ubiquitin-specific protease 1 inhibitors

Abstract

This invention relates to the field of pharmaceutical technology, specifically to ubiquitin-specific protease 1 inhibitor compounds, pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof, pharmaceutical compositions and formulations containing said compounds, pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof, methods for preparing said compounds, pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof, and the use of said compounds, pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof in the preparation of medicaments for the treatment and / or prevention of USP1-mediated diseases and related diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to ubiquitin-specific protease 1 inhibitor compounds, pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof, pharmaceutical compositions and formulations containing said compounds, pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof, methods for preparing said compounds, pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof, and the use of said compounds, pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof in the preparation of medicaments for the treatment and / or prevention of USP1-mediated diseases and related diseases. Background Technology

[0002] There are many relevant targets in the occurrence and development of tumors. Deubiquitination enzymes (DUB) are encoded by more than 100 human genes and are divided into 6 families. Among them, ubiquitin-specific proteases (USP) contain more than 50 members and are the largest DUB family. Ubiquitination is a reversible process. DUB acts on the ubiquitin-protease system, cleaving the isopeptide bond between lysine and the C-terminus of UBQ, affecting cell proliferation, cell cycle, apoptosis, DNA damage response, tumor suppression, occurrence, and metastasis.

[0003] USP1 (Ubiquitin-specific protease 1) is a member of the USP family, a cysteine ​​isopeptidase containing a triplet structure of Cys90, His593, and Asp751. The human USP1 gene was cloned in 1998 and encodes a 785-amino acid protein. In its normal state, USP1 is relatively inactive. It is activated upon binding to UAF1 (USP1-associated factor 1, a cofactor containing a WD40 repeat sequence that binds to and regulates USP1 activity) to form a heterodimeric complex, where it acts as a deubiquitinating enzyme, stabilizing the replication fork and localizing to the cell nucleus.

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

[0005] These DNA damage response (DDR) pathways are crucial for repairing DNA damage induced by DNA cross-linking agents such as cisplatin and ultraviolet radiation. In the TLS pathway, PCNA affected by USP1, along with USP1 / UAF1 and BRCA1 / 2, participates in DNA break repair. After replication fork arrest, RAD18-mediated PCNA monoubiquitination promotes the conversion of PCNA binding from replication-type polymerases (polδ / ε) to TLS polymerases (such as POLK). After bypassing the lesion via TLS polymerase, USP1 then deubiquitinates PCNA, promoting its conversion back to replication-type polymerase. Inhibition of USP1 leads to replication fork instability and, in conjunction with BRCA mutations, synthetic lethality.

[0006] USP1 inhibitors suppress DNA break repair involving PCNA, USP1 / UAF1, and BRCA1 / 2, leading to replication fork instability. Therefore, using small molecule inhibitors to suppress USP1 has the potential for treating cancer and other diseases, but it is not yet commercially available or in clinical development. Summary of the Invention

[0007] The purpose of this invention is to provide a ubiquitin-specific protease 1 inhibitor and its application. The specific technical solution is as follows:

[0008] In some embodiments, the present invention first provides compounds of general formula (I), pharmaceutically acceptable salts, esters, deuterated derivatives thereof, or stereoisomers thereof:

[0009]

[0010] in,

[0011] X1 X 2 X 6 X 7 Each is independently selected from N, C, or CH;

[0012] X 3 X 4 X 5 Selected independently from N or CR a ;

[0013] Each Y is independently selected from -CR a1 R b -、-NR c -, -CO-, -O-, -S- or -SO;

[0014] Ring A and ring B are independently selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclic, 6-10 membered aryl or 5-8 membered heteroaryl;

[0015] The ring C is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, or 5-12 membered heteroaryl;

[0016] Each R 1 R 2 Each R 3 Each R 4 The C groups are independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, sulfonamide, and 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 alkyl carbonyl, C 1-6 alkoxycarbonyl, C 1-6 Alkylaminoyl, C 1-6 Alkyl amide, C 1-6 alkylsulfonyl, C 1-6 Alkylsulfonamide, C 1-6 Alkylaminosulfonyl, -(L1) s -C 1-6 Alkyl group, -(L1) s -C 2-6 Alkenyl, -(L1) s -C 2-6 Alkyne group, -(L1) s -C 1-6 Alkoxy group, -(L1) s -6-10 aryl, -(L1)s -5-12 heteroaryl groups, -(L1) s -3-8 membered cycloalkyl or -(L1) s -3-8 membered heterocyclic group;

[0017] Each Q1 is independently selected from deuterium, cyano, carboxyl, hydroxyl, amino, halogen, and optionally C-groups substituted with deuterium. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, 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 C 1-6 Alkyl, Halogenated C 1-6 Alkoxy group, -(L1) s -6-10 aryl, -(L1) s -5-12 heteroaryl groups, -(L1) s -3-12 membered cycloalkyl or -(L1) s -3-12-membered heterocyclic group;

[0018] Each L and each L1 are independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O)2-, and -NR. c1 -、-CR a2 R b1 -;

[0019] Each R a Each R a1 Each R a2 Each R b Each R b1 The C groups are independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, and cyano groups, with the C group optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Alkylaminoyl, C 1-6 Alkyl amide, C 1-6 Alkylsulfonamide, C 1-6 Alkylaminosulfonyl, 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;

[0020] Each R c Each R c1 The C atoms are independently selected from deuterium and hydrogen, respectively, and are optionally deuterated. 1-6 Alkyl, 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;

[0021] ------ can be a single or double bond, and adjacent ------ cannot both be double bonds;

[0022] s, t, p, and q are each an independent integer from 0 to 4;

[0023] m and n are independent integers from 1 to 4.

[0024] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein X1 is selected from C or CH.

[0025] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated form or its stereoisomer, wherein X1 is selected from N.

[0026] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated form or its stereoisomer, wherein X2 is selected from C or CH.

[0027] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or stereoisomer thereof, wherein X2 is selected from N.

[0028] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein X3 is selected from CR a .

[0029] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated form or its stereoisomer, wherein X3 is selected from N.

[0030] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein X4 is selected from CR a .

[0031] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated form or its stereoisomer, wherein X4 is selected from N.

[0032] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein X5 is selected from CR a .

[0033] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated form or its stereoisomer, wherein X5 is selected from N.

[0034] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein X6 is selected from C or CH.

[0035] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein X6 is selected from N.

[0036] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated form or its stereoisomer, wherein X7 is selected from C or CH.

[0037] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated form or its stereoisomer, wherein X7 is selected from N.

[0038] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each Y is independently selected from -CR a1 R b -、-NR c -、-O-.

[0039] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each Y is independently selected from -CR a1 R b -

[0040] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein ring A and ring B are independently selected from 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups.

