧啶-5-基)-7,7-二氟-5-甲基-9-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-5,7,8,9-四氢-6H-嘧啶[4,5-b][1,4]二氮卓-6-酮(化合物8)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)
Figure PCTCN2022115739-appb-000048
Figure PCTCN2022115739-appb-000048
步骤1：2,2-二氟-3-((4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)氨基)丙酸乙酯(8C)Step 1: Ethyl 2,2-difluoro-3-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)propanoate ( 8C)
室温下，将8B(352.8mg,1.9mmol)和8A(473.0mg,1.9mmol)溶解于二氯甲烷(20mL)中。所得溶液在0度下加入三乙酰氧基硼氢化钠(1.2g,5.6mmol)，并在0℃搅拌反应2小时。减压旋蒸除去溶剂，所得残留物用硅胶柱纯化(PE:EA＝3:1-0:1)过柱纯化制得8C(580mg,收率80％)。m/z(ESI):392.1[M+H] +. 8B (352.8 mg, 1.9 mmol) and 8A (473.0 mg, 1.9 mmol) were dissolved in dichloromethane (20 mL) at room temperature. Sodium triacetoxyborohydride (1.2 g, 5.6 mmol) was added to the resulting solution at 0°C, and the reaction was stirred at 0°C for 2 hours. The solvent was removed by rotary evaporation under reduced pressure, and the obtained residue was purified by silica gel column (PE:EA=3:1-0:1) to obtain 8C (580 mg, yield 80%). m/z(ESI):392.1[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.95–7.91(m,1H),7.67(d,J＝8.3Hz,2H),7.44(d,J＝8.3Hz,2H),4.30(q,J＝7.1Hz,2H),3.80(s,2H),3.78(s,3H),3.15(t,J＝14.1Hz,2H),1.25(d,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO-d 6 )δ7.95–7.91(m,1H),7.67(d,J=8.3Hz,2H),7.44(d,J=8.3Hz,2H),4.30(q, J=7.1Hz, 2H), 3.80(s, 2H), 3.78(s, 3H), 3.15(t, J=14.1Hz, 2H), 1.25(d, J=7.1Hz, 3H).
参照化合物7合成中步骤2-4类似的方法和操作，可以合成化合物8D。m/z(ESI):587.2。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.
参照化合物7合成中步骤5类似的方法和操作，可以合成化合物8。m/z(ESI):601.2。Referring to the method and operation similar to step 5 in the synthesis of compound 7, compound 8 can be synthesized. m/z (ESI): 601.2.
1H NMR(400MHz,DMSO-d 6)δ8.64(s,1H),8.62(s,1H),7.95–7.93(m,1H),7.69(d,J＝8.3Hz,2H),7.42(d, J＝8.3Hz,2H),4.97(s,2H),4.23(t,J＝12.9Hz,2H),3.84(s,3H),3.77(s,3H),3.46(s,3H),1.72(m,1H),0.99(m,2H),0.83(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.64(s, 1H), 8.62(s, 1H), 7.95–7.93(m, 1H), 7.69(d, J=8.3Hz, 2H), 7.42( d, J＝8.3Hz, 2H), 4.97(s, 2H), 4.23(t, J＝12.9Hz, 2H), 3.84(s, 3H), 3.77(s, 3H), 3.46(s, 3H), 1.72(m,1H),0.99(m,2H),0.83(m,2H).
实施例9：5-环丙基-2-(4-环丙基-6-甲氧基嘧啶-5-基)-7,7-二氟-9-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-5,7,8,9-四氢-6H-嘧啶[4,5-b][1,4]二氮卓-6-酮(化合物9)Example 9: 5-cyclopropyl-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7,7-difluoro-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-keto (Compound 9)
Figure PCTCN2022115739-appb-000049
Figure PCTCN2022115739-appb-000049
将8D(60.0mg,102.3μmol)，环丙基硼酸(17.6mg,204.6μmol)，吡啶(8.1mg,102.3μmol,8.2μL)，醋酸铜(18.6mg,102.3μmol)，碳酸铯(16.7mg,51.2μmol)混合于甲苯(10.0mL)中。所得混合反应液在80℃氧气氛围下搅拌反应4h。减压浓缩所得残余物经prep HPLC制备(Waters AutoP，Xbridge-C18，19*150mm，20-80％乙腈的水溶液梯度洗脱，15mL/min)得化合物9(10mg,收率16％)。m/z(ESI):627.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.70(s,1H),8.62(s,1H),7.94(s,1H),7.68(d,J＝8.2Hz,2H),7.38(d,J＝8.2Hz,2H),4.94(s,2H),4.20(t,J＝12.6Hz,2H),3.84(s,3H),3.76(s,3H),3.42(m,1H),1.67(m,1H),1.06–0.93(m,4H),0.83(m,2H),0.59–0.51(m,2H). 8D (60.0mg, 102.3μmol), cyclopropylboronic acid (17.6mg, 204.6μmol), pyridine (8.1mg, 102.3μmol, 8.2μL), copper acetate (18.6mg, 102.3μmol), cesium carbonate (16.7mg, 51.2 μmol) was mixed in toluene (10.0 mL). The resulting mixed reaction solution was stirred and reacted for 4 h at 80° C. under an oxygen atmosphere. The resulting residue was concentrated under reduced pressure and prepared by prep HPLC (Waters AutoP, Xbridge-C18, 19*150mm, gradient elution of 20-80% acetonitrile in water, 15mL/min) to obtain compound 9 (10 mg, yield 16%). m/z (ESI): 627.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.70(s, 1H), 8.62(s, 1H), 7.94(s, 1H), 7.68(d, J=8.2Hz, 2H), 7.38(d, J＝8.2Hz, 2H), 4.94(s, 2H), 4.20(t, J＝12.6Hz, 2H), 3.84(s, 3H), 3.76(s, 3H), 3.42(m, 1H), 1.67( m,1H),1.06–0.93(m,4H),0.83(m,2H),0.59–0.51(m,2H).
实施例10：2'-(4-环丙基-6-甲氧基嘧啶-5-基)-9'-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-8',9'-二氢螺[环丁烷-1,5'-嘧啶并[4,5-e][1,4]二氮
Figure PCTCN2022115739-appb-000050
]-7'(6'H)-酮(化合物10) 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
Figure PCTCN2022115739-appb-000050
]-7'(6'H)-one (Compound 10)
Figure PCTCN2022115739-appb-000051
Figure PCTCN2022115739-appb-000051
步骤1：N-环亚丁基-2-甲基丙烷-2-亚磺酰胺(10C)Step 1: N-Cyclobutylene-2-methylpropane-2-sulfinamide (10C)
将10A(10.0g,142.0mmol)和10B(15.7g,130mmol)溶于四氢呋喃(100mL)中，加入钛酸四乙酯(88.8g,389.0mmol)。所得混合物于50℃下反应5h。向反应液中加入冰水(200mL)和乙酸乙酯(200mL)，然后再加入饱和碳酸氢钠(40.0mL)，继续搅拌1h。将混合物过滤，滤饼用乙酸乙酯洗涤，滤液用无水硫酸钠干燥，过滤，浓缩。所得粗品经硅胶柱纯化(石油醚：乙酸乙酯＝10:1-3:1)10C(13g,收率58％)。10A (10.0 g, 142.0 mmol) and 10B (15.7 g, 130 mmol) were dissolved in tetrahydrofuran (100 mL), and tetraethyl titanate (88.8 g, 389.0 mmol) was added. The resulting mixture was reacted at 50 °C for 5 h. Ice water (200 mL) and ethyl acetate (200 mL) were added to the reaction solution, and then saturated sodium bicarbonate (40.0 mL) was added, and stirring was continued for 1 h. The mixture was filtered, the filter cake was washed with ethyl acetate, the filtrate was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by silica gel column (petroleum ether:ethyl acetate=10:1-3:1) 10C (13g, yield 58%).
