Heterocyclic pyrimidine compound and application thereof

Abstract

Provided are a compound of formula (I) or a pharmaceutically acceptable salt thereof as a USP1 inhibitor, a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, the compound and the pharmaceutical composition being useful for the prevention or treatment of USP1-related diseases. # imgabs0 #

Description

Heterocyclic pyrimidine compounds and their applications

[0001] This disclosure claims priority to a prior application filed with the State Intellectual Property Office of China on July 28, 2022, with patent application number 202310900509.6, entitled “Heterocyclic and pyrimidine compounds and their applications.” The entire text of the prior application is incorporated herein by reference. Technical Field

[0002] 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 their use as ubiquitin-specific protease 1 (USP1) inhibitors in preventing or treating diseases associated with USP1. Background Art

[0003] Ubiquitination is a reversible process that involves a series of deubiquitinating enzymes (DUBs) that regulate various cellular processes by deubiquitinating substrates. DUBs are encoded by approximately 100 human genes and are divided into 6 families, the largest of which is the ubiquitin-specific proteases (USPs) with more than 50 members. DUBs and their substrate proteins are often dysregulated in cancer, a phenomenon that supports the hypothesis that targeting specific DUB enzymes can increase the ubiquitination and degradation of oncogenic substrates and regulate the activity of other key proteins involved in tumor growth, survival, differentiation, and tumor microenvironment maintenance (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)).

[0004] Ubiquitin-specific protease 1 (USP1) is a cysteine ​​isopeptidase of the USP subfamily of DUBs. The full-length human USP1 consists of 785 amino acids, including a catalytic triad consisting of Cys90, His593 and Asp751 (Nijman, SMB, 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 can only obtain full enzymatic activity when it combines with the auxiliary factor UAF1 to form a complex required for deubiquitinase activity. The USP1 / UAF1 complex deubiquitinates monoubiquitinated PCNA (proliferating cell nuclear antigen) and monoubiquitinated FANCD2 (Fanconi anemia group complementary group USP1 is a key protein in the repair of DNA damage caused by DNA crosslinking agents such as cisplatin and mitomycin C (MMC). The USP1 / UAF1 complex also deubiquitinates FANCI (Fanconi anemia complementation group 1). 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 to inhibit DNA repair can induce apoptosis in multiple myeloma cells and enhance the sensitivity of lung cancer cells to cisplatin. These findings suggest that USP1 is a promising target for chemotherapy of certain cancers.

[0005] In summary, targeted inhibition of USP1 protein is a potential approach to prevent or treat cancer and other diseases. Therefore, the development of small molecule inhibitors of USP1 is necessary.

[0006] Summary of the Invention

[0007] In one aspect, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0008] in, Indicates a single bond or a double bond;

[0009] X is selected from N, CR 3 NR 3 or C(O);

[0010] Y is selected from NR 4 or C(O);

[0011] Z is selected from CR 5 or NR 5 ;

[0012] R 3 、R 4 、R 5 independently selected from H, halogen, CN, OH, NH2, -C(O)OR x 、-C(O)R x , -O-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group, the NH2, -O-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R x replace;

[0013] Ring A is selected from C6-C 10 Aryl or 5-10 membered heteroaryl, the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R a replace;

[0014] Ring B is selected from C6-C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C4-C 10 Cycloalkenyl or C3-C 10 Cycloalkyl, the C6-C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C4-C 10 Cycloalkenyl or C3-C 10 The cycloalkyl group is optionally substituted with one or more R b replace;

[0015] Ring C is selected from C6-C 10 Aryl or 5-10 membered heteroaryl, the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R c replace;

[0016] Every R a 、R b 、R c independently selected from halogen, CN, OH, NH2, -C(O)OR x , C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 10Cycloalkyl or 4-10 membered heterocyclic group, the NH2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group is optionally replaced by R x replace,

[0017] or R b 、R c and the atoms they are connected to form C4-C 10 Cycloalkenyl or 4-10 membered heterocyclic group, the C4-C 10 Cycloalkenyl or 4-10 membered heterocyclic group is optionally replaced by R x replace;

[0018] R 1 、R 2 independently selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group is optionally replaced by R x replace,

[0019] or R 1 、R 2 and the atoms they are connected to form C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group, the C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R x replace;

[0020] R x is selected from halogen, CN, OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by C1-C6 alkyl, C3-C 10 The cycloalkyl group or the 4-7 membered heterocyclic group is substituted.

[0021] In some embodiments, R 3 、R 4 、R 5 independently selected from H, -C(O)OR x 、-C(O)R x , -O-C1-C6 alkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group, said -O-C1-C6 alkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R x replace.

[0022] In some embodiments, R 3 、R 4、R 5 Independently selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group, the C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R x replace.

[0023] In some embodiments, R 3 、R 4 、R 5 independently selected from H, CH3, CH2CH3, cyclopropyl, oxetanyl or azetidinyl, wherein the CH3, CH2CH3, cyclopropyl, oxetanyl or azetidinyl is optionally replaced by R x replace.

[0024] In some embodiments, R 3 、R 4 、R 5 Independently selected from H, CH3, CH2CH3, CH2CH2N(CH3)2, cyclopropyl, oxetanyl or

[0025] In some embodiments, R 4 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group, the C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R x replace.

[0026] In some embodiments, R 4 is selected from H, CH3, CH2CH3, cyclopropyl, oxetanyl, azetidinyl, tetrahydrofuranyl or tetrahydropyrrolyl, wherein the CH3, CH2CH3, cyclopropyl, oxetanyl, azetidinyl, tetrahydrofuranyl or tetrahydropyrrolyl is optionally replaced by R x replace.