[0041] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein ring A and ring B are independently selected from 5-6 member nitrogen-containing heterocyclic groups or 5-6 member nitrogen-containing heteroaryl groups.

[0042] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or stereoisomer thereof, wherein ring A and ring B are independently selected from pyrrole, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazole, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, dihydropyrrole, dihydrothiazolyl, dihydroisothiazolyl, dihydrothiadiazolyl, dihydrooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrotriazolyl, pyrroleyl, imidazolyl, and pyrazolylalkyl.

[0043] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, its deuterated derivative, or its stereoisomer, wherein ring A and ring B are each independently selected from...

[0044] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein the ring C is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl or 5-8 membered heteroaryl.

[0045] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein the ring C is selected from 3-6 membered cycloalkyl, 3-6 membered heterocyclic, phenyl or 5-6 membered heteroaryl.

[0046] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein the ring C is selected from 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups.

[0047] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or stereoisomer thereof, wherein the ring C is selected from phenyl, furanyl, thiophene, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, 2-pyridoneyl, 4-pyridoneyl, pyrimidinyl, pyridazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetraazinyl.

[0048] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, its deuterated derivative, or its stereoisomer, wherein ring C is selected from...

[0049] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein,

[0050] Selected from the following structure:

[0051]

[0052] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein,

[0053] Selected from

[0054] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each R 1 R 2 Each R 3 Each R 4 The C groups are independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, sulfonamide, and 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 group, -(L1) s -C 1-6 Alkyl group, -(L1) s -C 1-6 Alkoxy group, -(L1) s -Phenyl, -(L1) s -5-6 aryl heteroaryl, -(L1) s -3-6 membered cycloalkyl or -(L1) s -3-6-membered heterocyclic group.

[0055] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each R 1 R 2 Each R 3 Each R 4 C1 groups are independently selected from hydrogen, deuterium, halogen, and cyano groups, and are optionally substituted with 1 to 4 substituents Q1. 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, Halogenated C1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl or 3-6 membered heterocyclic group.

[0056] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each R 1 R 2 Each R 3 Each R 4 Halogenated C groups, independently selected from hydrogen, deuterium, halogen, and cyano groups, and optionally substituted with 1-3 substituents Q1. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocyclic group.

[0057] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each R 1 R 2 Each R 3 Each R 4 The groups are independently selected from hydrogen, deuterium, halogen, cyano, and optionally substituted with 1-3 substituents Q1: monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, pyrrolidinyl, imidazolidinyl, pyrazolyl, piperidinyl, and piperazinyl.

[0058] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each R 1 Selected independently from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0059] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each R1 Each of the following is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 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, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0060] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 2 R 3 They are either hydrogen or deuterium, respectively.

[0061] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 4 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group.

[0062] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each Q1 is independently selected from deuterium, cyano, carboxyl, hydroxyl, amino, halogen, and optionally deuterated C-terminals. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group.

[0063] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each Q1 is independently selected from deuterium, cyano, halogen, and optionally deuterated C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C1-4 Alkyl group.

[0064] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives or stereoisomers thereof, wherein each Q1 is independently selected from deuterium, cyano, halogen, and optionally deuterated substituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, hydroxymethyl, aminomethyl, carboxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy.

[0065] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein each L and each L1 are independently selected from -O-, -NR. c1 -、-CR a2 R b1 -

[0066] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein each L and each L1 is independently -CH2-.

[0067] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each R a Each R a1 Each R a2 Each R b Each R b1 The C groups are independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, and cyano groups, with the C group optionally deuterated. 1-6 Alkyl, 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, carboxyl C 1-6 alkyl.

[0068] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each R a Each R a1 Each R a2 Each R b Each R b1 The C atoms are independently selected from deuterium and hydrogen, respectively, and are optionally deuterated. 1-6Alkyl, 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, carboxyl C 1-6 alkyl.

[0069] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each R a Each R a1 Each R a2 Each R b Each R b1 The groups are independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, and optionally deuterated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, aminomethyl, and carboxymethyl.

[0070] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each R a Each R a1 Each R a2 Each R b Each R b1 The compounds are independently selected from deuterium, hydrogen, and optionally deuterated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, aminomethyl, and carboxymethyl.

[0071] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each R c Each R c1 The C atoms are independently selected from deuterium and hydrogen, respectively, and are optionally deuterated. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 alkyl.

[0072] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each R c Each R c1 The compounds are independently selected from deuterium, hydrogen, and optionally deuterated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, aminomethyl, and carboxymethyl.

[0073] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each R a Each R a1 Each R a2 Each R b Each R b1 Each R c Each R c1 Each independently can be either hydrogen or C. 1-6 alkyl.

[0074] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein s, t, p, q are independently 0, 1, 2, 3, respectively.

[0075] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein m and n are independently 1, 2, 3 and 4, respectively.

[0076] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein,

[0077] Each Y is independently selected from -CR a1 R b -、-NR c -、-O-;

[0078] Ring A and ring B are independently selected from 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups;

[0079] The ring C is selected from 3-6 membered cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl;

[0080] Each R 1 R 2 Each R 3 Each R 4 C1 groups are independently selected from hydrogen, deuterium, halogen, and cyano groups, and are optionally substituted with 1 to 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 Alkyl, C 1-6 Alkoxy, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl or 3-6 membered heterocyclic group;

[0081] Each Q1 is independently selected from deuterium, cyano, carboxyl, hydroxyl, amino, halogen, and optionally C-groups substituted with deuterium. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0082] Each L is independently selected from -O- and -NR. c1 -、-CR a2 R b1 -;

[0083] Each R a Each R a1 Each R a2 Each R b Each R b1 The C groups are independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, and cyano groups, with the C group optionally deuterated. 1-6 Alkyl, 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, carboxyl C 1-6 alkyl;

[0084] Each R c Each R c1 The C atoms are independently selected from deuterium and hydrogen, respectively, and are optionally deuterated. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, hydroxy C 1-4Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 alkyl;

[0085] t, p, and q are 0, 1, 2, and 3 respectively.

[0086] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein,

[0087] Each R 1 R 2 Each R 3 Each R 4 The groups are independently selected from hydrogen, deuterium, halogen, cyano, and optionally substituted with 1-3 substituents Q1: monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, pyrrolidinyl, imidazolidinyl, pyrazolyl, piperidinyl, and piperazinyl.

[0088] Each Q1 is independently selected from deuterium, cyano, halogen, and optionally substituted with deuterium, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, hydroxymethyl, aminomethyl, carboxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0089] Each R a Each R a1 Each R a2 Each R b Each R b1 Each of the following groups is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, and optionally deuterated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, aminomethyl, and carboxymethyl.

