Ubiquitin-specific protease 1 inhibitors and uses thereof

Abstract

The present application relates to the technical field of medicine, and particularly relates to ubiquitin-specific protease 1 inhibitor compounds, pharmaceutically acceptable salts, esters, deuterium or stereoisomers thereof, pharmaceutical compositions and preparations containing the compounds, pharmaceutically acceptable salts, esters, deuterium or stereoisomers thereof, a method for preparing the compounds, pharmaceutically acceptable salts, esters, deuterium or stereoisomers thereof, and the use of the compounds, pharmaceutically acceptable salts, esters, deuterium or stereoisomers thereof in the preparation of drugs for treating and / or preventing diseases mediated by USP1 and related diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to ubiquitin specific protease 1 inhibitor compounds, pharmaceutically acceptable salts, esters, deuterium or stereoisomers thereof, pharmaceutical compositions and preparations containing the compounds, pharmaceutically acceptable salts, esters, deuterium or stereoisomers thereof, methods for preparing the compounds, pharmaceutically acceptable salts, esters, deuterium or stereoisomers thereof, and uses of the compounds, pharmaceutically acceptable salts, esters, deuterium or stereoisomers thereof in the preparation of drugs for treating and / or preventing diseases mediated by USP1 and related diseases. BACKGROUND

[0002] There are many related targets in the occurrence and development of tumors, deubiquitylating enzymes (DUBs) are encoded by more than 100 human genes and divided into six families, among which ubiquitin-specific proteases (USPs) contain more than 50 members and are the largest family of DUBs. Ubiquitination is a reversible process, DUBs act on the ubiquitin-proteasome system to cleave the isopeptide bond between lysine and the C-terminal of UBQ, affecting cell proliferation, cycle, apoptosis, DNA damage response, tumor suppression, occurrence and metastasis.

[0003] USP1 (Ubiquitin specific protease 1) is a member of the USP family and is a cysteine isopeptidase containing a triad of Cys90, His593 and Asp751. The human USP1 gene was cloned in 1998 and encodes a protein of 785 amino acids. Under normal conditions, USP1 is relatively inactive and is activated after binding to UAF1 (USP1-associated factor 1, a WD40 repeat-containing auxiliary factor that binds to and regulates USP1 activity) to form a heterodimeric complex, and then exerts the deubiquitination enzyme effect, stabilizes the replication fork and is localized in the nucleus.

[0004] USP1 is highly expressed in breast cancer, ovarian cancer and other cancers, and its expression is also elevated in other cancers. Overexpression of USP1 is associated with breast cancer / ovarian cancer BRCA1 deficiency. USP1 deubiquitination is involved in various processes related to cancer, affecting Fanconi anemia (FA), translesion DNA synthesis (TLS), cell differentiation and other pathways. In FA, USP1 deubiquitinates FANCD2 (Fanconi anaemia group D2 protein); in TLS, USP1 deubiquitinates PCNA (Proliferating cell nuclear antigen); and in cell differentiation, USP1 affects ubiquitination of ID (DNA-binding protein inhibitor family), regulating cell proliferation and differentiation.

[0005] These DNA damage response (DDR) pathways are essential for the repair of DNA damage induced by DNA crosslinking agents such as cisplatin and UV radiation. In the TLS pathway, USP1 affects PCNA, which is involved in DNA break repair together with USP1 / UAF1 and BRCA1 / 2. After replication fork stalling, PCNA monoubiquitination mediated by RAD18 promotes the switch of PCNA binding from replicative polymerases (polδ / ε) to TLS polymerases (such as POLK). After bypassing the lesion by TLS polymerases, USP1 deubiquitinates PCNA, promoting the switch of PCNA binding back to replicative polymerases. Inhibition of USP1 leads to replication fork instability and synthetic lethality with BRCA mutations.

[0006] USP1 inhibitors inhibit DNA break repair involving PCNA together with USP1 / UAF1 and BRCA1 / 2, leading to replication fork instability. Therefore, the use of small molecule inhibitors to inhibit USP1 has potential for the treatment of cancer and other diseases, and there is no commercialization or clinical development. SUMMARY

[0007] The purpose of the present application is to provide a ubiquitin-specific protease 1 inhibitor and its application. The specific technical solutions are as follows:

[0008] In some embodiments, the present application first provides a compound represented by general formula (I), a pharmaceutically acceptable salt, ester, deuteride or stereoisomer thereof:

[0009]

[0010] wherein,

[0011] X1 and X2 are independently selected from N, C or CR a ;

[0012] X4 is selected from N or C;

[0013] X3 and X5 are independently selected from N, NR a , C, CR a or CR a R b ;

[0014] R 1 、R 2 are independently selected from deuterium, hydrogen, carboxyl, cyano, nitro, amino, halogen, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, halo C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or halogenated C 1-6 alkoxy;

[0015] Each R 3 , each R 5 are independently selected from deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, sulfonylamino, C optionally substituted with 1-4 substituents Q1 1-6 Alkylamino, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkyl aminoacyl, C 1-6 Alkyl amido, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylamino, C 1-6 Alkylaminosulfonyl, -(L1) m -C 1-6 Alkyl, -(L1) m -C 2-6 Alkenyl, -(L1) m -C 2-6 Alkynyl, -(L1) m -C 1-6 Alkoxy, -(L1)m -6-10 membered aryl, -(L1) m -5-12 membered heteroaryl, -(L1) m -3-8 membered cycloalkyl or -(L1) m -3-8 membered heterocyclyl;

[0016] each R 4 is independently selected from the group consisting of halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 alkylamino, di(C 1-6 alkyl)amino, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylaminoacyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, C 1-6 alkylaminosulfonyl, -(L1) m -C 1-6 alkyl, -(L1) m -C 1-6 alkoxy, -(L1) m -6-10 membered aryl, -(L1) m -5-12 membered heteroaryl, -(L1) m -3-8 membered cycloalkyl or -(L1) m -3-8 membered heterocyclyl;

[0017] each Q1is independently selected from the group consisting of deuterium, cyano, carboxyl, hydroxyl, amino, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylaminoacyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -(L1) m -6-10 membered aryl, -(L1) m -5-12 membered heteroaryl, -(L1)m -3-12 membered cycloalkyl or -(L1) m -3-12 membered heterocyclyl, each q is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, hydroxyC 1-6 alkyl, carboxyC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl and haloC 1-6 alkoxy;

[0018] each L, each L1is independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O)2-, -NR c -, -CR a R b -;

[0019] each R a , each R b is independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl;

[0020] each R c is independently selected from deuterium, hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl;

[0021] is a single or double bond, and the adjacent are not both double bonds;

[0022] s is an integer from 1-4;

[0023] each m, m1, n, t is independently an integer from 0-4.

[0024] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, of the preceding Schemes, wherein X1is selected from C or CH.

[0025] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, of the preceding Schemes, wherein X1is selected from N.

[0026] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, of the preceding Schemes, wherein X2is selected from C or CH.

[0027] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, of the preceding Schemes, wherein X2is selected from N.

[0028] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, of the preceding Schemes, wherein X3is selected from C, CH, or CH2.

[0029] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, of the preceding Schemes, wherein X3is selected from N or NH.

[0030] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, of the preceding Schemes, wherein X4is selected from C.

[0031] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, of the preceding Schemes, wherein X4is selected from N.

[0032] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, of the preceding Schemes, wherein X5is selected from N or NH.

[0033] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, of the preceding Schemes, wherein X5is selected from C, CH, or CH2.

[0034] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof of the preceding formula, wherein,

[0035] is selected from

[0036] each R 5 , each t is as defined in any of the preceding aspects.

[0037] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof of the preceding formula, wherein,

[0038] is selected from

[0039] each R 5 , each t is as defined in any of the preceding aspects.

[0040] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof of the preceding formula, wherein,

[0041] is selected from the following structures:

[0042] each R 3 , each n is as defined in any of the preceding aspects.

[0043] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof of the preceding formula, wherein,

[0044] R 1 , R 2 are each independently selected from deuterium, hydrogen, halogen, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl, or haloC 1-6 alkoxy.

[0045] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof of the preceding formula, wherein,

[0046] R 1 , R2 are independently selected from deuterium, hydrogen, halogen, optionally deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy.

[0047] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, ester, deuterated substance or stereoisomer thereof, wherein,

[0048] R 1 、R 2 Each is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0049] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, ester, deuterated substance or stereoisomer thereof, wherein,

[0050] Each R 3 , each R 5 are independently selected from deuterium, halogen, C optionally substituted with 1-4 substituents Q1 1-6 Alkylamino, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L1) m -C 1-6 Alkyl, -(L1) m -C 1-6 Alkoxy, -(L1) m -phenyl, -(L1) m -5-6 membered heteroaryl, -(L1) m -3-6 membered cycloalkyl or -(L1) m -3-6 membered heterocyclic group;

[0051] Each Q1 is independently selected from deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkyl aminoacyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, halogenated C1-6 alkyl, haloC 1-6 alkoxy.