[0027] In some embodiments, R 4 Selected from H, CH3, CH2CH3, CHF2, CH2CH2F, CH2CHF2, CH2CF3, CH2CH2N(CH3)2, cyclopropyl, oxetanyl,

[0028] In some embodiments, R 5 Selected from H or C1-C6 alkyl.

[0029] In some embodiments, R 5 Selected from H or CH3.

[0030] In some embodiments, ring A is selected from phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted with one or more R a replace.

[0031] In some embodiments, Ring A is selected from phenyl, pyridinyl, or pyrimidinyl, optionally substituted by one or more R a replace.

[0032] In some embodiments, Ring B is selected from C6-C 10 Aryl or 5-10 membered heteroaryl, the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R b replace.

[0033] In some embodiments, Ring B is selected from C6-C 10 Aryl, the C6-C 10 The aryl group is optionally substituted with one or more R b replace.

[0034] In some embodiments, Ring B is selected from phenyl, optionally substituted with one or more R b replace.

[0035] In some embodiments, Ring C is selected from 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R c replace.

[0036] In some embodiments, Ring C is selected from 5-6 membered heteroaryl, said 5-6 membered heteroaryl being optionally substituted with one or more R c replace.

[0037] In some embodiments, Ring C is selected from pyrazolyl or imidazolyl, which is optionally substituted with one or more R c replace.

[0038] In some embodiments, each R a 、R b 、R c independently selected from halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group, the C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group is optionally replaced by R x replace.

[0039] In some embodiments, each R a 、R b 、R cindependently selected from halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-6 membered heterocyclic group, wherein the C1-C6 alkyl, -O-C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group is optionally replaced by R x replace.

[0040] In some embodiments, each R a 、R b 、R c independently selected from halogen, CH3, -CH(CH3)2, -CH2CH3, -O-CH3, cyclopropyl, oxetanyl or azetidinyl, wherein the CH3, -CH(CH3)2, -CH2CH3, -O-CH3, cyclopropyl, oxetanyl or azetidinyl is optionally replaced by R x replace.

[0041] In some embodiments, each R a 、R b 、R c Independently selected from F, CH3, -CH(CH3)2, -CH2CH3, -CHF2, -CF3, -O-CH3, -O-CHF2, cyclopropyl, oxetanyl or

[0042] In some embodiments, R a Selected from C1-C6 alkyl, -O-C1-C6 alkyl or C3-C 10 Cycloalkyl, the C1-C6 alkyl, O-C1-C6 alkyl or C3-C 10 The cycloalkyl group is optionally replaced by R x replace.

[0043] In some embodiments, R a is selected from isopropyl, -O-CH3, -O-CHF2 or cyclopropyl.

[0044] In some embodiments, R b Selected from halogen or -O-C1-C6 alkyl.

[0045] In some embodiments, R b Selected from F or -O-CH3.

[0046] In some embodiments, R c Selected from C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group, the C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group is optionally replaced by R x replace.

[0047] In some embodiments, R c is selected from C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group is optionally replaced by R x replace.

[0048] In some embodiments, R c Selected from CH3, -CH(CH3)2, -CH2CH3, -CF3, cyclopropyl, oxetanyl or

[0049] In some embodiments, R b 、R c and the atoms to which they are attached together form a 4-10 membered heterocyclic group, the 4-10 membered heterocyclic group being optionally replaced by R x replace.

[0050] In some embodiments, R 1 、R 2 independently selected from H, halogen, C1-C6 alkyl or C3-C 10 Cycloalkyl, the C1-C6 alkyl or C3-C 10 The cycloalkyl group is optionally replaced by R x replace.

[0051] In some embodiments, R 1 and R 2 Both are H.

[0052] In some embodiments, R x is selected from halogen, NH2 or C1-C6 alkyl, wherein the NH2 or C1-C6 alkyl is optionally replaced by C1-C6 alkyl, C3-C 10 The cycloalkyl group or the 4-7 membered heterocyclic group is substituted.

[0053] In some embodiments, R x is selected from halogen, NH2 or C1-C6 alkyl, wherein the NH2 is optionally substituted by C1-C6 alkyl.

[0054] In some embodiments, R x Selected from F, N(CH3)2 or C1-C6 alkyl.

[0055] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0056] Ring A, Ring B, Ring C, R 1 、R 2 、R 4 、R 5As defined above.

[0057] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (III) or a pharmaceutically acceptable salt thereof,

[0058] in, Indicates a single bond or a double bond; Ring A, Ring B, Ring C, R 1 、R 2 , X, and Z are as defined above.

[0059] In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (III-a) or a pharmaceutically acceptable salt thereof,

[0060] Ring A, Ring B, Ring C, R 1 、R 2 、R 5 As defined above.

[0061] In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (III-b) or a pharmaceutically acceptable salt thereof,

[0062] Ring A, Ring B, Ring C, R 1 、R 2 、R 3 、R 5 As defined above.

[0063] In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (III-c) or a pharmaceutically acceptable salt thereof,

[0064] Ring A, Ring B, Ring C, R 1 、R 2 、R 3 、R 5 As defined above.

[0065] 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,

[0066] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0067] 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, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0068] In another aspect, the present disclosure provides 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 a disease mediated by USP1.

[0069] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating a disease mediated by USP1.

[0070] 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 a disease mediated by USP1.

[0071] In some embodiments, the USP1 -mediated disease is a tumor.

[0072] In some embodiments, the tumor is, for example, a solid tumor, an adenocarcinoma, or a hematological cancer.

[0073] Definitions and Explanations of Terms

[0074] Unless otherwise indicated, the terms used in this disclosure have the following meanings. The definitions of groups and terms described in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the examples, may be combined and coupled with each other in any manner. A particular term should not be considered as undefined or unclear unless specifically defined, but should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0075] In this article Indicates the attachment site.

