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WO2024022519A1 - Composé de pyrimidine fusionné à un hétérocycle et son utilisation - Google Patents

Composé de pyrimidine fusionné à un hétérocycle et son utilisation Download PDF

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Publication number
WO2024022519A1
WO2024022519A1 PCT/CN2023/109974 CN2023109974W WO2024022519A1 WO 2024022519 A1 WO2024022519 A1 WO 2024022519A1 CN 2023109974 W CN2023109974 W CN 2023109974W WO 2024022519 A1 WO2024022519 A1 WO 2024022519A1
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Prior art keywords
alkyl
pharmaceutically acceptable
cycloalkyl
acceptable salt
formula
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PCT/CN2023/109974
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English (en)
Chinese (zh)
Inventor
祝伟
陈祥
汪涛
孙天文
李正涛
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Hainan Simcere Zaiming Pharmaceutical Co Ltd
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Simcere Zaiming Pharmaceutical Co Ltd
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Priority to CN202380054125.XA priority Critical patent/CN119604500A/zh
Publication of WO2024022519A1 publication Critical patent/WO2024022519A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure belongs to the field of medical technology and relates to a class of heterocyclic pyrimidine compounds, or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and as ubiquitin-specific protease 1 (USP1) inhibitors in the prevention or treatment of Use in USP1-related diseases.
  • USP1 ubiquitin-specific protease 1
  • Ubiquitination is a reversible process that involves a series of deubiquitinating enzymes (DUBs) that regulate a variety of cellular processes by deubiquitinating substrates.
  • DUBs are encoded by approximately 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 often dysregulated in cancer, which supports the idea that targeting specific DUB enzymes can participate in tumor growth, survival, differentiation, and maintenance of the tumor microenvironment by improving ubiquitination and degradation of oncogenic substrates and regulating them.
  • Ubiquitin-specific protease 1 is a cysteine isopeptidase of the USP subfamily of DUBs.
  • Full-length human USP1 consists of 785 amino acids, including 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 full enzymatic activity can only be obtained by combining with the cofactor UAF1 to form a complex required for deubiquitinating enzyme activity.
  • USP1/UAFl complex Deubiquitinated monoubiquitinated PCNA (proliferating cell nuclear antigen) and monoubiquitinated FANCD2 (Fanconi anemia group complementary group D2), these two proteins are involved in translation synthesis (TLS) and Fanconi anemia ( FA) pathway. These two pathways are required to repair DNA damage caused by DNA cross-linking agents such as cisplatin and mitomycin C (MMC).
  • TLS translation synthesis
  • FA Fanconi anemia
  • the USPl/UAFl complex also deubiquitinates FANCI( Fanconi anemia complementation group I). The importance of these findings was further confirmed by experiments showing that mice lacking USP1 are highly sensitive to DNA damage. Interestingly, USP1 expression is significantly increased in many cancers.
  • Blocking USP1 inhibits DNA repair , can induce apoptosis in multiple myeloma cells and can also enhance the sensitivity of lung cancer cells to cisplatin. These indicate that USP1 is a promising target for chemotherapy in certain cancers.
  • the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof,
  • X is selected from N, CR 3 , NR 3 or C(O);
  • Y is selected from NR 4 or C(O);
  • Z is selected from CR 5 or NR 5 ;
  • R 3 , R 4 , R 5 are independently selected from H, halogen, CN, OH, NH 2 , -C(O)OR x , -C(O)R x , -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl, the NH 2 , -OC 1 -C 6 Alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by R x ;
  • Ring A is selected from C 6 -C 10 aryl or 5-10 membered heteroaryl, which is optionally substituted by one or more R a ;
  • Ring B is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C 4 -C 10 cycloalkenyl or C 3 -C 10 cycloalkyl, the C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C 4 -C 10 cycloalkenyl or C 3 -C 10 cycloalkyl optionally substituted by one or more R b ;
  • Ring C is selected from C 6 -C 10 aryl or 5-10 membered heteroaryl, which is optionally substituted by one or more R c ;
  • Each R a , R b , R c is independently selected from halogen, CN, OH, NH 2 , -C(O)OR x , C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclyl, the NH 2 , C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-10 membered Heterocyclyl is optionally substituted with Rx ,
  • R b , R c and the atoms to which they are connected together form a C 4 -C 10 cycloalkenyl group or a 4-10 membered heterocyclyl group, and the C 4 -C 10 cycloalkenyl group or 4-10 membered heterocyclyl group can be any
  • the chosen land is replaced by R x ;
  • 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 4-10 membered heterocyclyl, the OH, NH 2.
