Heterocyclic pyrimidine compound, pharmaceutical composition and application thereof

Abstract

The present disclosure discloses compounds of formula (I) or pharmaceutically acceptable salts thereof as USP1 inhibitors, pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts thereof, and their use in the prevention or treatment of USP1 mediated diseases. # imgabs0 #

Description

Heterocyclic-fused pyrimidine compounds, pharmaceutical compositions thereof and uses thereof

[0001] This disclosure claims the priority of a prior application filed with the China National Intellectual Property Administration on October 09, 2022, with patent application number 202211229728.2 and invention title "Heterocyclic-fused pyrimidine compounds, pharmaceutical compositions thereof and uses thereof". The entire text of the above prior application is incorporated herein by reference.

[0002] This disclosure belongs to the field of pharmaceutical technology and relates to a class of heterocyclic-fused pyrimidine compounds, or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and their use as ubiquitin-specific protease 1 (USP1) inhibitors in the prevention or treatment of USP1-related diseases.

[0003] Ubiquitination is a reversible process that involves a series of deubiquitinating enzymes (DUBs) that regulate multiple cellular processes by deubiquitinating substrates. DUBs are encoded by approximately 100 human genes and are divided into 6 families, with the largest family being the ubiquitin-specific proteases (USPs) with more than 50 members. DUBs and their substrate proteins are often dysregulated in cancer, which supports the hypothesis that targeting specific DUB enzymes can regulate the activity of other key proteins involved in tumor growth, survival, differentiation, and maintenance of the tumor microenvironment by enhancing the ubiquitination and degradation of oncogenic substrates (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 among DUBs. Full-length human USP1 consists of 785 amino acids, including a catalytic triad composed of Cys90, His593, and Asp751 (Nijman, S.M.B., et al. "The deubiquitinating enzyme USP1 regulates the fanconi anemia pathway." Mol. Cell 17, 331-339 (2005)). USP1 plays a role in DNA damage repair. USP1 itself is relatively inactive and can only acquire complete enzyme activity when it binds to the cofactor UAF1 to form a complex required for deubiquitinase activity. The USP1 / UAFl complex deubiquitinates monoubiquitinated PCNA (proliferating cell nuclear antigen) and monoubiquitinated FANCD2 (Fanconi anemia complementation group D2), and these two proteins play important roles in the translesion synthesis (TLS) and Fanconi anemia (FA) pathways, respectively. These two pathways are necessary for repairing DNA damage caused by DNA cross-linking agents such as cisplatin and mitomycin C (MMC). The USP1 / UAF1 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, the expression of USP1 is significantly increased in many cancers. Blocking USP1 to inhibit DNA repair can induce apoptosis in multiple myeloma cells and also enhance the sensitivity of lung cancer cells to cisplatin. These suggest that USP1 is a promising target for chemotherapy of certain cancers.

[0005] In summary, targeted inhibition of the USP1 protein is a potential method for preventing or treating cancers and other diseases. Therefore, it is necessary to develop small molecule inhibitors of USP1.

[0006]

[0007] On the one hand, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0008] wherein,

[0009] selected from the following structures:

[0010] R 3a 、R 3b 、R 4 、R 5a 、R 5b are each independently selected from H, halogen, CN, OH, NH 2 、-C(O)OR x 、-C(O)R x 、-NHC(O)R x 、-O-C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group, the NH 2 、-O-C 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 a 4- to 10-membered heterocyclic group is optionally substituted by R x ;

[0011] Or R 3a 、R 3b together with the carbon atom to which it is attached form a C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group, the C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group is optionally substituted by R x ;

[0012] Or R 5a 、R 5b together with the carbon atom to which it is attached form a C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group, the C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group is optionally substituted by R x ;

[0013] Ring A is selected from C6 -C 10 is an aryl or a 5- to 10-membered heteroaryl, and the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted by R a ;

[0014] Ring B is selected from C 6 -C 10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group, C 4 -C 10 cycloalkenyl or C 3 -C 10 cycloalkyl, and the C 6 -C 10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group, C 4 -C 10 cycloalkenyl or C 3 -C 10 cycloalkyl is optionally substituted by R b ;

[0015] Ring C is selected from C 6 -C 10 aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic group, and the C 6 -C 10 aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic group is optionally substituted by R c ;

[0016] Each R a , R b , R c is independently selected from halogen, CN, OH, NH 2 , -C(O)OR x , -C(O)R x , C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4- to 10-membered heterocyclic group, and the NH 2 , C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4- to 10-membered heterocyclic group is optionally substituted by R x ;

[0017] Alternatively, R b , R cTogether with the atoms to which it is attached, they jointly form a C 4 -C 10 cycloalkenyl group or a 4- to 10-membered heterocyclic group, and the C 4 -C 10 cycloalkenyl group or 4- to 10-membered heterocyclic group is optionally substituted by R x ;

[0018] 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 a 4- to 10-membered heterocyclic group, and the OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group is optionally substituted by R x ;

[0019] Alternatively, R 1 and R 2 together with the atoms to which they are attached jointly form a C 3 -C 10 cycloalkyl group or a 4- to 7-membered heterocyclic group, and the C 3 -C 10 cycloalkyl group or 4- to 7-membered heterocyclic group is optionally substituted by R x ;

[0020] R x is selected from halogen, CN, OH, NH 2 or C 1 -C 6 alkyl, and the OH, NH 2 or C 1 -C 6 alkyl is optionally substituted by C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or a 4- to 7-membered heterocyclic group;

[0021] Provided that when is selected from , R 5a is selected from halogen, CN, OH, NH 2 , -C(O)OR x , -C(O)R x , -O-C 1 -C 6 alkyl, C1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl or a 4- to 9-membered heterocyclic group, the NH 2 、-O-C 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 a 4- to 9-membered heterocyclic group is optionally substituted by R x substituted;

[0022] Alternatively, R 5a 、R 5b and the carbon atom to which it is attached form a C 4 -C 10 cycloalkyl or a 4- to 9-membered heterocyclic group, the C 4 -C 10 cycloalkyl or a 4- to 9-membered heterocyclic group is optionally substituted by R x substituted.

[0023] In some embodiments, R 3a 、R 3b 、R 4 、R 5a 、R 5b are independently selected from H, -C(O)OR x 、-C(O)R x 、-O-C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group, the -O-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group is optionally substituted by R x substituted.

[0024] In some embodiments, R 3a 、R3b , R 4 , R 5a , R 5b are independently selected from H, C 1 -C 6 deuterated alkyl, C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl is optionally substituted by R x .

[0025] In some embodiments, R 3a , R 3b , R 4 , R 5a , R 5b are independently selected from H, CH 3 , CD 3 or cyclopropyl.

[0026] In some embodiments, R 3a , R 3b are independently selected from H, C 1 -C 6 deuterated alkyl or C 1 -C 6 alkyl, and the C 1 -C 6 alkyl is optionally substituted by R x .

[0027] In some embodiments, R 4 is selected from H or C 1 -C 6 alkyl, and the C 1 -C 6 alkyl is optionally substituted by R x .

[0028] In some embodiments, R 5a is selected from halogen, CN, OH, NH 2 , -C(O)OR x , -C(O)R x , -O-C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C6 Alkynyl, C 3 -C 10 Cycloalkyl or 4- to 9-membered heterocyclic group, the NH 2 -, -O-C 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- to 9-membered heterocyclic group is optionally substituted by R x Substituted.

[0029] In some embodiments, R 5a Is selected from C 1 -C 6 Deuterated alkyl, C 1 -C 6 Alkyl or C 3 -C 10 Cycloalkyl, the C 1 -C 6 Alkyl or C 3 -C 10 Cycloalkyl is optionally substituted by R x Substituted.

[0030] In some embodiments, R 5b Is selected from H or C 1 -C 6 Alkyl, the C 1 -C 6 Alkyl is optionally substituted by R x Substituted.

[0031] In some embodiments, R 5a , R 5b Together with the carbon atom to which it is attached form a C 3 -C 10 Cycloalkyl, the C 3 -C 10 Cycloalkyl is optionally substituted by R x Substituted.

[0032] In some embodiments, R 5a , R 5b Together with the carbon atom to which it is attached form a C 4 -C 10 Cycloalkyl, the C 4 -C 10 Cycloalkyl is optionally substituted by R x Substituted.

[0033] In some embodiments, R 5a , R 5b and the carbon atom to which it is attached form a C 4 -C 6 cycloalkyl, and the C 4 -C 6 cycloalkyl is optionally substituted with R x .

[0034] In some embodiments, R 5a , R 5b and the carbon atom to which it is attached form a cyclobutyl group, and the cyclobutyl group is optionally substituted with R x .

[0035] In some embodiments, is selected from the following structures:

[0036] In some embodiments, is selected from the following structures:

[0037] In some embodiments, ring A is selected from 5- to 10-membered heteroaryl groups, and the 5- to 10-membered heteroaryl groups are optionally substituted with R a .

[0038] In some embodiments, ring A is selected from 5- to 6-membered heteroaryl groups, and the 5- to 6-membered heteroaryl groups are optionally substituted with R a .

[0039] In some embodiments, ring A is selected from pyrimidinyl groups, and the pyrimidinyl groups are optionally substituted with R a .

[0040] In some embodiments, ring B is selected from C 6 -C 10 aryl or 5- to 10-membered heteroaryl groups, and the C 6 -C 10 aryl or 5- to 10-membered heteroaryl groups are optionally substituted with R b .

[0041] In some embodiments, ring B is selected from C 6 -C 10 aryl groups, and the C 6 -C 10 aryl groups are optionally substituted with R b .