[0090] Each R c Each R c1 The compounds are independently selected from deuterium, hydrogen, and optionally deuterated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, aminomethyl, and carboxymethyl.

[0091] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated derivative, or its stereoisomer, has the structure shown in formula (II).

[0092]

[0093] Ring C, X 3 X 4 X 5 Each Y, each R a Each R a1 Each R a2 Each R b Each R b1 Each R c Each R c1 Each R 1 R 2 Each R 3 Each R 4 The definitions of each L, each L1, each Q1, s, m, n, p, q, and t are as described in any of the aforementioned schemes.

[0094] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated derivative, or its stereoisomer, has the structure shown in formula (III).

[0095]

[0096] Ring C, each Y, each R a Each R a1 Each R b Each R c Each R 1 R 2 Each R 3 Each R 4 The definitions of each L1, each Q1, s, m, p, q, and t are as described in any of the aforementioned schemes.

[0097] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated derivative, or stereoisomer thereof, has the structure shown in formula (III), wherein,

[0098] Ring C is selected from

[0099] Each R 1 R 2 Each R 3 Each R 4Halogenated C groups, independently selected from hydrogen, deuterium, halogen, and cyano groups, and optionally substituted with 1-3 substituents Q1. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Alkoxy, cyclopropyl, cyclobutyl, cyclopentyl;

[0100] Each Q1 is independently selected from deuterium, cyano, halogen, and C atoms optionally substituted with deuterium. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy;

[0101] Each R a Each R a1 Each R b The C groups are independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, and cyano groups, with the C group optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0102] Each R c The C atoms are independently selected from deuterium and hydrogen, respectively, and are optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0103] p, q, and t are each an independent integer between 0 and 3;

[0104] m is an integer from 1 to 4.

[0105] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated derivative, or its stereoisomer, has the structure shown in formula (IV).

[0106]

[0107] Every Y, every R a Each R a1 Each R b Each R c Each R 1 R 2 Each R 3 Each R 4 The definitions of each L1, each Q1, s, m, p, q, and t are as described in any of the aforementioned schemes.

[0108] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or their stereoisomers,

[0109] Where Y is selected from -CR a1 R b -;

[0110] Each R 1 R 2 Each R 3 Each R 4 Halogenated C groups, independently selected from hydrogen, deuterium, halogen, and cyano groups, and optionally substituted with 1-3 substituents Q1. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Alkoxy, cyclopropyl, cyclobutyl, cyclopentyl;

[0111] Each Q1 is independently selected from deuterium, cyano, halogen, and C atoms optionally substituted with deuterium. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy;

[0112] Each R a Each R a1 Each R b The C groups are independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, and cyano groups, with the C group optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0113] m is 2 or 3;

[0114] n is 1, 2, or 3;

[0115] t, p, and q are 0, 1, 2, and 3 respectively.

[0116] The selection of any substituent in any embodiment of the present invention can be combined with each other, and the combined technical solution is still included within the protection scope of the present invention.

[0117] In some embodiments of the present invention, the structures of the provided compounds, their pharmaceutically acceptable salts, esters, deuterated derivatives, or stereoisomers thereof are shown below:

[0118]

[0119]

[0120]

[0121] The present invention also provides a pharmaceutical composition comprising a compound represented by the aforementioned general formulas (I), (II), (III), (IV), a pharmaceutically acceptable salt, ester, deuterated form or stereoisomer thereof, and one or more second therapeutic agents, optionally, the pharmaceutical composition further comprising one or more pharmaceutical carriers and / or diluents.

[0122] The present invention also provides a pharmaceutical preparation comprising a compound represented by the aforementioned general formulas (I), (II), (III), and (IV), a pharmaceutically acceptable salt, ester, deuterated compound or stereoisomer thereof, and one or more pharmaceutical carriers and / or diluents; the pharmaceutical preparation being any clinically or pharmaceutically acceptable dosage form.

[0123] In some embodiments of the present invention, the above-described pharmaceutical preparations can be administered to patients or subjects requiring such treatment via oral, parenteral, rectal, or pulmonary administration. For oral administration, the pharmaceutical composition can be formulated into oral preparations, such as conventional oral solid dosage forms like tablets, capsules, pills, granules, etc.; or into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When formulating oral preparations, suitable fillers, binders, disintegrants, lubricants, etc., can be added. For parenteral administration, the above-described pharmaceutical preparations can also be formulated into injectable preparations, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When formulating injectable preparations, conventional methods in the existing pharmaceutical field can be used. When preparing injectable preparations, excipients may not be added, or suitable excipients may be added depending on the properties of the drug. For rectal administration, the pharmaceutical composition can be formulated into suppositories, etc. For pulmonary administration, the pharmaceutical composition can be formulated into inhalers or sprays, etc.

[0124] The pharmaceutical carriers and / or diluents used in the pharmaceutical compositions or formulations of the present invention can be any conventional carriers and / or diluents in the field of pharmaceutical formulation. The selection of a specific carrier and / or diluent will depend on the route of administration or the type and state of disease for treating a particular patient. The preparation method of a suitable pharmaceutical composition for a specific route of administration is entirely within the knowledge of those skilled in the art of pharmaceuticals. For example, pharmaceutical carriers and / or diluents may 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., conventional in the pharmaceutical field. If necessary, flavoring agents, preservatives, and sweeteners, etc., may also be added to the pharmaceutical composition.

[0125] The present invention also provides the use of the compounds represented by the aforementioned general formulas (I), (II), (III), and (IV), their pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof, the aforementioned pharmaceutical preparations or the aforementioned pharmaceutical compositions in the preparation of medicaments for the treatment and / or prevention of USP1-mediated diseases and related diseases; wherein the USP1-mediated diseases and related diseases are selected from cancer or benign tumors.

[0126] The present invention also provides the use of the compounds represented by the aforementioned general formulas (I), (II), (III), and (IV), their pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof, the aforementioned pharmaceutical preparations or the aforementioned pharmaceutical compositions in the treatment and / or prevention of USP1-mediated diseases and related diseases; wherein the USP1-mediated diseases and related diseases are selected from cancer or benign tumors.

[0127] The present invention also provides a method for treating a disease, the method comprising administering to a patient in need a therapeutically effective amount of a compound represented by the aforementioned general formulas (I), (II), (III), (IV), a pharmaceutically acceptable salt, ester, deuterated form or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition, wherein the disease is a USP1-mediated disease or related disease; the USP1-mediated disease or related disease is selected from cancer or benign tumors.

[0128] The cancers or benign tumors mentioned include, but are 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, stomach cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, colon cancer, bladder cancer, prostate cancer, testicular cancer, skin cancer, bone cancer, and hematologic malignancies; the lung cancers mentioned include, but are not limited to, small cell lung cancer and non-small cell lung cancer; the hematologic malignancies mentioned include, but are not limited to, leukemia, lymphoma, and myeloma; the brain cancers mentioned include, but are not limited to, glioma, neuroblastoma, astrocytoma, and meningioma.