[0052] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterides, or stereoisomers thereof, as shown in the foregoing Schemes, wherein,

[0053] each R 3 , each R 5 is independently selected from deuterium, halogen, C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl;

[0054] each Q1is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy.

[0055] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterides, or stereoisomers thereof, as shown in the foregoing Schemes, wherein,

[0056] each R 3 is independently selected from deuterium, halogen, C 1-4 alkyl, haloC 1-4 alkoxy, hydroxyC 1-4 alkyl, aminoC 1-4 alkyl, carboxyC 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl.

[0057] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterides, or stereoisomers thereof, as shown in the foregoing Schemes, wherein,

[0058] each R 3Each of the following groups is independently selected from deuterium, fluorine, chlorine, bromine, and iodine, and optionally substituted with 1-3 substituents Q1: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0059] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, ester, deuterated substance or stereoisomer thereof, wherein,

[0060] Each R 3 are independently selected from halogenated C optionally substituted by 1-3 substituents Q1 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl.

[0061] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, ester, deuterated substance or stereoisomer thereof, wherein,

[0062] Each R 3 Each independently selected from halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0063] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, ester, deuterated substance or stereoisomer thereof, wherein,

[0064] Each R 3 They are independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated isobutyl, deuterated sec-butyl, deuterated tert-butyl, deuterated methoxy, deuterated ethoxy, deuterated propoxy, deuterated isopropoxy and cyclopropyl, and the number of deuterations is 1, 2 or 3.

[0065] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, ester, deuterated substance or stereoisomer thereof, wherein,

[0066] Each R 5 are independently selected from deuterium, halogen, halogenated C optionally substituted with 1-3 substituents Q11-4 alkyl, haloC 1-4 alkoxy, hydroxyC 1-4 alkyl, aminoC 1-4 alkyl, carboxyC 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy.

[0067] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof as shown in the preceding Schemes, wherein,

[0068] each R 5 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, optionally substituted with 1-3 substituents Q1.

[0069] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof as shown in the preceding Schemes, wherein,

[0070] each R 4 is independently selected from halogen, C 1-6 alkylamino, di(C 1-6 alkyl)amino, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl, -(L1) m -C 1-6 alkyl, -(L1) m -C 1-6 alkoxy, -(L1) m -phenyl, -(L1) m -5-6 membered heteroaryl, -(L1) m -3-6 membered cycloalkyl or -(L1) m -3-6 membered heterocyclyl;

[0071] each Q1is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylaminoacyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl, haloC1-6 alkyl, haloC 1-6 alkoxy.

[0072] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof as shown in the foregoing Schemes, wherein,

[0073] each R 4 is independently selected from the group consisting of halogen, haloC 1-4 alkyl, haloC 1-4 alkoxy, hydroxyC 1-4 alkyl, aminoC 1-4 alkyl, carboxyC 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy;

[0074] each Q1is independently selected from the group consisting of deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy.

[0075] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof as shown in the foregoing Schemes, wherein,

[0076] each R 4 is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluoro, chloro, bromo, iodo, difluoro, trifluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, optionally substituted with one to three substituents Q1.

[0077] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof as shown in the foregoing Schemes, wherein,

[0078] each R 4 is independently selected from the group consisting of fluorine, chlorine, bromine, iodine.

[0079] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof as shown in the foregoing Schemes, wherein,

[0080] each Q1is independently selected from the group consisting of deuterium, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy.

[0081] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof as shown in the preceding paragraphs, wherein,

[0082] each Q1is independently selected from deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy.

[0083] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof as shown in the preceding paragraphs, wherein,

[0084] each L, each L1is independently selected from -O-, -NR c -, -CR a R b -.

[0085] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof as shown in the preceding paragraphs, wherein,

[0086] each L, each L1is independently selected from -CR a R b -.

[0087] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof as shown in the preceding paragraphs, wherein,

[0088] each R a , each R b is independently selected from deuterium, hydrogen, halogen, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl;

[0089] each R c is independently selected from deuterium, hydrogen, C 1-6 alkyl optionally substituted with deuterium, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy.

[0090] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof as shown in the preceding paragraphs, wherein,

[0091] each R a , each R b is independently selected from deuterium, hydrogen, halogen, C 1-4 alkyl optionally substituted with deuterium, C 1-4 alkoxy optionally substituted with deuterium, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, carboxy C 1-4 alkyl;

[0092] each R c is independently selected from deuterium, hydrogen, C 1-4 alkyl optionally substituted with deuterium, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy.

[0093] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, as illustrated in the foregoing Schemes, wherein,

[0094] each R a , each R b is independently selected from deuterium, hydrogen, C c alkyl optionally substituted with deuterium.

[0095] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, as illustrated in the foregoing Schemes, wherein,

[0096] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, as illustrated in the foregoing Schemes, wherein,

[0097] each R a , each R b , each R c is independently hydrogen.

[0098] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, as illustrated in the foregoing Schemes, wherein,

[0099] s is an integer from 1 to 3.

[0100] each m, m1, n, t is independently an integer from 0 to 3.

[0101] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof as shown in the preceding paragraph, wherein,

[0102] s is 1, 2;

[0103] each m, m1, n, t is independently an integer from 0 to 3.

[0104] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof as shown in the preceding paragraph, having the structure of Formula (I-1),

[0105]

[0106] X1, X2, X3, X4, X5, each R a , each R b , each R c , R 1 , R 2 , each R 3 , each R 4 , each R 5 , each Q1, n, s, t are as defined in any of the preceding paragraphs.

[0107] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof as shown in the preceding paragraph, having the structure of Formula (I-2),

[0108]

[0109] X3, X4, X5, each R a , each R b , each R c , R 1 , R 2 , each R 3 , each R 4 , each R 5 , each Q1, n, s, t are as defined in any of the preceding paragraphs.

[0110] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof as shown in the preceding paragraph, having the structure of Formula (I-3),

[0111]

[0112] X3, X4, X5, each R3 each R 4 each R 5 each Q1, n, s, t are as described in any of the preceding Schemes.

[0113] In certain embodiments, a compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof, represented by the preceding Schemes, having the structure of Formula (I-4),

[0114]

[0115] R 1 each R 2 each R a each R b each R 3 each R 4 each R 5 each Q1, n, s, t are as described in any of the preceding Schemes.

[0116] In certain embodiments, a compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof, represented by the preceding Schemes, having the structure of Formula (I-5),

[0117]

[0118] each R 3 each R 4 each R 5 each Q1, n, s, t are as described in any of the preceding Schemes.

[0119] In certain embodiments, a compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof, represented by the preceding Schemes, having the structure of Formula (I-6),

[0120]

[0121] R 3 each R 4 each R 5 each Q1, s, t are as described in any of the preceding Schemes.

[0122] In certain embodiments, a compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof, represented by the preceding Schemes, wherein,

[0123] X1, X2are each independently selected from N, C, or CH;

[0124] X4is selected from N or C;

[0125] X3, X5are independently selected from N, NH, C, CH or CH2;

[0126] R 1 , R 2 are independently selected from deuterium, hydrogen, halogen, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy optionally substituted with deuterium, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl or halogenated C 1-6 alkoxy;

[0127] each R 3 , each R 5 is independently selected from deuterium, halogen, C 1-6 alkyl optionally substituted with 1-4 substituents Q1, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl, -(L1) m -C 1-6 alkyl, -(L1) m -C 1-6 alkoxy, -(L1) m -phenyl, -(L1) m -5-6 membered heteroaryl, -(L1) m -3-6 membered cycloalkyl or -(L1) m -3-6 membered heterocyclyl;

[0128] each R 4 is independently selected from halogen, C 1-6 alkyl optionally substituted with 1-4 substituents Q1, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl, -(L1) m -C 1-6 alkyl, -(L1) m -C 1-6 alkoxy, -(L1) m -phenyl, -(L1) m-5-6 membered heteroaryl, -(L1) m -3-6 membered cycloalkyl or -(L1) m -3-6 membered heterocyclyl;

[0129] each Q1is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylaminoacyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy;

[0130] each L, each L1is independently selected from -O-, -NR c -, -CR a R b -;

[0131] each R a , each R b is independently selected from deuterium, hydrogen, halogen, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy optionally substituted with deuterium, C 1-6 alkylamino, di(C 1-6 alkyl)amino, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl;

[0132] each R c is independently selected from deuterium, hydrogen, C 1-6 alkyl optionally substituted with deuterium, haloC 1-6 alkyl, haloC 1-6 alkoxy;

[0133] s is an integer from 1-3;

[0134] each m, m1, n, t is independently an integer from 0-3.