  • C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R x ,
  • R 1 , R 2 and the atoms to which they are connected together form a C 3 -C 10 cycloalkyl group or a 4-7 membered heterocyclyl group, and the C 3 -C 10 cycloalkyl group or 4-7 membered heterocyclyl group can be any
  • the chosen land is replaced by R x ;
  • R 3 , R 4 , R 5 are independently selected from H, -C(O)OR x , -C(O)R x , -OC 1 -C 6 alkyl, C 1 -C 6 Alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl, the -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4- The 7-membered heterocyclyl is optionally substituted with Rx .
  • R 3 , R 4 , and R 5 are independently selected from H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or 4-7 membered heterocyclyl, and the C 1 - C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by R x .
  • R 3 , R 4 , R 5 are independently selected from H, CH 3 , CH 2 CH 3 , cyclopropyl, oxetanyl or azetidinyl, said CH 3 , CH 2CH3 , cyclopropyl , oxetanyl or azetidinyl is optionally substituted by Rx .
  • R 3 , R 4 , R 5 are independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 N(CH 3 ) 2 , cyclopropyl, oxetanyl, or
  • R 4 is selected from H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or 4-7 membered heterocyclyl, said C 1 -C 6 alkyl, C 3 - C 10 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by Rx .
  • R 4 is selected from H, CH 3 , CH 2 CH 3 , cyclopropyl, oxetanyl, azetidinyl, tetrahydrofuryl, or tetrahydropyrrolyl, said CH 3 , CH 2CH3 , cyclopropyl , oxetanyl, azetidinyl, tetrahydrofuryl or tetrahydropyrrolyl is optionally substituted by Rx .
  • R4 is selected from H , CH3 , CH2CH3 , CHF2 , CH2CH2F , CH2CHF2 , CH2CF3 , CH2CH2N ( CH3 ) 2 , cyclopropyl, oxetanyl,
  • R5 is selected from H or Ci - C6 alkyl.
  • R5 is selected from H or CH3 .
  • Ring A is selected from phenyl or 5-6 membered heteroaryl, which is optionally substituted with one or more Ra .
  • Ring A is selected from phenyl, pyridyl, or pyrimidinyl, which is optionally substituted with one or more Ra .
  • Ring B is selected from C 6 -C 10 aryl or 5-10 membered heteroaryl optionally substituted by one or more Replaced by R b .
  • Ring B is selected from C 6 -C 10 aryl optionally substituted with one or more R b .
  • Ring B is selected from phenyl, optionally substituted with one or more Rb .
  • Ring C is selected from 5-10 membered heteroaryl groups optionally substituted with one or more Rc .
  • Ring C is selected from 5-6 membered heteroaryl groups optionally substituted with one or more Rc .
  • Ring C is selected from pyrazolyl or imidazolyl, which is optionally substituted with one or more Rc .
  • each Ra , Rb , Rc is independently selected from halogen, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or 4- 10-membered heterocyclyl group, the C 1 -C 6 alkyl group, -OC 1 -C 6 alkyl group, C 3 -C 10 cycloalkyl group or 4-10 membered heterocyclyl group is optionally substituted by R x .
  • each Ra , Rb , Rc is independently selected from halogen, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or 4- 6-membered heterocyclyl, the C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted by R x .
  • each Ra , Rb , Rc is independently selected from halogen, CH3 , -CH( CH3 ) 2 , -CH2CH3 , -O- CH3 , cyclopropyl, oxygen Heterocyclidyl or azetidinyl, the CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 3 , -O-CH 3 , cyclopropyl, oxetanyl or azetidinyl
  • the group is optionally substituted by Rx .