[0129] In the specification and claims of this application, compounds are named according to their chemical structural formulas. If the name of the compound and its chemical structural formula do not match when referring to the same compound, the chemical structural formula shall prevail.

[0130] In this application, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the invention, definitions of some terms are provided below. When the definitions and interpretations of terms provided in this application differ from the meanings commonly understood by those skilled in the art, the definitions and interpretations provided in this application shall prevail.

[0131] The "halogen" mentioned in this invention refers to fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred.

[0132] In this invention, "halogenation" means that any hydrogen in the substituent can be replaced by one or more identical or different halogens. "Halogen" is as defined above.

[0133] The "C" described in this invention 1-6 "Alkyl" refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms, including, for example, "C". 1-5 Alkyl", C 1-4 Alkyl", C 1-3 Alkyl", C 1-2 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 groups, etc., specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 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, etc. The "C" in this invention... 1-4 "alkyl" refers to C 1-6 Specific examples of alkyl groups containing 1-4 carbon atoms.

[0134] The "C" described in this invention 1-6 "alkylene" refers to the C mentioned above. 1-6 Alkyl groups formed by removing a hydrogen atom include, 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 include but are not limited to: methylene, ethylene, propylene, butylene, pentylene, hexylene, etc. The "C" mentioned in this invention... 1-4 "alkylene" refers to C 1-6 Specific examples of alkylene groups containing 1-4 carbon atoms.

[0135] The "C" described in this invention 2-6 "Alkenyl" refers to a straight-chain, branched, or cyclic alkenyl group containing at least one double bond and having 2-6 carbon atoms, including, for example, "C". 2-5 "alkenyl", "C" 2-4 "alkenyl", "C" 2-3 "Alkenyl", etc., specific examples include but are not limited to: vinyl, 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, etc.

[0136] The "C" described in this invention 2-6 "Alkyne group" refers to a straight-chain or branched alkynyl group containing 2-8 carbon atoms with a triple bond, including, for example, "C". 2-5 "Alkyne", "C" 2-4 "Alkyne", "C" 2-3 "Alynyl", etc., 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, etc.

[0137] The “C” mentioned in this article 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Alkylaminoyl, C1-6 Alkyl amide, C 1-6 alkylsulfonyl, C 1-6 Alkylsulfonamide, C 1-6 alkylaminosulfonyl, C 1-6 alkyl carbonyl, C 1-6 "Alkoxycarbonyl" refers to a group with C 1-6 Alkyl-O-, C 1-6 Alkyl-NH-, (C 1-6 Alkyl)2-N-, C 1-6 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 A group formed in the alkyl-OC(O)- manner, wherein "C" 1-6 The definition of "alkyl" is as described above.

[0138] The “C” mentioned in this article 1-4 Alkoxy, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, C 1-4 Alkylaminoyl, C 1-4 Alkyl amide, C 1-4 alkylsulfonyl, C 1-4 Alkylsulfonamide, C 1-4 alkylaminosulfonyl, C 1-4 alkyl carbonyl, C 1-4 "Alkoxycarbonyl" refers to a group with 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 A group formed in the alkyl-OC(O)- manner, wherein "C" 1-4 The definition of "alkyl" is as described above.

[0139] The "halogenated C" mentioned in this article 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6Alkyl, carboxyl C 1-6 Alkyl, Halogenated C 1-6 "Alkoxy" refers to one or more (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxyl, amino, and carboxyl groups that respectively replace C. 1-6 Alkyl, C 1-6 Alkylene, C 1-6 A group formed by the hydrogen atom in an alkoxy group.

[0140] The "halogenated C" mentioned in this article 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, Halogenated C 1-4 "Alkoxy" refers to one or more (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxyl groups, and amino groups that have substituted C for C. 1-4 Alkyl, C 1-4 A group formed by the hydrogen atom in an alkoxy group.

[0141] The "3-12 membered cycloalkyl" mentioned in this invention refers to a saturated or partially saturated cycloalkyl group containing 3-12 carbon atoms that is not aromatic, including "3-12 membered saturated cycloalkyl" and "3-1 membered partially saturated cycloalkyl"; preferably "3-4 membered cycloalkyl", "3-5 membered cycloalkyl", "3-6 membered cycloalkyl", "3-7 membered cycloalkyl", "3-8 membered cycloalkyl", "3-10 membered cycloalkyl", "4-5 membered cycloalkyl", "4-6 membered cycloalkyl", "4-7 membered cycloalkyl", "4-8 membered cycloalkyl", "5-6 membered cycloalkyl", and "5-7 membered cycloalkyl". The terms "alkyl", "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", etc. Specific examples of the "3-8 saturated cycloalkyl group" include, but are not limited to: cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane (cycloheptyl), cyclooctane (cyclooctyl), etc.; specific examples of the "3-8 partially saturated cycloalkyl group" include, but are not limited to: cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1,3-diene, cyclohex-1,4-diene, cycloheptenyl, cycloheptenyl-1,3-diene, cycloheptenyl-1,4-diene, cycloheptenyl-1,3,5-trienyl, cyclooctenyl, cyclooctyl-1,3-diene, cyclooctyl-1,4-diene, cyclooctyl-1,5-diene, cyclooctyl-1,3,5-trienyl, cyclooctatetraenyl, etc.

[0142] The "3-12 membered heterocyclic group" described in this invention refers to a saturated or partially saturated monocyclic or fused-ring group containing at least one heteroatom (e.g., 1, 2, 3, 4, or 5) and having 3-12 ring atoms, and lacking aromaticity. The heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom. Optionally, the ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the ring structure can be substituted with oxygen. The "3-12 membered heterocyclic group" described in this invention includes "3-12 membered saturated heterocyclic groups" and "3-12 membered partially saturated heterocyclic groups." Preferably, the "3-12 membered heterocyclic group" described in this invention contains 1-3 heteroatoms; preferably, the "3-12 membered heterocyclic group" described in this invention contains 1-2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and / or oxygen atoms; preferably, the "3-12 membered heterocyclic group" described in this invention contains 1-2 nitrogen atoms. The "3-12 membered heterocyclic group" is preferably a "3-10 membered heterocyclic group", "3-8 membered heterocyclic group", "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 propane, 2H-aziridine propane, diaziridine propane, 3H-diazacyclopropenyl, aziridine butane, 1,4-dioxanehexane, 1,3-dioxanehexane, 1,3-dioxanepentane, 1,4-dioxanehexadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrroleyl, pyrroleyl, imidazoyl, 4,5-dihydroimidazoyl, pyrazolyl , 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisooxazolyl, 2,3-dihydroisooxazolyl, 2H-1,2-oxazinyl, 6H-1,3-oxazinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-one, 3,4-dihydro-2H-pyranyl.