[0042] In some embodiments, ring B is selected from phenyl groups, and the phenyl groups are optionally substituted with R b .

[0043] In some embodiments, ring B is selected from phenyl.

[0044] In some embodiments, ring C is selected from 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic, and the 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic is optionally substituted with R c substituted.

[0045] In some embodiments, ring C is selected from 5- to 6-membered heteroaryl or 4- to 8-membered heterocyclic, and the 5- to 6-membered heteroaryl or 4- to 8-membered heterocyclic is optionally substituted with R c substituted.

[0046] In some embodiments, ring C is selected from pyrazolyl, imidazolyl or the pyrazolyl, imidazolyl or is optionally substituted with R c substituted.

[0047] In some embodiments, each R a 、R b 、R c is independently selected from halogen, C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, C 3 - C 10 cycloalkyl or 4- to 10-membered heterocyclic, and the C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4- to 10-membered heterocyclic is optionally substituted with R x substituted.

[0048] In some embodiments, each R a 、R b 、R c is independently selected from halogen, C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4- to 6-membered heterocyclic, and the C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4- to 6-membered heterocyclic is optionally substituted with Rx Substituted.

[0049] In some embodiments, each R a , R b , R c is independently selected from C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or a 4-6 membered heterocyclic group, wherein the C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or a 4-6 membered heterocyclic group is optionally substituted with R x .

[0050] In some embodiments, each R a , R b , R c is independently selected from CH 3 , CH(CH 3 ) 2 , -O-CH 3 , cyclopropyl, oxetanyl or pyrrolidinyl, wherein the CH 3 , CH(CH 3 ) 2 , -O-CH 3 , cyclopropyl, oxetanyl or pyrrolidinyl is optionally substituted with R x .

[0051] In some embodiments, each R a , R b , R c is independently selected from CH 3 , CH(CH 3 ) 2 , CF 3 , -O-CH 3 , -O-CHF 2 , cyclopropyl, oxetanyl or

[0052] In some embodiments, each R a is independently selected from -O-C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl, wherein the -O-C 1 -C 6Alkyl or C 3 -C 10 Cycloalkyl is optionally substituted with R x .

[0053] In some embodiments, each R a is independently selected from -O-CH 3 or cyclopropyl, and the -O-CH 3 or cyclopropyl is optionally substituted with R x .

[0054] In some embodiments, each R a is independently selected from -O-CH 3 , -O-CHF 2 or cyclopropyl.

[0055] In some embodiments, each R c is independently selected from C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4- to 10-membered heterocyclic group, and the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4- to 10-membered heterocyclic group is optionally substituted with R x .

[0056] In some embodiments, each R c is independently selected from CH 3 , CH(CH 3 ) 2 , cyclopropyl, oxetanyl or pyrrolidinyl, and the CH 3 , CH(CH 3 ) 2 , cyclopropyl, oxetanyl or pyrrolidinyl is optionally substituted with R x .

[0057] In some embodiments, each R c is independently selected from CH 3 , CH(CH 3 ) 2 , CF 3 , cyclopropyl, oxetanyl or

[0058] In some embodiments, R b , R c and the atoms to which they are attached together form a 4- to 10-membered heterocyclic group, and the 4- to 10-membered heterocyclic group is optionally substituted with R x .

[0059] In some embodiments, R 1 , R 2 are independently selected from H, halogen, C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl is optionally substituted with R x .

[0060] In some embodiments, R 1 and R 2 are both H.

[0061] In some embodiments, R x is selected from halogen, NH 2 or C 1 -C 6 alkyl, and the NH 2 or C 1 -C 6 alkyl is optionally substituted with C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or a 4- to 7-membered heterocyclic group.

[0062] In some embodiments, R x is selected from halogen or C 1 -C 6 alkyl.

[0063] In some embodiments, R x is selected from F or CH 3 .

[0064] The present disclosure also provides a compound selected from the following or a pharmaceutically acceptable salt thereof:

[0065] On the other hand, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) of the present disclosure or the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0066] On the other hand, the present disclosure provides a method for treating a disease mediated by USP1 in a mammal, comprising administering to a mammal in need of such treatment, preferably a human, a therapeutically effective amount of a compound of formula (I) or the above compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0067] On the other hand, the present disclosure provides the use of a compound of formula (I) or the above-mentioned compound 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.

[0068] On the other hand, the present disclosure provides the use of a compound of formula (I) or the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating a disease mediated by USP1.

[0069] On the other hand, the present disclosure provides a compound of formula (I) or the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a disease mediated by USP1.

[0070] In some embodiments, the disease mediated by USP1 is a tumor.

[0071] In some embodiments, the tumor is, for example, a solid tumor, an adenocarcinoma or a hematological tumor.

[0072] Any embodiment of any aspect of the present invention can be combined with other embodiments without contradiction. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the corresponding technical feature in other embodiments without contradiction. Term Definitions and Explanations

[0073] Unless otherwise specified, the terms used in the present disclosure have the following meanings. The definitions of the groups and terms described in the present disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other arbitrarily. A specific term should not be considered uncertain or unclear without a special definition, 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 product or its active ingredient.

[0074] As used herein represents a linking site.

[0075] The graphical representation of a racemate or an enantiomerically pure compound in this document is from Maehr, J. Chem. Ed. 1985, 62: 114 - 120. Unless otherwise specified, wedge bonds and dashed wedge bonds are used to represent the absolute configuration of a stereocenter, and solid black bonds and dashed bonds are used to represent the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0076] The term "tautomer" refers to functional group isomers resulting from the rapid movement of a particular atom within a molecule between two positions. The compounds of the present disclosure may exhibit tautomerism. Tautomers of a compound can exist in two or more interconvertible forms. Tautomers generally exist in an equilibrium form, and attempting to isolate a single tautomer usually results in a mixture whose physical and chemical properties are consistent with those of a mixture of the compounds. The position of the equilibrium depends on the chemical characteristics 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.

[0077] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms within a molecule, including cis-trans isomers, enantiomers, and diastereomers.

[0078] The compounds of the present disclosure may have asymmetric atoms such as carbon, sulfur, nitrogen, phosphorus atoms, or asymmetric double bonds, and thus the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and their racemic mixtures or other mixtures, such as enantiomer- or diastereomer-enriched mixtures. All of these isomers and their mixtures are within the scope of the definition of the compounds of the present disclosure. Additional asymmetric carbon, sulfur, nitrogen, or phosphorus atoms may be present in substituents such as alkyl groups, and all such isomers and their mixtures involved in the substituents are also included within the scope of the definition of the compounds of the present disclosure. Compounds of the present disclosure containing asymmetric atoms may be isolated in optically pure form or in racemic form. The optically pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0079] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence of the particular atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.

[0080] The term "optionally" or "optionally" means that the subsequent described event or situation may or may not occur, and the description includes both the occurrence and non-occurrence of the described event or situation. For example, "optionally" substituted by a halogen for ethyl means that ethyl can be unsubstituted (CH 2 CH 3 ), monosubstituted (CH 2 CH 2 F, CH2 CH 2 Cl, etc.), polysubstituted (CHFCH 2 F, CH 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2 etc.) or fully substituted (CF 2 CF 3 , CF 2 CCl 3 , CCl 2 CCl 3 etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized will be introduced.

[0081] When any variable (e.g., R a , R b ) appears more than once in the composition or structure of a compound, its definition in each case is independent. For example, if a group is substituted by two R b , then each R b has independent options.

[0082] When the connecting group involved in this article does not specify its connection direction, its connection direction is arbitrary. For example, when the structural unit the L 1 is selected from "C 1 -C 3 alkylene-O", at this time L 1 can either connect the ring Q and R 1 in the left-to-right direction to form "ring Q-C 1 -C 3 alkylene-O-R 1 ", or connect the ring Q and R 1 in the right-to-left direction to form "ring Q-O-C 1 -C 3 alkylene-R 1 ".

[0083] When the bond of a substituent cross-connects to two atoms on a ring, such a substituent can be bonded to any atom on this ring. For example, the structural unit represents that R 5 can be substituted at any position on the benzene ring.

[0084] The C m -C nrefers to an alkyl group having an integer number of carbon atoms in the range of m - n. For example, "C 1 -C 10 " means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0085] The term "alkyl" refers to a hydrocarbon group having the general formula C n H 2n+1 , and the alkyl group can be straight-chain or branched-chain. The term "C 1 -C 10 alkyl" can be understood to represent a straight-chain or branched-chain saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of the alkyl group 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 "C 1 -C 6 alkyl" can be understood to represent 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 "C 1 -C 3 alkyl" can be understood to represent a straight-chain or branched-chain saturated alkyl group having 1 to 3 carbon atoms. The said "C 1 -C 10 alkyl" can include a range such as "C 1 -C 6 alkyl" or "C 1 -C 3 alkyl", and the said "C 1 -C 6 alkyl" can further include "C 1 -C 3 alkyl".

[0086] The term "deuterated alkyl" refers to an alkyl group in which the hydrogen is replaced by deuterium, including mono-deuterated alkyl and multi-deuterated alkyl. For example, the term "C 1-6 deuterated alkyl" means a C 1-6 alkyl as defined above that is substituted by one or more deuteriums, including but not limited to CD3 , CH 2 CD 3 etc.