步骤2：N-(1-(2-氯-4-(甲硫基)嘧啶-5-基)环丁基)-2-甲基丙烷-2-亚磺酰胺(10E)Step 2: N-(1-(2-Chloro-4-(methylthio)pyrimidin-5-yl)cyclobutyl)-2-methylpropane-2-sulfinamide (10E)
将10D(1.5g,6.4mmol)溶于甲苯(12.0mL)中，氮气置换3次，于-78℃下逐滴加入正丁基锂(1.6M,4.7mL)，-78℃下反应5分钟，然后缓慢加入10C(1.0g,5.8mmol)的甲苯(12.0mL)溶液。所得反应液于-78℃下搅拌反应30分钟。将反应液直接浓缩旋干，所得粗品经硅胶柱纯化(二氯甲烷：甲醇＝100:1-10:1)得到化合物10E(0.9g,收率47％)。m/z(ESI):334.1[M+H] +。 Dissolve 10D (1.5g, 6.4mmol) in toluene (12.0mL), replace with nitrogen three times, add n-butyllithium (1.6M, 4.7mL) dropwise at -78°C, and react at -78°C for 5 minutes , then a solution of 10C (1.0 g, 5.8 mmol) in toluene (12.0 mL) was added slowly. The resulting reaction solution was stirred and reacted at -78°C for 30 minutes. The reaction solution was directly concentrated and spin-dried, and the obtained crude product was purified by silica gel column (dichloromethane:methanol=100:1-10:1) to obtain compound 10E (0.9 g, yield 47%). m/z (ESI): 334.1 [M+H] + .
步骤3：1-(2-氯-4-(甲硫基)嘧啶-5-基)环丁烷-1-胺(10F)Step 3: 1-(2-Chloro-4-(methylthio)pyrimidin-5-yl)cyclobutane-1-amine (10F)
将10E(300.0mg,898.0μmol)溶于盐酸-乙酸乙酯(2.0mol/L，3.0mL)中，于室温反应1h。反应液中加入乙酸乙酯(5.0mL)稀释，然后加入水(15.0mL)，搅拌后分离水相。将水相用饱和碳酸氢钠溶液调节到pH＝8,再用乙酸乙酯(10.0mL*3)萃取。所得有机相合并后经无水硫酸钠干燥，过滤，浓缩后得到粗品10F(300mg,粗品)。10E (300.0 mg, 898.0 μmol) was dissolved in hydrochloric acid-ethyl acetate (2.0 mol/L, 3.0 mL), and reacted at room temperature for 1 h. Ethyl acetate (5.0 mL) was added to the reaction solution for dilution, and then water (15.0 mL) was added, and the aqueous phase was separated after stirring. The aqueous phase was adjusted to pH=8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (10.0 mL*3). The obtained organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 10F (300 mg, crude product).
步骤4：(1-(2-氯-4-(甲硫基)嘧啶-5-基)环丁基)氨基甲酸叔丁酯(10G)Step 4: tert-butyl (1-(2-chloro-4-(methylthio)pyrimidin-5-yl)cyclobutyl)carbamate (10G)
将10F(300.0mg,1.3mmol)溶于二氯甲烷(3.0mL)中，再加入N,N-二异丙基乙胺(422.0mg,568.0μL)和二碳酸二叔丁酯(570.0mg,600.0μL)。所得混合溶液于室温反应2h。将反应液直接浓缩，所得粗品经硅胶柱纯化(PE:EA＝100:1-10:1)得到10G(280mg,收率65％)。m/z(ESI):330.1[M+H] +。 Dissolve 10F (300.0mg, 1.3mmol) in dichloromethane (3.0mL), then add N,N-diisopropylethylamine (422.0mg, 568.0μL) and di-tert-butyl dicarbonate (570.0mg, 600.0 μL). The resulting mixed solution was reacted at room temperature for 2 h. The reaction solution was directly concentrated, and the obtained crude product was purified by silica gel column (PE:EA=100:1-10:1) to obtain 10G (280 mg, yield 65%). m/z (ESI): 330.1 [M+H] + .
步骤5：(1-(2-氯-4-(甲磺酰)嘧啶-5-基)环丁基)氨基甲酸叔丁酯(10H)Step 5: tert-butyl (1-(2-chloro-4-(methylsulfonyl)pyrimidin-5-yl)cyclobutyl)carbamate (10H)
将10G(280.0mg,848.0μmol)溶于二氯甲烷(3.0mL)中，加入间氯过氧苯甲酸(465.0mg,2.3mmol)。所得混合物于室温下反应3h。反应液中加入二氯甲烷(10.0mL)稀释，再用饱和硫代硫酸钠(10.0mL)洗涤。有机相再用饱和碳酸氢钠(10.0mL)洗涤后经无水硫酸钠干燥，过滤，浓缩后所得粗品经硅胶柱纯化(石油醚：乙酸乙酯＝10:1-3:1)得到10H(190mg，收率62％).m/z(ESI):362.1[M+H] +。 10G (280.0 mg, 848.0 μmol) was dissolved in dichloromethane (3.0 mL), and m-chloroperoxybenzoic acid (465.0 mg, 2.3 mmol) was added. The resulting mixture was reacted at room temperature for 3 h. Dichloromethane (10.0 mL) was added to the reaction solution for dilution, and then washed with saturated sodium thiosulfate (10.0 mL). The organic phase was washed with saturated sodium bicarbonate (10.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated and the resulting crude product was purified by silica gel column (petroleum ether: ethyl acetate = 10:1-3:1) to obtain 10H ( 190 mg, yield 62%). m/z (ESI): 362.1 [M+H] + .
步骤6：(1-(2-氯-4-((4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)氨基)嘧啶-5-基)环丁基)氨基甲酸叔丁酯(10I)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)
将中间体1E(106.0mg,414.0μmol)溶于N,N-二甲基甲酰胺(1.0mL)中，加入N,N-二异丙基乙胺(161.0mg,1.2mmol)，然后加入10H(150.0mg,414.0μmol)。所得混合物在室温反应3h。反应液中加水(10.0mL)稀释，再用乙酸乙酯(10.0mL*3)进行萃取，有机相再用饱和食盐水(10.0mL)洗涤后经无水硫酸钠干燥，过滤，浓缩后所得粗品经硅胶柱纯化(石油醚：乙酸乙酯＝10:1-2:1)得到10I(100mg,收率45％)。m/z(ESI):537.1[M+H] +。 Intermediate 1E (106.0 mg, 414.0 μmol) was dissolved in N,N-dimethylformamide (1.0 mL), N,N-diisopropylethylamine (161.0 mg, 1.2 mmol) was added, followed by 10H (150.0 mg, 414.0 μmol). The resulting mixture was reacted at room temperature for 3 h. The reaction solution was diluted with water (10.0 mL), then extracted with ethyl acetate (10.0 mL*3), the organic phase was washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product Purification by silica gel column (petroleum ether: ethyl acetate = 10:1-2:1) gave 10I (100 mg, yield 45%). m/z (ESI): 537.1 [M+H] + .
步骤7：5-(1-氨基环丁基)-2-氯-N-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)嘧啶-4-胺(10J)Step 7: 5-(1-Aminocyclobutyl)-2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) Pyrimidin-4-amine (10J)
将中间体10I(80.0mg,149.0μmol)溶于盐酸-二氧六环(1.0mL)中，于室温反应1h。反应液直接旋干得到10J(80mg,粗品)。m/z(ESI):437.1[M+H] +。 Intermediate 10I (80.0 mg, 149.0 μmol) was dissolved in hydrochloric acid-dioxane (1.0 mL), and reacted at room temperature for 1 h. The reaction solution was directly spin-dried to obtain 10J (80mg, crude product). m/z (ESI): 437.1 [M+H] + .