[0143] The “6-10 aryl” mentioned in this invention refers to an aromatic cyclic group containing 6-10 cyclic carbon atoms, including “6-8 monocyclic aryl” and “8-10 fused cyclic aryl”.

[0144] The “6-8 membered monocyclic aryl” mentioned in this invention refers to a monocyclic aryl group containing 6-8 ring carbon atoms, examples of which include, but are not limited to, phenyl, cyclooctatetraenyl, etc.; preferably phenyl.

[0145] The “8-10 fused-ring aryl” mentioned in this invention refers to an unsaturated, aromatic cyclic group containing 8-10 cyclic carbon atoms formed by two or more cyclic structures sharing two adjacent atoms, preferably a “9-10 fused-ring aryl”, such as naphthyl.

[0146] The "5-12-membered heteroaryl" mentioned in this invention refers to an aromatic cyclic group 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, and 5-12-membered sulfur-containing heteroaryl. It also includes "5-8-membered monoheteroaryl" and "8-10-membered fused heteroaryl".

[0147] The "5-8-membered monoheteroaryl" as described in this invention refers to an aromatic monocyclic cyclic group containing 5-8 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, oxygen atom, or sulfur atom). Optionally, the ring atoms (e.g., carbon atom, nitrogen atom, or sulfur atom) in the cyclic structure can be substituted with oxygen. "5-8-membered monoheteroaryl" includes, for example, "5-7-membered monoheteroaryl," "5-6-membered monoheteroaryl," "5-6-membered nitrogen-containing monoheteroaryl," "5-membered nitrogen-containing monoheteroaryl," etc. Specific examples of “5-8 membered monocyclic heteroaryl groups” include, but are not limited to, furanyl, thiopheneyl, 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-pyridonel, 4-pyridonel, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetraazinyl, aziridine-heptadienyl, 1,3-diazacyclicheptadienyl, aziridine-octatetraenyl, etc. The term "5-6 membered heteroaryl" refers to a specific example of a 5-8 membered heteroaryl containing 5-6 cyclic atoms.

[0148] The "8-10 fused aryl" as described in this invention refers to an unsaturated aromatic cyclic structure consisting of 8-10 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, oxygen atom, or sulfur atom) formed by two or more cyclic structures sharing two adjacent atoms. Optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms, or sulfur atoms) in the cyclic structure may be oxidized. This includes "9-10 fused heteroaryl", "8-9 fused heteroaryl", etc., whose fusion mode can be benzo5-6 heteroaryl, 5-6 heteroaryl and 5-6 heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furanolothiophene, pyrazolooxazole, benzofuranyl, benzoisofuranyl, benzothiopheneyl, indolyl, isoindolyl, benzooxazolyl, benzoimidazolyl, indazole, benzotriazolyl, quinolinyl, 2-quinolinoneyl, 4-quinolinoneyl, 1-isoquinolinoneyl, isoquinolinyl, acridineyl, phenanthridineyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthinyl, etc.

[0149] The phrase "optionally replaced by..." as described in this invention includes both "replaced" and "not replaced".

[0150] The term "--" in this invention is selected from single bonds or double bonds, and adjacent "--" are not simultaneously double bonds.

[0151] The "pharmaceutically acceptable salt" as described in this invention refers to the addition salt of pharmaceutically usable acids and bases, such as metal salts, ammonium salts, salts formed with organic acids, salts formed with organic bases, salts formed with inorganic acids, and salts formed with acidic or basic amino acids.

[0152] The term "ester" as used in this invention refers to a pharmaceutically acceptable ester, particularly esters that are hydrolyzed in vivo and include esters that readily decompose in the human body, leaving behind a parent compound (the compound of general formula (I)) or its salt. The term "ester" as used in this invention may, for example, be selected from the following group: (1) carboxylic acid esters obtained by esterification with carboxylic acid compounds, wherein the non-carbonyl portion of the carboxylic acid compound is selected, for example, C 1-20 Straight-chain or branched alkyl groups, C 1-12 Straight-chain or branched alkyl groups, C 1-8 Straight-chain or branched alkyl groups, C 1-6 Straight-chain or branched alkyl groups (e.g., methyl, ethyl, n-propyl, tert-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 6-10Aryl (e.g., phenyl, optionally replaced by, for example, halogen, C) 1-4 Alkyl or C 1-4 (1) Alkoxy or amino substituted); (2) sulfonates, such as alkylsulfonyl or aralkylsulfonyl (e.g., methylsulfonyl); (3) amino acid esters (e.g., L-valine or L-isoleucyl); and (4) mono-, di-, or triphosphate esters, etc.; (4) esters obtained by esterification with alcohols, wherein the non-hydroxyl portion of the alcohol is selected from, for example, C 1-20 Straight-chain or branched alkyl groups, C 1-12 Straight-chain or branched alkyl groups, C 1-8 Straight-chain or branched alkyl groups, C 1-6 Straight-chain or branched alkyl groups (e.g., methyl, ethyl, n-propyl, tert-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 replaced by, for example, halogen, C) 1-4 Alkyl or C 1-4 (alkoxy or amino substitution).

[0153] The term "stereoisomer" as used in this invention refers to compounds containing one or more asymmetric centers, thus allowing them to exist as racemic mixtures and racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. Compounds of this invention may have asymmetric centers, each of which independently produces two optical isomers. The scope of this invention includes all possible optical isomers and mixtures thereof. If the compounds of this invention contain an alkene double bond, unless otherwise specified, they include cis and trans isomers. Compounds of this invention may exist as tautomers (a type of functional group isomer) having different hydrogen connection points through one or more double bond shifts; for example, ketones and their enol forms are keto-enol tautomers. All tautomers and mixtures thereof are included within the scope of this invention. All enantiomers, diastereomers, racemic mixtures, mesomixes, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are included within the scope of this invention.

[0154] 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 the structure is defined as H, i.e., hydrogen (Hl), that position contains only naturally occurring isotopes. Similarly, unless otherwise specified, when a position in the structure is defined as D, i.e., deuterium (H₂), that position contains an isotope amount at least 3340 times greater than the amount of naturally occurring isotopes (0.015%) (i.e., at least 50.1% deuterium isotopes). When one or more positions in the structure of the compounds of this application are defined as D, i.e., deuterium (H₂), the content of the compound shown 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%.