[0087] The term "alkenyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. The term "C 2 -C 10 alkenyl" can be understood to represent a straight-chain or branched-chain unsaturated hydrocarbon group that contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. "C 2 -C 10 alkenyl" is preferably "C 2 -C 6 alkenyl", more preferably "C 2 -C 4 alkenyl", even more preferably C 2 or C 3 alkenyl. It can be understood that in the case where the alkenyl contains more than one double bond, the double bonds can be separated or conjugated with each other. 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.

[0088] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. The term "C 2 -C 10 alkynyl" can be understood to represent a straight-chain or branched-chain unsaturated hydrocarbon group that contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Examples of "C 2 -C 10 alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH 3、 -CH 2 C≡CH), but-1-ynyl, but-2-ynyl, or but-3-ynyl. "C 2 -C 10 alkynyl" can contain "C 2 -C 3 alkynyl". Examples of "C 2 -C 3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH 3 ), prop-2-ynyl (-CH 2 C≡CH).

[0089] The term "cycloalkyl" refers to a completely saturated carbocyclic ring that exists in the form of a monocyclic, fused-ring, bridged-ring, or spiro-ring, etc. Unless otherwise indicated, the carbocyclic ring is usually a 3- to 10-membered ring. The term "C 3 -C 10 cycloalkyl" can be understood to represent a saturated monocyclic, fused-ring, spiro-ring, or bridged-ring having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, etc. The term "C 3 -C 10 cycloalkyl" may contain "C 3 -C 6 cycloalkyl", and the term "C 3 -C 6 cycloalkyl" can be understood to represent a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, or 6 carbon atoms, and specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, etc.

[0090] The term "cycloalkenyl" refers to an unsaturated non-aromatic carbocyclic ring that exists in the form of a monocyclic, fused-ring, bridged-ring, or spiro-ring, etc. Unless otherwise indicated, the carbocyclic ring is usually a 5- to 8-membered ring. Specific examples of the cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl, etc.

[0091] The term "heterocyclic group" refers to a completely saturated or partially saturated (not an aromatic heteroaryl as a whole) monocyclic, fused-ring, spiro-ring, or bridged-ring group, the ring atoms of which contain 1, 2, 3, 4, or 5 heteroatoms or heteroatom groups (i.e., atomic groups containing heteroatoms), and the "heteroatoms or heteroatom 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-, etc. The term "3- to 10-membered heterocyclic group" refers to a heterocyclic group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and having 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms or heteroatom groups in its ring atoms. The "3- to 10-membered heterocyclic group" includes the "4- to 7-membered heterocyclic group". Among them, specific examples of the 4-membered heterocyclic group include, but are not limited to, azetidinyl or oxetanyl; specific examples of the 5-membered heterocyclic group include, but are not limited to, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrroline, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of the 6-membered heterocyclic group include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridyl or 4H-[1,3,4]thiadiazinyl; specific examples of the 7-membered heterocyclic group include, but are not limited to, diazepanyl. The heterocyclic group may also be a bicyclic group. Among them, specific examples of the 5,5-bicyclic group include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of the 5,6-bicyclic group 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- to 7-membered heterocyclic group, and specific examples include, but are not limited to, dihydroisoquinolinyl, etc. The "4- to 10-membered heterocyclic group" may include ranges such as "5- to 10-membered heterocyclic group", "4- to 7-membered heterocyclic group", "5- to 6-membered heterocyclic group", "6- to 8-membered heterocyclic group", "4- to 10-membered heterocyclic alkyl group", "5- to 10-membered heterocyclic alkyl group", "4- to 7-membered heterocyclic alkyl group", "5- to 6-membered heterocyclic alkyl group", "6- to 8-membered heterocyclic alkyl group", etc. The "4- to 7-membered heterocyclic group" may further include ranges such as "4- to 6-membered heterocyclic group", "5- to 6-membered heterocyclic group", "4- to 7-membered heterocyclic alkyl group", "4- to 6-membered heterocyclic alkyl group", "5- to 6-membered heterocyclic alkyl group", etc. Although some bicyclic heterocyclic groups in the present disclosure partially contain a benzene ring or a heteroaryl ring, the heterocyclic group as a whole is still non-aromatic.

[0092] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. The aryl may have 6 to 20 carbon atoms, 6 to 14 carbon atoms or 6 to 12 carbon atoms. The term "C 6 -C 20 aryl" can be understood as an aryl having 6 to 20 carbon atoms. In particular, a ring having 6 carbon atoms ("C 6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C 9"aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring having 13 carbon atoms ("C 13 aryl"), such as fluorenyl; or a ring having 14 carbon atoms ("C 14 aryl"), such as anthryl. The term "C 6 -C 10 aryl" can be understood as an aryl having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C 6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C 9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. The term "C 6 -C 20 aryl" may include "C 6 -C 10 aryl".

[0093] The term "heteroaryl" refers to a monocyclic or fused polycyclic system having aromaticity, wherein the ring atoms include at least one ring atom selected from N, O, S, and the remaining ring atoms are aromatic ring groups of C. The term "5-10 membered heteroaryl" can be understood to include such monocyclic or bicyclic aromatic ring systems: having 5, 6, 7, 8, 9 or 10 ring atoms, especially 5 or 6 or 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, etc. and their benzo derivatives, such as quinolinyl, quinazolinyl or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, etc. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and containing 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.

[0094] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0095] The term "therapeutically effective amount" means: (i) an amount of a compound of the present disclosure that 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 described herein.

[0096] The amount of the compound of the present 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 those skilled in the art based on their own knowledge and the present disclosure.

[0097] The term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0098] The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable acids or bases, including salts formed by the compound with inorganic acids or organic acids, and salts formed by the compound with inorganic bases or organic bases.

[0099] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present disclosure to an organism.

[0100] The term "pharmaceutically acceptable excipient" refers to those excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0101] The word "comprise" or "comprising" and its English variants such as "comprises" or "comprising" can be understood in an open, non-exclusive sense, i.e., "including but not limited to".

[0102] The present disclosure also includes isotopically labeled compounds of the present disclosure that are the same as those described herein, but in which one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number normally 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, etc.

[0103] Certain isotopically labeled compounds of the present disclosure (e.g., labeled with 3 H and 14 C) can be used in compound and / or substrate tissue distribution analysis. Tritiation (i.e., 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 substituting unlabeled reagents with isotopically labeled reagents through procedures similar to those described in the protocols and / or examples disclosed below.

[0104] 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.

[0105] Typical routes of administration of the compounds of the present disclosure, or pharmaceutically acceptable salts 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.

[0106] The pharmaceutical compositions of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, emulsifying, freeze-drying, etc.

[0107] 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, syrups, suspensions, etc. for oral administration to a patient.

[0108] Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. For example, they can be obtained by the following method: mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or dragee. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.

[0109] The pharmaceutical composition is also suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

[0110] In all methods of administration of the compounds of formula (I) described herein, or the above-mentioned compounds or their pharmaceutically acceptable salts, the daily dose is from 0.01 mg / kg to 200 mg / kg body weight, in single or divided doses.

[0111] The invention will be described in detail below by way of examples, which does not mean any adverse limitation to the present disclosure. The present disclosure has been described in detail herein, and its specific embodiments have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0112] Unless otherwise stated, the ratios represented by mixed solvents are volume mixing ratios. For example, "the eluent is 10%-75% acetonitrile-water" means that during the gradient elution process, the volume ratio of acetonitrile to water is 10:90 - 75:25.

[0113] Unless otherwise stated, % refers to wt%.

[0114] The compounds are named manually or by software, and commercially available compounds use the supplier catalog names.

[0115] The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half-maximal inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

[0116] Abbreviations:

[0117] THF: tetrahydrofuran; Ti(OEt) 4:Tetraethyl orthotitanate; Toluene: Toluene; n-BuLi: n-Butyllithium; EA: Ethyl acetate; DCM: Dichloromethane; DIEA: N,N-Diisopropylethylamine; Boc 2 O: Di-tert-butyl dicarbonate; m-CPBA: m-Chloroperoxybenzoic acid; DMF: N,N-Dimethylformamide; dioxane: Dioxane; CDI: N,N'-Carbonyldiimidazole; XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II); MeI: Methyl iodide; Cs 2 CO 3 : Cesium carbonate; 2-iodo-propane: 2-Iodopropane; LiAlH 4 : Lithium aluminum hydride; Acetone: Acetone; EtOH: Absolute ethanol; TEA or Et 3 N: Triethylamine; CD 3 I: Deuterated methyl iodide; Pd(OAc) 2 : Palladium acetate; PPh 3 : Triphenylphosphine; Pd(OH) 2 : Palladium hydroxide; SOCl 2 : Thionyl chloride; HFIP: Hexafluoroisopropanol; KF: Potassium fluoride; MeCN or CH 3 CN: Acetonitrile; MeMgBr: Methylmagnesium bromide; Pd 2 (dba) 3 : Tris(dibenzylideneacetone)dipalladium; PCy 3 : Tricyclohexylphosphine; TsOH: p-Toluenesulfonic acid; CH 2 O: Formaldehyde.

[0118] Example 1: 7'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclobutane-1,4'-pyrimido[4,5-d]pyrimidine]-2'(3'H)-one (Compound 1)

[0119] Step 1: Synthesis of Intermediate 1C

[0120] Cyclobutanone 1A (10.0 g, 142.0 mmol) and intermediate 1B (15.7 g, 130 mmol) were dissolved in tetrahydrofuran (100 mL), and then tetraethyl titanate (88.8 g, 389.0 mmol) was added. The reaction was carried out at 50 °C for 5 hours. Ice water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, and then saturated aqueous sodium bicarbonate solution (20.0 mL) was added and stirred for 1 hour. The resulting mixture was filtered, the filter cake was washed with ethyl acetate, the filtrate was dried over anhydrous sodium sulfate, filtered, concentrated to obtain the crude product, and then purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 - 3:1) to obtain intermediate 1C (13 g, yield 58%).