[0135] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof shown in the preceding schemes, wherein,

[0136] R 1 , R 2 are independently selected from deuterium, hydrogen, halogen, C1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl or haloC 1-4 alkoxy;

[0137] each R 3 is each independently selected from the group consisting of deuterium, halogen, haloC 1-4 alkyl, haloC 1-4 alkoxy, hydroxyC 1-4 alkyl, aminoC 1-4 alkyl, carboxyC 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;

[0138] each R 4 is each independently selected from the group consisting of halogen, haloC 1-4 alkyl, haloC 1-4 alkoxy, hydroxyC 1-4 alkyl, aminoC 1-4 alkyl, carboxyC 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy;

[0139] each R 5 is each independently selected from the group consisting of deuterium, halogen, haloC 1-4 alkyl, haloC 1-4 alkoxy, hydroxyC 1-4 alkyl, aminoC 1-4 alkyl, carboxyC 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy;

[0140] each Q1is independently selected from the group consisting of deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy;

[0141] each R a , each R b is each independently selected from the group consisting of deuterium, hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, haloC 1-4 alkyl, haloC 1-4 alkoxy, hydroxyC1-4 alkyl, amino C 1-4 alkyl, carboxy C 1-4 alkyl;

[0142] each R c are each independently selected from deuterium, hydrogen, C 1-4 alkyl, halo C 1-4 alkyl, halo C 1-4 alkoxy.

[0143] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, as shown in the foregoing Schemes, wherein,

[0144] R 1 , R 2 are each independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy;

[0145] each R 3 are each independently selected from deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy;

[0146] each R 4 are each independently selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy;

[0147] each R 5 are each independently selected from deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy;

[0148] each Q1is independently selected from deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy;

[0149] each R a , each R b is independently selected from deuterium, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, aminomethyl, carboxymethyl, wherein each R

[0150] each R c is independently selected from deuterium, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

[0151] s is 1, 2;

[0152] n, t are each independently 0, 1, 2.

[0153] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated forms, or stereoisomers thereof, as shown in the foregoing Schemes, wherein

[0154] R 1 , R 2 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy;

[0155] each R 3 is independently selected from C 1-6 alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl, optionally substituted with 1-3 substituents Q1;

[0156] each R 4 is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy;

[0157] each Q1 is independently selected from deuterium, C 1-6 alkyl, C 1-6 alkoxy;

[0158] each R 5 is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy;

[0159] each R a , each Rb each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy.

[0160] In certain embodiments, a compound, a pharmaceutically acceptable salt thereof, an ester, a deuterated derivative, or a stereoisomer thereof as depicted by the foregoing Schemes, wherein,

[0161] R 1 , R 2 are each independently hydrogen;

[0162] each R 3 is independently selected from C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl;

[0163] each R 4 is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy;

[0164] each Q1is independently selected from deuterium, C 1-4 alkyl, C 1-4 alkoxy;

[0165] each R 5 is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy;

[0166] each R a , each R b is independently hydrogen.

[0167] In certain embodiments, a compound, a pharmaceutically acceptable salt thereof, an ester, a deuterated derivative, or a stereoisomer thereof as depicted by the foregoing Schemes, having a structure according to Formula (I-4),

[0168]

[0169] wherein R 1 , R 2 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy;

[0170] each R 3 is independently selected from C 1-6 alkyl, C 1-6 alkoxy, deuterated C1-6 alkyl, deuterated C 1-6 alkoxy, 3-6 membered cycloalkyl;

[0171] each R 4 is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy;

[0172] each R 5 is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy;

[0173] R a , R b is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy;

[0174] n, s, t are each independently 1, 2, 3.

[0175] In certain embodiments, the compounds, pharmaceutically acceptable salts thereof, esters, deuterated compounds, or stereoisomers thereof shown in the foregoing schemes, having the structure shown in Formula (I-6),

[0176]

[0177] wherein R 3 is selected from C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkyl, deuterated C 1-4 alkoxy;

[0178] each R 4 is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy;

[0179] each R 5 is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy;

[0180] s, t are each independently 1, 2.

[0181] In certain embodiments, the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof shown in the foregoing schemes, has a structure according to Formula (I-6),

[0182] wherein R 3 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated isobutyl, deuterated sec-butyl, deuterated t-butyl, deuterated methoxy, deuterated ethoxy, deuterated propoxy, deuterated isopropoxy;

[0183] each R 4 is independently selected from fluorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy;

[0184] each R 5 is independently selected from fluorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy;

[0185] s, t are each independently 1, 2.

[0186] The selection of any substituent in any of the embodiments described herein can be combined with each other, and the combination thereof is still within the protection scope of the present application.

[0187] In some embodiments of the present application, the structure of the provided compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof is as follows:

[0188]

[0189] The present application also provides a pharmaceutical composition containing the compound, pharmaceutically acceptable salt thereof, ester, deuterated derivative, or stereoisomer thereof shown in the foregoing general formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), and one or more second therapeutically active agents, optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and / or diluents.

[0190] The present application also provides a pharmaceutical preparation containing the compound, pharmaceutically acceptable salt, ester, deuteride or stereoisomer thereof represented by the aforementioned general formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), and one or more pharmaceutically acceptable carriers and / or diluents; the pharmaceutical preparation is any clinically or pharmaceutically acceptable dosage form.

[0191] In some embodiments of the present application, the above-mentioned pharmaceutical preparation can be administered to a patient or subject in need of such treatment by oral, parenteral, rectal or pulmonary administration, etc. When used for oral administration, the pharmaceutical composition can be prepared into oral preparations, for example, into conventional oral solid preparations such as tablets, capsules, pills, granules, etc.; or into oral liquid preparations such as oral solutions, oral suspensions, syrups, etc. When prepared into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. When used for parenteral administration, the above-mentioned pharmaceutical preparation can also be prepared into injections, including injection solutions, sterile powders for injection and concentrated solutions for injection. When prepared into injections, conventional methods in the field of pharmaceutical production can be used, and no additional agents can be added or suitable additional agents can be added according to the nature of the drug when the injection is prepared. When used for rectal administration, the pharmaceutical composition can be prepared into suppositories, etc. When used for pulmonary administration, the pharmaceutical composition can be prepared into inhalants or sprays, etc.

[0192] The pharmaceutically acceptable carriers and / or diluents that can be used in the pharmaceutical composition or pharmaceutical preparation of the present application can be any conventional carrier and / or diluent in the field of pharmaceutical preparations, and the selection of a specific carrier and / or diluent will depend on the mode of administration or the type and state of the disease for the treatment of a specific patient. The preparation method of suitable pharmaceutical compositions for a specific mode of administration is well within the knowledge of those skilled in the art of pharmaceuticals. For example, the pharmaceutically acceptable carriers and / or diluents can include solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, binders, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, and antioxidants, etc. in the field of pharmacy. If necessary, flavoring agents, preservatives and sweeteners, etc. can also be added to the pharmaceutical composition.

[0193] The present application also provides the use of the compound, pharmaceutically acceptable salt, ester, deuteride or stereoisomer thereof represented by the aforementioned general formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in the preparation of a medicament for the treatment and / or prevention of USP1-mediated diseases and related diseases; the USP1-mediated diseases and related diseases are selected from cancer or benign tumor.

[0194] The application also provides application of the aforementioned compound represented by general formula (I), pharmaceutically acceptable salt, ester, deuterium or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in treating and / or preventing USP1 mediated diseases and related diseases; the USP1 mediated diseases and related diseases are selected from cancer or benign tumor.

[0195] The application also provides a method for treating diseases, which comprises administering a therapeutically effective amount of the aforementioned compound represented by general formula (I), pharmaceutically acceptable salt, ester, deuterium or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition to a patient in need, wherein the diseases are USP1 mediated diseases and related diseases; the USP1 mediated diseases and related diseases are selected from cancer or benign tumor.

[0196] The cancer or benign tumor includes but is not limited to breast cancer, ovarian cancer, endometrial cancer, cervical cancer, brain cancer, head and neck cancer, thyroid cancer, lung cancer, bronchial cancer, esophageal cancer, gastric cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, colon cancer, bladder cancer, prostate cancer, testicular cancer, skin cancer, bone cancer and hematoma; the lung cancer includes but is not limited to small cell lung cancer and non-small cell lung cancer; the hematoma includes but is not limited to leukemia, lymphoma and myeloma; the brain cancer includes but is not limited to glioma, neuroblastoma, astrocytoma and meningioma.

[0197] In the specification and claims of the present application, the compounds are named according to the chemical structure formula, and if the naming of the compounds is not consistent with the chemical structure formula when indicating the same compound, the chemical structure formula is used as the standard.

[0198] In the present application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by a person skilled in the art, however, in order to better understand the present application, the definitions of some terms are provided below. When the definitions and explanations of the terms provided in the present application are not consistent with the meanings commonly understood by a person skilled in the art, the definitions and explanations of the terms provided in the present application are used as the standard.

[0199] The "halogen" in the present application refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

[0200] The "halogenated" in the present application refers to any hydrogen in the substituent group can be replaced by one or more same or different halogen. The "halogen" is as defined above.