  • each Ra, Rb , Rc is independently selected from F, CH3 , -CH( CH3 ) 2 , -CH2CH3 , -CHF2 , -CF3 , -O- CH 3 , -O-CHF 2 , cyclopropyl, oxetanyl or
  • R a is selected from C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl, said C 1 -C 6 alkyl, OC 1 -C 6 alkyl or C 3 -C 10 cycloalkyl is optionally substituted by R x .
  • Ra is selected from isopropyl, -O- CH3 , -O- CHF2 , or cyclopropyl.
  • R b is selected from halogen or -OC 1 -C 6 alkyl.
  • Rb is selected from F or -O- CH3 .
  • Rc is selected from C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or 4-10 membered heterocyclyl, said C 1 -C 6 alkyl, C 3 -C 10 Cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by Rx .
  • R c is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-6 membered heterocyclyl, said C 1 -C 6 alkyl, C 3 -C 6 Cycloalkyl or 4-6 membered heterocyclyl is optionally substituted by Rx .
  • Rc is selected from CH3 , -CH( CH3 ) 2 , -CH2CH3 , -CF3 , cyclopropyl , oxetanyl, or
  • R b , R c and the atoms to which they are attached together form a 4-10 membered heterocyclyl group that is optionally substituted with R x .
  • R 1 and R 2 are independently selected from H, halogen, C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl, said C 1 -C 6 alkyl or C 3 -C 10 Cycloalkyl is optionally substituted with Rx .
  • R 1 and R 2 are both H.
  • Rx is selected from halogen, NH2 , or C1 - C6 alkyl optionally replaced by C1 - C6alkyl , C3- C 10 cycloalkyl or 4-7 membered heterocyclyl substituted.
  • Rx is selected from halogen, NH2 , or Ci - C6 alkyl, with the NH2 optionally substituted by Ci - C6 alkyl.
  • Rx is selected from F, N( CH3 ) 2 , or Ci - C6 alkyl.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • Ring A, Ring B, Ring C, R 1 , R 2 , R 4 and R 5 are as defined above.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • Ring A, Ring B, Ring C, R 1 , R 2 , X and Z are as defined above.
  • the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds represented by formula (III-a) or a pharmaceutically acceptable salt thereof,
  • Ring A, Ring B, Ring C, R 1 , R 2 and R 5 are as defined above.
  • the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds represented by formula (III-b) or a pharmaceutically acceptable salt thereof,
  • Ring A, Ring B, Ring C, R 1 , R 2 , R 3 and R 5 are as defined above.
  • the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds represented by formula (III-c) or a pharmaceutically acceptable salt thereof,
  • Ring A, Ring B, Ring C, R 1 , R 2 , R 3 and R 5 are as defined above.
  • 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
  • a pharmaceutical composition comprising a 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 to a mammal in need of the treatment, preferably a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof.
  • the present disclosure provides the use of a 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 USP1-mediated diseases.
  • 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 neoplasia.
  • the tumor is, for example, a solid tumor, adenocarcinoma, or hematologic cancer.
  • tautomer refers to a functional group isomer resulting from the rapid movement of an atom in a molecule between two positions.
  • Compounds of the present disclosure may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually yield a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant; in phenols, the enol form is dominant. This disclosure encompasses all tautomeric forms of the compounds.
  • stereoisomer refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.
  • 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 therefore 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 compounds of the present disclosure. There may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups.
  • the compounds of the present disclosure containing asymmetric atoms can be isolated in an optically active pure form or in a racemic form.
  • the optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents. .
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • the ethyl group is "optionally" substituted by halogen, which means that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (CH 2 CH 2 F, CH 2 CH 2 Cl, etc.), or polysubstituted. (CHFCH 2 F, CH 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2, etc.) or completely substituted (CF 2 CF 3 , CF 2 CCl 3 , CCl 2 CCl 3, etc.). It will be understood by those skilled in the art that any substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will not be introduced for any group containing one or more substituents.
  • variable e.g, R a , R b
  • R a , R b its definition in each instance is independent. For example, if a group is replaced by 2 R b , there are separate options for each R b .
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
  • the direction of connection is arbitrary.
  • L 1 when the structural unit When L 1 is selected from “C 1 -C 3 alkylene-O", then L 1 can connect ring Q and R 1 in the direction from left to right to form “ring QC 1 -C 3 alkylene Group -OR 1 ”, you can also connect ring Q and R 1 from right to left to form “ring QOC 1 -C 3 alkylene group -R 1 ”.