[0121] Step 2: Synthesis of intermediate 1E

[0122] Compound 1D (1.5 g, 6.4 mmol) was dissolved in toluene (12.0 mL), purged with nitrogen three times, and n-butyllithium (1.6 M, 4.7 mL) was added dropwise at -78 °C. The reaction was carried out at -78 °C for 5 min, and then intermediate 1C (1.0 g, 5.8 mmol) was dissolved in toluene (12.0 mL) and added dropwise to the above reaction solution. The reaction was stirred at -78 °C for 30 min. The reaction solution was directly concentrated, and the obtained crude product was purified by silica gel column (eluent: dichloromethane: methanol = 100:1 - 10:1) to obtain intermediate 1E (0.9 g, yield 47%). m / z (ESI): 334.1 [M+H] + .

[0123] Step 3: Synthesis of intermediate 1F

[0124] Intermediate 1E (300 mg, 898 μmol) was dissolved in hydrochloric acid - ethyl acetate (2.0 mol / L, 3.0 mL), and the reaction was carried out at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (10 mL), and then water (20 mL) was added for extraction. The separated aqueous phase was adjusted to pH = 9 with saturated sodium carbonate solution, and then extracted with ethyl acetate (15 mL * 3). The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 1F (300 mg, crude product), which could be directly used for the next step.

[0125] Step 4: Synthesis of intermediate 1G

[0126] The intermediate 1F (300.0 mg, about 0.90 mmol) prepared in the previous step was dissolved in dichloromethane (3.0 mL), and then N,N-diisopropylethylamine (422.0 mg, 568.0 μL) and di-tert-butyl dicarbonate (570.0 mg, 600.0 μL) were added. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was directly concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100:1 - 10:1) to obtain intermediate 1G (280 mg, yield 94%). m / z (ESI): 330.1 [M+H] + .

[0127] Step 5: Synthesis of intermediate 1H

[0128] The intermediate 1G (280.0 mg, 0.85 mmol) was dissolved in dichloromethane (3.0 mL), and m-chloroperbenzoic acid (465.0 mg, 2.3 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. Dichloromethane (10 mL) was added to dilute the reaction solution, and then it was washed with saturated aqueous sodium thiosulfate solution (5.0 mL). The separated organic phase was washed with saturated aqueous sodium bicarbonate solution (10.0 mL) and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 - 3:1) to obtain intermediate 1H (190 mg, yield 62%). m / z (ESI): 362.1 [M+H] + .

[0129] Step 6: Synthesis of intermediate 1J

[0130] Compound 1I (106.0 mg, 414.0 μmol) was dissolved in N,N-dimethylformamide (1.0 mL), then N,N-diisopropylethylamine (161.0 mg, 1.2 mmol) was added, and then intermediate 1H (150.0 mg, 414.0 μmol) was added. The resulting mixture was stirred at room temperature for 3 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 - 2:1) to obtain intermediate 1J (100 mg, yield 45%). m / z (ESI): 537.1 [M+H] + .

[0131] Step 7: Synthesis of intermediate 1K

[0132] The intermediate 1J (80.0 mg, 149.0 μmol) was dissolved in hydrochloric acid-dioxane (1.0 mL) and reacted at room temperature for 1 hour. The reaction solution was directly concentrated to obtain intermediate 1K (80 mg, crude product) which was directly used in the next step.

[0133] Step 8: Synthesis of intermediate 1L

[0134] Intermediate 1K (50.0 mg, 114.5 μmol) was dissolved in dichloromethane (3.0 mL), and then N,N-diisopropylethylamine (68.3 mg, 528.0 μmol) and N,N'-carbonyldiimidazole (45.6 mg, 281.5 μmol) were added. The resulting mixture was reacted at room temperature for 1 hour. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 - 3:1) to obtain Intermediate 1L (40 mg, yield 82%). m / z (ESI): 463.0 [M+H] + .

[0135] Step 9: Synthesis of 7'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclobutane-1,4'-pyrimido[4,5-d]pyrimidine]-2'(3'H)-one (Compound 1)

[0136] Intermediate 1L (40.0 mg, 86.4 μmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (36.8 mg, 190.0 μmol), potassium phosphate (55.0 mg, 259.0 μmol), and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (27.2 mg, 34.6 μmol) were added to a mixed solution of dioxane (1.0 mL) and water (50 μL). The resulting reaction solution was stirred and reacted at 100 °C under nitrogen protection for 4 hours. The reaction solution was concentrated, and the residue was purified by preparative chromatography (Waters Xbridge C 18 150*19 mm, 10 μm, eluent: 10% - 75% acetonitrile - water) to obtain the title compound 1 (14 mg, yield 28%).

[0137] LC-MS: m / z (ESI): 577.1 [M+H] + .

[0138] 1 H NMR (400 MHz, CDCl 3)δ8.80(s,1H),8.66(s,1H),7.55 - 7.48(m,4H),7.29(s,1H),5.80(s,1H),5.32(s,2H),3.92(s,3H),3.73(s,3H),2.76 - 2.64(m,2H),2.62 - 2.46(m,2H),2.13 - 2.01(m,2H),1.71 - 1.68(m,1H),1.24 - 1.19(m,2H),0.87 - 0.82(m,2H).

[0139] Example 2: 7'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-3'-methyl-1'-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclobutane-1,4'-pyrimido[4,5-d]pyrimidine]-2'(3'H)-one (Compound 2)

[0140] Compound 1 (10.0 mg, 17.3 μmol) was dissolved in N,N-dimethylformamide (0.5 mL), and cesium carbonate (16.9 mg, 52.0 μmol) and methyl iodide (4.9 mg, 34.7 μmol) were added. The resulting mixture was stirred at room temperature for 2 h. 0.5 mL of water was added to the reaction solution, and the obtained solution was directly purified by preparative chromatography (Waters Xbridge C 18 150*19 mm, 10 μm, eluent: 10%-75% acetonitrile-water) to obtain the title compound 2 (2.3 mg, yield 22%).

[0141] LC-MS: m / z(ESI): 591.2[M + H] + .

[0142] 1 H NMR(400 MHz, CDCl 3 )δ8.81(s,1H),8.66(s,1H),7.55 - 7.46(m,4H),7.29(s,1H),5.34(s,2H),3.93(s,3H),3.73(s,3H),3.26(s,3H),3.04 - 2.93(m,2H),2.52 - 2.41(m,2H),2.13 - 2.04(m,2H),1.71 - 1.69(m,1H),1.23 - 1.17(m,2H),0.89 - 0.84(m,2H).

[0143] Example 3

[0144] Using a similar route and synthesis method as in steps 2 to 9 of Example 1, replacing intermediate 1C in step 2 with compound A in the following table, the corresponding compounds 3 - 5 in the table were prepared.

[0145] Example 4

[0146] Using a similar route and synthesis method as in steps 2 to 9 of Example 1, replacing intermediate 1C in step 2 with compound B in the following table, and using compound C in the following table to replace 1I in step 6, the corresponding compounds 6 and 7 in the table were prepared.

[0147] Example 5

[0148] Using a similar synthesis method as in Example 2, replacing compound 1 with compounds 3, 4, 6, and 7 respectively, the corresponding compounds 8 - 11 in the table were prepared.

[0149] Example 6: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-methyl-5,8-dihydropteridine-6,7-dione (Compound 12)

[0150] Step 1: Synthesis of intermediate 12B

[0151] At room temperature, add intermediate 12A (8.8 g, 37.0 mmol), 2-iodopropane (12.6 g, 74.0 mmol), potassium carbonate (10.2 g, 74.0 mmol) and N,N-dimethylformamide (100 mL) to a reaction flask. The resulting mixture was stirred at 60 °C for 2 hours. The reaction solution was poured into 200 mL of ice water and extracted 3 times with 100 mL of ethyl acetate. The combined organic phases were washed with saturated brine and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1 - 1:1) to obtain intermediate 12B (3.4 g, yield: 33%). m / z (ESI): 280.1 [M + H] + .

[0152] Step 2: Synthesis of intermediate 12C

[0153] At room temperature, intermediate 12B (3.4 g, 12.2 mmol) was dissolved in tetrahydrofuran (30 mL), and lithium aluminum hydride (924.1 mg, 24.4 mmol) was added portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour and then slowly warmed to room temperature and stirred for an additional 1 hour. After cooling the reaction mixture to 0 °C, 0.1 mL of water, 0.1 mL of 15% aqueous sodium hydroxide solution, and 0.2 mL of water were added successively. The resulting mixture was stirred at room temperature for 1 hour, filtered through diatomaceous earth, and the filter cake was rinsed with dichloromethane. The filtrate was concentrated to give intermediate 12C (3.4 g, yield: 100%), which was used directly in the next step. m / z (ESI): 284.1 [M+H] + .

[0154] Step 3: Synthesis of intermediate 12E

[0155] At room temperature, 2,4-dichloro-5-nitropyrimidine (1.2 g, 6.0 mmol) was dissolved in tetrahydrofuran (30 mL), and N,N-diisopropylethylamine (1.6 g, 12.0 mmol) was added. After cooling the reaction mixture to 0 °C, intermediate 12C (1.7 g, 6.0 mmol, 1 eq.) was added with stirring. The resulting mixture was stirred at 0 °C for 0.5 hour and then slowly warmed to room temperature and stirred for an additional 2 hours. The resulting reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1 - 1:1) to give intermediate 12E (1.4 g, yield: 52%). m / z (ESI): 441.1 [M+H] + .