[0201] The "C 1-6 The "alkyl" represents a straight chain or branched alkyl group containing 1-6 carbon atoms, including, for example, "C 1-5 The "alkyl", "C 1-4 The "alkyl", "C 1-3 The "alkyl", "C1-2 alkyl", "C 2-6 alkyl", "C 2-5 alkyl", "C 2-4 alkyl", "C 2-3 alkyl", "C 3-6 alkyl", "C 3-5 alkyl", "C 3-4 alkyl", "C 4-6 alkyl", "C 4-5 alkyl", "C 5-6 alkyl", etc., specific examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, i-hexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, and the like. As used herein, the term "C 1-4 alkyl" refers to a straight, branched, or cyclic alkyl group having from 1 to 4 carbon atoms. 1-6 Specific examples of C

[0202] As used herein, the term "C 1-6 alkylene" refers to a straight, branched, or cyclic alkyl group having from 1 to 4 carbon atoms. 1-6 alkyl minus one hydrogen atom, including, for example, "C 1-5 alkylene", "C 1-4 alkylene", "C 1-3 alkylene", "C 1-2 alkylene", "C 2-6 alkylene", "C 2-5 alkylene", "C 2-4 alkylene", "C 2-3 alkylene", "C 3-6 alkylene", "C 3-5 alkylene", "C 3-4 alkylene", "C 4-6 alkylene", "C 4-5 alkylene", "C 5-6 alkylene", etc., specific examples of which include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like. As used herein, the term "C 1-4 alkylene" refers to a straight, branched, or cyclic alkyl group having from 1 to 4 carbon atoms. 1-6 Specific examples of C

[0203] As used herein, the term "C 2-6 alkenyl" refers to a straight, branched, or cyclic alkenyl group having from 2 to 6 carbon atoms and at least one double bond, including, for example, "C2-5 Alkenyl", "C 2-4 Alkenyl", "C 2-3 Specific examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl -1-pentenyl, 1-methyl-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-1-butenyl, 2-ethyl-1-butenyl, 2-ethyl-3-butenyl, and the like.

[0204] The "C 2-6 "Alkynyl" refers to a straight or branched chain alkynyl group with 2 to 8 carbon atoms containing a triple bond, including, for example, "C 2-5 Alkynyl", "C 2-4 Alkynyl", "C 2-3 Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1,1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, and the like.

[0205] The “C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkyl aminoacyl, C 1-6 Alkyl amido, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylamino, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylcarbonyl, C 1-6 "Alkoxycarbonyl" refers to a C 1-6 Alkyl-O-, C 1-6 Alkyl-NH-, (C 1-6 Alkyl) 2-N-, C1-6 alkyl-NH-C(O)-, C 1-6 alkyl-C(O)-NH-, C 1-6 alkyl-S(O)2-, C 1-6 alkyl-S(O)2-NH-, C 1-6 alkyl-NH-S(O)2-, C 1-6 alkyl-C(O)-, C 1-4 alkyl-O-C(O)-, wherein "C 1-6 alkyl" is as previously described.

[0206] "C 1-4 alkoxy", "C 1-4 alkylamino", "di(C 1-4 alkyl)amino", "C 1-4 alkylaminoacyl", "C 1-4 alkylamido", "C 1-4 alkylsulfonyl", "C 1-4 alkylsulfonamido", "C 1-4 alkylaminosulfonyl", "C 1-4 alkylcarbonyl", "C 1-4 alkoxycarbonyl" means a group of the formula: -C(O)-O-alkyl, wherein "C 1-4 alkyl-O-, C 1-4 alkyl-NH-, (C 1-4 alkyl)2-N-, C 1-4 alkyl-NH-C(O)-, C 1-4 alkyl-C(O)-NH-, C 1-4 alkyl-S(O)2-, C 1-4 alkyl-S(O)2-NH-, C 1-4 alkyl-NH-S(O)2-, C 1-4 alkyl-C(O)-, C 1-4 alkyl-O-C(O)-, wherein "C 1-4 alkyl" is as previously described.

[0207] "haloC 1-6 alkyl", "hydroxyC 1-6 alkyl", "aminoC 1-6 alkyl", "carboxyC 1-6 alkyl", "haloC 1-6 alkoxy" means one to multiple (e.g., 1-4, 1-3, 1-2) halo atoms, hydroxy, amino, carboxy groups replacing hydrogen atoms in a C 1-6 alkyl", "C 1-6 alkylene", "C 1-6 alkoxy".

[0208] "haloC1-4 alkyl, hydroxyC 1-4 alkyl, aminoC 1-4 alkyl, carboxyC 1-4 alkyl, haloC 1-4 alkoxy" means a group of one to more (e.g., 1-4, 1-3, 1-2) halo atoms, hydroxy, amino groups respectively replacing the hydrogen atoms of aC 1-4 alkyl, C 1-4 alkoxy.

[0209] The "3-8 membered cycloalkyl" according to the present application means a cyclic alkyl group having 3-8 carbon atoms, which is saturated or partially saturated and has no aromaticity, and includes "3-8 membered saturated cycloalkyl" and "3-8 membered partially saturated cycloalkyl"; preferably "3-4 membered cycloalkyl", "3-5 membered cycloalkyl", "3-6 membered cycloalkyl", "3-7 membered cycloalkyl", "4-5 membered cycloalkyl", "4-6 membered cycloalkyl", "4-7 membered cycloalkyl", "4-8 membered cycloalkyl", "5-6 membered cycloalkyl", "5-7 membered cycloalkyl", "5-8 membered cycloalkyl", "6-7 membered cycloalkyl", "6-8 membered cycloalkyl", "7-8 membered cycloalkyl", "3-6 membered saturated cycloalkyl", "4-7 membered saturated cycloalkyl", "4-8 membered saturated cycloalkyl", "5-8 membered saturated cycloalkyl", "5-7 membered saturated cycloalkyl", "5-6 membered saturated cycloalkyl", "3-6 membered partially saturated cycloalkyl", "4-7 membered partially saturated cycloalkyl", "4-8 membered partially saturated cycloalkyl", "5-8 membered partially saturated cycloalkyl", "5-7 membered partially saturated cycloalkyl", "5-6 membered partially saturated cycloalkyl", and the like. Specific examples of the "3-8 membered saturated cycloalkyl" include, but are not limited to, cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane (cycloheptyl), cyclooctane (cyclooctyl), and the like; and specific examples of the "3-8 membered partially saturated cycloalkyl" include, but are not limited to, cyclopropene, cyclobutene, cyclopentene, cyclopenta-2,4-diene, cyclohexene, cyclohexa-1,3-diene, cyclohexa-1,4-diene, cycloheptene, cyclohepta-1,3-diene, cyclohepta-1,4-diene, cyclohepta-1,3,5-triene, cyclooctene, cycloocta-1,3-diene, cycloocta-1,4-diene, cycloocta-1,5-diene, cycloocta-1,3,5-triene, cyclooctatetraene, and the like.

[0210] The "3-8 membered heterocyclic group" of the present invention refers to a saturated or partially saturated monocyclic or condensed ring cyclic group containing at least one heteroatom (e.g., 1, 2, 3, 4, or 5) and 3-8 ring atoms, and having no aromaticity, wherein the heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom. Optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms, or sulfur atoms) in the cyclic structure may be oxo-substituted. The "3-8 membered heterocyclic group" of the present invention includes "3-8 membered saturated heterocyclic groups" and "3-8 membered partially saturated heterocyclic groups." Preferably, the "3-8 membered heterocyclic group" of the present invention contains 1-3 heteroatoms; preferably, the "3-8 membered heterocyclic group" of the present invention contains 1-2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and / or oxygen atoms; preferably, the "3-8 membered heterocyclic group" of the present invention contains 1-2 nitrogen atoms. The “3-8 membered heterocyclic group” is preferably a “4-8 membered heterocyclic group”, “3-6 membered heterocyclic group”, “3-6 membered saturated heterocyclic group”, “3-6 membered nitrogen-containing heterocyclic group”, “3-6 membered saturated nitrogen-containing heterocyclic group”, “5-6 membered heterocyclic group”, “5-6 membered saturated heterocyclic group”, etc. Specific examples of the “3-8 membered heterocyclic group” include, but are not limited to, aziridine, 2H-aziridine, diaziridine, 3H-diazirinyl, azetidinyl, 1,4-dioxane, 1,3-dioxane, 1,3-dioxolane, 1,4-dioxadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl , 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, 2H-1,2-oxazinyl, 6H-1,3-oxazinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3,4-dihydro-2H-pyranyl.

[0211] The "6-10 membered aryl group" described in the present invention refers to an aromatic cyclic group containing 6-10 ring carbon atoms, including "6-8 membered monocyclic aryl groups" and "8-10 membered condensed ring aryl groups".

[0212] The "6-8 membered monocyclic aromatic group" described in the present invention refers to a monocyclic aromatic group containing 6-8 ring carbon atoms, examples of which include but are not limited to phenyl, cyclooctatetraenyl, etc.; preferably phenyl.

[0213] The "8-10 membered fused ring aromatic group" described in the present invention refers to an unsaturated aromatic cyclic group containing 8-10 ring carbon atoms, which is formed by two or more cyclic structures sharing two adjacent atoms. It is preferably a "9-10 membered fused ring aromatic group", and specific examples include naphthyl.