步骤8：2-氯-N-(1-(2-氯-4-((4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)氨基)嘧啶-5-基)环丁基)乙酰胺(10L)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)
0℃下将氯乙酰氯(24.8mg,219.9μmol)的二氯甲烷(0.5mL)溶液缓慢加入到10L(100.0mg,219.9μmol)和N,N-二异丙基乙胺(91.2mg,706.9μmol)的无水二氯甲烷(5mL)溶液中。所得混合物搅拌2小时后，将反应液加入到水和乙酸乙酯的混合溶剂中，并用乙酸乙酯萃取三次，合并有机相并旋干，粗品经柱层析(二氯甲烷:甲醇＝100:0-98:2)得10L(100mg,收率82％)。m/z(ESI):513.0[M+H] +。 At 0°C, a solution of chloroacetyl chloride (24.8 mg, 219.9 μmol) in dichloromethane (0.5 mL) was slowly added to 10 L (100.0 mg, 219.9 μmol) and N,N-diisopropylethylamine (91.2 mg, 706.9 μmol) in anhydrous dichloromethane (5 mL) solution. After the resulting mixture was stirred for 2 hours, the reaction solution was added to a mixed solvent of water and ethyl acetate, and extracted three times with ethyl acetate, the organic phases were combined and spin-dried, and the crude product was subjected to column chromatography (dichloromethane:methanol=100: 0-98:2) to obtain 10L (100mg, yield 82%). m/z (ESI): 513.0 [M+H] + .
步骤9：2-氯-9'-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-8',9'-二氢螺[环丁烷-1,5'-嘧啶并[4,5-e][1,4]重氮基庚英]-7'(6'H)-酮(10M)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)
室温下，将碳酸钾(80.8mg,584.4μmol)加入到10L(100.0mg,194.8μmol)的N’N-二甲基甲酰胺(20mL)溶液中。混合物在50℃下搅拌反应2小时后，于反应液加入20mL水，并用二氯甲烷(10.0mL*3)进行萃取。合并有机相并旋干，经柱层析(二氯甲烷:甲醇＝100:0–95:5)得到10M(80mg,收率86％)。m/z(ESI):477.1[M+H] +.步骤10：2'-(4-环丙基-6-甲氧基嘧啶-5-基)-9'-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-8',9'-二氢螺[环丁烷-1,5'-嘧啶并[4,5-e][1,4]二氮
Figure PCTCN2022115739-appb-000052
]-7'(6'H)-酮(化合物10) Potassium carbonate (80.8 mg, 584.4 μmol) was added to a solution of 10 L (100.0 mg, 194.8 μmol) of N'N-dimethylformamide (20 mL) at room temperature. After the mixture was stirred and reacted at 50° C. for 2 hours, 20 mL of water was added to the reaction liquid, and extracted with dichloromethane (10.0 mL*3). The organic phases were combined and spin-dried, and 10M (80mg, yield 86%) was obtained by column chromatography (dichloromethane:methanol=100:0-95:5). m/z (ESI): 477.1[M+H] + . 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
Figure PCTCN2022115739-appb-000052
]-7'(6'H)-one (Compound 10)
将10M(47.0mg,98.6μmol)，1K(38.2mg,197.1μmol)，XPhos Pd G2(15.5mg,19.7μmol)，磷酸钾(62.8mg,295.7μmol)加入到水(0.1mL)和二氧六环(1.0mL)的混合溶剂中。所得混合物在氮气保护下100℃搅拌反应2小时后，加入10mL水，并用二氯甲烷萃取(10mL*6)。合并有机相，旋干，经柱层析(二氯甲烷:甲醇＝100:0-96:4)得到化合物10(20mg,收率34％)。m/z(ESI):591.2[M+H] +。。 1H NMR(400MHz,DMSO-d 6)δ8.61(s,1H),8.60(s,1H),8.58(s,1H),7.95–7.91(m,1H),7.64(d,J＝8.3Hz,2H),7.36(d,J＝8.4Hz,2H),5.01(s,2H),4.10(s,2H),3.81(s,3H),3.76(s,3H),2.80–2.70(m,2H),2.47–2.38(m,2H),1.99–1.89(m,2H),1.76–1.67(m,1H),0.96–0.91(m,2H),0.80–0.72(m,2H). Add 10M (47.0mg, 98.6μmol), 1K (38.2mg, 197.1μmol), XPhos Pd G2 (15.5mg, 19.7μmol), potassium phosphate (62.8mg, 295.7μmol) to water (0.1mL) and dioxane ring (1.0 mL) in the mixed solvent. The resulting mixture was stirred and reacted at 100° C. under nitrogen for 2 hours, then 10 mL of water was added, and extracted with dichloromethane (10 mL*6). The organic phases were combined, spin-dried, and compound 10 (20 mg, yield 34%) was obtained by column chromatography (dichloromethane:methanol=100:0-96:4). m/z (ESI): 591.2 [M+H] +. . 1 H NMR (400MHz,DMSO-d 6 )δ8.61(s,1H),8.60(s,1H),8.58(s,1H),7.95–7.91(m,1H),7.64(d,J＝8.3 Hz,2H),7.36(d,J＝8.4Hz,2H),5.01(s,2H),4.10(s,2H),3.81(s,3H),3.76(s,3H),2.80–2.70(m ,2H),2.47–2.38(m,2H),1.99–1.89(m,2H),1.76–1.67(m,1H),0.96–0.91(m,2H),0.80–0.72(m,2H).
实施例11：2'-(4-环丙基-6-甲氧基嘧啶-5-基)-6'-甲基-9'-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-8',9'-二氢螺[环丁烷-1,5'-嘧啶并[4,5-e][1,4]二氮卓]-7'(6'H)-酮(化合物11)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)
Figure PCTCN2022115739-appb-000053
Figure PCTCN2022115739-appb-000053
将碘甲烷(21.6mg,152.4μmol)的N’N-二甲基甲酰胺(0.5mL)溶液滴加到化合物10(30.0mg,50.8μmol)和碳酸铯(49.7mg,152.4μmol)的N’N-二甲基甲酰胺(1mL)溶液中。混合物在室温下反应2h。混合物直接经prep HPLC制备(Waters AutoP，Xbridge-C18，19*150mm，20-75％乙腈的水溶液梯度洗脱，15mL/min)得化合物11(4mg,收率13％)。m/z(ESI):605.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.60(s,1H),8.56(s,1H),7.95(s,1H),7.66(d,J＝8.2Hz,2H),7.35(d,J＝8.1Hz,2H),5.03(s,2H),4.29(s,2H),3.81(s,3H),3.76(s,3H),2.77(s,3H),2.75–2.69(m,2H),2.65–2.60(m,2H),1.81–1.70(m,3H),0.99–0.91(m,2H),0.83–0.75(m,2H). A solution of iodomethane (21.6mg, 152.4μmol) in N'N-dimethylformamide (0.5mL) was added dropwise to the N' of compound 10 (30.0mg, 50.8μmol) and cesium carbonate (49.7mg, 152.4μmol) N-dimethylformamide (1 mL) solution. The mixture was reacted at room temperature for 2h. The mixture was directly prepared by prep HPLC (Waters AutoP, Xbridge-C18, 19*150mm, gradient elution of 20-75% acetonitrile in water, 15mL/min) to obtain compound 11 (4 mg, yield 13%). m/z(ESI):605.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.60(s, 1H), 8.56(s, 1H), 7.95(s, 1H), 7.66(d, J=8.2Hz, 2H), 7.35(d, J＝8.1Hz,2H),5.03(s,2H),4.29(s,2H),3.81(s,3H),3.76(s,3H),2.77(s,3H),2.75–2.69(m,2H ),2.65–2.60(m,2H),1.81–1.70(m,3H),0.99–0.91(m,2H),0.83–0.75(m,2H).
实施例12：2-(4-环丙基-6-甲氧基嘧啶-5-基)-5,5-二甲基-9-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-5,6,8,9-四氢-7H-嘧啶[4,5-e][1,4]二氮卓-7-酮(化合物12)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)
Figure PCTCN2022115739-appb-000054
Figure PCTCN2022115739-appb-000054
参照化合物10类似的合成路线和步骤，在步骤1中用丙酮替代环丁酮可以制的化合物12。m/z(ESI):579.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.44(s,1H),7.93(s,1H),7.85(s,1H),7.61-7.54(m,2H),7.34-7.26(m,2H),4.92(s,2H),4.12(s,2H),3.74(s,3H),3.69(s,3H),1.66(s,6H),1.65(m,1H),0.88(m,2H),0.72(m,2H). Referring to the similar synthetic route and steps of compound 10, compound 12 can be prepared by substituting acetone for cyclobutanone in step 1. m/z (ESI): 579.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.44(s,1H),7.93(s,1H),7.85(s,1H),7.61-7.54(m,2H),7.34 -7.26(m,2H),4.92(s,2H),4.12(s,2H),3.74(s,3H),3.69(s,3H),1.66(s,6H),1.65(m,1H), 0.88(m,2H),0.72(m,2H).
