USP1 inhibitors and their uses

Abstract

This invention relates to the field of pharmaceutical technology, specifically to a class of compounds that can be used as USP1 inhibitors, their deuterated derivatives, pharmaceutically acceptable salts or stereoisomers thereof, pharmaceutical compositions and formulations containing said compounds, their deuterated derivatives, pharmaceutically acceptable salts or stereoisomers thereof, methods for preparing said compounds, their deuterated derivatives, pharmaceutically acceptable salts or stereoisomers thereof, and the use of said compounds, their deuterated derivatives, pharmaceutically acceptable salts or stereoisomers thereof in the preparation of medicaments for treating and / or preventing USP1-mediated diseases and related diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a kind of USP1 inhibitor compound, its pharmaceutically acceptable salt or stereoisomer thereof, pharmaceutical composition and preparation containing the compound, its pharmaceutically acceptable salt or stereoisomer, the method for preparing the compound, its pharmaceutically acceptable salt or stereoisomer, and the use of the compound, its pharmaceutically acceptable salt or stereoisomer in the preparation of the drug for treating and / or preventing the disease mediated by USP1 and related diseases. BACKGROUND

[0002] There are many related targets in the occurrence and development of tumor, deubiquitylating enzyme DUB (Deubiquitylating enzyme), coding more than 100 human genes, divided into six families, wherein ubiquitin-specific protease (USP) contains more than 50 members, and is the largest family of DUB. Ubiquitination is a reversible process, and DUB acts on ubiquitin-proteasome system, cleaves the isopeptide bond between lysine and the C-terminal of UBQ, affects cell proliferation, cycle, apoptosis, DNA damage response, tumor suppression, occurrence and metastasis.

[0003] USP1 (Ubiquitin specific protease 1, ubiquitin-specific protease 1) is a member of USP family, and is a cysteine isopeptidase containing Cys90, His593 and Asp751 triplet structure. 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 being combined into heterodimeric complex with UAF1 (USP1-associated factor 1, USP1-associated factor 1, an auxiliary factor containing WD40 repeat sequence and regulating USP1 activity), and plays a deubiquitinating enzyme role, stabilizes replication fork, and is located in the nucleus.

[0004] USP1 is highly expressed in breast cancer, ovarian cancer and other cancers, and its overexpression is associated with BRCA1 deficiency in breast cancer / ovarian cancer. 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 the 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 ultraviolet radiation, etc.). 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, RAD18-mediated PCNA monoubiquitination promotes the conversion of PCNA binding from replication polymerase (polδ / ε) to TLS polymerase (such as POLK). After bypassing the lesion by TLS polymerase, USP1 deubiquitinates PCNA, promoting the conversion of PCNA binding back to replication polymerase. Inhibition of USP1 leads to replication fork instability and has synthetic lethality with BRCA mutations.

[0006] USP1 inhibitors inhibit the DNA break repair involving PCNA together with USP1 / UAF1 and BRCA1 / 2, leading to replication fork instability. Therefore, USP1 inhibitors can have synthetic lethality on BRCA1 / 2 mutant (or HRD positive) cells, and can be used in combination with PARP1 / 2 inhibitors to enhance efficacy or solve part of the drug resistance problem. Therefore, the use of small molecule inhibitors to inhibit USP1 has potential for the treatment of cancer and other diseases, and there is currently no commercialized USP1 inhibitor drug. SUMMARY

[0007] The present application aims to provide a USP1 inhibitor compound with novel structure and good inhibitory activity on USP1. Further, the compound can be used to inhibit the USP1 kinase activity, thereby enhancing the immune effect of the body on tumors. Further, the compound can also be used to treat or prevent related diseases mediated by USP1, especially cancer. The compound has good inhibitory effect on various cancer cells and good drugability.

[0008] The specific technical solutions are as follows:

[0009] In one aspect, the present application provides a compound represented by general formula (I), a deuterated compound thereof, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

[0010]

[0011] wherein,

[0012] X 1 , X 2 are each independently selected from C, CH or N;

[0013] X 3 , X 4 , X 5 are each independently selected from CR a or N;

[0014] X 6 , X 7 are each independently selected from C, CR a or N;

[0015] Ring A is selected from phenyl or 5-8 membered heteroaryl optionally substituted with one or more Q1;

[0016] Ring B is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-12 membered heteroaryl optionally substituted with one or more Q2;

[0017] R 1 , R 2 , R 3 are each independently selected from deuterium, hydrogen, carboxyl, cyano, nitro, amino, 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, haloC 1-6 alkoxy or null;

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

[0019] each Y is independently selected from -CR a R b -, -NR c -, -CO-, -O-, -S-, or -SO-;

[0020] each Q1and each Q2is independently selected from deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, optionally deuterated C 1-6 alkyl, 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, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylaminoacyl, C 1-6 alkylacylamino, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, C 1-6 alkylaminosulfonyl, -(CH2) t -6-10 membered aryl, -(CH2) t -5-12 membered heteroaryl, -(CH2) t -3-8 membered cycloalkyl, -(CH2) t -3-8 membered heterocyclyl, -CO-C 1-6 alkylene-NH2or -CO-C 1-6 alkyl;

[0021] each R a , each R b is independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylaminoacyl, C 1-6 alkylacylamino, C 1-6 alkylsulfonamido, C 1-6 alkylaminosulfonyl, haloC1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl;

[0022] each R c is independently selected from deuterium, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl;

[0023] m, n are each independently an integer from 0-6;

[0024] each t is independently selected from 0, 1, or 2;

[0025] each is independently selected from a single or double bond, and adjacent two are both single bonds or one of them is a double bond.