  • substituents When a substituent's bond is cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
  • structural unit Indicates that R 5 can be substituted at any position on the benzene ring.
  • bonds depicted by solid and dashed lines Represents a single or double bond.
  • structural unit Include
  • Cm - Cn refers to 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 C n H 2n+1 , which alkyl group may be straight or branched.
  • C 1 -C 10 alkyl is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • alkyl group examples include, but are not limited to, 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, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 6 alkyl "can be understood to mean
  • C 1 -C 3 alkyl is understood to mean a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms.
  • the "C 1 -C 10 alkyl” may include “C 1 -C 6 alkyl” or “C 1 -C 3 alkyl” and other ranges, and the “C 1 -C 6 alkyl” may further include “ C 1 -C 3 alkyl”.
  • alkenyl refers to a linear or branched unsaturated lipid composed of carbon atoms and hydrogen atoms and having at least one double bond. Aliphatic hydrocarbon group.
  • C 2 -C 10 alkenyl is understood to mean a straight-chain or branched unsaturated hydrocarbon radical 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", and even more preferably C 2 or C 3 alkenyl.
  • alkenyl group contains more than one double bond
  • the double bonds may be separated or conjugated to each other.
  • 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.
  • alkynyl refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond.
  • C 2 -C 10 alkynyl is understood to mean a linear or branched unsaturated hydrocarbon radical 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, butyl -2-alkynyl or but-3-ynyl.
  • C 2 -C 10 alkynyl may include “C 2 -C 6 alkynyl” and “C 2 -C 3 alkynyl", and 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 that exists in the form of a single ring, a branched ring, a bridged ring or a spiro ring. Unless otherwise indicated, the carbocyclic ring is generally 3 to 10 membered.
  • C 3 -C 10 cycloalkyl is understood to mean a saturated monocyclic, paracyclic, spirocyclic or bridged ring having 3 to 10 carbon atoms.
  • cycloalkyl group 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]decyl, etc.
  • C 3 -C 10 cycloalkyl may include “C 3 -C 6 cycloalkyl”, and the term “C 3 -C 6 cycloalkyl” is understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, etc.
  • cycloalkenyl refers to a non-aromatic carbon ring that is not fully saturated and exists in the form of a single ring, a branched ring, a bridged ring or a spiro ring. Unless otherwise indicated, the carbocyclic ring is generally 3 to 10 membered. "C 3 -C 10 cycloalkenyl” may include “C 4 -C 10 cycloalkenyl" and "C 5 -C 8 cycloalkenyl".
  • cycloalkenyl group examples include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl, and the like.
  • heterocyclyl refers to a fully saturated or partially saturated (not aromatic heteroaromatic as a whole) monocyclic, paracyclic, spirocyclic or bridged cyclic group containing 1 to 5 ring atoms.
  • Heteroatom or heteroatom group that is, an atomic group containing heteroatoms
  • 3-10 membered heterocyclyl refers to a heterocyclyl with a number of ring atoms of 3, 4, 5, 6, 7, 8, 9 or 10, and its ring atoms contain 1 to 5 independently selected from the above The heteroatom or heteroatom group.
  • 3--10-membered heterocyclyl includes “4-7-membered heterocyclyl", wherein specific examples of 4-membered heterocyclyl include but are not limited to azetidinyl or oxetanyl; 5-membered heterocyclyl Heterocyclyl Specific examples include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydroxazolyl or 2,5-dihydroxazolyl.
  • 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianiyl Alkyl, tetrahydropyridyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclyl include but are not limited to diazepanyl.
  • the heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrole-2(1H)-yl; 5,6-membered bicyclic groups. Specific examples include, but are not limited to, hexahydropyrro[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 benzo-fused cyclic group of the above-mentioned 4-7 membered heterocyclic group, and specific examples include but are not limited to dihydroisoquinolyl and the like.
  • “4-10-membered heterocyclyl” may include “5-10-membered heterocyclyl", “4-7-membered heterocyclyl”, “5-6-membered heterocyclyl”, “6-8-membered heterocyclyl” , "4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered "Heterocycloalkyl” and other scopes, "4-7 membered heterocyclyl” may further include "4-6 membered heterocyclyl", “5-6 membered heterocyclyl", “4-7 membered heterocyclyl” , "4-6 membered heterocycloalky
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ electron system.