[0214] The "5-12 membered heteroaryl" as used herein refers to a cyclic group having aromaticity, containing 5-12 ring atoms, at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom. Examples include 5-12 membered nitrogen-containing heteroaryl, 5-12 membered oxygen-containing heteroaryl, 5-12 membered sulfur-containing heteroaryl, and the like. Included are "5-8 membered mono-heteroaryl" and "8-10 membered fused-heteroaryl".

[0215] The "5-8 membered mono-heteroaryl" as used herein refers to a monocyclic cyclic group having aromaticity, containing 5-8 ring atoms, at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom. Optionally, a ring atom in the cyclic structure, such as a carbon atom, a nitrogen atom, or a sulfur atom, can be oxidized. Included are "5-7 membered mono-heteroaryl", "5-6 membered mono-heteroaryl", "5-6 membered nitrogen-containing mono-heteroaryl", "5 membered nitrogen-containing mono-heteroaryl", and the like. Specific examples of "5-8 membered mono-heteroaryl" include, but are not limited to, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azepinyl, 1,3-diazepinyl, azocinyl, and the like. The "5-6 membered heteroaryl" refers to a specific example of 5-8 membered heteroaryl containing 5-6 ring atoms.

[0216] The "8-10 membered fused-heteroaryl" as used herein refers to a cyclic group having aromaticity, containing 8-10 ring atoms, at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom, formed by two or more cyclic structures sharing two adjacent atoms with each other. Optionally, a ring atom in the cyclic structure, such as a carbon atom, a nitrogen atom, or a sulfur atom, can be oxidized. Included are "9-10 membered fused-heteroaryl", "8-9 membered fused-heteroaryl", and the like, which can be fused in a manner of benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl, 5-6 membered heteroaryl, and the like. Specific examples include, but are not limited to, pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furanothiophene, pyrazaloxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinonyl, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, and the like.

[0217] The "optionally substituted" according to the present application includes both the "substituted" and "unsubstituted" cases.

[0218] The "substituent" according to the present application includes the following groups: selected from a single bond or a double bond, and the adjacent are not simultaneously a double bond.

[0219] The "pharmaceutically acceptable salt" according to the present application means a pharmaceutically acceptable addition salt of an acid and a base, such as a metal salt, an ammonium salt, a salt with an organic acid, a salt with an organic base, a salt with an inorganic acid, a salt with an acidic amino acid or a basic amino acid, and the like.

[0220] The "ester" according to the present application means a pharmaceutically acceptable ester, and particularly an ester which is hydrolyzed in vivo and includes an ester which is easily decomposed in the human body to leave a parent compound (a compound according to the general formula (I)) or a salt thereof. The "ester" according to the present application can be selected, for example, from the following groups: (1) a carboxylic acid ester obtained by esterification with a carboxylic acid compound, wherein the non-carbonyl moiety of the carboxylic acid compound is selected from, for example, C 1-20 straight chain or branched alkyl, C 1-12 straight chain or branched alkyl, C 1-8 straight chain or branched alkyl, C 1-6 straight chain or branched alkyl (e.g., methyl, ethyl, n-propyl, t-butyl or n-butyl), C 1-6 alkoxy C 1-6 alkyl (e.g., methoxymethyl), C 6-10 aryl C 1-6 alkyl (e.g., benzyl), C 6-10 aryloxy C 1-6 alkyl (e.g., phenoxymethyl), C 6-10 aryl (e.g., phenyl, optionally substituted with, for example, halogen, C 1-4 alkyl or C 1-4 alkoxy or amino); (2) a sulfonic acid ester, such as an alkylsulfonyl or aralkylsulfonyl (e.g., methylsulfonyl); (3) an amino acid ester (e.g., L-valyl or L-isoleucyl); and (4) a mono-, di- or triphosphate, and the like; (4) an ester obtained by esterification with an alcohol compound, wherein the non-hydroxy moiety of the alcohol compound is selected from, for example, C 1-20 straight chain or branched alkyl, C 1-12 straight chain or branched alkyl, C 1-8 straight chain or branched alkyl, C 1-6 straight chain or branched alkyl (e.g., methyl, ethyl, n-propyl, t-butyl or n-butyl), C 1-6 alkoxy C 1-6 alkyl (e.g., methoxymethyl), C 6-10 aryl C 1-6Alkyl (such as benzyl), C 6-10 Aryloxy C 1-6 Alkyl (e.g. phenoxymethyl), C 6-10 Aryl (e.g. phenyl, optionally substituted with, for example, halogen, C 1-4 Alkyl or C 1-4 substituted with alkoxy or amino groups).

[0221] As used herein, "stereoisomers" refer to compounds of the present invention that contain one or more asymmetric centers and can therefore exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers. Compounds of the present invention may have asymmetric centers, each of which independently gives rise to two optical isomers. The scope of the present invention includes all possible optical isomers and their mixtures. Compounds of the present invention that contain olefinic double bonds include cis- and trans-isomers, unless otherwise specified. Compounds of the present invention may exist as tautomers (a type of functional group isomer) that have different points of hydrogen attachment due to the displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and their mixtures are included within the scope of the present invention. Enantiomers, diastereomers, racemates, mesomorphs, cis- and trans-isomers, tautomers, geometric isomers, epimers, and mixtures thereof of all compounds are included within the scope of the present invention.

[0222] Unless otherwise specified, any atom in the compounds of this application may represent any stable isotope of that atom. Unless otherwise specified, when a position in a structure is designated as H, i.e., hydrogen (Hl), that position contains only the naturally occurring isotope. Similarly, unless otherwise specified, when a position in a structure is designated as D, i.e., deuterium (H-2), that position contains an isotope at least 3340 times greater than the naturally occurring isotope (0.015%) (i.e., at least 50.1% deuterium isotope). When one or more positions in the structure of a compound of this application are designated as D, i.e., deuterium (H-2), the content of the compound depicted in that structure may be at least 52.5%, at least 60%, at least 67.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98.5%, at least 99%, or at least 99.5%.

[0223] The deuterium incorporation of the compounds of the present application is the ratio of the amount of the isotopic content of the synthesis label to the amount of the naturally occurring isotope. The deuterium incorporation of each specified deuterium atom of the compounds of the present application can be at least 3500 fold (52.5%), at least 4000 fold (60%), at least 4500 fold (67.5%), at least 5000 fold (75%), at least 5500 fold (82.5%), at least 6000 fold (90%), at least 6333.3 fold (95%), at least 6466.7 fold (97%), at least 6566.7 fold (98.5%), at least 6600 fold (99%), at least 6633.3 fold (99.5%).

[0224] Isotopologues, as used herein, refer to compounds that differ only in isotopic composition of the chemical structure. Compounds herein that contain deuterium at a particular position will also contain a very small amount of the hydrogen isotopologues at that position. The amount of hydrogen isotopologues at a deuterated position in a deuterated compound of the present application will depend on a number of factors, including the deuterium isotopic purity of the deuterium incorporation reagent (D2O, D2, NaBD4, LiAlD4, etc.) and the effectiveness of the method of synthesis used to introduce the deuterium isotopes. However, as noted above, the total amount of hydrogen isotopologues at a deuterated position will be less than 49.9%. The total amount of hydrogen isotopologues at a deuterated position in a deuterated compound of the present application will be less than 47.5%, 40%, 32.5%, 25%, 17.5%, 10%, 5%, 3%, 1%, or 0.5%.

[0225] In the present application, each atom not designated as deuterium is present at its natural isotopic abundance.

[0226] As used herein, "deuterated" means that one or more hydrogen atoms of a group are replaced by one or more deuterium atoms. For example, a deuterated compound can contain only one deuterium. In some embodiments, a deuterated compound contains only two deuteriums. In some embodiments, a deuterated compound contains only three deuteriums. In some embodiments, a deuterated compound contains four deuteriums.

[0227] As used herein, "optionally deuterated" includes both deuterated and non-deuterated groups, wherein "deuterated" is as defined above.

[0228] As used herein, "therapeutically effective amount" means that amount of the aforementioned compound, pharmaceutical formulation, pharmaceutical composition which, when administered to a patient, is capable of at least alleviating the symptoms of the patient's condition. The actual amount which constitutes a "therapeutically effective amount" will vary depending on a number of factors, including but not limited to the particular condition being treated, the severity of the condition, the size and health of the patient, and the route of administration. A skilled medical practitioner can readily determine the appropriate amount using methods known in the medical arts.

[0229] Advantages of the Invention

[0230] (1) The compound, pharmaceutically acceptable salt, ester, deuterium or stereoisomer thereof has excellent USP1 inhibitory activity, and can treat and / or prevent USP1 mediated diseases and related diseases;

[0231] (2) The compound has good inhibitory effect on tumor cells;

[0232] (3) The compound, pharmaceutically acceptable salt, ester, deuterium or stereoisomer thereof has good pharmacokinetic properties, longer lasting effect and high bioavailability;

[0233] (4) The compound, pharmaceutically acceptable salt, ester, deuterium or stereoisomer thereof has good safety;

[0234] (5) The compound has simple preparation process, high drug purity, stable quality and is easy to produce on a large scale.