[0026] In certain embodiments, compounds represented by the foregoing general Formula (I), deuterium isotope thereof, pharmaceutically acceptable salt thereof, or stereoisomer thereof, wherein,

[0027] X 1 , X 2 are each independently selected from C, CH, or N;

[0028] X 3 , X 4 , X 5 are each independently selected from CR a or N;

[0029] X 6 , X 7 are each independently selected from C, CR a , N;

[0030] Ring A is selected from phenyl or 5-6 membered heteroaryl optionally substituted with one or more Q1;

[0031] Ring B is selected from phenyl, 5-6 membered heterocyclyl, or 5-6 membered heteroaryl optionally substituted with one or more Q2;

[0032] R 1 , R 2 , R 3 are each independently selected from deuterium, hydrogen, halogen, C 1-6 alkyl, C1-6 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, Halogenated C 1-6 Alkoxy groups may be absent;

[0033] Each L is independently selected from -NR c -or-CR a R b -;

[0034] Each Y is independently selected from -CR a R b -、-NR c -, -CO-, -O-, -S- or -SO-;

[0035] Each Q1 and each Q2 is independently selected from deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and optionally deuterated C. 1-4 Alkyl, C 1-4 Alkoxy, 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, carboxyl C 1-4 Alkyl, C 1-4 alkyl carbonyl, C 1-4 Alkoxycarbonyl group, -(CH2) t -phenyl, -(CH2) t -5-6 aryl groups, -(CH2) t -3-6 membered cycloalkyl or -(CH2) t -3-6 membered heterocyclic group;

[0036] Each R a Each R b The C atoms are independently selected from deuterium, hydrogen, and halogen, and are optionally deuterated. 1-4 Alkyl, C 1-4 Alkoxy, 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, carboxyl C 1-4 alkyl;

[0037] each R is independently selected from the group consisting of deuterium, hydrogen, C c is independently selected from the group consisting of deuterium, hydrogen, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy;

[0038] each m and n is independently an integer from 0 to 5;

[0039] each t is independently selected from 0, 1 or 2;

[0040] each R is independently selected from the group consisting of deuterium, hydrogen, C is independently selected from the group consisting of a single bond or a double bond, and two adjacent are both single bonds or one of them is a double bond.

[0041] In certain embodiments of the foregoing compounds of Formula (I), deuterated forms, pharmaceutically acceptable salts, or stereoisomers thereof, wherein:

[0042] Ring A is selected from phenyl optionally substituted with 1-3 Q1, or 5-6 membered nitrogen-containing heteroaryl;

[0043] Ring B is selected from phenyl optionally substituted with 1-3 Q2, 5-6 membered nitrogen-containing heterocyclyl, or 5-6 membered nitrogen-containing heteroaryl;

[0044] R 1 , R 2 , R 3 is independently selected from the group consisting of deuterium, hydrogen, halogen, C 1-4 alkyl optionally substituted with deuterium, C 1-4 alkoxy, haloC 1-4 alkyl, di(C 1-4 alkyl)amino, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, aminoC 1-4 alkyl, carboxyC 1-4 alkyl, haloC 1-4 alkoxy or is absent;

[0045] each L is independently selected from -NR c - or -CR a R b -;

[0046] each Y is independently selected from -CR a R b -, -NR c -, -CO-, -O-, -S- or -SO-;

[0047] each Q1and each Q2is independently selected from deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, optionally deuterated 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, hydroxyC 1-4 alkyl, aminoC 1-4 alkyl, carboxyC 1-4 alkyl, -(CH2) t -phenyl, -(CH2) t -5-6 membered heteroaryl, -(CH2) t -3-6 membered cycloalkyl or -(CH2) t -3-6 membered heterocyclyl;

[0048] each R a , each R b is independently selected from deuterium, hydrogen, halogen, optionally deuterated 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, hydroxyC 1-4 alkyl, aminoC 1-4 alkyl, carboxyC 1-4 alkyl;

[0049] each R c is independently selected from deuterium, hydrogen, optionally deuterated C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy;

[0050] m, n are independently integers from 0-4;

[0051] each t is independently selected from 0 or 1;

[0052] each is independently selected from a single bond or a double bond, and the two adjacent are both single bonds or one of them is a double bond.

[0053] In certain embodiments, compounds according to the general formula (I) as described previously, deuterium isomers thereof, pharmaceutically acceptable salts thereof, or stereoisomers thereof, wherein

[0054] Ring A is selected from a 5-6 membered nitrogen-containing heteroaryl optionally substituted with 1-3 Q1; preferably, Ring A is selected from a 6 membered nitrogen-containing heteroaryl optionally substituted with 1-3 Q1;

[0055] Ring B is selected from a 5-6 membered nitrogen-containing heteroaryl optionally substituted with 1-3 Q2; preferably, Ring B is selected from a 5 membered nitrogen-containing heteroaryl optionally substituted with 1-3 Q2;

[0056] R 1 , R 2 , R 3 are each independently selected from deuterium, hydrogen, halogen, C 1-4 alkyl optionally substituted with deuterium, C 1-4 alkoxy optionally substituted with deuterium, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, or null;

[0057] each L is independently selected from CR a R b -;

[0058] each Y is independently selected from -CR a R b -, -NR c -, -O- or -S-;

[0059] each Q1and each Q2is independently selected from deuterium, halogen, C 1-4 alkyl optionally substituted with deuterium, C 1-4 alkoxy optionally substituted with deuterium, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, -(CH2) t -3-6 membered cycloalkyl or -(CH2) t -3-6 membered heterocyclyl;

[0060] 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, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy;

[0061] each R c is independently selected from deuterium, hydrogen, C 1-4 alkyl optionally substituted with deuterium or C 1-4 alkoxy;

[0062] m is selected from 1, 2 or 3;

[0063] n is selected from 0, 1, 2 or 3;

[0064] each t is independently selected from 0 or 1;

[0065] each is independently selected from a single bond or a double bond, and two adjacent are both single bonds or one of them is a double bond.