[0156] Step 4: Synthesis of intermediate 12F

[0157] At room temperature, reduced iron powder (1.8 g, 31.8 mmol) was added to water (10 mL) and ethanol (30 mL), ammonium chloride (1.7 g, 31.8 mmol) was added, and then intermediate 12E (1.4 g, 3.2 mmol) was added. The resulting mixture was reacted at 80 °C for 2 hours, and then diluted with 100 mL of ethyl acetate. The mixture was filtered, the filter cake was rinsed with ethyl acetate, and the combined filtrates were washed with saturated brine and concentrated to give crude intermediate 12F (1.4 g, yield: 100%), which was used directly in the next step. m / z (ESI): 411.1 [M+H] + .

[0158] Step 5: Synthesis of intermediate 12H

[0159] At room temperature, 12F (1.2 g, 2.9 mmol) was added to acetone (20 mL), and then potassium carbonate (806.2 mg, 5.8 mmol) was added. The reaction solution was cooled to 0 °C, and ethyl 2-chloro-2-oxoacetate (398.8 mg, 2.9 mmol) was slowly added with stirring, and the reaction was carried out at this temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1 - 1:1) to obtain intermediate 12H (1.2 g, yield: 80%). m / z (ESI): 511.1 [M + H] + .

[0160] Step 6: Synthesis of intermediate 12I

[0161] Intermediate 12H (1.2 g, 2.4 mmol) was added to anhydrous ethanol (10 mL), and then triethylamine (474.5 mg, 4.7 mmol) was added. The resulting mixture was heated and stirred at 120 °C for 2 hours and then concentrated. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1 - 1:1) to obtain intermediate 12I (600 mg, yield: 55%). m / z (ESI): 465.1 [M + H] + .

[0162] Step 7: Synthesis of intermediate 12J

[0163] Intermediate 12I (100.0 mg, 215.1 μmol) was added to anhydrous N,N-dimethylformamide (2 mL), and then potassium carbonate (59.4 mg, 430.3 μmol) and methyl iodide (61.1 mg, 430.3 μmol) were added. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was added to 20 mL of water and extracted three times with ethyl acetate (20 mL * 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1 - 1:1) to obtain intermediate 12J (100 mg, yield: 97%). m / z (ESI): 479.1 [M + H] + .

[0164] Step 8: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-methyl-5,8-dihydropteridine-6,7-dione (Compound 12)

[0165] Intermediate 12J (100.0 mg, 208.8 μmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (83.5 mg, 430.3 μmol), potassium phosphate (91.2 mg, 430.3 μmol), and XPhos Pd G2 (33.9 mg, 43.0 μmol) were added to dioxane (4 mL) and water (0.4 mL). The resulting mixture was stirred at 100 °C for 4 hours under nitrogen protection. After concentrating the reaction solution, 3 mL of acetonitrile was added, and the solid was removed by filtration. The obtained filtrate was purified by preparative chromatography (Waters Xbridge C 18 150*19 mm, 10 μm, eluent: 10%-75% acetonitrile-water) to obtain the title compound 12 (50 mg, yield: 39%).

[0166] LC-MS: m / z (ESI): 593.2 [M+H] + .

[0167] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.96 (s, 1H), 8.67 (s, 1H), 8.18 (s, J = 1.4 Hz, 1H), 7.54–7.42 (m, 4H), 5.45 (s, 2H), 4.40 (d, J = 6.6 Hz, 1H), 3.81 (s, 3H), 3.61 (s, 3H), 1.70–1.61 (m, 1H), 1.38 (d, J = 6.7 Hz, 6H), 1.03–0.95 (m, 2H), 0.77–0.68 (m, 2H).

[0168] Example 7: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-5-methyl-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-5,8-dihydropteridine-6,7-dione (Compound 13)

[0169] Using a similar route and synthetic method as in Steps 3 to 8 of Example 6, Intermediate 6I was used to replace Intermediate 12C in Step 3 to prepare Compound 13.

[0170] MS m / z (ESI): 565.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ8.95(s,1H),8.67(s,1H),7.61–7.41(m,4H),6.75(s,1H),5.44(s,2H),3.80(s,3H),3.60(s,3H),2.30(s,3H),1.72–1.57(m, 1H),1.06–0.94(m,2H),0.83–0.65(m,2H).

[0171] Example 8: 2-(4-Cyclopropyl-6-difluoromethoxypyrimidin-5-yl)-5-methyl-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-5,8-dihydropteridine-6,7-dione (Compound 14)

[0172] Using a similar route and synthetic method as in Steps 3 to 8 of Example 6, replacing Intermediate 12C in Step 3 with Intermediate 6I and replacing (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid in Step 8 with Intermediate 14M, Compound 14 was prepared.

[0173] MS m / z(ESI):601.2[M+H] + .

[0174] 1 H NMR(400MHz,DMSO-d 6 )δ9.02(s,1H),8.80(s,1H),8.01–7.63(m,2H),7.63–7.59(m,2H),7.50(m,2H),5.45(s,2H),3.74(s,3H),3.62(s,3H),1.78(m,1H),1.06(m,2H),0.82(m,2H).

[0175] Example 9: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-5-(methyl-d3)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one (Compound 15)

[0176] Step 1: Synthesis of 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-nitropyrimidin-4-amine (15A)

[0177] At room temperature, 2,4-dichloro-5-nitropyrimidine (0.71 g, 3.7 mmol) and N,N-diisopropylethylamine (1.0 g, 7.8 mmol, 2.0 eq) were dissolved in tetrahydrofuran (20 mL). After cooling to 0 °C, 1I (0.93 g, 3.7 mmol, 1.0 eq) was added to the reaction solution. The resulting mixture was stirred at 0 °C for 0.5 h and then slowly warmed to room temperature and reacted for 2 h. The reaction solution was added to ice water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed once with saturated brine (50 mL). After removing the solvent by distillation under reduced pressure, the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 - 3:1) to give yellow solid 15A (0.90 g, yield 60%). m / z (ESI): 413 [M + H] + 。

[0178] Step 2: Synthesis of 2-chloro-N 4 -(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidine-4,5-diamine (15B)

[0179] At room temperature, compound 15A (0.5 g, 1.2 mmol), reduced iron powder (0.68 g, 12 mmol, 10 eq) were added to water (5 mL) and ethanol (5 mL), and then ammonium chloride (0.65 g, 12 mmol, 10 eq) was added. The resulting mixture was stirred at 80 °C for 2 h. After diluting the reaction solution with 50 mL of ethyl acetate and filtering while hot, the filter cake was rinsed with ethyl acetate. After removing the solvent by distillation under reduced pressure, the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give tan solid 15B (0.35 g, yield 76%). m / z (ESI): 383 [M + H] + 。

[0180] Step 3: Synthesis of 2-chloro-N-(2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)acetamide (15D)

[0181] At room temperature, 15B (0.5 g, 1.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). After the resulting solution was cooled to 0 °C, chloroacetyl chloride (0.15 g, 1.3 mmol, 1 eq) was slowly added, and then potassium carbonate (0.36 g, 2.61 mmol, 2 eq) was added. After the resulting mixture was reacted at 0 °C for 2 h, water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. After the solvent was removed by distillation under reduced pressure, the resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 - 1:1) to obtain white solid 15D (0.4 g, yield 67%). m / z (ESI): 459 [M+H] + 。

[0182] Step 4: Synthesis of 2-chloro-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one (15E)

[0183] At room temperature, 15D (0.3 g, 0.65 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and potassium carbonate (0.18 g, 1.3 mmol, 2 eq) was added. After the resulting mixture was heated to 50 °C and stirred for 2 h, water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate and filtered. After the solvent was removed by distillation under reduced pressure, the resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 - 1:1) to obtain white solid 15E (0.12 g, yield 44%). m / z (ESI): 423 [M+H] + 。

[0184] Step 5: Synthesis of 2-chloro-5-(methyl-d3)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one (15F)

[0185] Intermediate 15E (200.0 mg, 473.1 μmol) was added to N,N-dimethylformamide (2 mL), and cesium carbonate (308.3 mg, 946.1 μmol) was added. The reaction solution was cooled to 0 °C, and methyl iodide-d3 (82.3 mg, 567.7 μmol) was slowly added with stirring. The reaction was carried out at 0 °C for 2 h. After the resulting reaction solution was concentrated, the resulting residue was purified by silica gel column (eluent: petroleum ether:ethyl acetate = 1:1 - 1:4) to obtain intermediate 15F (160.0 mg, 363.8 μmol, yield 77%). m / z (ESI): 440.8 [M+H]+ .

[0186] Step 6: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(methyl-d3)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one (Compound 15)

[0187] Intermediate 15F (50.0 mg, 113.7 μmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (39.7 mg, 204.6 μmol), potassium phosphate (72.4 mg, 341.0 μmol), XPhos Pd G2 (17.8 mg, 22.7 μmol) were added to 1,4-dioxane (2 mL) and water (0.4 mL). The resulting mixture was stirred at 100 °C for 4 hours under nitrogen protection. After concentration of the reaction solution, 3 mL of acetonitrile was added to the concentrated reaction solution, and the solid was removed by filtration. The obtained filtrate was purified by preparative chromatography (Waters Xbridge C 18 150*19 mm, 10 μm, eluent: 10%-75% acetonitrile-water) to obtain Compound 15 (25.0 mg, 45.2 μmol, yield 40%).