实施例13：2-(4-环丙基-6-甲氧基嘧啶-5-基)-5,5-二甲基-9-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓(化合物13)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)
Figure PCTCN2022115739-appb-000055
Figure PCTCN2022115739-appb-000055
化合物12(20.0mg,34.6μmol)溶于四氢呋喃(0.4mL)中，再加入氢化铝锂(1M,51.8μL)，混合物于70℃反应1h。于反应液中加水淬灭，并将反应液旋干，粗品溶解于N-甲基吡咯烷酮中并过滤，滤液经prep HPLC制备(Waters AutoP，Xbridge-C18，19*150mm，20-75％乙腈的水溶液梯度洗脱，15mL/min)得化合物13(12mg,收率62％)。m/z(ESI):565.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.58(s,1H),8.40(s,1H),7.92(s,1H),7.73 (d,J＝8.1Hz,2H),7.41(d,J＝8.1Hz,2H),4.87(s,2H),3.82(s,3H),3.76(s,3H),3.34(m,2H),2.94(t,J＝5.7Hz,2H),1.71(m,1H),1.48(s,6H),0.96(m,2H),0.80(m,2H). Compound 12 (20.0 mg, 34.6 μmol) was dissolved in tetrahydrofuran (0.4 mL), and lithium aluminum hydride (1M, 51.8 μL) was added, and the mixture was reacted at 70° C. for 1 h. Add water to the reaction solution to quench, and spin the reaction solution to dryness. The crude product is dissolved in N-methylpyrrolidone and filtered. The filtrate is prepared by prep HPLC (Waters AutoP, Xbridge-C18, 19*150mm, 20-75% acetonitrile Gradient elution in aqueous solution, 15 mL/min) gave compound 13 (12 mg, yield 62%). m/z (ESI): 565.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.58(s, 1H), 8.40(s, 1H), 7.92(s, 1H), 7.73 (d, J=8.1Hz, 2H), 7.41(d, J＝8.1Hz, 2H), 4.87(s, 2H), 3.82(s, 3H), 3.76(s, 3H), 3.34(m, 2H), 2.94(t, J＝5.7Hz, 2H), 1.71( m,1H),1.48(s,6H),0.96(m,2H),0.80(m,2H).
实施例14：2-(4-环丙基-6-二氟甲氧基嘧啶-5-基)-5,5-二甲基-9-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-5,6,8,9-四氢-7H-嘧啶[4,5-e][1,4]二氮卓-7-酮(化合物14)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)
Figure PCTCN2022115739-appb-000056
Figure PCTCN2022115739-appb-000056
参照化合物10类似的合成路线和步骤，在步骤1中用丙酮替代环丁酮，在步骤10中用化合物14A替代1K可以制得化合物14。m/z(ESI):615.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.57(s,1H),8.01(s,1H),7.92(m,1H),7.79(s,1H),7.64(d,J＝8.0Hz,2H),7.37(d,J＝8.0Hz,2H),5.01(s,2H),4.20(s,2H),3.75(s,3H),1.84(m,1H),1.74(s,6H),1.02(m,2H),0.87(m,2H). Referring to the similar synthetic route and steps of compound 10, compound 14 can be prepared by substituting acetone for cyclobutanone in step 1 and substituting compound 14A for 1K in step 10. m/z (ESI): 615.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.57(s,1H),8.01(s,1H),7.92(m,1H),7.79(s,1H),7.64(d ,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H),5.01(s,2H),4.20(s,2H),3.75(s,3H),1.84(m,1H),1.74 (s,6H),1.02(m,2H),0.87(m,2H).
Figure PCTCN2022115739-appb-000057
Figure PCTCN2022115739-appb-000057
实施例15：6-环丙基2-(4-环丙基-6-甲氧基嘧啶-5-基)-5,5-二甲基-9-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-5,6,8,9-四氢-7H-嘧啶[4,5-e][1,4]二氮卓-7-酮(化合物14)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)
Figure PCTCN2022115739-appb-000058
Figure PCTCN2022115739-appb-000058
参照化合物9类似的合成方法，用化合物12代替化合物8D可以制得化合物15。m/z(ESI):619.3[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.41(s,1H),7.58(s,1H)，7.51(d,J＝8.0Hz，2H),7.32(d,J＝8.0Hz，2H),4.97(s,2H),4.30(s,2H),3.81(s,3H),3.68(s,3H)，2.40(m,1H),1.95(s,6H),1.67(m,1H),1.20(m,2H),0.98(m,2H),0.82(m,2H),0.77(m,2H). Referring to the similar synthesis method of compound 9, compound 15 can be prepared by substituting compound 12 for compound 8D. m/z(ESI):619.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.45(s, 1H), 8.41(s, 1H), 7.58(s, 1H), 7.51(d, J=8.0Hz, 2H), 7.32(d, J =8.0Hz, 2H), 4.97(s, 2H), 4.30(s, 2H), 3.81(s, 3H), 3.68(s, 3H), 2.40(m, 1H), 1.95(s, 6H), 1.67 (m,1H),1.20(m,2H),0.98(m,2H),0.82(m,2H),0.77(m,2H).
除了在实施例1-15中合成的化合物之外的其它化合物可以通过参考实施例1-15中的合成路径和材料合成得到。Compounds other than those synthesized in Examples 1-15 can be synthesized by referring to the synthesis routes and materials in Examples 1-15.
测试例1：USP1酶体外活性检测实验Test Example 1: In vitro activity detection experiment of USP1 enzyme
实验仪器：laboratory apparatus:
仪器名称equipment name 设备厂家Equipment manufacturers 型号model
振荡器oscillator BoxunBoxun BSD-YX3400BSD-YX3400
读板仪Plate reader PerkinElmerPerkinElmer EnvisionEnvision
离心机centrifuge EppendorfEppendorf Eppendorf MixmateEppendorf Mixmate
化合物稀释及加样仪Compound Dilution and Sampler PerkinElmerPerkinElmer EchoEcho
实验材料：Experimental Materials:
实验所用USP1酶(Recombinant Human His6-USP1/His6-UAF1Complex Protein,CF)，购自R&D Systems，货号E-568-050。N端带有6个HIS-tag的USP1和N端带有6个HIS-tag的UAF1酶复合体，用真核细胞杆状 病毒表达***表达。用基于镍柱的亲和层析的方法纯化，纯度为80％以上，浓度为1mg/mL，分装后-80℃保存。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.
检测用试剂盒(Ub-CHOP2-Reporter Deubiquitination Assay Kit)购自Lifesensors公司，货号为PR1101。分装后-80℃保存。试剂盒包含泛素化的报告酶，当被USP1/UAF1去泛素化后，产生活性，催化底物后，使底物受485nm激光激发产生531nm的发射光信号。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.
实验所需其它试剂及耗材信息如下：Other reagents and consumables required for the experiment are as follows:
试剂Reagent 品牌brand 货号Item No.