  • Aryl groups 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.
  • a ring with 6 carbon atoms for example phenyl; or a ring with 9 carbon atoms (“C 9 aryl”), for example indanyl or indenyl; or a ring with 10 or a ring of 13 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.
  • a ring with 6 carbon atoms (“C 6 aryl”), for example phenyl; or a ring with 9 carbon atoms (“C 9 aryl”), for example indanyl or indenyl; or a ring with 10
  • C 10 aryl A ring of 10 carbon atoms
  • C 6 -C 20 aryl may include "C 6 -C 10 aryl"
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, and S, and the remaining ring atoms are C.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, and S, and the remaining 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 group is selected from the group consisting of 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 quinolyl, quinazole Phylline or isoquinolyl, etc.; or azocinyl, indolizinyl, purinyl, etc.
  • 5-6 membered heteroaryl refers to an aromatic ring system having 5 or 6 ring atoms and containing 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • 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. based on its own knowledge and the contents of 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 tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to salts of pharmaceutically acceptable acids or bases, including salts of compounds with inorganic or organic acids, and salts of compounds with 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 pharmaceutical compositions is to facilitate administration of the compounds of the present disclosure to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious irritating effect on the organism and do 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, etc.
  • the present disclosure also includes isotopically labeled compounds that are the same as those described herein, but in which one or more atoms are replaced by an atom having an atomic weight or mass number different from that typically found in nature.
  • isotopes that may be incorporated into the 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 respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • Certain isotopically labeled compounds of the present disclosure can be used in compound and/or substrate tissue distribution analyses. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are particularly preferred due to 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. This can generally be accomplished by the following procedures similar to those disclosed in the Schemes and/or Examples below, Isotopically labeled compounds of the present disclosure are prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they 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 the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present disclosure can be manufactured using methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, etc.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical compositions may 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, dragees, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or sugar-coated core.
  • suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • dosages of 0.01 mg/kg to 200 mg/kg body weight are administered daily, in single or divided doses.
  • the obtained residue was purified using a silica gel column (the eluent phase was a mixed solvent of petroleum ether containing 30% ethyl acetate) to obtain the title compound 1-2 (1.82g, 8.2mmol, yield: 82%) as a white oil.
  • the obtained residue was purified using a silica gel column (the eluent phase was a mixed solvent of petroleum ether containing 35% ethyl acetate) to obtain the title compound 1-4 (0.61g, 2.25mmol, yield: 41%) as a white oil.
  • Step 4 2-(4'-cyclopropyl-5-(dimethoxymethyl)-6'-methoxy-[2,5'-bipyrimidin]-4-yl)acetate (1 -5)
  • the reaction solution was then cooled to room temperature, the solvent was evaporated under reduced pressure, and water (50 mL) was added to the residue.
  • the resulting mixture was extracted with ethyl acetate (30 mL ⁇ 3 times).
  • the organic phases were mixed, washed with saturated brine (30 mL ⁇ 3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified using a silica gel column (the eluent phase was a mixed solvent of petroleum ether containing 80% ethyl acetate) to obtain the title compound 1-5 as a white solid (0.63g, 1.62mmol, yield: 72%).
  • Step 5 2-(4'-cyclopropyl-5-(dimethoxymethyl)-6'-methoxy-[2,5'-bipyrimidin]-4-yl)-3-(4 -(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)propionic acid ethyl ester (1-6)
  • Dissolve compound 1-5 (0.39g, 1mmol, 1.0eq) in N,N-dimethylformamide (10mL), add sodium hydride (0.05g, 1.2mmol, 1.2eq) at 0°C, and stir 0.5 hours.
  • reactant 5B (0.38g, 1.2mmol, 1.2eq) was added, reacted for 2 hours, the solvent was distilled off under reduced pressure, and water (30mL) was added to the residue.
  • the resulting mixture was extracted with ethyl acetate (30 mL ⁇ 3 times). The organic phases were mixed, washed with saturated brine (30 mL ⁇ 3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified using a silica gel column (the eluent phase was a mixed solvent of petroleum ether containing 60% ethyl acetate) to obtain the title compound 1-6 (0.32g, 0.51mmol, yield: 51%) as a light yellow oil.