[0188] LC-MS: m / z (ESI): 554.2 [M+H] + .

[0189] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.62 (s, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 4.83 (s, 2H), 4.23 (s, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 1.76 - 1.83 (m, 1H), 0.99 - 1.02 (m, 2H), 0.82 - 0.86 (m, 2H).

[0190] Example 10: 2-(4-cyclopropyl-6-difluoromethoxypyrimidin-5-yl)-5-(methyl-d3)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one (Compound 16)

[0191] Using a synthetic method similar to Step 6 in Example 9, Compound 16 was prepared by replacing (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid with Intermediate 14M.

[0192] LC-MS: m / z (ESI): 590.2 [M+H] + .

[0193] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.74 (s, 1H), 8.18 (s, 1H), 7.92 (s, 1H), 7.74 (t, J=62.7 Hz, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 4.85 (s, 2H), 4.24 (s, 2H), 3.76 (s, 3H), 1.93 (m, 1H), 1.07 (m, 2H), 0.94 (m, 2H).

[0194] Example 11

[0195] Using a similar route and synthesis method as in Steps 1 to 6 of Example 9, compound D in the following table was used to replace intermediate 1I in Step 1, and iodomethane was used to replace deuterated iodomethane in Step 5 to obtain the corresponding compounds 17 - 19 in the table.

[0196] Among them, the synthesis of intermediate 17A:

[0197] First step: Synthesis of intermediate 17AC

[0198] Under nitrogen protection, intermediate 17AA (2.3 g, 7.2 mmol) was added to N,N-dimethylformamide (20 mL), and then palladium acetate (161.1 mg, 719.1 μmol), triphenylphosphine (377.2 mg, 1.4 mmol), intermediate 17AB (1.06 g, 10.8 mmol), and triethylamine (1.45 g, 14.4 mmol) were added. After stirring evenly, the reaction was carried out at 100 °C for 3 hours. The reaction solution was poured into 100 mL of water, and extracted with ethyl acetate (50 mL * 3). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate, filtered. After the solvent was removed by rotary evaporation under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1 - 10:1) to obtain intermediate 17AC (1.5 g, yield: 72%). m / z (ESI): 320.1 [M+H] + .

[0199] Second step: Synthesis of intermediate 17AD

[0200] Under nitrogen protection, intermediate 17AC (1.54 g, 4.9 mmol) was added to ethanol (20 mL), and then palladium hydroxide (150.0 mg) and palladium on carbon (150.0 mg) were added. The mixture was stirred evenly, purged with hydrogen three times, and stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain crude intermediate 17AD (1.1 g, yield: 65%), which was directly used for the next step. m / z (ESI): 324.1 [M+H] + .

[0201] Step 3: Synthesis of intermediate 17AE

[0202] Intermediate 17AD (500.0 mg, 1.5 mmol) was added to chloroform (20 mL). The temperature was cooled to 0 °C in an ice-water bath, and thionyl chloride (184.0 mg, 1.5 mmol) was slowly added. Then the temperature was restored to room temperature, and the mixture was stirred and reacted for 3 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1) to obtain intermediate 17AE (300 mg, yield: 60%). m / z (ESI): 342.1 [M+H] + .

[0203] Step 4: Synthesis of intermediate 17AF

[0204] Intermediate 17AE (300.0 mg, 876.0 μmol) was added to N,N-dimethylformamide (10 mL), and then cesium carbonate (570.0 mg, 1.7 mmol) was added. The temperature was raised to 100 °C, and the mixture was stirred and reacted for 1 hour. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1) to obtain intermediate 17AF (100 mg, yield: 37%). m / z (ESI): 306.1 [M+H] + .

[0205] Step 5: Synthesis of intermediate 17A

[0206] Intermediate 17AF (100.0 mg, 327 μmol) was added to tetrahydrofuran (5.0 mL), and lithium aluminum hydride (62.9 mg, 1.7 mmol) was slowly added in portions with stirring. The mixture was reacted at room temperature for 2 hours. 1.0 g of sodium sulfate decahydrate was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with 10 mL of ethyl acetate and filtered, and the filtrate was concentrated to obtain crude intermediate 17A (100 mg) directly for the next step. m / z (ESI): 310.1 [M+H] + .

[0207] Synthesis of intermediate 18A:

[0208] Step 1: Synthesis of Intermediate 18AC

[0209] Add Intermediate 18AA (3.6 g, 20 mmol) to 20 mL of hexafluoroisopropanol, and add triethylamine (5.1 g, 50.5 mmol) and Intermediate 18AB (2.5 g, 20 mmol). Heat the resulting mixture to 70 °C and stir for 1 hour. Concentrate the reaction solution, add 50 mL of water, extract with ethyl acetate (30 mL * 3), combine the organic phases and concentrate under reduced pressure. The resulting residue is purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1 - 1:2) to obtain the target Intermediate 18AC (3.4 g, yield 75.9%). m / z (ESI): 224.1 [M + H] + .

[0210] Step 2: Synthesis of Intermediate 18A

[0211] Add Intermediate 18AC (2.0 g, 8.9 mmol) to tetrahydrofuran (20 mL), then add lithium aluminum hydride (667 mg, 17.6 mmol) at low temperature, and stir the reaction at room temperature for 2 hours. Dropwise add water (1.0 mL) at 0 °C, then successively add water (1.0 mL), 15% aqueous sodium hydroxide solution (1.0 mL), and water (3.0 mL) to quench the excess lithium aluminum hydride, filter through diatomaceous earth, wash the filter cake with dichloromethane, combine the organic phases and evaporate to dryness. The residue obtained after concentrating the filtrate is purified by reverse-phase C18 silica gel column (eluent: 5 - 50% aqueous acetonitrile solution) to obtain Intermediate 18A (1.8 g, yield: 88%). m / z (ESI): 228.2 [M + H] + .

[0212] Synthesis of Intermediate 19A:

[0213] Step 1: Synthesis of Intermediate 19AC

[0214] Add Intermediate 19AA (3.6 g, 20 mmol) to a mixed solvent of 5 mL of water and 25 mL of tetrahydrofuran, and add sodium bicarbonate (3.5 g, 41.6 mmol). Stir for 30 minutes, then add Intermediate 19AB (3.2 g, 20 mmol). After reacting the resulting mixture at room temperature for 30 minutes, heat to 70 °C and continue stirring for 30 minutes. Add the reaction solution to 50 mL of water, extract with ethyl acetate (30 mL * 3), combine the organic phases and concentrate under reduced pressure. The resulting residue is purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1 - 1:2) to obtain the target Intermediate 19AC (695 mg, yield 16.5%). m / z (ESI): 210.1 [M + H] + .

[0215] Step 2: Synthesis of Intermediate 19AE

[0216] Intermediate 19AC (690.5 mg, 3.3 mmol) was added to acetonitrile (20 mL), and then potassium fluoride (575.6 mg, 9.9 mmol) and diethyl bromodifluoromethylphosphonate (1.8 g, 6.6 mmol) were added. The reaction was carried out overnight at 60 °C. After the reaction was completed, the solvent was evaporated under reduced pressure. The reaction solution was added to water, and extracted with ethyl acetate (30 mL × 3). The residue obtained after concentration was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1 - 1:2) to obtain Intermediate 19AE (727 mg, yield: 85%). m / z (ESI): 260.2 [M+H] + .

[0217] Step 3: Synthesis of Intermediate 19A

[0218] Intermediate 19AE (710 mg, 2.7 mmol) was added to tetrahydrofuran (20 mL), and then lithium aluminum hydride (207.6 mg, 5.5 mmol) was added at low temperature. The reaction was stirred at room temperature for 2 hours. Water (1.0 mL) was added dropwise at 0 °C, and then water (1.0 mL), 15% aqueous sodium hydroxide solution (1.0 mL), and water (3.0 mL) were added successively to quench the excess lithium aluminum hydride. After filtration through diatomaceous earth, the filter cake was washed with dichloromethane. The organic phases were combined and evaporated under reduced pressure. The residue obtained after concentration of the filtrate was purified by reverse-phase C18 silica gel column chromatography (eluent: 5 - 50% aqueous acetonitrile solution) to obtain Intermediate 19A (680 mg, yield: 94%). m / z (ESI): 264.2 [M+H] + .