[0066] In certain embodiments, the compound represented by the foregoing general Formula (I), deuterium isotope thereof, pharmaceutically acceptable salt thereof, or stereoisomer thereof, wherein,

[0067] Ring A is selected from phenyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, or 1,2,4,5-tetrazinyl, optionally substituted with 1-3 Q1;

[0068] Ring B is selected from aziridinyl, azetidinyl, azepanyl, azacyclohexyl, piperazinyl, phenyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, or 1,2,4,5-tetrazinyl, optionally substituted with 1-3 Q2;

[0069] R 1 , R 2 , R 3 are independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, methyl optionally substituted with deuterium, ethyl optionally substituted with deuterium, propyl optionally substituted with deuterium, isopropyl optionally substituted with deuterium, butyl optionally substituted with deuterium, isobutyl optionally substituted with deuterium, sec-butyl optionally substituted with deuterium, t-butyl optionally substituted with deuterium, methoxy optionally substituted with deuterium, ethoxy optionally substituted with deuterium, propoxy optionally substituted with deuterium, isopropoxy optionally substituted with deuterium, methylamino optionally substituted with deuterium, dimethylamino optionally substituted with deuterium, monofluoromethyl optionally substituted with deuterium, difluoromethyl optionally substituted with deuterium, trifluoromethyl optionally substituted with deuterium, hydroxymethyl optionally substituted with deuterium, hydroxyethyl optionally substituted with deuterium, hydroxypropyl optionally substituted with deuterium, hydroxybutyl optionally substituted with deuterium, aminomethyl optionally substituted with deuterium, carboxymethyl optionally substituted with deuterium, carboxyethyl optionally substituted with deuterium, monofluoromethoxy optionally substituted with deuterium, difluoromethoxy optionally substituted with deuterium, trifluoromethoxy optionally substituted with deuterium, or null;

[0070] each L is independently selected from -CR a R b -;

[0071] each Y is independently selected from -CR a R b -, -NR c -, -O-, or -S-;

[0072] each Q1and each Q2is independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, carboxy, hydroxy, amino, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propyloxy, isopropyloxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy, optionally substituted with deuterium; t - phenyl, -(CH2) t - pyridyl, -(CH2) t - pyrimidinyl, -(CH2) t - pyridazinyl, -(CH2) t - pyrazinyl, -(CH2) t - cyclopropyl, -(CH2) t - cyclobutyl, -(CH2) t - cyclopentyl, -(CH2) t - cyclohexyl, -(CH2) t - aziridinyl, -(CH2) t - azetidinyl, or -(CH2) t - pyrrolidinyl;

[0073] each R a , each R b is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propyloxy, isopropyloxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy, optionally substituted with deuterium;

[0074] each R c is independently selected from deuterium, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propyloxy, isopropyloxy, monofluoromethyl, difluoromethyl, trifluoromethyl, or trifluoromethoxy, optionally substituted with deuterium;

[0075] each m, each n is independently 0, 1, 2, or 3;

[0076] each t is independently selected from 0 or 1;

[0077] each is independently selected from a single bond or a double bond, and the two adjacent are both single bonds or one of them is a double bond.

[0078] In some embodiments, the compound represented by the aforementioned general formula (I), its deuterated derivative, its pharmaceutically acceptable salt, or its stereoisomer,

[0079] Wherein, ring A is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl or 1,2,4,5-tetraazinyl, which are optionally substituted with 1 to 3 Q1s;

[0080] Ring B is selected from thiophene, pyrrole, thiazolyl, isothiazol, thiadiazol, oxazol, isoxazol, oxadiazol, imidazolyl, pyrazol, 1,2,3-triazol or 1,2,4-triazol, which are substituted with 1 to 3 Q2 groups.

[0081] R 1 R 2 R 3 Each is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, and optionally methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or none.

[0082] Each L is independently selected from -CR a R b -;

[0083] Each Y is independently selected from -CR a R b -、-NR c -、-O- or -S-;

[0084] Each Q1 and each Q2 are independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, carboxyl, hydroxyl, amino, nitro, and optionally deuterated methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, -(CH2). t -Cyclopropyl, -(CH2) t -cyclobutyl, -(CH2) t -cyclopentyl or -(CH2) t - Cyclohexyl;

[0085] Each R a Each R bEach of the following is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, and optionally deuterated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy;

[0086] Each R c The compounds are independently selected from deuterium, hydrogen, and optionally deuterated methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0087] m and n are independently 0, 1, 2 or 3.

[0088] In some implementations, X 1 X 2 Each is independently selected from C, CH, or N;

[0089] X 3 X 4 X 5 Each is independently selected from CH or N;

[0090] X 6 X 7 Each is independently selected from C, CH, or N.

[0091] In some embodiments, each Q1 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, and optionally deuterated methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, -(CH2). t -Cyclopropyl, -(CH2) t -cyclobutyl, -(CH2) t -cyclopentyl or -(CH2) t - Cyclohexyl.