  • Step 6 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-methyl-8-(4-(1-methyl-4-(trifluoromethyl)-1H -Imidazol-2-yl)benzyl)pyrido[4,3-d]pyrimidin-7(6H)-one (Compound 1)
  • Dissolve compound 1-6 (0.12g, 0.2mmol, 1.0eq) in toluene (2mL) and acetic acid (2mL), then add the reactant methylamine hydrochloride (0.02g, 0.6mmol, 3eq), and heat the reaction solution to The reaction was carried out at 110°C for 2 hours, the solvent was evaporated under reduced pressure, and water (30 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (30 mL ⁇ 3 times). The organic phases were mixed, washed with saturated brine (30 mL ⁇ 3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Compound 18 in the following table can be synthesized by using similar synthetic steps and methods in Example 1 and using different raw materials c in the following table instead of compound 4B in step 4 in Example 1.
  • Test Example 1 USP1 enzyme in vitro activity detection experiment
  • the USP1 enzyme (Recombinant Human His6-USP1/His6-UAF1 Complex Protein, CF) used in the experiment was purchased from R&D Systems, catalog number E-568-050. After aliquot, store at -80°C.
  • the detection kit (Ub-CHOP2-Reporter Deubiquitination Assay Kit) was purchased from Lifesensors Company, product number is PR1101. After aliquot, store at -80°C. The kit contains a ubiquitinated reporter enzyme. When deubiquitinated by USP1/UAF1, it becomes active. After catalyzing the substrate, the substrate is excited by a 485nm laser to produce a 535nm emission light signal.
  • the IC 50 value of the compound's inhibitory activity on enzyme activity was calculated using the four-parameter Logistic Model method.
  • x represents the logarithmic form of the compound concentration
  • A, B, C and D are four parameters.
  • IC 50 values were further calculated into best fit curves using Xlfit Concentration of compound required for 50% inhibition of enzyme activity.
  • Test Example 2 Inhibition experiment of the disclosed compounds on MDA-MB-436 cell proliferation
  • MDA-MB-436 The cells used in the experiment, MDA-MB-436, were purchased from Kebai Biotechnology Co., Ltd., product number CBP60385. The cells were subcultured in culture medium (DMEM containing 10% FBS) and frozen in liquid nitrogen when the cell passage number was low. The cells used in the experiment did not exceed 15 generations.
  • Detection kit (Luminescent Cell Viability Assay) was purchased from Promega, Cat. No. for G7573. After aliquot, store at -30°C. The kit is a homogeneous detection method for detecting the number of viable cells in culture by quantitatively measuring ATP. The kit produces a luminescent signal proportional to the amount of ATP present, which is directly proportional to the number of cells in the culture.
  • DMEM containing 10% FBS culture medium
  • the highest concentration starts from 10 ⁇ M and is diluted 4 times for a total of 8 concentration points.
  • the chemical luminescence value [RLU] cpd was obtained for 7 days in the drug-added group, and the chemical luminescence value [RLU]cpd was obtained in the DMSO-only group without drug addition for 7 days.
  • Luminescence value [RLU] cell, parallel CTG test on day 0 of the DMSO-free group obtained the chemiluminescence value [RLU] background on day 0.
  • Inhibition rate of compound on proliferation Inhibition rate (%) [1-([RLU]cpd–[RLU]background)/([RLU]cell–[RLU]background)] ⁇ 100%, inhibitory activity of compound on proliferation GI
  • the 50 value is calculated using the four-parameter Logistic Model method.
  • x represents the logarithmic form of the compound concentration
  • A, B, C and D are four parameters.
  • the GI 50 value was further calculated as the compound concentration required for 50% inhibition of proliferation in the best-fit curve using Xlfit.
  • the inhibitory activity of the compounds of the present disclosure on the proliferation of MDA-MB-436 was measured through the above test.
  • the measured GI 50 value is shown in Table 2.
  • Test Example 3 CYP enzyme inhibition test of compounds of the present disclosure
  • CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5 were used to evaluate representative substrate metabolic responses of the five major human CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5).