[0219] Example 12: 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (Compound 20)

[0220] Step 1: Synthesis of Ethyl 2-chloro-4-((4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidine-5-carboxylate (20C)

[0221] At room temperature, ethyl 2,4-dichloropyrimidine-5-carboxylate (220 mg, 1.0 mmol, 1.0 eq) was dissolved in acetonitrile (10 mL), and then (4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine 20B (300 mg, 1.0 mmol, 1.0 eq) and triethylamine (200 mg, 2.0 mmol, 2.0 eq) were successively added. The resulting mixture was stirred at room temperature for 10 hours. Water (10 mL) was added to the reaction system, and the resulting solution was extracted with ethyl acetate three times (10 mL * 3). The combined organic phases were washed with saturated brine (10 mL), 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 (eluent: petroleum ether: ethyl acetate = 2:1 - 1:2) to obtain intermediate 20C (360 mg, yield 75%). m / z (ESI): 482.1 [M+H] + 。

[0222] Step 2: Synthesis of 2-(2-chloro-4-((4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)propan-2-ol (20D)

[0223] Intermediate 20C (0.3 g, 0.62 mmol) was dissolved in tetrahydrofuran (10 mL), and then methylmagnesium bromide (3.0 M, 1.75 mL) was added portionwise under ice bath conditions. The reaction was maintained overnight under ice bath conditions. The reaction was quenched by adding water (10 mL), and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phases were 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 (eluent: petroleum ether: ethyl acetate = 2:1 - 1:2) to obtain intermediate 20D (285 mg, 0.61 mmol, yield 81%). LC-MS: m / z (ESI): 468.1 [M+H] + ;

[0224] Step 3: Synthesis of 7-chloro-1-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,4-dimethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (20E)

[0225] Dissolve N,N'-carbonyldiimidazole (0.18 g, 1.1 mmol) in dichloromethane (2.0 mL), then add diisopropylethylamine (0.16 g, 1.2 mmol, 0.21 mL), and then add intermediate 20D (0.18 g, 38.5 mmol). The reaction is stirred overnight at room temperature. Quench with ammonium chloride solution (10 mL), then extract with dichloromethane (10 mL * 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent by distillation under reduced pressure. The resulting residue is purified by silica gel column (eluent: petroleum ether: ethyl acetate = 2:1 - 1:2) to obtain intermediate 20E (160 mg, yield 84%). m / z (ESI): 494.1 [M+H] + ;

[0226] Step 4: Synthesis of 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (Compound 20)

[0227] At room temperature, dissolve compound 20E (75 mg, 0.15 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid 1 M (62 mg, 0.32 mmol) in 1,4-dioxane (3.0 mL), then add 0.5 mL of water, and then add tris(dibenzylideneacetone)dipalladium (83 mg, 0.091 mmol, 0.1 eq), tricyclohexylphosphine (51 mg, 0.18 mmol), potassium carbonate (0.38 g, 2.7 mmol). The resulting mixture is subjected to microwave reaction for 30 minutes under a nitrogen atmosphere at 100 °C. Concentrate the resulting reaction solution, dissolve the residue in 3 mL of acetonitrile and filter. The resulting filtrate is purified by preparative chromatography (Waters Xbridge C 18 150 * 19 mm, 10 μm, eluent: 10% - 75% acetonitrile - water) to obtain compound 20 (13 mg, yield 14%).

[0228] LC-MS: MS m / z (ESI): 608.2 [M+H] + .

[0229] 1 H NMR (400 MHz, DMSO-d 6)δ8.84(s,1H),8.66(s,1H),8.48(m,1H),7.58–7.31(m,4H),5.48 (m,1H),5.24(s,2H),4.82(m,4H),3.82(s,3H),1.78(s,6H),1.73(m,1H),1.00(m,2H),0.80(m,2H).

[0230] Example 13: 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(4-(1-(1-methylpyrrolidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (Compound 21)

[0231] Using a synthetic route and method similar to those in Step 1-4 of Example 12, and replacing Intermediate 20B with Intermediate 21B, Compound 21 was prepared.

[0232] LC-MS: m / z (ESI): 635.3 [M+H] + .

[0233] 1 1H NMR (400 MHz, DMSO-d 6 )δ8.84(s,1H),8.66(s,1H),8.00(s,1H),7.51(d,J = 8.2Hz,2H),7.43(d,J = 8.1Hz,2H),5.25(s,2H),4.80–4.68(m,1H),3.82(s,3H),3.03–2.94(m,1H),2.89–2.80(m,1H),2.58–2.54(m,1H),2.46–2.38(m,1H),2.29(s,3H),2.26–2.18(m,1H),1.99–1.90(m,1H),1.79(s,6H),1.74–1.65(m,1H),1.03–0.96(m,2H),0.82–0.73(m,2H).

[0234] Synthesis of Intermediate 21B:

[0235] First step: Synthesis of Intermediate 21BC

[0236] Intermediate 21BA (2.8 g, 11.7 mmol) was dissolved in N,N-dimethylformamide (20.0 mL), then Intermediate 21BB (3.0 g, 11.7 mmol) and potassium carbonate (4.9 g, 35.3 mmol) were added, and the reaction was carried out at 80 °C for 12 h. Water (60.0 mL) was added to dilute the reaction solution, and it was extracted with ethyl acetate (30.0 mL × 3). After the organic phases were combined and the solvent was removed by distillation under reduced pressure, the obtained residue was purified by silica gel column (methylene chloride:methanol = 20:1) to obtain Intermediate 21BC (550 mg, yield: 15%). m / z (ESI): 321.2 [M+H] + .

[0237] Step 2: Synthesis of Intermediate 21B

[0238] Intermediate 21BC (400.0 mg, 1.25 mmol) was dissolved in tetrahydrofuran (4.0 mL), and lithium aluminum hydride (105.0 mg, 2.8 mmol) was added portionwise at -20 °C, and the reaction was carried out at room temperature for 20 min. Water (1.0 mL) was added dropwise at 0 °C, then water (1.0 mL), 15% sodium hydroxide (1.0 mL), and water (3.0 mL) were added successively to quench the excess lithium aluminum hydride. The reaction solution was filtered, and the filtrate was concentrated. The obtained residue was purified by reverse-phase C18 silica gel column (the eluent was 5 - 50% aqueous acetonitrile solution) to obtain Intermediate 21B (200 mg, yield: 50%). m / z (ESI): 325.3 [M+H] + .

[0239] Example 14: 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazine (Compound 22)

[0240] Using a synthetic route and method similar to Steps 1 - 2 in Example 12, Intermediate 22A was prepared by replacing Intermediate 20B with Intermediate 1I in Step 1. Then, using a synthetic method similar to Step 4 in Example 12, Intermediate 22B was prepared by replacing Intermediate 20E with Intermediate 22A.

[0241] Intermediate 22B (80.0 mg, 0.15 mmol) and p-toluenesulfonic acid (7.7 mg, 0.044 mmol) were added to toluene (0.5 mL) and aqueous formaldehyde solution (0.5 mL). The obtained mixture was reacted at 110 °C for 0.5 h, and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by preparative chromatography (Waters Xbridge C 18(150 * 19 mm, 10 μm, with the eluent being 10% - 75% acetonitrile - water), the title compound 22 (20 mg, yield: 24%) was obtained.

[0242] LC - MS: m / z (ESI): 552.2 [M + H] + .

[0243] 1 1H NMR (400 MHz, DMSO - d6) δ 8.60 (s, 1H), 8.31 (s, 1H), 7.92 (s, 1H), 7.69–7.65 (m, 2H), 7.41 (d, J = 8.2 Hz, 2H), 4.98 (s, 2H), 4.83 (s, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 1.72 (m, 1H), 1.57 (s, 6H), 0.97 (m, 2H), 0.81 (m, 2H).

[0244] Example 15: 2 - (4 - Cyclopropyl - 6 - difluoromethoxypyrimidin - 5 - yl) - 5 - methyl - 8 - (4 - (1 - methyl - 4 - (trifluoromethyl) - 1H - imidazol - 2 - yl)benzyl) - 7,8 - dihydropteridin - 6(5H) - one (Compound 23)

[0245] Using a synthetic method similar to Steps 5 - 6 in Example 9, substituting methyl iodide for deuterated methyl iodide in Step 5 and replacing (4 - cyclopropyl - 6 - methoxypyrimidin - 5 - yl)boronic acid with Intermediate 14M, the title compound 23 was prepared.

[0246] LC - MS: m / z (ESI): 587.1 [M + H] + .

[0247] 1 1H NMR (400 MHz, DMSO - d 6 ) δ 8.74 (s, 1H), 8.19 (s, 1H), 7.93 (m, 1H), 7.82 (s, 1H), 7.64 (m, 2H), 7.52–7.47 (m, 2H), 4.85 (s, 2H), 4.24 (s, 2H), 3.76 (s, 3H), 3.31 (s, 3H), 1.93 (m, 1H), 1.07 (m, 2H), 0.93 (m, 2H).

[0248] Test Example 1: In vitro Activity Detection Experiment of USP1 Enzyme

[0249] Experimental Instruments:

[0250] Experimental materials:

[0251] The USP1 enzyme used in the experiment (Recombinant human his6-USP1 / His6-UAF1 Complex Protein, CF) was purchased from R&D, with the catalog number E-568-050. After aliquoting, it was stored at -80 °C.

[0252] The detection kit (Ub-CHOP2-Reporter Deubiquitination Assay Kit) was purchased from Lifesensors, with the catalog number PR1101. After aliquoting, it was stored at -80 °C. The kit contains a ubiquitinated reporter enzyme, which becomes active after being deubiquitinated by USP1 / UAF1. After catalyzing the substrate, the substrate is excited by a 485 nm laser to generate an emission light signal at 531 nm.

[0253] Information on other reagents and consumables required for the experiment is as follows:

[0254] Experimental methods:

[0255] The test compound was dissolved in DMSO to 10 mM. The compound and pure DMSO were pipetted into each well of a 384-well plate using a compound dilutor and pipettor. The highest concentration started from 3 μM and was diluted 3-fold, with a total of 8 concentration points. 50 nL of the test compound or DMSO (as a control) was added to each well, and the instrument obtained gradient-diluted sample concentrations through different ratios. The enzyme was diluted with freshly prepared reaction solution (20 mM Tris-HCl (pH 8.0), 2 mM CaCl 2 , 2 mM β-mercaptoethanol, 0.05% CHAPS (CHAPS was diluted with ddH 2 O)). 5 μL of the diluted enzyme reaction solution was added to each well, and the enzyme and compound were mixed by centrifugation and shaking, and then placed on ice after centrifugation. The kit reporting system and substrate were diluted with the reaction solution, and 5 μL of the diluted liquid was added to each well and mixed by centrifugation. Incubate at room temperature for 0.5 hours. The fluorescence signal was measured using an Envision plate reader (PerkinElmer, excitation wavelength 485 nm, emission wavelength 530 nm) for each well. The inhibitory activity IC 50 value of the compound on enzyme activity was calculated using the four-parameter Logistic Model method.