[0092] In some embodiments, each Q2 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, and optionally deuterated methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0093] In some embodiments, the compound represented by general formula (I), its deuterated derivative, its pharmaceutically acceptable salt, or its stereoisomer, has the structure represented by general formula (II).

[0094]

[0095] Among them, R 1 R 2 The C atoms are independently selected from deuterium, hydrogen, and halogen, and are optionally deuterated. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl or halogenated C 1-4 Alkoxy; preferably, R 1 R 2 Each of the following is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy;

[0096] Ring A, Ring B, X 3 X 4 X 5 X 6 X 7 ,L,Y,Q1,Q2,m,n,R a R b R c ,t, The definition is as described in any of the preceding implementation schemes.

[0097] In some implementations, R 1 R 2 The C atoms are independently selected from deuterium, hydrogen, and halogen, and are optionally deuterated. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkyl group.

[0098] In some implementations, R 1 R 2 Each of the following is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0099] In some implementations, R 1 R 2Each is independently selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, or trifluoromethoxy; preferably, R 1 R 2 Each is hydrogen, independently.

[0100] In some embodiments, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl groups optionally substituted with 1 to 3 Q1 groups; preferably, ring A is selected from the following groups optionally substituted with 1 to 3 Q1 groups: Preferably, ring A is selected from those arbitrarily replaced by 1-3 Q1s. Each Q1 is independently selected from deuterium, fluorine, chlorine, bromine, and optionally deuterated methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0101] In some embodiments, ring B is selected from pyrrole, imidazolyl, pyrazolyl, 1,2,3-triazolyl, or 1,2,4-triazolyl groups optionally substituted with 1-3 Q2 groups; preferably, ring B is selected from groups optionally substituted with 1-3 Q2 groups. Each Q2 is independently selected from deuterium, fluorine, chlorine, bromine, and optionally deuterated methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0102] In some embodiments, the compound represented by general formula (I), its deuterated derivative, its pharmaceutically acceptable salt, or its stereoisomer, has the structure represented by general formula (II-1).

[0103]

[0104] in,

[0105] X 3 X 4 X 5 Selected independently from CR a Or N;

[0106] X 6 X 7 Each is independently selected from C, CH, or N;

[0107] s is selected from 1, 2, or 3;

[0108] Ring B is selected from thiophene, pyrrole, thiazolyl, isothiazol, thiadiazol, oxazol, isoxazol, oxadiazol, imidazolyl, pyrazol, 1,2,3-triazol or 1,2,4-triazol, which are substituted with 1 to 3 Q2 groups.

[0109] Each L is independently selected from -CR a R b -;

[0110] Each Y is independently selected from -CR a R b -、-NR c -、-O- or -S-;

[0111] Each Q1 and each Q2 are independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, carboxyl, hydroxyl, amino, nitro, and optionally deuterated methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, -(CH2). t -Cyclopropyl, -(CH2) t -cyclobutyl, -(CH2) t -cyclopentyl or -(CH2) t - Cyclohexyl;

[0112] Each R a Each R b Each of the following is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, and optionally deuterated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy;

[0113] Each R c The compounds are independently selected from deuterium, hydrogen, and optionally deuterated methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0114] m and n are independently 0, 1, 2 or 3;

[0115] Each t is independently selected from 0 or 1;

[0116] Selected from single or double bonds.

[0117] In some embodiments, the compound represented by the aforementioned general formula (I), its deuterated derivative, its pharmaceutically acceptable salt, or its stereoisomer, has the structure represented by general formula (II-2).

[0118]

[0119] Where s is selected from 1, 2, or 3; rings B and X 3 X 4 X 5 ,L,Y,Q1,Q2,m,n,R 1 R 2 R a R b R c ,t, The definition is as described in any of the preceding implementation schemes.

[0120] In some embodiments, the compound represented by general formula (I), its deuterated derivative, its pharmaceutically acceptable salt, or its stereoisomer, has the structure represented by general formula (II-3).

[0121]

[0122] Among them, (L) n Selected from -CR a R b -or-CR a R b -CR a R b -;

[0123] (Y) m Selected from -CR a R b -CR a R b -、-CR a R b -CR a R b -CR a R b -、-NR c -CR a R b -CR a R b -、-CR a R b -CR a R b -NR c -、-O-CR a R b -CR a R b -、-CRa R b -O-CR a R b -、-CR a R b -NR c -CR a R b -、-CR a R b -CR a R b -NR c -or-CR a R b -CR a R b -O-;

[0124] s and q are independently selected from 1, 2, or 3, respectively;

[0125] X 3 X 4 X 5 Q1, Q2, R a R b R c The definition is as described in any of the implementation schemes.

[0126] In some implementations, each R a The C atoms are independently selected from deuterium, hydrogen, and halogen, and are optionally deuterated. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkyl group.

[0127] In some implementations, each R a Each is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, and optionally deuterated methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0128] In some implementations, each R b The C atoms are independently selected from deuterium and hydrogen, respectively, and are optionally deuterated. 1-4 Alkyl, C 1-4 Alkyl group.

[0129] In some implementations, each R b Each is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, and optionally methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy that has been deuterated.

[0130] In some implementations, each R cThe C atoms are independently selected from deuterium, hydrogen, and halogen, and are optionally deuterated. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkyl group.