[0155] The deuteration rate of the compounds in this application refers to the ratio of the content of the labeled synthetic isotope to the amount of the naturally occurring isotope. The deuteration rate of each specified deuterium atom in the compounds in this application may be at least 3500 times (52.5%), at least 4000 times (60%), at least 4500 times (67.5%), at least 5000 times (75%), at least 5500 times (82.5%), at least 6000 times (90%), at least 6333.3 times (95%), at least 6466.7 times (97%), at least 6566.7 times (98.5%), at least 6600 times (99%), and at least 6633.3 times (99.5%).

[0156] In this application, isotopes refer to compounds that differ only in their isotopic composition in terms of chemical structure. The deuterium-containing compounds at specific positions in this application will also contain very small amounts of hydrogen isotopes at those positions. The amount of hydrogen isotopes at the deuterated positions in the deuterated compounds of this application depends on many factors, including the deuterotopic purity of the deuterating reagent (D₂O, D₂, NaBD₄, L₁AID₄, etc.) and the effectiveness of the deuterotope synthesis method. However, as mentioned above, the total amount of hydrogen isotopes at such deuterated positions will be less than 49.9%. The total amount of hydrogen isotopes at the deuterated positions in the deuterated compounds of this application will be less than 47.5%, 40%, 32.5%, 25%, 17.5%, 10%, 5%, 3%, 1%, or 0.5%.

[0157] In this application, any atom not designated as deuterium exists at its natural isotopic abundance.

[0158] In this invention, "deuteration" refers to the substitution of one or more hydrogen atoms on a deuterated group by one or more deuterium atoms. This can be partial or complete deuteration. For example, a deuterated compound may contain only one deuterium atom. In some embodiments, the deuterated compound contains only two deuterium atoms. In some embodiments, the deuterated compound contains only three deuterium atoms. In some embodiments, the deuterated compound contains four deuterium atoms.

[0159] The "optionally deuterated" in this invention includes two cases: the group is deuterated and the group is not deuterated, wherein "deuterated" is as defined above.

[0160] The "therapeutic effective amount" as described in this invention refers to the amount of the aforementioned compound, pharmaceutical preparation, or pharmaceutical composition that, when administered to a patient, at least alleviates the patient's symptoms. The actual amount comprising the "therapeutic effective amount" can vary depending on various factors, including but not limited to the specific condition being treated, the severity of the condition, the patient's physical and health condition, and the route of administration. Skilled medical practitioners can easily determine the appropriate amount using methods known in the medical field.

[0161] Beneficial effects of the invention

[0162] (1) The compounds of the present invention, their pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof have excellent USP1 inhibitory activity and can treat and / or prevent USP1-mediated diseases and related diseases.

[0163] (2) The compounds of the present invention have a good inhibitory effect on tumor cells;

[0164] (3) The compounds of the present invention, their pharmaceutically acceptable salts, esters, deuterated derivatives or their stereoisomers have good pharmacokinetic properties, longer duration of action and high bioavailability;

[0165] (4) The compounds of the present invention, their pharmaceutically acceptable salts, esters, deuterated derivatives or their stereoisomers have good safety;

[0166] (5) The compound preparation process of the present invention is simple, the drug has high purity and stable quality, and it is easy to carry out large-scale industrial production.

[0167] The following experiments further illustrate the beneficial effects of the compounds provided in the embodiments of the present invention, but this should not be construed as the compounds provided in the embodiments of the present invention having only the following beneficial effects.

[0168] Experimental Example 1: In vitro cellular activity of the compounds of the present invention

[0169] Test samples: Some of the compounds of this invention, the chemical names and structures of which are given in the preparation examples.

[0170] The cell lines used in the following experiments are as follows:

[0171] MDA-MB-436: BRCA1-mutated human breast cancer cells; Caov-3: Homologous recombination repair deficient (HRD+) human ovarian cancer cells.

[0172] Experimental Method (CelltiterGlo assay)

[0173] 1. Prepare cells

[0174] 1.1 Cell Culture:

[0175] All cells were adherent cells. MDA-MB-436 cells were cultured in DMEM + 10% FBS + 1% ITS-G + 16 μg / ml glutathione, and Caov-3 cells were cultured in DMEM + 10% FBS. The cells were tested during the logarithmic growth phase.

[0176] 1.2 Preparation of cell suspension:

[0177] Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was assessed using the trypan blue rejection assay to ensure it was above 90%. The concentration was adjusted, and 90 μL of cell suspension was added to each well of a 96-well plate.

[0178] Table 1 Cell Seeding Number

[0179]

[0180] 2. Preparation of test compounds

[0181] 2.1 Prepare DMSO stock solutions for the test compounds, with a stock solution concentration of 10 mM for each test compound.

[0182] 2.2 Preparation of working stock solution for test compounds

[0183] The 10 mM stock solution of the test compound was serially diluted 3-fold with DMSO to obtain 8 concentrations. Then, 2 μL of each serially diluted compound with DMSO was added to 198 μL of culture medium to prepare the working stock solution of the test compound (the compound concentration was 10 times the final concentration, with the highest concentration being 100 μM).

[0184] 2.3 Compound Treatment

[0185] Add 10 μL of the compound working stock solution (10-fold dilution, final DMSO concentration 0.1%) to each well of a 96-well plate seeded with cells.

[0186] The final concentrations of the tested compounds were: 10000.00 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, and 4.57 nM.

[0187] 2.4 Setting of reference holes

[0188] Solvent control: 0.1% DMSO.

[0189] Blank control: 96-well plate readings at 0h after drug administration.

[0190] 2.5 Place the 96-well plate in a 37°C, 5% CO2 cell culture incubator and culture for 7 days.

[0191] 3. Testing

[0192] Melt the CTG reagent and equilibrate the 96-well plate to room temperature for 30 minutes. Add 60 μL of reagent (Celltiter Gloassay kit) to each well, shake for 2 minutes to mix (protect from light), and incubate at room temperature for 20 minutes (protect from light). Read the light signal value using a multi-functional microplate reader.

[0193] 4. Data Processing

[0194] 1) Inhibition rate (%) = (DMSO solvent control well reading - test sample well reading) / (DMSO solvent control well reading - blank control well reading) × 100%;

[0195] 2) Input the data into GraphPad Prism to plot the curve and obtain the IC. 50 .