[0235] The advantages of the compound provided by the embodiments of the present application are further illustrated by the following experiments, but this should not be understood as the compound provided by the embodiments of the present application only has the following advantages.

[0236] In vitro enzymatic activity of compounds of the application

[0237] Test sample: The compound synthesized by the embodiments of the present application, the chemical name and structure of which are shown in the preparation examples.

[0238] Experimental reagents:

[0239]

[0240] Experimental consumables:

[0241] Consumables Vendor Cat No. 384-Well plate Perkin Elmer 6007279

[0242] Experimental method:

[0243] 1. Compound dilution

[0244] 1) The compound of the present application is prepared to 10 mM using DMSO as a test stock solution.

[0245] 2) The compound stock solution of the present application is diluted by 4 times gradient to 10 concentrations, and the highest concentration is 10 mM.

[0246] 3) The diluted compound of the present application is transferred to a 384-well plate using Echo550, 1000 times dilution, 2 replicate wells are set for each concentration, and the final concentration of DMSO is 1%.

[0247] 4) Test compound final concentration: 10000 nM, 2500 nM, 625 nM, 156 nM, 39 nM, 9.8 nM, 2.4 nM, 0.61 nM, 0.15 nM, 0.038 nM.

[0248] 2. Enzyme reaction experiment

[0249] 1) Prepare enzyme solution in 1x test buffer.

[0250] 2) Add Ubiquitin Rhodamine 110 Protein, CF (Ub-Rho) in 1x test buffer to make substrate solution.

[0251] 3) Transfer 10 μL enzyme solution and 1x reaction buffer to 384-well plate.

[0252] 4) Incubate at room temperature for 60 minutes.

[0253] 5) Start reaction by adding 10 μL substrate solution per well, centrifuge for 30 s, shake for 30 s.

[0254] 3. Result detection

[0255] 1) Read plate on SpectraMax Paradigm for 30 minutes, excitation wavelength 480 nm, emission wavelength 540 nm.

[0256] 2) Collect data on SpectraMax Paradigm.

[0257] 4. Data analysis

[0258] Calculate inhibition (%inh) using the following formula:

[0259]

[0260] Where Max represents luminescent signal intensity of positive control well without compound;

[0261] Min represents luminescent signal intensity of negative control well without enzyme;

[0262] Signal represents luminescent signal intensity of test compound;

[0263] Calculate IC using the following formula: 50

[0264]

[0265] Where Y represents %inhibition;

[0266] ​X represents: the concentration of the compound.

[0267] Experimental results:

[0268] Table 1 Inhibitory activity of the compounds of the present application on USP-1

[0269]

[0270] From the above experimental results, it can be seen that the compound prepared by the present application can effectively inhibit the activity of USP1, and is an effective USP1 inhibitor.

[0271] In vitro cellular activity of compounds of the application

[0272] Test sample: part of the compounds of the present application, the chemical name and structure of which are shown in the preparation examples.

[0273] The cell strains used in the following experiments are as follows:

[0274] MDA-MB-436: BRCA1 mutant human breast cancer cells; Caov-3: homologous recombination repair deficient (HRD+) human ovarian cancer cells

[0275] Experimental method (CelltiterGlo assay)

[0276] 1. Preparation of cells

[0277] 1.1 Cell culture:

[0278] All cells are adherent cells, the culture medium of MDA-MB-436 cells is DMEM + 10% FBS + 1% ITS-G + 16 μg / ml glutathione, and the culture medium of Caov-3 cells is DMEM + 10% FBS, and the cells are in the logarithmic growth phase for the experiment.

[0279] 1.2 Preparation of cell suspension:

[0280] Harvest the cells in the logarithmic growth phase and count the cells using a platelet counter. The cell viability is detected by the trypan blue exclusion method to ensure that the cell viability is above 90%. Adjust to the appropriate concentration, and add 90 μL of cell suspension to the 96-well plate, respectively.

[0281] Table 2 Cell seeding number

[0282]

[0283] 2. Preparation of test compounds

[0284] 2.1 Prepare the DMSO stock solution of the test compound, and the concentration of each test compound stock solution is 10 mM.

[0285] 2.2 Preparation of test compound working stock solutions

[0286] A 10 mM stock solution of the test compound was serially diluted 3-fold with DMSO for a total of 8 concentrations. 2 μL of each DMSO-diluted compound was then added to 198 μL of culture medium to form a working stock solution of the test compound (compound concentration was 10 times the final concentration, with a maximum concentration of 100 μM).

[0287] 2.3 Compound treatment

[0288] 10 μL of compound working stock solution (10-fold dilution, final DMSO concentration of 0.1%) was added to each well of a 96-well plate seeded with cells.

[0289] The final concentrations of the test compounds were: 10000.00 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, 4.57 nM.

[0290] 2.4 Control well setting

[0291] Solvent control: 0.1% DMSO.

[0292] Blank control: 96-well plate detection reading at 0 h after drug addition.

[0293] 2.5 Place the 96-well plate in a 37°C, 5% CO2 cell culture incubator and culture for 7 days.

[0294] 3. Detection

[0295] Thaw CTG reagent and equilibrate a 96-well plate to room temperature for 30 minutes. Add 60 μL of reagent (Celltiter Gloassay kit) to each well, shake on a shaker for 2 minutes to mix (protect from light), and incubate at room temperature for 20 minutes (protect from light). Read the light signal using a multifunctional microplate reader.

[0296] 4. Data Processing

[0297] 1) Inhibition rate (%) = (DMSO solvent control well reading - test substance well reading) / (DMSO solvent control well reading - blank control well reading) × 100%;

[0298] 2) Input GraphPad Prism to draw a graph and obtain the curve and IC 50 .

[0299] Experimental results and conclusions

[0300] Table 3 In vitro cytological activities of the compounds of the present invention (IC 50 ,nM)

[0301]

[0302] As shown in Table 3, the compound of the present application can effectively inhibit the proliferation of MDA-MB-436 and Caov-3 cells, indicating that the compound of the present application has clinical application potential for treating HRD positive (homologous recombination deficiency) cancer diseases.

[0303] Pharmacokinetic experiment of compounds of the application

[0304] Test product The compound of the present application, the preparation of which is described in the examples in the present application.

[0305]

[0306] Preparation of test product solution

[0307] 1. Preparation of compound solution

[0308] (1) Intravenous bolus administration (iv): Take the compound, add an appropriate amount of DMSO, and ultrasonically vortex to dissolve; then add an appropriate amount of PEG 400, vortex to mix; finally add 28% HP-β-CD solution, vortex to mix, and prepare a final concentration of 1 mg / ml of the drug solution.

[0309] (2) Oral administration (po): Take an appropriate amount of compound into a tissue grinder, add solvent 2% HPC+0.1% Tween, and grind thoroughly; transfer the grinding solution into a glass bottle; shake to mix, and prepare a final concentration of 1 mg / ml of the drug solution.

[0310] Experimental method

[0311] 1. Drug administration

[0312] The test product is administered intravenously (iv) at a dose of 5 mg / kg, and the administration volume is 5 ml / kg;

[0313] Oral administration (po) is performed at a dose of 10 mg / kg, and the administration volume is 10 ml / kg.

[0314] 2. Blood sampling

[0315] At 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 h after administration, tail vein blood sampling is performed, about 100 μl of whole blood is taken at each time point, centrifuged in a high-speed centrifuge at 8000 rpm for 6 min to separate the plasma, and the plasma is stored in a-80℃ refrigerator.

[0316] 3. Analysis of plasma samples

[0317] Protein precipitation method: take 20 μl of plasma into a 96-well deep well plate, add 200 μl of internal standard solution, vortex for 10 min, then centrifuge at 4000 rpm for 20 min, take 100 μl of supernatant, add 100 μL of water, vortex for 3 min; LC-MS / MS for analysis.

[0318] Experimental results and conclusions

[0319] The experimental results show that the compound of the present application has high exposure, suitable half-life and clearance rate in the body after intravenous injection or oral administration, exhibits good pharmacokinetic properties, and has good clinical application prospects. DETAILED DESCRIPTION

[0320] The technical solutions of the present application will be described below in combination with specific embodiments. The described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0321] The meanings of the abbreviations used in the following experiments are as follows:

[0322] Xphos-Pd-G2: chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; LAH: lithium aluminum hydride; DMF: dimethylformamide; DIBAL-H: diisobutylaluminum hydride

[0323] Preparation of 4-(4-cyclopropyl-6-methoxy pyrimidin-5-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline

[0324] (1) Preparation of 2-(bis(methylthio)methylene)cyclohexane-1,3-dione

[0325] Dissolve 1,3-cyclohexanedione (20 g, 178.4 mmol) in DMF (200 mL), add potassium carbonate (74 g, 535.2 mmol), and react at 20°C for 0.5 h. Add carbon disulfide (20 g, 267.6 mmol), and react at 20°C for 1 h. Add iodomethane (76 g, 535.2 mmol), and react at 20°C for 1 h. Concentrate to obtain a crude product, which is directly used in the next step.