[0076] The diagrammatic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge and dotted wedge keys are used. To indicate the absolute configuration of a stereocenter, use black real and imaginary bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0077] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a 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 predominates, while in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

[0078] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0079] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so that the compounds of the present invention 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 mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and mixtures thereof. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of which are within the definition of the compounds of the present invention and mixtures thereof. Compounds of the present disclosure containing an asymmetric atom 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 reagents.

[0080] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0081] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group may 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 comprising one or more substituents, any sterically impossible and / or incomposable replacement or substitution pattern will not be introduced.

[0082] When any variable (such as R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options.

[0083] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0084] When one of the variables is selected from a chemical bond or does not exist, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0085] When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary. L in 1 When selected from "C1-C3 alkylene-O", L 1 You can connect rings Q and R from left to right. 1 Constitute "ring Q-C1-C3 alkylene-OR 1 ", you can also connect rings Q and R from right to left 1 Constitute the "ring QO-C1-C3 alkylene-R 1 ”.

[0086] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. Represents R 5 Substitution can occur at any position on the benzene ring.

[0087] In this paper, the bonds depicted by solid and dashed lines represents a single bond or a double bond. For example, the structural unit Include

[0088] In this article, C m -C n It means having an integer number of carbon atoms in the range mn. For example, "C1-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.

[0089] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10 The term "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. Specific examples of the alkyl radical 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- dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C1-C6 alkyl" can be understood to mean an alkyl group having 1 to 6 carbon atoms, and specific examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C3 alkyl" can be understood to mean a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms. The "C1-C 10 The term "alkyl" may include "C1-C6 alkyl" or "C1-C3 alkyl" and the like, and the "C1-C6 alkyl" may further include "C1-C3 alkyl".

[0090] 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. 10 "Alkenyl" is understood to mean a linear 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, "C2-C 10"Alkenyl" is preferably "C2-C6 alkenyl", further preferably "C2-C4 alkenyl", and further preferably C2 or C3 alkenyl. It will be understood that when the alkenyl contains more than one double bond, the double bonds may be separated from each other or conjugated. Specific examples of the alkenyl 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, etc.

[0091] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. 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. "C2-C 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH 3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl or but-3-ynyl. "C2-C 10 The term "alkynyl" may include "C2-C6 alkynyl" and "C2-C3 alkynyl". Examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), and prop-2-ynyl (-CH2C≡CH).

[0092] The term "cycloalkyl" refers to a fully saturated carbon ring that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring. The term "C3-C 10 The term "cycloalkyl" is understood to mean a saturated monocyclic, bicyclic, spirocyclic or bridged ring having 3 to 10 carbon atoms. Specific examples of the cycloalkyl group 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, and the like. The term "C3-C 10 "Cycloalkyl" may include "C3-C6 cycloalkyl". The term "C3-C6 cycloalkyl" may be 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.

[0093] The term "cycloalkenyl" refers to a non-aromatic carbon ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged or spirocyclic ring. Unless otherwise indicated, the carbon ring is usually a 3- to 10-membered ring. "C3-C 10 The cycloalkenyl group may contain a C4-C 10 "Cycloalkenyl" and "C5-C8 cycloalkenyl". Specific examples of the cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl, etc.

[0094] The term "heterocyclyl" refers to a fully saturated or partially saturated (heteroaromatic group that is not aromatic as a whole) monocyclic, fused, spirocyclic or bridged ring group, which contains 1 to 5 heteroatoms or heteroatomic groups (i.e., heteroatom-containing groups) in its ring atoms, wherein the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (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-. The term "3-10 membered heterocyclyl" refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1 to 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms in its ring atoms. “3-10 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; specific examples of 5 membered heterocyclic group 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 group include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7 membered heterocyclic group 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]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups 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 benzo-fused ring group of the above-mentioned 4-7-membered heterocyclic groups, specific examples of which include but are not limited to dihydroisoquinolinyl 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", etc., and "4-7 membered heterocyclyl" may further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", etc. Although some bicyclic heterocyclyl groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl group as a whole is still non-aromatic.

[0095] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 20 "Aryl" is understood to be an aromatic radical having 6 to 20 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 or a ring having 13 carbon atoms ("C 13 aryl) such as fluorenyl; or a ring having 14 carbon atoms ("C 14 The term "C6-C 10 "Aryl" is understood to be an aromatic radical having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 The term "C6-C 20 "Aryl" may contain "C6-C 10 "Aryl"

[0096] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system with aromatic character, which contains at least one ring atom selected from N, O, S, and the remaining 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 containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or acinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "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.

[0097] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0098] The term "therapeutically effective amount" means

[0099] An amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein.

[0100] The amount of a compound of the disclosure that constitutes a "therapeutically effective amount" varies 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 their own knowledge and this disclosure.

[0101] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0102] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0103] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0104] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0105] The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0106] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 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 et al.

[0107] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 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. Isotopically-labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.

[0108] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and 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.

[0109] Typical routes of administration of the disclosed compounds, 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.

[0110] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0111] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound 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 a patient.

[0112] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0113] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0114] In all methods of administration of the compounds of formula (I) described herein, the dosage administered per day is 0.01 mg / kg to 200 mg / kg body weight, in the form of single or divided doses. DETAILED DESCRIPTION

[0115] The present disclosure is described in detail below with reference to the embodiments, but the following embodiments should not be construed as limiting the scope of the present disclosure.

[0116] Example 1 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)

[0117] Step 1: 2,4-dichloro-5-(dimethoxymethyl)pyrimidine (1-2)

[0118] 2,4-Dichloropyrimidine-5-carboxaldehyde (1.75 g, 10 mmol, 1 eq) and trimethyl orthoformate (2.12 g, 20 mmol, 2 eq) were dissolved in methanol (20 mL) and stirred at 65°C for 5 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and water (50 mL) was added to the resulting residue. The resulting mixture was extracted with ethyl acetate (50 mL x 3 times). The organic phases were combined, washed with saturated brine (30 mL x 3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 30% ethyl acetate) to obtain the title compound 1-2 as a white oil (1.82 g, 8.2 mmol, yield: 82%).