  • Liquid chromatography tandem mass spectrometry (LC/MS/MS) was used to determine the response of test compounds at different concentrations to phenacetin (CYP1A2), diclofenac sodium (CYP2C9), S-mephenytoin (CYP2C19), and bufuralol hydrochloride. Effects of salt (CYP2D6) and midazolam (CYP3A4/5) metabolic reactions.
  • concentration of the compound to be tested is 0.1, 0.3, 1, 3, 10, 30 ⁇ mol/L or the reaction system of positive compound or blank control and mixed human liver microsomes (0.2mg/mL) is 200 ⁇ L (100mmol/L phosphate buffer, pH 7.4, containing 0.3% DMSO, 0.6% acetonitrile, and 0.1% methanol by volume) and incubated at 37°C for 5 minutes.
  • Peak areas were calculated from the chromatograms.
  • the residual activity ratio (%) is calculated using the following formula:
  • Peak area ratio metabolite peak area/internal standard peak area
  • Residual activity ratio (%) peak area ratio of the compound group to be tested/peak area ratio of the blank group
  • CYP half inhibitory concentration (IC 50 ) was calculated by Excel XLfit 5.3.1.3.
  • Test Example 4 Caco-2 permeability test of compounds of the present disclosure
  • the apparent permeability coefficient (P app ) of the drug was measured and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) in Caco-2 cell model.
  • Caco-2 cells were purchased from the American Type Culture Collection (ATCC), 4-hydroxyethylpiperazineethanesulfonic acid (HEPES) was purchased from Beijing Solebao Technology Co., Ltd., and Hank's Balanced Salt Solution (HBSS) and non-essential amino acids (NEAA) were purchased from Thermo Fisher Scientific, penicillin, streptomycin and trypsin/EDTA were purchased from Solebac, fetal bovine serum (FBS) and DMEM culture medium were purchased from Corning Company , HTS-96-well Transwell plate and other sterile consumables were purchased from Corning Company, Millicell resistance measurement system was purchased from Millipore, K2 was purchased from Nexcelom Bioscience, the Infinite 200 PRO microplate reader was purchased from Tecan, and the MTS2/4 orbital shaker was purchased from IKA Labortechnik.
  • ATCC American Type Culture Collection
  • HPES 4-hydroxyethylpiperazineethanesulfonic acid
  • HBSS Hank
  • the first step cell culture and seeding plate
  • Caco-2 was cultured in a cell culture flask, and the incubator was set to 37°C, 5% CO 2 , and a relative humidity of 95%.
  • Cells can be used to seed Transwell plates when they reach 70-90% confluence. Before cell seeding, add 50 ⁇ L of cell culture medium to each well of the Transwell plate, and add 25 mL of cell culture medium to the lower culture plate. Place the culture plate in a 37°C, 5% CO2 incubator and incubate it for 1 hour before seeding cells. After cell digestion, transfer the cell suspension to a round-bottomed centrifuge tube and centrifuge at 120g for 5 minutes. Resuspend cells in cell culture medium to a final concentration of 6.86 ⁇ 10 5 cells/mL.
  • the cell suspension was added to the 96-well Transwell plate chamber at 50 ⁇ L/well, and the final seeding density was 2.4 ⁇ 10 5 cells/cm 2 . Start changing the medium 24 hours after inoculation, culture for 14-18 days, and change the medium every other day.
  • Caco-2 reaches confluence and completes differentiation after approximately 14 days of culture. At this time, it can be applied to penetration testing.
  • DMSO dilute the 1 mM DMSO solution stock solution of the compound to be tested with transport buffer to obtain a 5 ⁇ M test solution.
  • the control compound digoxin was diluted to 2mM with DMSO and diluted to 10 ⁇ M with the above transport buffer to obtain a control compound test solution.
  • DMSO was also diluted with the above transport buffer to a receiving end solution containing 0.5% DMSO.
  • the integrity of the cell monolayer after 2 hours of incubation was evaluated by the leakage of Lucifer Yellow, and the Lucifer Yellow stock solution was diluted using transport buffer solution (10mM HEPES, pH 7.4) to a final concentration of 100 ⁇ M.