[0196] Experimental Results and Conclusions

[0197] Table 2. In vitro cellular activities (IC50) of the compounds of this invention. 50 ,nM)

[0198]

[0199] As shown in Table 2, the compounds of the present invention can effectively inhibit the proliferation of MDA-MB-436 and Caov-3 cells, indicating that the compounds of the present invention have the potential for clinical application in treating HRD-positive (homologous recombination defect) cancers. Detailed Implementation

[0200] The technical solution of the present invention will now be described with reference to specific embodiments. These embodiments are merely some, not all, of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0201] The abbreviations used in the following experiments have the following meanings:

[0202] 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; DEAD: diethyl azodicarbonate; THF: tetrahydrofuran; LAH: lithium aluminum hydride; DMF: dimethylformamide; EA: ethyl acetate; DIEA: N,N-diisopropylethylamine; DCE: dichloroethane; DCM: dichloromethane

[0203] Example 1 Preparation of 9-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9H-imidazo[5,1-f]purine-9-yl)methyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza (Compound 1)

[0204] (1) Preparation of methyl 4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-benzoate

[0205]

[0206] At 25 °C, methyl 3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (20.0 g, 57.5 mmol) and Cs₂CO₃ (37.4 g, 114.9 mmol) were dissolved in DMF (200 mL), and then added to benzyl bromide (11.8 g, 69.0 mmol) and stirred for 30 min. The reaction was then checked for completeness. The mixture was washed with water, extracted with ethyl acetate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give 23.0 g of the title compound, yield: 91.4%.

[0207] (2) Preparation of methyl 4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-(3-hydroxybut-1-yn-1-yl)benzoate

[0208]

[0209] Methyl 4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-bromobenzoate (23.0 g, 52.5 mmol), Pd(dppf)₂Cl₂ (7.4 g, 9.7 mmol), 3-butyn-2-ol (7.4 g, 105.6 mmol), and CuI (10.0 g, 52.5 mmol) were dissolved in pyridine (120 mL) and triethylamine (30 mL) at 100 °C. The mixture was purged with nitrogen, and the mixture was stirred for 16 h after the addition was complete. The reaction was then checked for completeness. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 10:3) to give 4.4 g of the title compound, yield: 19.6%.

[0210] (3) Preparation of methyl 3-(3-hydroxybutyl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

[0211]

[0212] Methyl 4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-(3-hydroxybut-1-yn-1-yl)benzoate (4.4 g, 10.3 mmol) was dissolved in MeOH (100 mL) at 35 °C, and Pd / C (4.0 g) was added. The reaction was reduced with hydrogen for 6 h. The reaction was stopped by LCMS. After diatomaceous earth filtration, the organic phase was concentrated and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 10:4) to give 2.8 g of the title compound, yield: 79.6%.

[0213] (4) Preparation of methyl 5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-carboxylic acid

[0214]

[0215] Methyl 3-(3-hydroxybutyl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (2.8 g, 8.2 mmol) and triphenylphosphine (8.6 g, 32.8 mmol) were dissolved in THF (50 mL) at 35 °C, purged with nitrogen, and then DEAD (5.7 g, 32.7 mmol) was added. The reaction was allowed to proceed for 60 min. The reaction was confirmed by LCMS. The organic phase was concentrated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10) to give 2.5 g of the title compound, yield: 94.2%.

[0216] (5) Preparation of (5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methanol

[0217]

[0218] Methyl 5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-carboxylic acid ester (2.5 g, 7.7 mmol) was dissolved in THF (200 mL), and LAH (879 mg, 23.1 mol) was added. The reaction was carried out at 0 °C for 30 min. The reaction was stopped by LCMS. Diatomaceous earth filtration yielded 2.2 g of the title compound, yield: 96.3%.

[0219] (6) Preparation of (5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methanesulfonate

[0220]

[0221] (5-Methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methanol (2.0 g, 6.8 mmol) was dissolved in THF (200 mL), and MsCl (1.1 g, 9.6 mmol) was added at 0 °C. The reaction was allowed to proceed for 30 min. The reaction was confirmed by LC-MS. The mixture was then filtered, evaporated to dryness under reduced pressure, and directly added to the next step without further processing.

[0222] (7) Preparation of tert-butyl ((5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methyl)aminodicarboxylate

[0223]

[0224] At 30 °C, crude (5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methanesulfonate and bis(tert-butyloxycarbonyl)amine (2.4 g, 11.4 mmol) were dissolved in DMF (20 mL), and Cs₂CO₃ (6.6 g, 20.2 mmol) was added. The mixture was stirred for 3 hours. The reaction was stopped by LCMS. The mixture was washed with water, extracted with ethyl acetate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give 2.0 g of the title compound. Two-step yield: 59.8%.

[0225] (8) Preparation of (5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methylamine hydrochloride

[0226]

[0227] At 30°C, tert-butyl ((5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methyl)aminodicarboxylate (1.8 g, 3.6 mmol) was dissolved in EA (20 mL), and EA / HCl (mL) was added. The mixture was stirred for 3 hours. The reaction was confirmed by LCMS. The solution was evaporated to dryness under reduced pressure without further processing and directly added to the next step.

[0228] (9) Preparation of 2-chloro-N-((5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methyl)-5-nitropyrimidine-4-amine

[0229]

[0230] Crude (5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methylamine hydrochloride was dissolved in DIEA (1.9 g, 14.4 mmol) in THF (100 mL) at -78 °C. Under nitrogen protection, 2,4-dichloro-5-nitropyrimidine (838 mg, 4.3 mmol) was added, and the mixture was stirred for 2 hours. The reaction was stopped by LCMS. The mixture was washed with water, extracted with ethyl acetate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:2) to give 1.3 g of the title compound. Two-step yield: 79.0%.

[0231] (10)2-Chloro-N 4 Preparation of -((5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methyl)pyrimidine-4,5-diamine

[0232]

[0233] 2-Chloro-N-((5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methyl)-5-nitropyrimidine-4-amine (1.3 g, 2.9 mmol), iron powder (325 mg, 5.8 mmol), and ammonium chloride (310 mg, 5.8 mmol) were dissolved in ethanol (50 mL) and water (10 mL) at 30 °C. The mixture was heated to 80 °C and stirred for 4 hours. The reaction was confirmed by LCMS. The solution was filtered through diatomaceous earth and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:5) to give 810 mg of the title compound, yield: 66.7%.

[0234] (11) Preparation of 9-((2-chloro-8-(chloromethyl)-9H-purine-9-yl)methyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzimidazole[1,2-a]aza

[0235]

[0236] 30℃, 2-chloro-N 4 -((5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methyl)pyrimidin-4,5-diamine (700 mg, 1.7 mmol), 2-chloro-1,1,1-trimethoxyethane (5.2 g, 33.6 mmol), and p-toluenesulfonic acid (59 mg, 0.34 mmol) were dissolved in dioxane (100 mL). The mixture was heated to 120 °C and stirred for 16 hours. The reaction was stopped by LCMS. The solution was evaporated to dryness under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:4) to give 300 mg of the title compound, yield: 37.6%.