[0119] Step 2: Diethyl 2-(2-chloro-5-(dimethoxymethyl)pyrimidin-4-yl)malonate (1-3)

[0120] Compound 2B (1.57 g, 9.84 mmol, 1.2 eq) was dissolved in tetrahydrofuran (20 mL). Sodium hydride (0.59 g, 9.84 mmol, 1.2 eq) was added at 0°C and stirred for 0.5 hours. Then, 2,4-dichloro-5-(dimethoxymethyl)pyrimidine (1.82 g, 8.2 mmol, 1 eq) was added. The reaction mixture was heated to 80°C for 2 hours. The reaction mixture was then cooled to room temperature and the solvent was removed by distillation under reduced pressure. Water (30 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The residue was purified on a silica gel column (eluting with a mixture of 20% ethyl acetate in petroleum ether) to obtain the title compound 1-3 (1.9 g, 5.5 mmol, yield: 67%) as a white oil.

[0121] Step 3: Ethyl 2-(2-chloro-5-(dimethoxymethyl)pyrimidin-4-yl)acetate (1-4)

[0122] Compound 1-3 (1.9 g, 5.5 mmol, 1.0 eq) was dissolved in ethanol (30 mL), and sodium ethoxide (0.025 g, 0.55 mmol, 0.1 eq) was added. The mixture was heated to 85°C and stirred for 10 hours. The reaction solution was then cooled to room temperature, and the solvent was removed by distillation under reduced pressure. Water (50 mL) was added to the resulting residue. The resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified on a silica gel column (eluting with a mixture of 35% ethyl acetate in petroleum ether) to obtain the title compound 1-4 (0.61 g, 2.25 mmol, yield: 41%) as a white oil.

[0123] Step 4: Ethyl 2-(4'-cyclopropyl-5-(dimethoxymethyl)-6'-methoxy-[2,5'-bipyrimidinyl]-4-yl)acetate (1-5)

[0124] Compound 1-4 (0.61 g, 2.25 mmol, 1.0 eq) and compound 4B (0.57 g, 2.92 mmol, 1.3 eq) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.2 g, 0.25 mmol, 0.1 eq) and potassium phosphate (0.95 g, 4.5 mmol, 2 eq) were added. The reaction mixture was heated to 100°C and stirred for 3 hours. The reaction mixture was then cooled to room temperature, and the solvent was removed by distillation under reduced pressure. Water (50 mL) was added to the resulting residue. The resulting mixture was extracted with ethyl acetate (30 mL x 3 times). The organic phases were combined, washed with saturated brine (30 mL x 3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column (eluting phase was a mixed solvent of petroleum ether containing 80% ethyl acetate) to give the title compound 1-5 as a white solid (0.63 g, 1.62 mmol, yield: 72%).

[0125] Step 5: Ethyl 2-(4'-cyclopropyl-5-(dimethoxymethyl)-6'-methoxy-[2,5'-bipyrimidinyl]-4-yl)-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)propanoate (1-6)

[0126] Compound 1-5 (0.39 g, 1 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (0.05 g, 1.2 mmol, 1.2 eq) was added at 0°C and stirred for 0.5 hours. Reactant 5B (0.38 g, 1.2 mmol, 1.2 eq) was then added and allowed to react for 2 hours. The solvent was then removed by distillation under reduced pressure, and water (30 mL) was added to the resulting residue. The resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified on a silica gel column (eluting with a mixture of 60% ethyl acetate and petroleum ether) to afford the title compound 1-6 (0.32 g, 0.51 mmol, yield: 51%) as a pale yellow oil.

[0127] 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)

[0128] Compound 1-6 (0.12 g, 0.2 mmol, 1.0 eq) was dissolved in toluene (2 mL) and acetic acid (2 mL). Methylamine hydrochloride (0.02 g, 0.6 mmol, 3 eq) was then added. The reaction mixture was heated to 110°C for 2 hours. The solvent was removed by distillation under reduced pressure, and water (30 mL) was added to the resulting residue. The resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by preparative chromatography (Waters Xbridge C18, gradient elution: 10-90% acetonitrile in water) to afford the title compound 1 as a yellow solid (21 mg, 19% yield). m / z (ESI): 548.2 [M+H] + .

[0129] 1 H NMR (400MHz, DMSO-d6) δ9.29(s,1H),9.24(s,1H),8.70(s,1H),7.88(s,1H),7.53(d,J=8.0Hz,2H),7.42(d ,J=8.1Hz,2H),4.20(s,2H),3.90(s,3H),3.78(s,3H),3.72(s,3H),1.86(s,1H),1.07(s,2H),0.89(s,2H).

[0130] Example 2

[0131] Using similar synthetic steps and methods as in Example 1, and using different raw materials a in the table below to replace the methylamine hydrochloride in step 6 of Example 1, compounds 2 to 12 in the table below can be synthesized.

[0132] Example 3

[0133] Using similar synthetic steps and methods as in Example 1, and replacing compound 5B in step 5 of Example 1 with different starting materials b in the table below, compounds 13 to 17 in the table below can be synthesized.

[0134] Example 4

[0135] Using similar synthetic steps and methods as in Example 1, and replacing compound 4B in step 4 of Example 1 with different starting materials c in the table below, compound 18 in the table below can be synthesized.