CHAPSCHAPS SangonSangon A600110-0001A600110-0001
1M Tris-HCl Solution,pH 8.01M Tris-HCl Solution, pH 8.0 SangonSangon B548127B548127
氯化钙二水calcium chloride dihydrate SangonSangon A501331A501331
β-mercaptoethanolβ-mercaptoethanol sigmaaldrichsigma aldrich M3148-100mlM3148-100ml
96孔板96-well plates ThermofisherThermofisher 249952249952
黑色384孔板Black 384-well plate PerkinelmerPerkinelmer 60072706007270
实验方法：experimental method:
待测化合物用DMSO溶解至10mM。使用化合物稀释及加样仪将化合物及纯DMSO打到384孔板的每个孔上，化合物和DMSO总体积为50nL，仪器通过不同的比例来获得梯度稀释的样品浓度。用新鲜配制的反应液(20mM Tris-HCl(pH 8.0),2mM CaCl 2,2mMβ-mercaptoethanol,0.05％CHAPS，ddH 2O)稀释酶。每个孔加入5μL稀释好的酶反应液，离心震荡混合酶与化合物，再离心后冰上放置。用反应液稀释试剂盒报告***和底物，每个孔加入5μL稀释好的液体，离心混合。在室温孵育0.5个小时。荧光信号使用Envision读板仪(PerkinElmer激发光波长485nm，发射光波长530nm)测量每个孔中的荧光信号。化合物对酶活的抑制活性IC 50值用四参数Logistic Model方法计算。 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 β-mercaptoethanol, 0.05% CHAPS, ddH 2 O). Add 5 μL of the diluted enzyme reaction solution to each well, centrifuge to mix the enzyme and compound, then centrifuge and place on ice. Dilute the kit reporter system and substrate with the reaction solution, add 5 μL of the diluted solution to each well, and centrifuge to mix. Incubate for 0.5 hours at room temperature. Fluorescent signal The fluorescent signal in each well was measured using an Envision plate reader (PerkinElmer excitation light wavelength 485 nm, emission light wavelength 530 nm). The IC 50 value of compound's inhibitory activity on enzyme activity was calculated by four-parameter Logistic Model method.
下列公式中x代表化合物浓度的对数形式；F(x)代表效应值(该浓度条件下对酶活的抑制率)：F(x)＝(A+((B-A)/(1+((C/x)^D))))。A,B,C和D为四个参数。用Xlfit将IC 50值进一步计算为最佳拟合曲线中50％酶活抑制所需的化合物浓度。 In the following formula, x represents the logarithmic form of compound concentration; F (x) represents effect value (the inhibitory rate to enzyme activity under this concentration condition): F (x)=(A+((BA)/(1+(((C /x)^D))))). 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.
测试结果见表1。The test results are shown in Table 1.
表1USP1酶体外抑制活性Table 1 Inhibitory activity of USP1 enzyme in vitro
化合物compound IC 50(nM) IC 50 (nM)
化合物1Compound 1 14.014.0
化合物2Compound 2 30.530.5
化合物3Compound 3 86.486.4
化合物4Compound 4 52.252.2
化合物5Compound 5 30.430.4
化合物7Compound 7 56.656.6
化合物8Compound 8 57.957.9
化合物9Compound 9 35.035.0
化合物10Compound 10 24.724.7
化合物12Compound 12 10.210.2
化合物14Compound 14 6.76.7
化合物15Compound 15 20.820.8

Claims (31)

  1. 一种式(I)化合物或其药学上可接受的盐，a compound of formula (I) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022115739-appb-100001
    Figure PCTCN2022115739-appb-100001
    其中，in,
    X 1选自N或CR 1a； X 1 is selected from N or CR 1a ;
    X 2选自O、NR 2a、CR 2aR 2b、C＝CR 2aR 2b、S、S(＝O)R 2a、C(＝O)、S(＝O) 2或C(＝NR 2a)； X 2 is selected from O, NR 2a , CR 2a R 2b , C=CR 2a R 2b , S, S(=O)R 2a , C(=O), S(=O) 2 or C(=NR 2a ) ;
    X 3选自CR 3aR 3b、CR 3a、NR 3a、N、C(＝O)、O或C(＝NR 3a)； X 3 is selected from CR 3a R 3b , CR 3a , NR 3a , N, C(=O), O or C(=NR 3a );
    X 4选自CR 4aR 4b、CR 4a或C(＝O)； X 4 is selected from CR 4a R 4b , CR 4a or C(=O);
    X 5选自CR 5aR 5b、C(＝O)或S(＝O) 2； X 5 is selected from CR 5a R 5b , C(=O) or S(=O) 2 ;
    环A选自芳基、5-10元杂芳基、4-10元杂环基或C 3-C 10环烷基； Ring A is selected from aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group or C 3 -C 10 cycloalkyl;
    环B选自亚芳基、5-10元亚杂芳基、4-10元亚杂环基或C 3-C 10亚环烷基； Ring B is selected from arylene, 5-10 membered heteroarylene, 4-10 membered heterocyclylene or C 3 -C 10 cycloalkylene;
    环C选自芳基、5-10元杂芳基或4-10元杂环基；Ring C is selected from aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group;
    R 1、R 2独立地选自H、卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基任选被R d取代； 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 ;
    或R 1、R 2以及它们所连接的原子共同形成C 3-C 10环烷基、4-8元杂环基，所述C 3-C 10环烷基、4-8元杂环基任选被R d取代； Or R 1 , R 2 and the atoms connected to them together form a C 3 -C 10 cycloalkyl group, a 4-8 membered heterocyclic group, and the C 3 -C 10 cycloalkyl group, a 4-8 membered heterocyclic group is any selected to be replaced by R d ;
    R 3选自H、卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基、4-8元杂环基、烯基、炔基，所述OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基、4-8元杂环基、烯基、炔基任选被R d取代； 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独立地选自H、卤素、CN、OH、NH 2、C 1-C 6烷基、烯基、C 3-C 10环烷基或4-10元杂环基，所述OH、NH 2、C 1-C 6烷基、烯基、C 3-C 10环烷基或4-10元杂环基任选被R d取代； 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独立地选自卤素、CN、OH、NH 2、SH、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基，所述OH、NH 2、SH、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基任选被R d取代； 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 ;
    或R 1a、R a与其连接的原子共同形成C 3-C 10环烷基、4-10元杂环基或C 3-C 10环烯基，所述C 3-C 10环烷基、4-10元杂环基或C 3-C 10环烯基任选被R d取代。 Or R 1a , R a and the atoms they connect together form a C 3 -C 10 cycloalkyl group, a 4-10 membered heterocyclyl group or a C 3 -C 10 cycloalkenyl group, and the C 3 -C 10 cycloalkyl group, 4 -10-membered heterocyclyl or C 3 -C 10 cycloalkenyl is optionally substituted by R d .