[0131] In some implementations, each R c Each is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, and optionally deuterated methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0132] In some embodiments, the aforementioned compound, its deuterated form, its pharmaceutically acceptable salt, or its stereoisomer,

[0133] Among them, (L) n Selected from -CR a R b -or-CR a R b -CR a R b -;

[0134] (Y) m Selected from -CR a R b -CR a R b -、-CR a R b -CR a R b -CR a R b -、-NR c -CR a R b -CR a R b -、-O-CR a R b -CR a R b -、-CR a R b -CR a R b -NR c -or-CR a R b -CR a R b -O-;

[0135] Each R a Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, Halogenated C 1-4Alkyl; preferably, each R a Each of the following is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, or trifluoromethyl;

[0136] Each R b Each is independently selected from hydrogen or C. 1-4 Alkyl; preferably, each R b Each is independently selected from hydrogen, methyl, ethyl, propyl, or isopropyl;

[0137] Each R c Selected independently from hydrogen and C 1-4 Alkyl or halogenated C 1-4 Alkyl; preferably, each Rc is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl.

[0138] In some embodiments, the aforementioned compound, its deuterated form, its pharmaceutically acceptable salt, or its stereoisomer,

[0139] Among them, (L) n Selected from -CHR a -or-CHR a -CH2-;

[0140] (Y) m Selected from -CHR a -CH2-、-CH2-CHR a -、-CHR a -CH2-CH2-、-NR c -CH2-CHR a -、-O-CH2-CHR a -、-CHR a -CH2-NR c -or-CHR a -CH2-O-;

[0141] Each R a Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl; preferably, each R a Each of the following is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, or trifluoromethyl;

[0142] Each R c Selected independently from hydrogen and C 1-4 Alkyl or halogenated C 1-4 Alkyl; preferably, each R cEach of the following is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0143] In some implementations, t is independently selected from 0 or 1.

[0144] In some implementations, m is selected from 1, 2, or 3.

[0145] In some implementations, n is 1.

[0146] In some implementations, s is 2.

[0147] 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.

[0148] In some embodiments of the present invention, the structures of the compounds of the aforementioned general formula (I), their pharmaceutically acceptable salts, or their stereoisomers are shown in Table 1 below:

[0149] Table 1

[0150]

[0151]

[0152] The "pharmaceutically acceptable salt" mentioned in this invention refers to the addition salt of pharmaceutically acceptable acids and bases.

[0153] The "stereoisomers" of the compounds represented by general formula (I) of this invention refer to the enantiomers produced when the compounds represented by formula (I) contain asymmetric carbon atoms; the cis-trans isomers produced when the compounds contain carbon-carbon double bonds or cyclic structures; and the tautomers produced when the compounds contain ketones or oximes. In some embodiments of this invention, stereoisomers include, but are not limited to: enantiomers, diastereomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof.

[0154] The present invention also provides a pharmaceutical composition comprising compounds represented by the aforementioned general formulas (I), (II), (II-1), (II-2), and (II-3), their deuterated derivatives, their pharmaceutically acceptable salts or stereoisomers thereof, and one or more second therapeutic agents. Optionally, the pharmaceutical composition further comprises one or more pharmaceutical carriers and / or diluents.

[0155] The present invention also provides a pharmaceutical preparation comprising the compounds represented by the aforementioned general formulas (I), (II), (II-1), (II-2), and (II-3), their deuterated derivatives, their pharmaceutically acceptable salts or stereoisomers thereof, and one or more pharmaceutical carriers and / or diluents; the pharmaceutical preparation being any clinically or pharmaceutically acceptable dosage form.

[0156] 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.

[0157] 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.

[0158] The present invention also provides the use of compounds, deuterated derivatives thereof, pharmaceutically acceptable salts thereof or stereoisomers thereof, the aforementioned pharmaceutical preparations or pharmaceutical compositions of general formulas (I), (II), (II-1), (II-2), and (II-3) 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.

[0159] This invention also provides the use of compounds, their deuterated derivatives, pharmaceutically acceptable salts or stereoisomers thereof, the aforementioned pharmaceutical preparations or pharmaceutical compositions represented by general formulas (I), (II), (II-1), (II-2), and (II-3) in the treatment and / or prevention of USP1-mediated diseases and related diseases; wherein the USP1-mediated diseases and related diseases are selected from cancers or benign tumors. The cancers are selected from bone cancer, glioma, brain cancer, thyroid cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer, colon cancer, bladder cancer, gastrointestinal stromal carcinoma, pancreatic cancer, bile duct cancer, CNS cancer, ovarian cancer, endometrial cancer, prostate cancer, kidney cancer, anaplastic large cell lymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma, and combinations thereof.

[0160] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, and breast cancer; in other embodiments, the cancer is triple-negative breast cancer.

[0161] 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 formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (II-3), its deuterated form, its pharmaceutically acceptable salt or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition, wherein the disease is a USP1-mediated disease and related diseases; the USP1-mediated disease and related diseases are selected from cancer or benign tumors.

[0162] 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.

[0163] 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.

[0164] The "halogen" mentioned in this invention refers to fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] The “C” mentioned in this article 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 alkylsulfonyl, C 1-6 Alkylsulfonamide, C 1-6 Alkylaminosulfonyl, C 1-6 alkyl carbonyl, C 1-6 "Alkoxycarbonyl" refers to a group with a carbonyl group of C10 and C20. 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.

[0169] 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.

[0170] The "halogenated C" mentioned in this article 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, Halogenated C 1-6 Alkylene, 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.

[0171] 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 Alkylene, 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 Alkylene, C 1-4 A group formed by the hydrogen atom in an alkoxy group.