[0136] Example 5 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-difluoromethyl-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[4,3-d]pyrimidin-7(6H)-one (Compound 19)

[0137] Compound 2 (20.0 mg, 0.037 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (1 mL), potassium carbonate (15.5 mg, 0.11 mmol, 3 eq) was added, followed by compound 19a (17.1 mg, 0.11 mmol, 3 eq). The reaction mixture was heated to 80°C for 2 hours. The resulting solution was directly purified by preparative chromatography (Waters Xbridge C18, mobile phase: 10-90% acetonitrile in water, gradient elution) to afford the title compound 19 as a solid (7 mg, 32% yield). m / z (ESI): 584.2 [M+H] + .

[0138] 1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.43(s,1H),8.75(s,1H),7.89(s,1H),7.96-7.94(m,1H),7.60-7.56(m,2H),7.4 1-7.38(m,2H),4.51-4.46(m,2H),3.88(s,3H),3.72(s,3H),1.80-1.74(m,1H),1.09-1.06(m,2H),0.89-0.82(m,2H).

[0139] Test Example 1: USP1 enzyme in vitro activity detection experiment

[0140] Experimental instruments:

[0141] Experimental Materials:

[0142] The USP1 enzyme (Recombinant Human His6-USP1 / His6-UAF1 Complex Protein, CF) used in this experiment was purchased from R&D Systems, Cat. No. E-568-050. Store at -80°C after aliquoting.

[0143] The detection kit (Ub-CHOP2-Reporter Deubiquitination Assay Kit) was purchased from LifeSensors, catalog number PR1101. Store at -80°C after aliquoting. The kit contains a ubiquitinated reporter enzyme, which becomes active after deubiquitination by USP1 / UAF1. Upon substrate excitation at 485 nm, the substrate emits a 535 nm light signal.

[0144] Other reagents and consumables required for the experiment are as follows:

[0145] Experimental methods:

[0146] Test compounds were dissolved in DMSO to 10 mM. Using an ECHO instrument, compounds and pure DMSO were plated into each well of a 384-well plate. Starting at a maximum concentration of 3 μM, 3-fold dilutions were performed for a total of eight concentration points. 50 nL of test compound or DMSO (as a control) was added to each well. The instrument used different ratios to generate a series of sample dilutions (3000 nM, 1000 nM, 333 nM, 111 nM, 37 nM, 12 nM, 4.1 nM, and 1.4 nM). The enzyme was diluted in freshly prepared reaction solution (20 mM Tris-HCl (pH 8.0), 2 mM CaCl2, 2 mM β-mercaptoethanol, 0.05% CHAPS (CHAPS diluted in ddH2O)). 5 μL of the diluted enzyme reaction solution was added to each well. The enzyme and compound were mixed by centrifugation and vortexing, then centrifuged again and placed on ice. The reporter system and substrate of the kit were diluted in the reaction solution, and 5 μL of the diluted solution was added to each well and centrifuged to mix. Incubate at room temperature for 0.5 hours. The fluorescence signal in each well was measured using a plate reader (excitation wavelength 485 nm, emission wavelength 535 nm). The inhibitory activity IC of the compound on enzyme activity 50 The values ​​were calculated using the four-parameter logistic model method. In the following formula, x represents the logarithm of the compound concentration; F(x) represents the effect value (the inhibition rate of enzyme activity under the conditions of this concentration): F(x) = (A + ((BA) / (1 + ((C / x)^D)))). A, B, C, and D are four parameters. IC was calculated using Xlfit. 50 The values ​​were further calculated as the compound concentration required for 50% inhibition of enzyme activity in the best-fit curve.

[0147] The test results are shown in Table 1.

[0148] Table 1 In vitro inhibitory activity of USP1 enzyme

[0149] Test Example 2: Experimental study on the inhibition of MDA-MB-436 cell proliferation by the disclosed compounds

[0150] Detection based on the CellTiter-Glo luminescent living cell detection system.

[0151] Experimental instruments:

[0152] Experimental Materials:

[0153] The MDA-MB-436 cells used in the experiment were purchased from Kebai Biotechnology Co., Ltd., catalog number CBP60385. The cells were subcultured in culture medium (DMEM containing 10% FBS) and frozen in liquid nitrogen at low cell passages. The cells used in the experiment did not exceed passage 15.

[0154] Detection kit ( The Luminescent Cell Viability Assay was purchased from Promega under the catalog number G7573. Store at -30°C after aliquoting. This assay is a homogenous method for determining the number of viable cells in culture by quantifying ATP. The luminescent signal generated by the assay is proportional to the amount of ATP present, which is directly proportional to the number of cells in the culture.

[0155] The information of other reagents and consumables required for the experiment is as follows

[0156] Experimental methods:

[0157] Cultured cells were digested with 0.25% Trypsin-EDTA solution, harvested, centrifuged, and resuspended in culture medium (DMEM supplemented with 10% FBS) at the adjusted concentration. The cells were seeded into 384-well plates (400 cells / 20 μL / well) and cultured overnight at 37°C in a 5% CO2 incubator. Test compounds were added to the 384-well plates using an Echo sonic pipetting system. Starting at a maximum concentration of 10 μM, the test compounds were diluted four-fold over a total of eight concentration points. 100 nL of test compound or DMSO (control) was added to each well to obtain a series of sample concentrations (10,000 nM, 2,500 nM, 625 nM, 156 nM, 39 nM, 10 nM, 2.4 nM, and 0.61 nM). 30 μL of culture medium was added to each well, mixed by centrifugation, and then centrifuged again. The cells were cultured in a cell culture incubator for 7 days (one column was treated with CTG (CellTiter-Glo) assay solution on the day the cells were treated). After the 7th day, 25 μL of CTG detection solution was added to each well, and the mixture was centrifuged and shaken, and then centrifuged again and placed in the dark at room temperature for 10 minutes. The chemiluminescent signal in each well was measured using a plate reader (emission wavelength 400-700 nm). The chemiluminescent value [RLU] cpd was obtained for the drug-added group on day 7, and the chemiluminescent value [RLU] cell was obtained for the DMSO-free group on day 7. In parallel, the chemiluminescent value [RLU] background was obtained for the CTG test on day 0 of the drug-free group on day 0. Inhibition rate (%) of the compound on proliferation = [1-([RLU] cpd–[RLU] background) / ([RLU] cell–[RLU] background)] × 100%, and the inhibitory activity GI of the compound on proliferation is GI. 50The values ​​were calculated using a four-parameter logistic model. In the following formula, x represents the logarithm of the compound concentration; F(x) represents the effect size (the rate of inhibition of proliferation at that concentration): F(x) = (A + ((BA) / (1 + ((C / x)^D)))). A, B, C, and D are the four parameters. Using Xlfit, GI 50 The values ​​were further calculated as the compound concentration required for 50% inhibition of proliferation in the best-fit curve.