    或R b、R c与其连接的原子共同形成C 3-C 10环烷基、4-10元杂环基或C 3-C 10环烯基，所述C 3-C 10环烷基、4-10元杂环基或C 3-C 10环烯基任选被R d取代； Or R b , R c and the atoms they connect together form a C 3 -C 10 cycloalkyl group, a 4-10 membered heterocyclic group or a C 3 -C 10 cycloalkenyl group, and the C 3 -C 10 cycloalkyl group, 4 -10-membered heterocyclyl or C 3 -C 10 cycloalkenyl is optionally substituted by R d ;
    或R 2a、R 3a与其连接的原子共同形成5-10元杂芳基、C 3-C 10环烷基或4-10元杂环基，所述5-10元杂芳基、C 3-C 10环烷基或4-10元杂环基任选被R d取代； Or R 2a , R 3a and the atoms they connect together form a 5-10 membered heteroaryl group, a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group, and the 5-10 membered heteroaryl group, C 3 - C 10 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R ;
    或R 2a、R 2b与其连接的原子共同形成C 3-C 10环烷基或4-10元杂环基，所述C 3-C 10环烷基或4-10元杂环基任选被R d取代； Or R 2a , R 2b and the atoms they connect together form a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group, and the C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group is optionally replaced by Rd replaces;
    或R 3a、R 4a与其连接的原子共同形成C 3-C 10环烷基、4-10元杂环基、5-10元杂芳基，所述C 3-C 10环烷基、4-10元杂环基、5-10元杂芳基任选被R d取代； Or R 3a , R 4a and the atoms they connect together form a C 3 -C 10 cycloalkyl group, a 4-10 membered heterocyclic group, a 5-10 membered heteroaryl group, the C 3 -C 10 cycloalkyl group, 4- The 10-membered heterocyclic group and the 5-10-membered heteroaryl group are optionally substituted by R d ;
    或R 3a、R 5a与其连接的原子共同形成C 3-C 10环烷基、4-10元杂环基、5-10元杂芳基，所述C 3-C 10环烷基、4-10元杂环基、5-10元杂芳基任选被R d取代； Or R 3a , R 5a and the atoms they connect together form a C 3 -C 10 cycloalkyl group, a 4-10 membered heterocyclic group, a 5-10 membered heteroaryl group, the C 3 -C 10 cycloalkyl group, 4- The 10-membered heterocyclic group and the 5-10-membered heteroaryl group are optionally substituted by R d ;
    或R 4a、R 4b与其连接的原子共同形成C 3-C 10环烷基、4-10元杂环基，所述C 3-C 10环烷基或4-10元杂环基任选被R d取代； Or R 4a , R 4b and the atoms they connect together form a C 3 -C 10 cycloalkyl group, a 4-10 membered heterocyclic group, and the C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group is optionally replaced by Rd replaces;
    或R 4a、R 5a与其连接的原子共同形成C 3-C 10环烷基、4-10元杂环基；所述C 3-C 10环烷基或4-10元杂环基任选被R d取代； Or R 4a , R 5a and the atoms they connect together form a C 3 -C 10 cycloalkyl group, a 4-10 membered heterocyclic group; the C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group is optionally Rd replaces;
    或R 5a、R 5b与其连接的原子共同形成C 3-C 10环烷基或4-10元杂环基；所述C 3-C 10环烷基或4-10元杂环基任选被R d取代； Or R 5a , R 5b and the atoms they connect together form a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group; the C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group is optionally replaced by Rd replaces;
    或R 2a、R 4a与其连接的原子共同形成5-10元杂芳基、C 3-C 10环烷基或4-10元杂环基，所述5-10元杂芳基、C 3-C 10环烷基或4-10元杂环基任选被R d取代； Or R 2a , R 4a and the atoms they connect together form a 5-10 membered heteroaryl group, a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group, and the 5-10 membered heteroaryl group, C 3 - C 10 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R ;
    或R 2a、R 5a与其连接的原子共同形成5-10元杂芳基、C 3-C 10环烷基或4-10元杂环基，所述5-10元杂芳基、C 3-C 10环烷基或4-10元杂环基任选被R d取代； Or R 2a , R 5a and the atoms they connect together form a 5-10 membered heteroaryl group, a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group, and the 5-10 membered heteroaryl group, C 3 - C 10 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R ;
    或X 2与X 3，X 3与X 4之间可选其一形成双键； Or one of X 2 and X 3 , X 3 and X 4 can be selected to form a double bond;
    每一个R d独立地选自卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基，所述OH、NH 2、 C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基任选被R e取代； 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选自卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-8元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-8元杂环基任选被R f取代； 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选自卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-8元杂环基； 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;
    m、n、p独立地选自0、1、2、3、4、5或6。m, n, p are independently selected from 0, 1, 2, 3, 4, 5 or 6.
  2. 根据权利要求1所述的式(I)化合物或其药学上可接受的盐，其特征在于，X 1选自N。 The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is selected from N.
  3. 根据权利要求1或2所述的式(I)化合物或其药学上可接受的盐，其特征在于，X 2选自O、NR 2a、CR 2aR 2b、C＝CR 2aR 2b、S、S(＝O)R 2a、C(＝O)或S(＝O) 2； The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X 2 is selected from O, NR 2a , CR 2a R 2b , C=CR 2a R 2b , S, S(=O)R 2a , C(=O) or S(=O) 2 ;
    或者，X 2选自O、NR 2a、CR 2aR 2b或C(＝O)。 Alternatively, X 2 is selected from O, NR 2a , CR 2a R 2b or C(=O).
  4. 根据权利要求1-3任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，X 3选自CR 3aR 3b、CR 3a、NR 3a、N、C(＝O)或C(＝NR 3a)。 According to the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein X 3 is selected from CR 3a R 3b , CR 3a , NR 3a , N, C( =O) or C (=NR 3a ).
  5. 根据权利要求1-4任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，X 4选自CR 4aR 4b或C(＝O)；或者，X 4选自CR 4aR 4b；或者，X 4选自CR 4a。 According to the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, it is characterized in that X 4 is selected from CR 4a R 4b or C(=O); or, X 4 is selected from CR 4a R 4b ; alternatively, X 4 is selected from CR 4a .
  6. 根据权利要求1-5任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，X 5选自CR 5aR 5b或C(＝O)。 The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein X 5 is selected from CR 5a R 5b or C(=O).
  7. 根据权利要求1-6任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，环A选自芳基或5-10元杂芳基；或者，环A选自
    Figure PCTCN2022115739-appb-100002
    According to the compound of formula (I) or a pharmaceutically acceptable salt thereof described in any one of claims 1-6, it is characterized in that Ring A is selected from aryl or 5-10 membered heteroaryl; or, Ring A selected from
    Figure PCTCN2022115739-appb-100002
  8. 根据权利要求1-7任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，环B选自亚芳基、4-8元亚杂环基或C 3-C 6亚环烷基；或者，环B选自亚芳基或4-8元亚杂环基；或者，环B选自
    Figure PCTCN2022115739-appb-100003
    Figure PCTCN2022115739-appb-100004
    According to the compound of formula (I) or a pharmaceutically acceptable salt thereof described in any one of claims 1-7, it is characterized in that ring B is selected from arylene group, 4-8 membered heterocyclic group or C3 -C Cycloalkylene; Or, ring B is selected from arylene or 4-8 membered heterocyclylene; Or, ring B is selected from
    Figure PCTCN2022115739-appb-100003
    Figure PCTCN2022115739-appb-100004
  9. 根据权利要求1-8任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，环C选自5-10元杂芳基；或者，环C选自
    Figure PCTCN2022115739-appb-100005
    According to the compound of formula (I) or a pharmaceutically acceptable salt thereof described in any one of claims 1-8, it is characterized in that ring C is selected from 5-10 membered heteroaryl; or ring C is selected from
    Figure PCTCN2022115739-appb-100005
  10. 根据权利要求1-9任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，R 1、R 2独立地选自H、卤素或C 1-C 6烷基，所述C 1-C 6烷基任选被R d取代；或者，R 1、R 2独立地选自H或C 1-C 6烷基，所述C 1-C 6烷基任选被R d取代；或者，R 1、R 2以及它们所连接的原子共同形成C 3-C 6环烷基，所述C 3-C 6环烷基任选被R d取代。 According to the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, it is characterized in that R 1 and R 2 are independently selected from H, halogen or C 1 -C 6 alkane The C 1 -C 6 alkyl group is optionally substituted by R d ; or, R 1 , R 2 are independently selected from H or C 1 -C 6 alkyl groups, and the C 1 -C 6 alkyl group is optionally is substituted by R d ; or, R 1 , R 2 and the atoms connected to them jointly form a C 3 -C 6 cycloalkyl group, and the C 3 -C 6 cycloalkyl group is optionally substituted by R d .
  11. 根据权利要求1-10任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，R 3选自H、卤素、CN、OH、C 1-C 6烷基、C 3-C 6环烷基、4-8元杂环基、烯基或炔基，所述OH、C 1-C 6烷基、C 3-C 6环烷基、4-8元杂环基、烯基或炔基任选被R d取代；或者，R 3选自H、卤素、CN、OH、C 1-C 6烷基或C 3-C 6环烷基，所述OH、C 1-C 6烷基或C 3-C 6环烷基任选被R d取代；或者，R 3选自H、卤素、OH或C 1-C 6烷基，所述OH或C 1-C 6烷基任选被R d取代；或者，R 3选自H。 According to the compound of formula (I) or pharmaceutically acceptable salt thereof described in any one of claims 1-10, it is characterized in that, R 3 is selected from H, halogen, CN, OH, C 1 -C 6 alkyl , C 3 -C 6 cycloalkyl, 4-8 membered heterocyclyl, alkenyl or alkynyl, the OH, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered hetero Cyclic, alkenyl or alkynyl is optionally substituted by R; alternatively, R 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 -C 6 cycloalkyl is optionally substituted by R d ; or, R 3 is selected from H, halogen, OH or C 1 -C 6 alkyl, the OH or C 1 - C6 alkyl is optionally substituted by Rd ; alternatively, R3 is selected from H.