[0326] (2) Preparation of 2-amino-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (2) Preparation of 2-amino-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one

[0327] Dissolve 2-(bis(methylthio)methylene)cyclohexane-l,3-dione (crude from previous step) in DMF (200 mL), add guanidine hydrochloride (17 g, 178.4 mmol), potassium carbonate (49.3 g, 356.8 mmol), and react at 100 °C for 16 h. Cool to 25 °C, add water (300 mL), filter to obtain the filter cake, and dry under vacuum to obtain the target compound 16.3 g in 44% yield.

[0328] (3) Preparation of 2-chloro-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one

[0329] Dissolve 2-amino-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (16.3 g, 78 mmol) in dichloromethane (150 mL), add titanium tetrachloride (14.8 g, 78 mmol), and tert-butyl nitrite (48 g, 468 mmol), and react at 25 °C for 3 h. Quench the reaction by adding water, filter to obtain the filtrate, concentrate, and purify by column chromatography (ethyl acetate / petroleum ether = 0-40%) to obtain the target compound 6.1 g in 34% yield.

[0330] (4) Preparation of 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-(methylthio)-7,8- dihydroquinazolin-5(6H)-one

[0331] Dissolve 2-chloro-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (1.2 g, 5.15 mmol) in 1,4-dioxane (30 mL), add (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid (1 g, 5.15 mmol), Xphos-Pd-G2 (408 mg, 0.52 mmol), Xphos (496 mg, 1.04 mmol), K3PO4 (1.2 g, 5.7 mmol), and water (10 mL), and react at 90 °C for 3 h under N2protection. After the reaction is completed, dry the solvent by rotary evaporation, and purify by normal phase preparation (ethyl acetate / petroleum ether = 0-50%) to obtain the target compound 830 mg in 47% yield.

[0332] (5) Preparation of 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-hydrazinyl-7,8- dihydroquinazolin-5(6H)-one

[0333] Dissolve 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-(methylthio)-7,8-dihydroquinazolin- 5(6H)-one (830 mg, 2.4 mmol) in ethanol (20 mL), add hydrazine hydrate (184 mg, 3.6 mmol), and react at 70 °C for 3 h. After the reaction is completed, concentrate to obtain the target compound 700 mg in 89%.

[0334] (6) Preparation of 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2,6,7,8- tetrahydro-pyrazolo[3,4,5-de]quinazoline

[0335] Dissolve 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-hydrazinyl-7,8- dihydroquinazolin-5(6H)-one (300 mg, 0.92 mmol) in N-methylpyrrolidone (5 mL), ethanol (60 mL), and react at 160 °C for 1 h under microwave. Isolate the target compound by column chromatography (methanol / water = 0-60%) to give 150 mg in a yield of 53%.

[0336] Example 1 Preparation of 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2-(2-fluoro-4-(1- methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydro-pyrazolo[3,4,5- de]quinazoline (Compound 1)

[0337]

[0338] (1) Preparation of methyl 2-fluoro-4-(4-(trifluoromethyl)-1H-imidazol-2- yl)benzoate

[0339] Dissolve 3,3-dibromo-1,1,1-trifluoropropan-2-one (6.7 g, 25.0 mmol) in water (20 mL), add sodium acetate (3.9 g, 48.0 mmol), and react at 100 °C for 1 h. Cool to 0 °C, add a solution of methyl 2-fluoro-4-formylbenzoate (3.6 g, 20.0 mmol) in methanol (60 mL), and add aqueous ammonia (20 mL). Warm to 100 °C and react for 16 h. After completion of the reaction, extract the reaction solution with ethyl acetate, collect the organic phase, dry, and purify by column chromatography on silica gel (PE:EA = 0-30%) to give the product (1.5 g, 26.3% yield).

[0340] (2) Preparation of methyl 2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzoate

[0341] Dissolve methyl 2-fluoro-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (1.3 g, 4.5 mmol) and K2CO3 (1.2 g, 9.0 mmol) in DMF (10 mL), stir for 30 min, add MeI (7.7 g, 5.4 mmol), and stir for 14 h after completion of the addition. Dilute with water, extract with ethyl acetate, dry the organic phase, concentrate, and purify the residue by column chromatography on silica gel (ethyl acetate: petroleum ether = 10:3) to give the title compound 1.1 g in a yield of 80.7%.

[0342] (3) Preparation of (2-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)methanol

[0343] Methyl 2-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzoate (600 mg, 2.0 mmol) was dissolved in THF (30 mL), LAH (228 mg, 6.0 mmol) was added, and the reaction was stirred at 0 °C for 30 min. The reaction was monitored by LCMS. The title compound was obtained by celite suction filtration (520 mg, yield: 95.5%).

[0344] (4) Preparation of 2-(4-(chloromethyl)-3-fluorophenyl)-l-methyl-4- (trifluoromethyl)-lH-imidazole

[0345] (2-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanol (520 mg, 1.9 mmol) was dissolved in DCE (4 mL) and SOCl2(2 mL), and the reaction was stirred at 50 °C for 30 min. The reaction was monitored by LCMS. The title compound was obtained by drying and concentrating the organic phase and purifying it by silica gel column chromatography (ethyl acetate: petroleum ether = 10:3) (500 mg, yield: 90.3%).

[0346] (5) Preparation of 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2-(2-fluoro-4-(l- methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5- de]quinazoline

[0347]

[0348] 30 °C, 2-(4-(chloromethyl)-3-fluorophenyl)-l-methyl-4-(trifluoromethyl)-lH-imidazole (200 mg, 0.68 mmol), 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2,6,7,8- tetrahydropyrazolo[3,4,5-de]quinazoline (232 mg, 0.75 mmol) were dissolved in DMF (20 mL), K2CO3(188 mg, 1.4 mmol) was added, and the reaction was stirred for 10 h. The reaction was monitored by LCMS. The title compound was obtained by washing with water, extracting with ethyl acetate, and purifying by silica gel column chromatography (petroleum ether: ethyl acetate = 1:4) (40 mg, yield: 10.4%).

[0349] Molecular Formula: C 28 H 24 F4N8O Molecular Weight: 564.55 LC-MS (M / e): 565.2 (M+H + )

[0350] 1 H-NMR(400MHz, CDCl3)δ:8.67(s,1H),7.43-7.36(m,3H),7.31(s,1H),5.36(s,2H),3.94(s,3H),3.78( s,3H),3.15-3.08(m,4H),2.45-2.39(m,2H),1.70-1.67(m,1H),1.32-1.24(m,2H),0.93-0.88(m,2H).

[0351] Example 2 Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (Compound 2)

[0352]

[0353] (1) Preparation of methyl 3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

[0354] Methyl 3-fluoro-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (1.0 g, 3.5 mmol) and K2CO3 (966 mg, 7.0 mmol) were dissolved in DMF (10 mL) at 30°C and stirred for 30 min. Then, MeI (596 mg, 4.2 mmol) was added. After addition was complete, the mixture was stirred for 3 h. The reaction was monitored for completion. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated, and the residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:5) to afford 1.0 g of the title compound in a yield of 95.4%.

[0355] (2) Preparation of (3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol

[0356] Dissolve methyl 3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (450 mg, 1.5 mmol) in THF (50 mL), add LAH (171 mg, 4.5 mol), and react at 0°C for 30 min. LCMS confirms the reaction is complete. Filter the reaction mixture through Celite to obtain 360 mg of the title compound in an 88.2% yield.

[0357] (3) Preparation of 2-(4-(chloromethyl)-2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole

[0358] (3-Fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanol (360 mg, 1.3 mmol) was dissolved in DCE (5 mL) and SOCl2(1 mL) and reacted at 50 °C for 30 min. The reaction was checked by LCMS. The organic phase was dried and concentrated and purified by silica gel column (ethyl acetate: petroleum ether = 0: 100-100:0) to give the title compound 333 mg, yield: 86.8%.

[0359] (4) Preparation of 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2-(3-fluoro-4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline

[0360] 30 °C, 2-(4-(chloromethyl)-2-fluorophenyl)-4-(trifluoromethyl)-lH-imidazole (100 mg, 0.34 mmol), 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2,6,7,8- tetrahydropyrazolo[3,4,5-de]quinazoline (95 mg, 0.31 mmol) were dissolved in DMF (20 mL), K2CO3(85 mg, 0.62 mmol) was added and stirred for 10 h. The reaction was checked by LCMS. The water was washed, extracted with ethyl acetate and purified by silica gel column (petroleum ether: ethyl acetate = 1:4) to give the title compound 95 mg, yield: 49.2%. Molecular formula: C 28 H 24 F4N8O Molecular weight: 564.5 LC-MS (M / e): 565.2 (M+H + )

[0361] 1 H-NMR (400 MHz, CDC13) δ: 8.68 (s, 1H), 7.61-7.57 (m, 1H), 7.36-7.33 (m, 2H), 7.28-7.23 (m, 1H), 5.68 (s, 2H), 3.95 (s, 3H), 3.64 (s, 3H), 3.16-3.10 (m, 4H), 2.47-2.40 (m, 2H), 1.69-1.63 (m, 1H), 1.29-1.25 (m, 2H), 0.94-0.92 (m, 2H).