[0172] The “3-10 membered cycloalkyl” mentioned in this invention refers to a saturated or partially saturated cycloalkyl group containing 3-10 carbon atoms that is not aromatic, including “3-8 membered monocycloalkyl” and “7-10 membered fused cycloalkyl”.

[0173] The "3-8 membered monocyclic alkyl" as described in this invention refers to a saturated or partially saturated monocyclic alkyl group containing 3-8 carbon atoms and lacking aromaticity, including "3-8 membered saturated monocyclic alkyl" and "3-8 membered partially saturated monocyclic alkyl". Preferably, it includes "3-4 membered monocyclic alkyl", "3-5 membered monocyclic alkyl", "3-6 membered monocyclic alkyl", "3-7 membered monocyclic alkyl", "4-5 membered monocyclic alkyl", "4-6 membered monocyclic alkyl", "4-7 membered monocyclic alkyl", "4-8 membered monocyclic alkyl", "5-6 membered monocyclic alkyl", "5-7 membered monocyclic alkyl", "5-8 membered monocyclic alkyl", "6-7 membered monocyclic alkyl", "6-8 membered monocyclic alkyl", "7-8 membered monocyclic alkyl", "3-6 membered saturated monocyclic alkyl", "5-8 membered saturated monocyclic alkyl", "5-7 membered saturated monocyclic alkyl", and "5-6 membered saturated monocyclic alkyl". Optionally, the cyclic carbon atom in the cyclic structure can be oxidized. Specific examples of the "3-8 saturated monocycloalkyl 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 monocycloalkyl 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.

[0174] The “7-10 fused cycloalkyl” mentioned in this invention refers to a saturated or partially saturated non-aromatic cyclic group containing 7-10 ring atoms, formed by two or more cyclic structures sharing two adjacent carbon atoms. One ring of the fused ring can be an aromatic ring, but the fused ring as a whole does not possess aromaticity. It includes “8-9 fused cycloalkyl”, “9-10 fused cycloalkyl”, etc., and its fusion mode can be: 5-6 cycloalkyl and 5-6 cycloalkyl, benzo5-6 cycloalkyl, benzo5-6 saturated cycloalkyl, etc. Examples include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, octahydrocyclopentadienyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthrene, bicyclo[3.1.0]hex-2-enyl, bicyclo[4.1.0]hept-3-enyl, bicyclo[3.2.0]hept-3-enyl, Bicyclo[4.2.0]octyl-3-enyl, 1,2,3,3a-tetrahydrocyclopentadienyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,5,6,8a-hexahydronaphthyl, 1,2,3,4,5,6,7,8,9,10-decahydrophenanthrene, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl, etc.

[0175] The “3-10 member heterocyclic group” mentioned in this invention includes “3-8 member monoheterocyclic group” and “7-10 member fused heterocyclic group”.

[0176] The "3-8 membered monoheterocyclic 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 3-8 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 cyclic structure can be substituted with oxygen. The "3-8 membered heterocyclic group" described in this invention includes "3-8 membered saturated heterocyclic groups" and "3-8 membered partially saturated heterocyclic groups." Preferably, the "3-8 membered monoheterocyclic group" described in this invention contains 1-3 heteroatoms; preferably, the "3-8 membered monoheterocyclic group" described in this invention contains 1-2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and / or oxygen atoms; preferably, the "3-8 membered monoheterocyclic group" described in this invention contains 1 nitrogen atom. The "3-8 member monoheterocyclic group" is preferably a "3-7 member monoheterocyclic group", "3-6 member monoheterocyclic group", "4-7 member monoheterocyclic group", "4-6 member monoheterocyclic group", "6-8 member monoheterocyclic group", "7-8 member monoheterocyclic group", "5-7 member monoheterocyclic group", "5-6 member monoheterocyclic group", "3-6 member saturated monoheterocyclic group", "5-6 member saturated monoheterocyclic group", "3-6 member nitrogen-containing monoheterocyclic group", "3-6 member saturated nitrogen-containing monoheterocyclic group", "5-6 member nitrogen-containing monoheterocyclic group", "5-6 member saturated nitrogen-containing monoheterocyclic group", etc. For example, it may contain only one or two nitrogen atoms, or it may contain one nitrogen atom and one or two other heteroatoms (e.g., oxygen atom and / or sulfur atom). Specific examples of "3-8 membered monoheterocyclic groups" include, but are not limited to: aziridine, 2H-aziridine, diaziridine, 3H-diazacyclopropenyl, aziridinebutyl, 1,4-dioxanehexyl, 1,3-dioxanehexyl, 1,3-dioxanepentyl, 1,4-dioxanehexadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolylalkyl, imidazoalkyl, 4,5-dihydroimidazoyl, pyrazolyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazoyl, thiazoalkyl, piperazine Pyridyl, tetrahydropyridyl, piperidinone, tetrahydropyridinone, dihydropiperidinone, piperazine, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisooxazolyl, 2,3-dihydroisooxazolyl, oxazolidinyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-one, 3,4-dihydro-2H-pyranyl, etc.