[0256] In the following formula, x represents the logarithmic form of the compound concentration; F(x) represents the effect value (the inhibition rate of enzyme activity under this concentration condition): F(x) = (A + ((B - A) / (1 + ((C / x)^D)))). A, B, C, and D are four parameters. Use Xlfit to further calculate the IC 50 value as the compound concentration required for 50% enzyme activity inhibition in the best-fit curve.

[0257] The test results are shown in Table 1.

[0258] Table 1 In vitro inhibitory activity of USP1

[0259] Test Example 2: Experiment on the inhibition of the proliferation of MDA-MB-436 cells by USP1 inhibitors:

[0260] Experimental instruments:

[0261] Experimental materials:

[0262] The cells used in the experiment, MDA-MB-436, were purchased from Kebai Biotechnology Co., Ltd., with the product number CBP60385. The cells were passaged and cultured in DMEM medium (containing 10% FBS), cryopreserved in liquid nitrogen when the cell passage number was low, and the cells used in the experiment did not exceed 15 passages.

[0263] The detection kit ( Luminescent Cell Viability Assay) was purchased from Promega Corporation, with the product number G7573. After aliquoting, it was stored at -30°C. The kit is a homogeneous detection method for detecting the number of viable cells in a culture by quantitatively measuring ATP. The kit produces a luminescent signal proportional to the amount of ATP present, and the amount of ATP is directly proportional to the number of cells in the culture.

[0264] Information on other reagents and consumables required for the experiment is as follows:

[0265] Experimental method:

[0266] Digest the cultured cells with 0.25% Trypsin-EDTA Solution, collect by centrifugation, resuspend with the culture medium DMEM (containing 10% FBS), seed the cells on a 384-well plate (400 cells / 20 μL / well), and incubate at 37°C, 5% CO 2Cultivate overnight in a cell incubator. Use an ECHO instrument to pipette the compounds and pure DMSO into each well of a 384-well plate. Start with the highest concentration at 10 μM and perform 4-fold dilutions for a total of 8 concentration points. Add 100 nL of the test compound or DMSO (as a control) to each well. The instrument obtains gradient-diluted sample concentrations through different ratios. Add 30 μL of culture medium to each well, centrifuge and vortex to mix, then centrifuge again and cultivate in the cell incubator for 7 days (for one column of cells, add CTG on the day of drug addition for detection). After 7 days, add 25 μL of CTG detection solution to each well, centrifuge and vortex to mix, then centrifuge again and place in the dark at room temperature for 10 minutes. Measure the chemiluminescence signal in each well using an Envision plate reader (PerkinElmer, emission wavelength 400 - 700 nm). Obtain the chemiluminescence value [RLU]cpd on the 7th day for the drug-treated group, the chemiluminescence value [RLU]cell on the 7th day for the DMSO-alone (untreated) group, and the chemiluminescence value [RLU]background from the CTG test on day 0 for the parallel DMSO-alone (untreated) group. The inhibition rate of the compound on proliferation (Inhibition rate, %) = [1 - ([RLU]cpd - [RLU]background) / ([RLU]cell - [RLU]background)] × 100%. The inhibitory activity GI 50 values are calculated using the four-parameter Logistic Model method. In the following formula, x represents the logarithmic form of the compound concentration; F(x) represents the effect value (the inhibition rate of proliferation under this concentration condition): F(x) = (A + ((B - A) / (1 + ((C / x)^D)))). A, B, C, and D are four parameters. Use Xlfit to further calculate the GI 50 values as the compound concentration required for 50% proliferation inhibition in the best-fit curve.

[0267] The inhibitory activity of the compounds of the present disclosure on the proliferation of MDA-MB-436 is determined through the above tests, and the measured GI 50 values are shown in Table 2.

[0268] Table 2 Inhibitory activity of the compounds of the present disclosure on the proliferation of MDA-MB-436 cells

Claims

A compound of formula (I) or a pharmaceutically acceptable salt thereof, Among them, Selected from the following structures: R 3a 、R 3b 、R 4 、R 5a 、R 5b are each independently selected from H, halogen, CN, OH, NH 2 、-C(O)OR x 、-C(O)R x 、-NHC(O)R x 、-O-C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group, the NH 2 、-O-C 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 a 4- to 10-membered heterocyclic group is optionally substituted by R x ; or R 3a 、R 3b together with the carbon atom to which it is attached form a C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group, the C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group is optionally substituted by R x ; or R 5a 、R 5b together with the carbon atom to which it is attached form a C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group, the C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group is optionally substituted by R x ; Ring A is selected from C 6 -C 10 aryl or a 5- to 10-membered heteroaryl, the C 6 -C 10 aryl or a 5- to 10-membered heteroaryl is optionally substituted by R a Substituted; Ring B is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 4 -C 10 cycloalkenyl or C 3 -C 10 cycloalkyl, and the C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 4 -C 10 cycloalkenyl or C 3 -C 10 cycloalkyl is optionally substituted by R b Substituted; Ring C is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, and the C 6 -C 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group is optionally substituted by R c Substituted; Each R a , R b , R c is independently selected from halogen, CN, OH, NH 2 , -C(O)OR x , -C(O)R x , C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclic group, and the NH 2 , C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x Substituted; Alternatively, R b , R c together with the atom to which it is attached forms C 4 -C 10 cycloalkenyl or 4-10 membered heterocyclic group, and the C 4 -C 10 cycloalkenyl or 4-10 membered heterocyclic group is optionally substituted by R x Substituted; R 1 , R 2 are independently selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group, said OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group is optionally substituted by R x ; or, R 1 , R 2 together with the atoms to which it is attached form a C 3 -C 10 cycloalkyl or a 4- to 7-membered heterocyclic group, said C 3 -C 10 cycloalkyl or a 4- to 7-membered heterocyclic group is optionally substituted by R x ; R x is selected from halogen, CN, OH, NH 2 or C 1 -C 6 alkyl, said OH, NH 2 or C 1 -C 6 alkyl is optionally substituted by C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or a 4- to 7-membered heterocyclic group; provided that when Selected from When R 5a is selected from halogen, CN, OH, NH 2 , -C(O)OR x , -C(O)R x , -O-C 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 a 4- to 9-membered heterocyclic group, and the NH 2 , -O-C 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 a 4- to 9-membered heterocyclic group is optionally substituted by R x ; or, R 5a , R 5b and the carbon atom to which it is attached form a C 4 -C 10 cycloalkyl or a 4- to 9-membered heterocyclic group, and the C 4 -C 10 cycloalkyl or a 4- to 9-membered heterocyclic group is optionally substituted by R x . The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, Wherein, R 3a 、R 3b 、R 4 、R 5a 、R 5b are independently selected from H, -C(O)OR x 、-C(O)R x 、-O-C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group, wherein the -O-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group is optionally substituted by R x ; or, R 3a 、R 3b 、R 4 、R 5a 、R 5b are independently selected from H, C 1 -C 6 deuterated alkyl, C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl, wherein the C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl is optionally substituted by R x . The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, Wherein, R 5a and R 5b form a C 3 -C 10 cycloalkyl with the carbon atom to which it is attached, and the C 3 -C 10 cycloalkyl is optionally substituted with R x . The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, Wherein, R 5a and the carbon atom to which it is attached form a C 5b -C 4 -cycloalkyl, and the C 10 -C 4 -cycloalkyl is optionally substituted with R 10 . x ​ The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, Wherein, Ring A is selected from 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl is optionally substituted by R a ; alternatively, Ring A is selected from 5- to 6-membered heteroaryl, and the 5- to 6-membered heteroaryl is optionally substituted by R a substituted. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, Wherein, Ring B is selected from C 6 -C 10 aryl or 5- to 10-membered heteroaryl, wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with R b ; or, ring B is selected from C 6 -C 10 aryl, wherein the C 6 -C 10 aryl is optionally substituted with R b substituted. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, Wherein, Ring C is selected from 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic group, and the 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic group is optionally substituted by R c ; alternatively, ring C is selected from 5- to 6-membered heteroaryl or 4- to 8-membered heterocyclic group, and the 5- to 6-membered heteroaryl or 4- to 8-membered heterocyclic group is optionally substituted by R c substituted. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, Wherein, Each R a 、R b 、R c is independently selected from halogen, C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group, and the C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocyclic group is optionally substituted with R x . The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, Wherein, R 1 、R 2 are independently selected from H, halogen, C 1 -C 6 -alkyl or C 3 -C 10 -cycloalkyl, and the C 1 -C 6 -alkyl or C 3 -C 10 -cycloalkyl is optionally substituted with R x . The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, Wherein, R x selected from halogen, NH 2 or C 1 -C 6 alkyl, said NH 2 or C 1 -C 6 alkyl is optionally substituted by C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or a 4- to 7-membered heterocyclic group. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, Wherein, Selected from the following structures: A compound selected from the following or a pharmaceutically acceptable salt thereof: A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-12 and a pharmaceutically acceptable excipient. A method for treating a disease mediated by USP1 in a mammal, comprising administering to a mammal in need of such treatment, preferably a human, a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, or the pharmaceutical composition according to claim 13. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, or the pharmaceutical composition according to claim 13, in the manufacture of a medicament for preventing or treating a disease mediated by USP1.

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