[0158] The inhibitory activity of the disclosed compounds on MDA-MB-436 proliferation was determined by the above test. The measured GI 50 See Table 2 for values.

[0159] Table 2 Inhibitory activity of the disclosed compounds on MDA-MB-436 cell proliferation

[0160] Test Example 3: CYP enzyme inhibition test of the disclosed compounds

[0161] The metabolic reactions of representative substrates of the five major human CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 / 5) were evaluated using 150 pooled human liver microsomes (Corning, Cat. No. 452117). The effects of varying concentrations of the test compounds on the metabolic reactions of phenacetin (CYP1A2), diclofenac sodium (CYP2C9), S-mephenytoin (CYP2C19), bufuralol hydrochloride (CYP2D6), and midazolam (CYP3A4 / 5) were determined by liquid chromatography-tandem mass spectrometry (LC / MS / MS).

[0162] A 200 μL reaction system (100 mmol / L phosphate buffer, pH 7.4, containing 0.3% DMSO, 0.6% acetonitrile, and 0.1% methanol by volume) containing 30 μM phenacetin, 10 μM diclofenac sodium, 35 μM S-mephenytoin, 5 μM bufuralol hydrochloride, 3 μM midazolam, 1 mM reduced nicotinamide adenine dinucleotide phosphate (NADPH), test compounds at concentrations of 0.1, 0.3, 1, 3, 10, and 30 μmol / L, or positive compounds or blank controls) was incubated with mixed human liver microsomes (0.2 mg / mL) at 37°C for 5 minutes. Then, 200 μL of an acetonitrile solution containing 3% formic acid and 40 nM internal standard verapamil was added, and the mixture was centrifuged at 4000 rpm for 50 minutes. The mixture was cooled on ice for 20 minutes and then centrifuged at 4000 rpm for 20 minutes to precipitate the protein. Take 200 μL of the supernatant for LC-MS / MS analysis.

[0163] Peak areas were calculated from the chromatograms.

[0164] The residual activity ratio (%) was calculated using the following formula:

[0165] Peak area ratio = metabolite peak area / internal standard peak area

[0166] Residual activity ratio (%) = peak area ratio of the test compound group / peak area ratio of the blank group

[0167] CYP half-maximal inhibitory concentration (IC 50 ) was calculated using Excel XLfit 5.3.1.3.

[0168] The CYP half-maximal inhibitory concentration (IC 50 ) values ​​are shown in Table 3.

[0169] Table 3. The half-maximal inhibitory concentration (IC) of the compounds of the present disclosure on CYP 50 )

[0170] Test Example 4: Caco-2 permeability test of the disclosed compounds

[0171] The apparent permeability coefficient (P) of the drug was determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS) using a Caco-2 cell model. app ).

[0172] In this test example, Caco-2 cells were purchased from the American Type Culture Collection (ATCC), 4-hydroxyethylpiperazineethanesulfonic acid (HEPES) was purchased from Beijing Solebold Technology Co., Ltd., 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 Solebold, fetal bovine serum (FBS) and DMEM medium were purchased from Corning, HTS-96-well Transwell plates and other sterile consumables were purchased from Corning, and the Millicell resistance measurement system was purchased from Millipore. K2 was purchased from Nexcelom Bioscience, Infinite 200 PRO microplate reader was purchased from Tecan, and MTS2 / 4 orbital shaker was purchased from IKA Labortechnik.

[0173] First step: cell culture and plating

[0174] Caco-2 was cultured in a cell culture flask in an incubator set at 37°C, 5% CO2, and a relative humidity of 95%. When the cell confluence reaches 70-90%, it can be used to inoculate the Transwell plate. Before cell inoculation, 50 μL of cell culture medium was added to each well of the Transwell plate chamber, and 25 mL of cell culture medium was added to the lower culture plate. The culture plate was placed in a 37°C, 5% CO2 incubator and incubated for 1 hour before it could be used to inoculate cells. After cell digestion, the cell suspension was transferred to a round-bottom centrifuge tube and centrifuged at 120g for 5 minutes. The cells were resuspended in cell culture medium to a final concentration of 6.86×10 5 The cell suspension was added to the chamber of a 96-well Transwell plate at 50 μL / well, with a final seeding density of 2.4×10 5 cells / cm 2 . Start changing the medium 24 hours after inoculation and culture for 14-18 days, changing the medium every other day.

[0175] Step 2: Evaluation of cell monolayer integrity

[0176] After about 14 days of culture, Caco-2 cells reach confluence and complete differentiation. At this point, they can be used for penetration tests. The resistance of the monolayer membrane is measured using a resistance meter (Millipore, USA), and the resistance of each well is recorded. After the measurement is completed, the cells are returned to the incubator. Calculation of resistance: Measured resistance (ohms) × membrane area (cm 2 )=TEER value (ohm·cm 2 ), if the TEER value is <230ohms·cm 2 , then the hole cannot be used for penetration test.