[0177] The "7-10 fused heterocyclic group" described in this invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 7-10 ring atoms, formed by two or more cyclic structures sharing two adjacent atoms, wherein at least one ring atom is a heteroatom. One ring in the fused ring may be an aromatic ring, but the fused ring as a whole does not possess 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 cyclic structure may be oxidized, including but not limited to... Limited to "8-9 fused heterocyclic groups", "9-10 fused heterocyclic groups", etc., the fusion mode can be 5-6 fused heterocyclic group with 5-6 fused heterocyclic group, 5-6 fused heterocyclic group with 5-6 fused cycloalkyl group, benzo5-6 fused heterocyclic group, benzo5-6 saturated heterocyclic group, 5-6 fused heteroaryl group with 5-6 fused heterocyclic group, 5-6 fused heteroaryl group with 5-6 saturated heterocyclic group; 5-6 fused heteroaryl group is as defined above; specific examples of "7-10 fused heterocyclic groups" include, but are not limited to: pyrrolidinyl cyclopropyl, cyclopentyl aziridine propyl. , pyrrolidinyl cyclobutyl, pyrrolidinyl pyrrolidinyl, pyrrolidinyl pyridine, pyrrolidinyl pyrazinyl, pyrrolidinyl morpholinyl, piperidinyl morpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzoimidazoalkyl, benzooxazolyl, benzothiazoalkyl, benzoisooxazolyl, benzoisothiazoalkyl, benzopiperidine, benzomorpholinyl, benzopiperazinyl, benzotetrahydropyranyl, pyridinyl cyclopentyl, pyridinyl cyclohexyl, pyridinyl pyridine tetrahydrofuranyl, pyridinyl pyridine Pyrrolyl, pyridinium imidazoalkyl, pyridinium oxazolyl, pyridinium thiazoalkyl, pyridinium isoxazolyl, pyridinium isothiazolyl, pyridinium piperidinyl, pyridinium morpholinyl, pyridinium piperazine, pyridinium tetrahydropyranyl, pyrimidinium cyclopentyl, pyrimidinium cyclohexyl, pyrimidinium tetrahydrofuranyl, pyrimidinium pyrrolyl, pyrimidinium imidazoalkyl, pyrimidinium oxazolyl, pyrimidinium isoxazolyl, pyrimidinium isothiazolyl, pyrimidinium piperidinyl, pyrimidinium morpholinyl, pyrimidinium piperazine, pyrimidinium tetrahydropyranyl;Tetrahydroimidazo[4,5-c]pyridyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3]dioxacyclopentenyl, 2H-chromenyl, 2H-chromenyl-2-one, 4H-chromenyl, 4H-chromenyl-4-one, 4H-1,3-benzoxazinyl, 4,6-dihydro-1H-furano[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-1H- Furano[3,4-d]imidazolyl, 4,6-dihydro-1H-thieno[3,4-d]imidazolyl, 4,6-dihydro-1H-pyrrolo[3,4-d]imidazolyl, octahydro-benzo[d]imidazolyl, decahydroquinolinyl, hexahydrothieno[d]imidazolyl, hexahydrofurano[d]imidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopenten[c]pyrrolel, 4H-1,3-benzoxazinyl, etc.

[0178] 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”.

[0179] 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.

[0180] 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.

[0181] 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".

[0182] 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.

[0183] 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.

[0184] The "deuterated product" mentioned in this invention refers to one or more of the following in the compound structure: 1 H was 2 Structures formed by H (also denoted as "D") substitution. One or more of the substituent structures in this invention. 1 H can be optionally defined by one or more 2 H (also represented as "D") was replaced.

[0185] The "carbon atom, nitrogen atom or sulfur atom being replaced by oxygen" mentioned in this invention refers to the formation of a structure of C=O, N=O, S=O or SO2.

[0186] The term "optionally substituted" in this invention refers to two situations in which one or more hydrogen atoms on the substituted group can be "substituted" or "not substituted" by one or more substituents.

[0187] 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.

[0188] Beneficial effects of the invention

[0189] (1) The compounds of the present invention, their deuterated derivatives, their pharmaceutically acceptable salts or their stereoisomers have excellent USP1 inhibitory activity and can treat USP1-mediated diseases and related diseases.

[0190] (2) The compounds of the present invention, their deuterated derivatives, their pharmaceutically acceptable salts or their stereoisomers have good pharmacokinetic properties, longer duration of action and high bioavailability.

[0191] (3) The compounds of the present invention, their deuterated derivatives, their pharmaceutically acceptable salts or their stereoisomers have good safety profiles.

[0192] (4) 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.

[0193] 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.

[0194] In vitro enzymatic activity of compounds of the application

[0195] Test sample: The compound in Table 1 of this invention, the structural formula and preparation method are shown in the preparation example.

[0196] Experimental reagents:

[0197]

[0198] Laboratory consumables:

[0199] Consumables Vendor Cat No. 384-Well plate Perkin Elmer 6007279

[0200] Experimental methods:

[0201] 1. Compound dilution

[0202] 1) The compound of the present invention was prepared to 10 mM using DMSO as a test stock solution.

[0203] 2) The stock solution of the compound of the present invention was serially diluted 4 times to 10 concentrations, with the highest concentration being 10 mM.

[0204] 3) Using an Echo550, transfer the diluted compounds of the present invention to 384-well plates, dilute 1000 times, set 2 replicates for each concentration, and set the final concentration of DMSO to 1%.

[0205] 4) The final concentrations of the tested compounds were 10000 nM, 2500 nM, 625 nM, 156 nM, 39 nM, 9.8 nM, 2.4 nM, 0.61 nM, 0.15 nM, and 0.038 nM.

[0206] 2. Enzyme reaction experiment

[0207] 1) Prepare the enzyme solution in 1× reaction buffer.

[0208] 2) Add Ubiquitin Rhodamine 110 Protein,CF (Ub-Rho) to 1× assay buffer to prepare substrate solution.

[0209] 3) Transfer 10 μL of enzyme solution and 1× reaction buffer to a 384-well plate.

[0210] 4) Incubate at room temperature for 60 minutes.