[0362] Example 3 Preparation of 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2-(3,5-difluoro-4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (Compound 3)

[0363]

[0364] (1) Preparation of methyl 3,5-difluoro-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

[0365] Methyl 3,5-difluoro-4-formylbenzoate (2.0 g, 10.0 mmol) was dissolved in 25 mL of methanol, and sodium acetate (1.0 g, 12.2 mmol) and dibromotrifluoroacetone (3.2 g, 11.9 mmol) were added. The system was cooled to 0°C and 6 mL of ammonia was added. After the addition was complete, the temperature was raised to 30°C and the reaction was carried out for 4.0 h. After the reaction was completed, the reaction solution was concentrated and the residue was purified by column chromatography to obtain 2.0 g of the target product in a yield of 65.3%.

[0366] (2) Preparation of methyl 3,5-difluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

[0367] Methyl 3,5-difluoro-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (1.9 g, 6.2 mmol) was dissolved in DMF (30 mL), and potassium carbonate (1.9 g, 13.7 mmol) and iodomethane (1.0 g, 7.0 mmol) were added. The mixture was reacted at 30°C for 2.0 h. After the reaction was completed, the mixture was quenched with water and concentrated. The residue was purified by column chromatography (EA:PE = 15%) to obtain 1.6 g of the target product in a yield of 80.5%.

[0368] (3) Preparation of (3,5-difluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol

[0369] Dissolve methyl 3,5-difluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (800 mg, 2.5 mmol) in 20 mL of THF, add DIBAL-H (2.0 mL, 3.0 mmol), and react at 30°C for 1.0 h. After reaction, quench with water, concentrate, and proceed directly to the next step.

[0370] (4) Preparation of 2-(4-(chloromethyl)-2,6-difluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole

[0371] The crude product from the previous step was dissolved in 30 mL of 1,2-dichloroethane, and 5 mL of thionyl chloride was added. The mixture was reacted at 50°C for 1.0 h. After the reaction, the reaction solution was concentrated and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate and concentrated. The residue was subjected to column chromatography (EA:PE = 15%) to obtain 500 mg of the product. The two-step yield was 64.4%.

[0372] (5) Preparation of 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2-(3,5-difluoro-4-(l- methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5- de]quinazoline

[0373] Dissolve 2-(4-(chloromethyl)-2,6-difluorophenyl)-l-methyl-4-(trifluoromethyl)-lH- imidazole (200 mg, 0.64 mmol) in 10 mL DMF, add potassium carbonate (160 mg, 1.2 mmol) and 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2,6,7,8- tetrahydropyrazolo[3,4,5-de]quinazoline (180 mg, 0.58 mmol), the system is reacted at 60 °C for 5.0 h, after the reaction is completed, it is concentrated, and the residue is subjected to column chromatography (EA: PE = 90%) to obtain 80 mg of the product, with a yield of 21.4%.

[0374] Dissolve 2-(4-(chloromethyl)-2,6-difluorophenyl)-l-methyl-4-(trifluoromethyl)-lH- imidazole (200 mg, 0.64 mmol) in 10 mL DMF, add potassium carbonate (160 mg, 1.2 mmol) and 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2,6,7,8- tetrahydropyrazolo[3,4,5-de]quinazoline (180 mg, 0.58 mmol), the system is reacted at 60 °C for 5.0 h, after the reaction is completed, it is concentrated, and the residue is subjected to column chromatography (EA: PE = 90%) to obtain 80 mg of the product, with a yield of 21.4%.

[0375] Molecular formula: C 28 H 23 F5N8O Molecular weight: 582.5 LC-MS (M / e): 583.2 (M+H + )

[0376] 1 H-NMR (400MHz, CDC13) δ: 8.67 (s, 1H), 7.39 (s, 1H), 7.09-7.07 (m, 2H), 5.64 (s, 2H), 4.11 (s, 3H), 3.98 (s, 3H), 3.19-3.05 (m, 4H), 2.42-2.38 (m, 2H), 1.64-1.62 (m, 1H), 1.29-1.22 (m, 2H), 0.94-0.92 (m, 2H).

[0377] The following compounds shown in the table were prepared using the same or similar method as described in the above examples:

[0378]

[0379] The USP1 inhibitors provided by the present application and the application thereof are described in detail above. The principles and implementation manners of the present application are described by using specific examples in the present document, and the above examples are only used to help understand the method and the central idea of the present application. It should be noted that, for those skilled in the art, without departing from the principles of the present application, some improvements and modifications can be made to the present application, and these improvements and modifications also fall within the protection of the claims of the present application.

Claims

1. A compound represented by general formula (I-4), or a pharmaceutically acceptable salt or deuterated substance thereof, in, R 1 、R 2 are independently selected from deuterium, hydrogen, carboxyl, cyano, nitro, amino, halogen, optionally deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or halogenated C 1-6 alkoxy; Each R 3 , each R 5 are independently selected from deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, sulfonylamino, C optionally substituted with 1-4 substituents Q1 1-6 Alkylamino, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L1) m -C 1-6 Alkyl, -(L1) m -C 1-6 Alkoxy or -(L1) m -3-6 membered cycloalkyl; Each R 4 are independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C optionally substituted with 1-4 substituents Q1 1-6 Alkylamino, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L1) m -C 1-6 Alkyl, -(L1) m -C 1-6 alkoxy; Each Q1 is independently selected from deuterium, cyano, carboxyl, hydroxyl, amino, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, haloC 1-6 Alkyl, halogenated C 1-6 alkoxy; Each L1 is independently selected from -CR a R b -; Each R a , each R b are independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, C 1-6 Alkyl, optionally deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy; s is an integer from 1 to 4; Each of m, n, and t is independently an integer of 0-4.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated substance thereof, in, R 1 、R 2 are independently selected from deuterium, hydrogen, halogen, optionally deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy; Each R 3 , each R 5 are independently selected from deuterium, halogen, C optionally substituted with 1-4 substituents Q1 1-6 Alkylamino, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L1) m -C 1-6 Alkyl, -(L1) m -C 1-6 Alkoxy or -(L1) m -3-6 membered cycloalkyl; Each R 4 are independently selected from halogen, optionally substituted with 1-4 substituents Q1 1-6 Alkylamino, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L1) m -C 1-6 Alkyl or -(L1) m -C 1-6 alkoxy; Each Q1 is independently selected from deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy; Each L1 is independently selected from -CR a R b -; Each R a , each R b are independently selected from deuterium, hydrogen, halogen, optionally deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy; s is an integer from 1 to 3; Each of m, n, and t is independently an integer from 0 to 3.

3. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated substance thereof, wherein: R 1 、R 2 are independently selected from deuterium, hydrogen, halogen, optionally deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 alkoxy; Each R 3 are independently selected from deuterium, halogen, halogenated C optionally substituted with 1-3 substituents Q1 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy or 3-6 membered cycloalkyl; Each R 4 are independently selected from halogen, optionally substituted with 1-4 substituents Q1, 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 1-4 Alkyl, C 1-4 alkoxy; Each R 5 are independently selected from deuterium, halogen, halogenated C optionally substituted with 1-3 substituents Q1 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 alkoxy; Each Q1 is independently selected from deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy; Each R a , each R b are independently selected from deuterium, hydrogen, halogen, optionally deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

4. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated substance thereof, which has the structure of formula (I-5), Each R 3 , each R 4 , each R 5 , n, s, t are defined as in claim 1.

5. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated substance thereof, wherein: R 1 、R 2 are independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy; Each R 3 Each independently selected from deuterium, fluorine, chlorine, bromine, iodine, and optionally substituted with 1-3 substituents Q1, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; Each R 4 methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, each independently selected from fluorine, chlorine, bromine, iodine, and optionally substituted with 1-3 substituents Q1; Each R 5 Each independently selected from deuterium, fluorine, chlorine, bromine, iodine, and optionally substituted with 1-3 substituents Q1, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy; Each Q1 is independently selected from deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy; Each R a , each R b are independently selected from deuterium, hydrogen, optionally deuterated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy; s is 1 or 2; n and t are independently 0, 1, and 2, respectively.

6. A compound, or a pharmaceutically acceptable salt or deuterated form thereof, having the following structure:

7. A pharmaceutical preparation comprising the compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt or deuterated substance thereof, and one or more pharmaceutically acceptable carriers and / or diluents; the pharmaceutical preparation is in any clinically or pharmaceutically acceptable dosage form.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt or deuterated form thereof, and one or more second therapeutically active agents; optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and / or diluents.

9. Use of the compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt or deuterated substance thereof, or the pharmaceutical preparation according to claim 7, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing USP1-mediated diseases and related diseases.

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