[0177] Step 3 Solution preparation

[0178] Weigh 2.38 g HEPES and 0.35 g sodium bicarbonate respectively, add 900 mL pure water to dissolve them, then add 100 mL 10× HBSS and stir evenly, adjust the pH to 7.4, and finally filter to obtain 1 L transport buffer (HBSS, 10 mM HEPES, pH 7.4).

[0179] A 1 mM stock solution of the test compound in DMSO was diluted with transport buffer to yield a 5 μM test solution. A control compound, digoxin, was diluted to 2 mM with DMSO and then to 10 μM with the aforementioned transport buffer to yield a control compound test solution. Separately, DMSO was also diluted with the aforementioned transport buffer to yield a 0.5% DMSO-containing receiver solution.

[0180] Step 4: Drug penetration test

[0181] Remove the Transwell plate from the incubator, rinse the cell monolayer twice with transport buffer (10 mM HEPES, pH 7.4), and incubate at 37°C for 30 minutes.

[0182] To measure the rate of compound transport from the apical to basolateral side, add 125 μL of test solution to each well of the upper (apical) chamber. Immediately transfer 50 μL of the solution from the apical side to 200 μL of acetonitrile containing the internal standard (0.1 μM tolbutamide) as the initial apical-to-basolateral sample. Add 235 μL of receiver solution to each well of the lower (basolateral) chamber.

[0183] To measure the rate of compound transport from the basolateral to the apical side, add 285 μL of the receiver solution to each well of the upper (apical) chamber. Immediately transfer 50 μL of the solution from the apical side to 200 μL of acetonitrile containing the internal standard (0.1 μM tolbutamide) as the initial basolateral-to-apical sample. Add 75 μL of the test solution to each well of the lower (basolateral) chamber.

[0184] Combine the upper and lower transport devices and incubate at 37°C for 2 hours.

[0185] After incubation, 50 μL of sample was taken from each well of the upper and lower chambers of the Transwell plate and added to a new sample tube. 200 μL of acetonitrile containing the internal standard (0.1 μM tolbutamide) was added to each sample tube. After vortexing for 10 minutes, the tube was centrifuged at 3220 g for 40 minutes. 150 μL of the supernatant was aspirated and diluted with 150 μL of water before analysis by LC-MS / MS. All samples were prepared in triplicate.

[0186] After 2 hours of incubation, the integrity of the cell monolayer was assessed by leakage of Lucifer Yellow. The Lucifer Yellow stock solution was diluted to a final concentration of 100 μM using transport buffer (10 mM HEPES, pH 7.4). 100 μL of Lucifer Yellow solution was added to each well of the upper Transwell insert, and 300 μL of transport buffer (10 mM HEPES, pH 7.4) was added to each well of the lower receiver plate. After incubation at 37°C for 30 minutes, 80 μL of the solution was aspirated from each well into a new 96-well plate. Fluorescence was measured using a microplate reader with an excitation wavelength of 485 nm and an emission wavelength of 530 nm.

[0187] Step 5: Data Analysis

[0188] All calculations were performed using Microsoft Excel. Peak areas were determined using extracted ion chromatograms.

[0189] Apparent permeability coefficient (P app , unit: cm / s×10 -6 ) is calculated using the following formula:

[0190] In the formula: V A is the volume of the receiving end solution (Ap→Bl is 0.3 mL, Bl→Ap is 0.1 mL), Area is the Transwell-96 well plate membrane area (0.143 cm 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 drug delivery end.

[0191] The efflux rate is calculated using the following formula:

[0192] In the formula: P app(B-A) is the apparent permeability from the base end to the top end;

[0193] P app(A-B) is the apparent permeability from the top to the base.

[0194] The recovery rate was calculated using the following formula:

[0195] In the formula: V A is the volume of the solution at the receiving end (unit: mL); V D is the volume of the solution at the administration end (unit: mL).

[0196] The leakage rate is calculated using the following formula:

[0197] In the formula: I receiver Refers to the fluorescence density of the receiving well (0.3 mL), I donor It refers to the fluorescence density of the drug-dosed well (0.1 mL), expressed as LY (%). LY < 1.5% indicates that the monolayer cell membrane is intact.

[0198] The Caco-2 permeability data of the compounds of the present disclosure obtained after testing are shown in Table 4.

[0199] Table 4. Caco-2 permeability data of compounds of the present disclosure

[0200] Test Example 5: In vitro metabolic stability test of rat hepatocytes of the disclosed compounds

[0201] The compound concentrations in the reaction system were determined by LC / MS / MS to calculate the intrinsic clearance of the test compounds and to evaluate their in vitro metabolic stability in rat hepatocytes.

[0202] 198 μL of 0.5×10 6 The reaction was initiated by adding a mixture of rat hepatocytes at 50 cells / mL and 2.0 μL of 100 μM test compound or positive control (verapamil) to the incubation plate. Incubation was performed at 37°C and 900 rpm. At 0, 15, 30, 60, 90, and 120 minutes, 25 μL of the incubation system was transferred to a stop plate (150 μL of acetonitrile containing 100 nM alprazolam, 200 nM caffeine, and 100 nM tosylbutamide per well). The plate was then vortexed for 5 minutes. The stop plate was centrifuged at 3220 g for 45 minutes. 100 μL of the supernatant of each compound was transferred to a 96-well sample plate, and 100 μL of purified water was added to dilute the sample.

[0203] The resulting samples were quantified by ion chromatogram. The residual rate was calculated based on the peak area of ​​the test compound or positive control. The slope k was determined by linear regression of the natural logarithm of the residual rate against the incubation time using Microsoft Excel.

[0204] Intrinsic clearance (in vitro CL int , μL / min / 10 6 cells) was calculated from the slope value according to the following equation:

[0205] in vitro CL int =-kV / N

[0206] V = incubation volume (0.25 mL);

[0207] N = number of cells per well (0.125 × 10 6 cell)

[0208] The measured rat hepatocyte intrinsic clearance values ​​are shown in Table 5.