  12. 根据权利要求1-11任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，R 1a、R 2a、R 2b、R 3a、R 3b、R 4a、R 4b、R 5a、R 5b独立地选自H、卤素、CN、OH、NH 2、C 1-C 6烷基、烯基、C 3-C 6环烷基或4-8元杂环基，所述OH、NH 2、C 1-C 6烷基、烯基、C 3-C 6环烷基或4-8元杂环基任选被R d取代；或者，R 1a、R 2a、R 2b、R 3a、R 3b、R 4a、R 4b、R 5a、R 5b独立地选自H、卤素、OH、NH 2、C 1-C 6烷基、烯基或C 3-C 6环烷基，所述OH、NH 2、C 1-C 6烷基、烯基或C 3-C 6环烷基任选被R d取代。 According to the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, characterized in that, R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a and 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 heterocyclyl, The OH, NH 2 , C 1 -C 6 alkyl, alkenyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocyclic group are optionally substituted by R d ; or, 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 cycloalkane The OH, NH 2 , C 1 -C 6 alkyl, alkenyl or C 3 -C 6 cycloalkyl is optionally substituted by R d .
  13. 根据权利要求1-12任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，R a、R b、R c独立地选自卤素、OH、NH 2、SH、C 1-C 6烷基、C 3-C 6环烷基或4-8元杂环基，所述OH、NH 2、SH、C 1-C 6烷基、C 3-C 6环烷基或4-8元杂环基任选被R d取代；或者，R a独立地选自OH、C 1-C 6烷基或C 3-C 6环烷基，所述OH、C 1-C 6烷基或C 3-C 6环烷基任选被R d取代；或者，R a选自-O-CH 3、甲基、乙基、异丙基或环丙基；或者，R b独立地选自卤素、OH或C 1-C 6烷基，所述OH或C 1-C 6烷基任选被R d取代；或者，R c独立地选自卤素、OH、C 1-C 6烷基或C 3-C 6环烷基，所述OH、C 1-C 6烷基或C 3-C 6环烷基任选被R d取代；或者，R c独立地选自OH、C 1-C 6烷基或C 3-C 6环烷基，所述OH、C 1-C 6烷基或C 3-C 6环烷基任选被R d取代；或者，R c独立地选自OH、甲基、乙基、异丙基或环丙基，所述OH、甲基、乙基、异丙基或环丙基任选被R d取代。 According to the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein 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 heterocyclic group, the OH, NH 2 , SH, C 1 -C 6 alkyl, C 3 -C 6 ring Alkyl or 4-8 membered heterocyclic group is optionally substituted by R d ; or, 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 cycloalkyl is optionally substituted by R d ; or, R a is selected from -O-CH 3 , methyl, ethyl, isopropyl or cyclopropyl; or, R b is independently selected from halogen , OH or C 1 -C 6 alkyl optionally substituted by R d ; or, R c is independently selected from halogen, OH, C 1 - C 6 alkyl or C 3 -C 6 cycloalkyl, said OH, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl is optionally substituted by R d ; or, 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 cycloalkyl is optionally substituted by R d ; or, R c is independently is selected from OH, methyl, ethyl, isopropyl or cyclopropyl optionally substituted by R d .
  14. 根据权利要求1-13任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，R 1a、R a与其连接的原子共同形成4-8元杂环基，所述4-8元杂环基任选被R d取代。 According to the compound of formula (I) or a pharmaceutically acceptable salt thereof described in any one of claims 1-13, it is characterized in that R 1a , R a and the atoms they are connected to together form a 4-8 membered heterocyclic group, The 4-8 membered heterocyclyl is optionally substituted by Rd .
  15. 根据权利要求1-14任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，R b、R c与其连接的原子共同形成4-8元杂环基，所述4-8元杂环基任选被R d取代。 According to the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-14, it is characterized in that R b , R c and the atoms they are connected to together form a 4-8 membered heterocyclic group, The 4-8 membered heterocyclyl is optionally substituted by Rd .
  16. 根据权利要求1-15任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，R 2a、R 2b与其连接的原子共同形成C 3-C 6环烷基或4-7元杂环基，所述C 3-C 6环烷基或4-7元杂环基任选被R d取代； According to the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-15, characterized in that, R 2a , R 2b and the atoms they connect together form a C 3 -C 6 cycloalkyl group Or a 4-7 membered heterocyclic group, the C 3 -C 6 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by R d ;
    或者，R 2a、R 2b与其连接的原子共同形成C 3-C 10环烷基，所述C 3-C 10环烷基任选被R d取代。 Alternatively, R 2a , R 2b and the atoms they are connected to together form a C 3 -C 10 cycloalkyl group, and the C 3 -C 10 cycloalkyl group is optionally substituted by R d .
  17. 根据权利要求1-16任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，R 2a、R 3a与其连接的原子共同形成5-10元杂芳基，所述5-10元杂芳基任选被R d取代；或者，R 2a、R 3a与其连接的原子共同形成
    Figure PCTCN2022115739-appb-100006
    所述
    Figure PCTCN2022115739-appb-100007
    任选被R d取代。     According to the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-16, it is characterized in that R 2a , R 3a and the atoms they are connected to together form a 5-10 membered heteroaryl group, The 5-10 membered heteroaryl group is optionally substituted by R d ; or, R 2a , R 3a and the atoms they are connected together form
    Figure PCTCN2022115739-appb-100006
    said
    Figure PCTCN2022115739-appb-100007
    is optionally substituted by Rd .
  18. 根据权利要求1-17任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，R 3a、R 4a与其连接的原子共同形成C 3-C 10环烷基或4-8元杂环基，所述C 3-C 10环烷基或4-8元杂环基任选被R d取代；或者，R 3a、R 4a与其连接的原子共同形成环丙基、
    Figure PCTCN2022115739-appb-100008
    所述环丙基、
    Figure PCTCN2022115739-appb-100009
    Figure PCTCN2022115739-appb-100010
    任选被R d取代。     According to the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-17, it is characterized in that R 3a , R 4a and the atoms they are connected to together form a C 3 -C 10 cycloalkyl group Or a 4-8 membered heterocyclic group, the C 3 -C 10 cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by R d ; or, R 3a , R 4a and the atoms they are connected to together form a cyclopropyl group ,
    Figure PCTCN2022115739-appb-100008
    The cyclopropyl,
    Figure PCTCN2022115739-appb-100009
    Figure PCTCN2022115739-appb-100010
    is optionally substituted by Rd .
  19. 根据权利要求1-18任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，R 3a、R 5a与其连接的原子共同形成C 3-C 10环烷基或4-8元杂环基，所述C 3-C 10环烷基或4-8元杂环基任选被R d取代；或者，R 3a、R 5a与其连接的原子共同形成
    Figure PCTCN2022115739-appb-100011
    所述
    Figure PCTCN2022115739-appb-100012
    任选被R d取代。     According to any one of claims 1-18, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3a , R 5a and the atoms they are connected to together form a C 3 -C 10 cycloalkyl group Or a 4-8 membered heterocyclic group, the C 3 -C 10 cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by R d ; or, R 3a , R 5a and the atoms they are connected to form together
    Figure PCTCN2022115739-appb-100011
    said
    Figure PCTCN2022115739-appb-100012
    is optionally substituted by Rd .
  20. 根据权利要求1-19任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，R 4a、R 4b与其连接的原子共同形成C 3-C 6环烷基或4-8元杂环基，所述C 3-C 6环烷基或4-8元杂环基任选被R d取代；或者，R 4a、R 4b与其连接的原子共同形成环丙基、环丁基或
    Figure PCTCN2022115739-appb-100013
    所述环丙基、环丁基或
    Figure PCTCN2022115739-appb-100014
    任选被R d取代。     According to the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-19, characterized in that, R 4a , R 4b and the atoms they connect together form a C 3 -C 6 cycloalkyl group Or a 4-8 membered heterocyclic group, the C 3 -C 6 cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by R d ; or, R 4a , R 4b and the atoms they are connected to together form a cyclopropyl group , cyclobutyl or
    Figure PCTCN2022115739-appb-100013
    The cyclopropyl, cyclobutyl or
    Figure PCTCN2022115739-appb-100014
    is optionally substituted by Rd .