[0237] (12) Preparation of (2-chloro-9-((5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methyl)-9H-purine-8-yl)methylamine

[0238]

[0239] At 55℃, 9-((2-chloro-8-(chloromethyl)-9H-purin-9-yl)methyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazole[1,2-a]aza (250 mg, 0.52 mmol) and hexamethylenetetramine (364 mg, 2.6 mmol) were dissolved in DCE (50 mL) and stirred for 4 h. The reaction was then checked for completeness. The solution was evaporated to dryness under reduced pressure, and ethanol (20 mL) and concentrated hydrochloric acid (10 mL) were added. The mixture was stirred at 25℃ for 3 h. The reaction was checked for completeness by LCMS. The pH was adjusted to 8 with ammonia, and the solution was evaporated to dryness under reduced pressure. The solution was purified by silica gel column chromatography (DCM:methanol = 10:1) to give 100 mg of the title compound, yield: 41.9%.

[0240] (13) Preparation of N-((2-chloro-9-((5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methyl)-9H-purine-8-yl)methyl)formamide

[0241]

[0242] At 25°C, formic acid (5 mL) was added dropwise to acetic anhydride (5 mL), and the mixture was stirred for 1 hour. Then, (2-chloro-9-((5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methyl)-9H-purin-8-yl)methylamine (100 mg, 0.22 mmol) was added, and the mixture was stirred for 1 hour. The reaction was confirmed by LCMS. The mixture was evaporated to dryness under reduced pressure and then directly introduced into the next step without further processing.

[0243] (14) Preparation of 9-((2-chloro-9H-imidazo[5,1-f]purine-9-yl)methyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza

[0244]

[0245] Crude N-((2-chloro-9-((5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-9-yl)methyl)-9H-purin-8-yl)methyl)formamide was dissolved in POCl3 (10 mL) at 100 °C and stirred for 1 hour. The reaction was stopped by LCMS. The mixture was washed with water, extracted with ethyl acetate, and the pH was adjusted to 7-8 with saturated sodium bicarbonate. The organic phase was washed, dried, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 5:1) to give 50 mg of the title compound. The two-step yield was 48.9%.

[0246] (15) Preparation of 9-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9H-imidazo[5,1-f]purine-9-yl)methyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza

[0247]

[0248] At 30℃, 9-((2-chloro-9H-imidazo[5,1-f]purine-9-yl)methyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza (50 mg, 0.11 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (41 mg, 0.22 mmol) were dissolved in dioxane / H2O (15 / 1.5 mL). K3PO4 (70 mg, 0.33 mmol), XPhosPdG2 (35 mg, 0.044 mmol), and XPhos (21 mg, 0.044 mmol) were added. The mixture was heated to 90℃ and stirred for 2 hours. The reaction was then analyzed by LCMS. Washed with water, extracted with ethyl acetate, and thin-layer chromatography (DCM:MeOH = 10:1) was performed to give 23 mg of the title compound, yield: 37.1%.

[0249] Molecular formula: C 30 H 26 F3N9O molecular weight: 585.6 LC-MS (M / e): 586.6 (M+H) + )

[0250] 1 H-NMR(400MHz,MeOD)δ:9.19(s,1H),8.65(s,1H),8.37(s,1H),7.80(s,1H),

[0251] 7.70-7.60(m,1H),7.55-7.45(m,2H),6.67(s,1H),5.55-5.45(m,2H),4.15-4.00(m,1H),

[0252] 3.96(s,3H),2.85-2.72(m,1H),2.62-2.55(m,1H),2.43-2.32(m,1H),2.15-2.10(m,1H),

[0253] 1.85-1.75(m,1H),1.60-1.50(d,J=6.6Hz,3H),1.29-1.11(m,2H),0.97-0.89(m,2H).

[0254] The compounds shown in the following table were prepared using the same or similar methods as those used in the above examples:

[0255]

[0256] The USP1 inhibitor and its applications provided by this invention have been described in detail above. Specific embodiments have been used to illustrate the principles and implementation methods of this invention. These embodiments are merely illustrative and are intended to help understand the method and central ideas of this invention. It should be noted that those skilled in the art can make various improvements and modifications to this invention without departing from its principles, and these improvements and modifications also fall under the protection of the claims of this invention.

Claims

1. A compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein, s, t, p, q are each independently an integer from 0 to 4; m is 3; n is 1.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, t, p, q are each independently 0, 1, 2, 3. X 3 , X 4 , X 5 are each independently selected from CR a ; each Y is independently selected from -CR a1 R b -; Ring C is selected from each R 1 , R 2 , each R 3 , each R 4 is independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, sulfonamido, 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) s -C 1-6 alkyl, -(L1) s -C 1-6 alkoxy, or -(L1) s -3-6 membered cycloalkyl; each Q1is independently selected from deuterium, cyano, carboxy, hydroxy, amino, halogen, C1-6alkyl optionally substituted with deuterium, 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl)amino, C 1-6 alkylamino, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl, halogenC 1-6 alkyl or halogenC 1-6 alkoxy; each L, each L1is independently selected from -CR a2 R b1 -; each R a , each R a1 , each R a2 , each R b , each R b1 is independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, 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, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl; 3. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, having a structure of Formula (III).

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having a structure of Formula (IV).

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, each Q1 is independently selected from deuterium, cyano, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, hydroxymethyl, aminomethyl, carboxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, optionally substituted with deuterium.

6. A compound of the following structure: or a pharmaceutically acceptable salt thereof. wherein each Y is independently selected from -CR a1 R b -; Ring C is selected from each R 1 , R 2 , each R 3 , each R 4 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl optionally substituted with 1-4 substituents Q1, C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy or 3-6 membered cycloalkyl; each Q1is independently selected from deuterium, cyano, carboxyl, hydroxyl, amino, halogen, C1-C6alkyl optionally substituted with deuterium, 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl, halogenC 1-6 alkyl, halogenC 1-6 alkoxy; each L is independently selected from -CR a2 R b1 -; each R a , each R a1 , each R a2 , each R b , each R b1 is independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, 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; 7. A pharmaceutical preparation comprising a compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or diluents; said pharmaceutical preparation being in any clinically or pharmaceutically acceptable dosage form.

8. A pharmaceutical composition comprising a compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and one or more second therapeutically active agents; optionally, said pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and / or diluents. ring C, each Y, each R a , each R 1 , R 2 , each R 3 , each R 4 , m, p, q, t are as defined in claim 1 or 2.

9. Use of a compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, or a pharmaceutical preparation of claim 7, or a pharmaceutical composition of claim 8, for the manufacture of a medicament for the treatment and / or prevention of breast cancer or ovarian cancer. each Y, each R a , each R 1 , R 2 , each R 3 , each R 4 , m, p, q, t are as defined in claim 1. ​ each R 1 , R 2 , each R 3 , each R 4 is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, optionally substituted by 1-3 substituents Q1, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; ​ each R a , each R a1 , each R a2 , each R b , each R b1 is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, aminomethyl, carboxymethyl, optionally substituted by deuterium. ​ ​ ​ ​

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