[0209] Table 5. Intrinsic clearance of compounds disclosed herein by rat hepatocytes

[0210] Test Example 6: Compound Solubility (PBS pH 7.4) Test

[0211] The solubility of the test compounds in PBS pH 7.4 was determined by LC / MS / MS.

[0212] Mix 6 μL of a 10 mM DMSO solution of the test compound with 194 μL of DMSO to create a 300 μM solution. Mix 5 μL of this solution with 5 μL of PBS pH 7.4 and add 490 μL of water and acetonitrile (1:1) containing the internal standard to create a 3 μM standard solution. The dilution factor of the standard solution can be adjusted based on the LC / MS response.

[0213] Take 15 μL of a 10 mM solution of the test compound in DMSO and add it to 485 μL of PBS, pH 7.4. Add a stir bar and shake the solubility vial at 25°C and 1100 rpm for 2 hours. After shaking, remove the stir bar, transfer the sample to a filter plate, and filter using a vacuum manifold. Mix 5 μL of the filtrate with 5 μL of PBS, pH 7.4, and add 490 μL of a 1:1 mixture of water and acetonitrile containing an internal standard to prepare the test solution. The dilution factor can be adjusted based on the solubility value and the strength of the LC / MS response.

[0214] The obtained samples were analyzed by LC / MS / MS. The sample solubility was calculated based on the peak areas of the test compound solution and the standard concentration solution. The calculation formula is as follows:

[0215] [Sample] is the solubility of the sample to be tested;

[0216] Area ratio sample is the ratio of the sample peak area to the internal standard peak area in the sample to be tested;

[0217] INJ VOL STD is the injection volume of the standard concentration solution;

[0218] DF sample is the dilution ratio of the sample solution to be tested;

[0219] [STD] is the concentration of the standard concentration solution;

[0220] INJ VOL sample is the injection volume of the sample solution to be tested;

[0221] Area ratio STD is the ratio of the sample peak area to the internal standard peak area in the standard concentration solution.

[0222] The solubility of the compounds measured by this method is shown in Table 6.

[0223] Table 6. Solubility of compounds of the present disclosure in PBS pH 7.4

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, Indicates a single bond or a double bond; 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 independently selected from H, halogen, CN, OH, NH2, -C(O)OR x 、-C(O)R x , -O-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group, the NH2, -O-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R x replace; Ring A is selected from C6-C 10 Aryl or 5-10 membered heteroaryl, the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R a replace; Ring B is selected from C6-C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C3-C 10 Cycloalkenyl or C3-C 10 Cycloalkyl, the C6-C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C3-C 10 Cycloalkenyl or C3-C 10 The cycloalkyl group is optionally substituted with one or more R b replace; Ring C is selected from C6-C 10 Aryl or 5-10 membered heteroaryl, the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R c replace; Every R a 、R b 、R c independently selected from halogen, CN, OH, NH2, -C(O)OR x , C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group, the NH2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group is optionally replaced by R x replace, or R b 、R c and the atoms they are connected to form C3-C 10 Cycloalkenyl or 4-10 membered heterocyclic group, the C3-C 10 Cycloalkenyl or 4-10 membered heterocyclic group is optionally replaced by R x replace; R 1 、R 2 independently selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group is optionally replaced by R x replace, or R 1 、R 2 and the atoms they connect to form C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group, the C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R x replace; R x is selected from halogen, CN, OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by C1-C6 alkyl, C3-C 10 The cycloalkyl group or the 4-7 membered heterocyclic group is substituted.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 3 、R 4 、R 5 independently selected from H, -C(O)OR x 、-C(O)R x , -O-C1-C6 alkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group, said -O-C1-C6 alkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R x replace.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: R 3 、R 4 、R 5 Independently selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group, the C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R x replace.

4. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that: Ring A is selected from phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted by one or more R a replace.

5. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 4, characterized in that: Ring B is selected from C6-C 10 Aryl or 5-10 membered heteroaryl, the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R b replace.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that: Ring B is selected from C6-C 10 Aryl, the C6-C 10 The aryl group is optionally substituted with one or more R b replace.

7. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 6, characterized in that: Ring C is selected from 5-10 membered heteroaryl, said 5-10 membered heteroaryl being optionally substituted by one or more R c replace.

8. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 7, characterized in that: Every R a 、R b 、R c independently selected from halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group, the C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group is optionally replaced by R x replace.

9. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 8, characterized in that: R 1 、R 2 independently selected from H, halogen, C1-C6 alkyl or C3-C 10 Cycloalkyl, the C1-C6 alkyl or C3-C 10 The cycloalkyl group is optionally replaced by R x replace.

10. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 9, characterized in that: R x is selected from halogen, NH2 or C1-C6 alkyl, wherein the NH2 or C1-C6 alkyl is optionally replaced by C1-C6 alkyl, C3-C 10 The cycloalkyl group or the 4-7 membered heterocyclic group is substituted.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, Ring A, Ring B, Ring C, R 1 、R 2 、R 4 、R 5 As defined in claim 1.

12. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 11, characterized in that: R 4 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group, the C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R x replace.

13. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 11 or 12, characterized in that: R 5 Selected from H or C1-C6 alkyl.

14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, in, Indicates a single bond or a double bond; Ring A, Ring B, Ring C, R 1 、R 2 , X, Z as defined in claim 1.

15. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof, 16. A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, and a pharmaceutically acceptable excipient.

17. Use of the compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 15, or the pharmaceutical composition according to claim 16, in the preparation of a medicament for preventing or treating a disease mediated by USP1.

18. 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 according to any one of claims 1 to 15, or a pharmaceutical composition according to claim 16 to a mammal, preferably a human, in need of such treatment.

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