  21. 根据权利要求1-20任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，R 4a、R 5a与其连接的原子共同形成C 3-C 6环烷基或4-8元杂环基；所述C 3-C 6环烷基或4-8元杂环基任选被R d取代；或者，R 4a、R 5a与其连接的原子共同形成环丙基或环丁基；所述环丙基或环丁基任选被R d取代。 According to the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-20, characterized in that, R 4a , R 5a and the atoms they are connected to together form a C 3 -C 6 cycloalkyl group Or a 4-8 membered heterocyclic group; the C 3 -C 6 cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by R d ; or, R 4a , R 5a and the atoms they are connected to together form a cyclopropyl group or cyclobutyl; said cyclopropyl or cyclobutyl is optionally substituted by R d .
  22. 根据权利要求1-21任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，R 5a、R 5b与其连接的原子共同形成C 3-C 6环烷基或4-8元杂环基；所述C 3-C 6环烷基或4-8元杂环基任选被R d取代；或者，R 5a、R 5b与其连接的原子共同形成C 3-C 6环烷基，所述C 3-C 6环烷基任选被R d取代；或者，R 5a、R 5b与其连接的原子共同形成环丙基或环丁基；所述环丙基或环丁基任选被R d取代。 According to the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-21, characterized in that, R 5a , R 5b and the atoms they are connected to together form a C 3 -C 6 cycloalkyl group or a 4-8 membered heterocyclic group; the C 3 -C 6 cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by R d ; or, R 5a , R 5b and the atoms they are connected together form a C 3 - C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is optionally substituted by R d ; or, R 5a , R 5b and the atoms they are connected to together form a cyclopropyl or cyclobutyl; the cyclopropyl or Cyclobutyl is optionally substituted with Rd .
  23. 根据权利要求1-22任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，每一个R d独立地选自卤素、OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基任选被R e取代；或者，每一个R d独立地选自卤素、OH、NH 2、C 1-C 6烷基或C 3-C 10环烷基，所述OH、NH 2、C 1-C 6烷基或C 3-C 10环烷基任选被R e取代。 The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-22, wherein 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 heterocyclic group, said OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-8 membered heterocyclic The ring group is optionally substituted by R e ; alternatively, each R d is independently selected from halogen, OH, NH 2 , C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl, said OH, NH 2 , C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl is optionally substituted by Re .
  24. 根据权利要求1-23任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，m选自1、2、3；或者m选自1或2。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-23, wherein m is selected from 1, 2, 3; or m is selected from 1 or 2.
  25. 根据权利要求1-24任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，n选自0、1、2；或者，n选自0或1。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-24, wherein n is selected from 0, 1, 2; or, n is selected from 0 or 1.
  26. 根据权利要求1-25任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，p选自1、2、3；或者，p选自1或2。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-25, wherein p is selected from 1, 2, 3; or, p is selected from 1 or 2.
  27. 根据权利要求1、7-26任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，所述的式(I)化合物或其药学上可接受的盐选自式(II)化合物或其药学上可接受的盐，According to the compound of formula (I) or its pharmaceutically acceptable salt described in any one of claims 1, 7-26, it is characterized in that, the compound of formula (I) or its pharmaceutically acceptable salt is selected from From a compound of formula (II) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022115739-appb-100015
    Figure PCTCN2022115739-appb-100015
    其中，in,
    X 1选自N或CR 1a； X 1 is selected from N or CR 1a ;
    X 2选自O、NR 2a、CR 2aR 2b、C＝CR 2aR 2b、S、C(＝O)、S(＝O) 2或C(＝NR 2a)； X 2 is selected from O, NR 2a , CR 2a R 2b , C=CR 2a R 2b , S, C(=O), S(=O) 2 or C(=NR 2a );
    X 3选自CR 3aR 3b、NR 3a、C(＝O)、O或C(＝NR 3a)； X 3 is selected from CR 3a R 3b , NR 3a , C(=O), O or C(=NR 3a );
    X 4选自CR 4aR 4b； X 4 is selected from CR 4a R 4b ;
    X 5选自CR 5aR 5b、C(＝O)或S(＝O) 2； X 5 is selected from CR 5a R 5b , C(=O) or S(=O) 2 ;
    环A、环B、环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和R 5b如权利要求1、7-26任一项中所定义。 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 any one of claims 1, 7-26.
  28. 根据权利要求1、10-26任一项中所述的式(I)化合物或其药学上可接受的盐，其特征在于，所述的式(I)化合物或其药学上可接受的盐选自式(III)化合物或其药学上可接受的盐，According to the compound of formula (I) or a pharmaceutically acceptable salt thereof described in any one of claims 1, 10-26, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from From a compound of formula (III) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022115739-appb-100016
    Figure PCTCN2022115739-appb-100016
    其中，in,
    X 1选自N或CR 1a； X 1 is selected from N or CR 1a ;
    X 2选自O、NR 2a、CR 2aR 2b、C＝CR 2aR 2b、S、C(＝O)、S(＝O) 2或C(＝NR 2a)； X 2 is selected from O, NR 2a , CR 2a R 2b , C=CR 2a R 2b , S, C(=O), S(=O) 2 or C(=NR 2a );
    X 3选自CR 3aR 3b、NR 3a、C(＝O)、O或C(＝NR 3a)； X 3 is selected from CR 3a R 3b , NR 3a , C(=O), O or C(=NR 3a );
    X 4选自CR 4aR 4b或C(＝O)； X 4 is selected from CR 4a R 4b or C(=O);
    X 5选自CR 5aR 5b、C(＝O)或S(＝O) 2； X 5 is selected from CR 5a R 5b , C(=O) or S(=O) 2 ;
    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和R 5b如权利要求1、10-26任一项中所定义。 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 As defined in any one of claims 1, 10-26.
  29. 根据权利要求1所述的式(I)化合物或其药学上可接受的盐，其特征在于，式(I)化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐，The compound of formula (I) or its pharmaceutically acceptable salt according to claim 1, characterized in that, the compound of formula (I) or its pharmaceutically acceptable salt is selected from the following compounds or its pharmaceutically acceptable salt ,
    Figure PCTCN2022115739-appb-100017
    Figure PCTCN2022115739-appb-100017
    Figure PCTCN2022115739-appb-100018
    Figure PCTCN2022115739-appb-100018
    Figure PCTCN2022115739-appb-100019
    Figure PCTCN2022115739-appb-100019
    Figure PCTCN2022115739-appb-100020
    Figure PCTCN2022115739-appb-100020
    Figure PCTCN2022115739-appb-100021
    Figure PCTCN2022115739-appb-100021
    Figure PCTCN2022115739-appb-100022
    Figure PCTCN2022115739-appb-100022
    Figure PCTCN2022115739-appb-100023
    Figure PCTCN2022115739-appb-100023
    Figure PCTCN2022115739-appb-100024
    Figure PCTCN2022115739-appb-100024
    Figure PCTCN2022115739-appb-100025
    Figure PCTCN2022115739-appb-100025
    Figure PCTCN2022115739-appb-100026
    Figure PCTCN2022115739-appb-100026
  30. 一种药物组合物，其包含权利要求1-29任一项中所述的式(I)化合物或其药学上可接受的盐和药学上可接受的辅料。A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials described in any one of claims 1-29.
  31. 一种权利要求1-29任一项中所述的式(Ⅰ)化合物或其药学上可接受的盐、或权利要求30所述的药物组合物在制备预防或者治疗USP1介导的疾病的药物中的用途。A compound of formula (I) described in any one of claims 1-29 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 30 in the preparation of a medicament for preventing or treating USP1-mediated diseases use in .
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