  • transport buffer solution 10mM HEPES, pH 7.4
  • the apparent permeability coefficient (P app , unit: cm/s ⁇ 10 -6 ) is calculated using the following formula:
  • V A is the volume of the receiving end solution (Ap ⁇ Bl is 0.3mL, Bl ⁇ Ap is 0.1mL), Area is the Transwell-96-well plate membrane area (0.143cm 2 ); time is the incubation time (unit: s ); [drug] receiver is the drug concentration at the receiving end; [drug] initial, donor is the initial drug concentration at the giving end. .
  • the efflux rate is calculated using the following formula:
  • P app (BA) is the apparent permeability coefficient from the base end to the top
  • P app(AB) is the apparent permeability coefficient from the tip to the base.
  • the recovery rate is calculated using the following formula:
  • V A is the solution volume at the receiving end (unit: mL);
  • V D is the solution volume at the giving end (unit: mL).
  • Leakage rate is calculated using the following formula:
  • I receiver refers to the fluorescence density of the receiving hole (0.3mL)
  • I donor refers to the fluorescence density of the dosing hole (0.1mL)
  • LY %. LY ⁇ 1.5% indicates that the single-layer cell membrane is intact.
  • Test Example 5 In vitro metabolic stability detection of rat liver cells of the disclosed compound
  • the resulting samples were quantified from ion chromatograms. Calculate the residual rate based on the peak area of the test compound or positive control. The slope k was determined from a linear regression of the natural logarithm of the residual rate versus incubation time using Microsoft Excel.
  • Intrinsic clearance (in vitro CL int , ⁇ L/min/ 10 cells) was calculated from the slope value according to the following equation:
  • N number of cells per well (0.125 ⁇ 10 6 cells)
  • the measured intrinsic clearance rate values of rat hepatocytes are shown in Table 5.
  • the solubility of the test compound in PBS pH 7.4 was determined using LC/MS/MS.
  • the obtained samples were detected by LC/MS/MS. Calculate the sample solubility based on the peak areas of the test compound solution and the standard concentration solution. Calculated as follows:
  • sample is the solubility of the sample to be tested
  • Area ratio sample is the ratio of the sample peak area to the internal standard peak area in the sample to be tested
  • INJ VOL STD is the injection volume of standard concentration solution
  • DF sample is the dilution factor of the sample solution to be tested
  • [STD] is the concentration of standard concentration solution
  • INJ VOL sample is the injection volume of the sample solution to be tested
  • Area ratio STD is the ratio of the sample peak area to the internal standard peak area in the standard concentration solution.

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Abstract

L'invention concerne un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci en tant qu'inhibiteur d'USP1 et une composition pharmaceutique comprenant le composé ou le sel pharmaceutiquement acceptable de celui-ci. Le composé et la composition pharmaceutique peuvent être utilisés pour prévenir ou traiter des maladies associées à USP1.
PCT/CN2023/109974 2022-07-28 2023-07-28 Composé de pyrimidine fusionné à un hétérocycle et son utilisation Ceased WO2024022519A1 (fr)

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WO2021175270A1 (fr) * 2020-03-03 2021-09-10 轶诺(浙江)药业有限公司 Nouvel inhibiteur de hpk1, son procédé de préparation et son application

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CN1503797A (zh) * 2001-02-26 2004-06-09 田边制药株式会社 吡啶并嘧啶或二氮杂萘衍生物
CN108473495A (zh) * 2015-11-20 2018-08-31 福马治疗有限公司 作为泛素-特异性蛋白酶1抑制剂的嘌呤酮
WO2018049152A1 (fr) * 2016-09-09 2018-03-15 Incyte Corporation Dérivés de pyrazolopyrimidine en tant que modulateurs de hpk1 et leurs utilisations pour le traitement du cancer
WO2020068729A1 (fr) * 2018-09-25 2020-04-02 Incyte Corporation Composés pyrazolo[4,3-d]pyrimidine en tant que modulateurs des alk2 et/ou fgfr
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Publication number Priority date Publication date Assignee Title
WO2025102016A1 (fr) 2023-11-10 2025-05-15 Vrise Therapeutics, Inc. Nouvelles molécules utilisées en tant qu'inhibiteurs de la voie de réparation des dommages à l'adn

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