[0211] 5) Add 10 μL of substrate solution to each well to start the reaction, centrifuge for 30 s, and shake for 30 s.

[0212] 3. Result Detection

[0213] 1) Read the plate on a SpectraMax Paradigm for 30 minutes, with an excitation wavelength of 480nm and an emission wavelength of 540nm.

[0214] 2) Collect data from SpectraMax Paradigm.

[0215] 4. Data Analysis

[0216] The inhibition rate (%inh) is calculated using the following formula:

[0217]

[0218] Where Max represents the luminescence signal intensity of the positive control well without the addition of the compound;

[0219] Min represents the luminescence signal intensity of the negative control well without enzyme addition;

[0220] Signal indicates the intensity of the luminescence signal of the tested compound;

[0221] IC is calculated using the following formula. 50 :

[0222]

[0223] Where Y represents: %inhibition;

[0224] X represents the concentration of the compound.

[0225] Experimental results:

[0226] Table 2 Inhibitory activity of the compounds of the present invention against USP-1

[0227]

[0228] The experimental results above show that the compound prepared in this invention can effectively inhibit the activity of USP1 and is an effective USP1 inhibitor.

[0229] In vitro cytological inhibitory activity of compounds of the application

[0230] Test substances: The compounds in Table 1 of this invention, whose chemical names and structures are given in the preparation examples.

[0231] Reagents used in the experiment:

[0232] DMEM: Dulbecco's Modified Eagle Medium

[0233] Glutathione (CTG): CellTiter-Glo Cell Viability Assay Kit

[0234] FBS: Fetal bovine serum ITS-G: Insulin-Transferrin-Selenium Additive

[0235] Cell lines used in the experiment:

[0236] MDA-MB-436: BRCA1-mutated human breast cancer cells;

[0237] Caov-3: Homologous recombination repair deficient (HRD+) human ovarian cancer cells

[0238] Experimental Method (CelltiterGlo assay)

[0239] 1. Prepare cells

[0240] 1.1 Cell Culture:

[0241] 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.

[0242] 1.2 Preparation of cell suspension:

[0243] 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.

[0244] Table 3 Cell Seeding Number

[0245]

[0246] 2. Preparation of test compounds

[0247] 2.1 Prepare DMSO stock solutions for the test compounds. The stock solution concentration for all test compounds was 10 mM.

[0248] 2.2 Preparation of working stock solution for test compounds

[0249] The stock solution of the test compound at 10 mM was serially diluted 3-fold with DMSO to obtain 9 concentrations. Then, 2 μL of each serially diluted compound with DMSO was added to 198 μL of culture medium to form the working stock solution of the test compound (the compound concentration was 10 times the final concentration, with the highest concentration being 100 μM).

[0250] 2.3 Compound Treatment

[0251] 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.

[0252] 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, 4.57 nM, and 1.52 nM.

[0253] 2.4 Setting of reference holes

[0254] Solvent control: 0.1% DMSO.

[0255] Blank control: 96-well plate readings at 0 h after drug administration.

[0256] 2.5 Place the 96-well plate in a 37°C, 5% CO2 cell culture incubator and culture for 7 days.

[0257] 3. Testing

[0258] Melt the CTG reagent and equilibrate the 96-well plate to room temperature for 30 minutes. Add 60 μL of reagent (Celltiter Gloassaykit) 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-mode microplate reader.

[0259] 4. Data Processing

[0260] 1) Inhibition rate (%) = (DMSO solvent control well reading - test sample well reading) / (DMSO solvent control well reading - blank control well reading) × 100%;

[0261] 2) Input GraphPad Prism to plot the curve and obtain the curve and IC. 50 .

[0262] Experimental Results and Conclusions

[0263] Table 4. In vitro cellular activities (IC50) of the compounds of this invention. 50 ,nM)

[0264]

[0265] Table 1 shows the IC50 values ​​of the compounds in this invention against MDA-MB-436 and Caov-3 cells. 50 The values ​​are all less than 500 nM. The compounds of this invention can effectively inhibit the proliferation of MDA-MB-436 and Caov-3 cells, indicating that the compounds of this invention have clinical application potential in treating HRD-positive (homologous recombination defective) cancers. Detailed Implementation

[0266] 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.

[0267] The abbreviations used in the following experiments have the following meanings:

[0268] Xphos-Pd-G2: Chlorine (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)Dioxane: Dioxane MsCl: Methanesulfonyl chloride LiAlH4: Lithium aluminum hydride

[0269] DCE: Dichloroethane; EA: Ethyl acetate; DMF: N,N-dimethylformamide; PE: Petroleum ether; DCM: Dichloromethane; THF: Tetrahydrofuran; SiO2: Silicon dioxide; XPhos: 2-Dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl. Example 1: Preparation of 8-((6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Compound 1)

[0270]

[0271] Preparation of methyl 1,3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (Int-1)

[0272] Sodium acetate (20.2 g, 246.3 mmol) was added to an aqueous solution of 3,3-dibromo-1,1,1-trifluoropropane-2-one (33.3 g, 123.4 mmol) in 150 mL, and the mixture was heated to 100 °C and reacted for 1 h. After the reaction was complete, the temperature was lowered to 0 °C, and methanol (300 mL), methyl 3-bromo-4-carboxybenzoate (20.0 g, 82.3 mmol), and ammonia (150 mL) were added to the reaction solution. The mixture was reacted at 25 °C for 1 h, and then heated to 100 °C for 3 h. The reaction was confirmed by LC-MS. The reaction solution was diluted with water, extracted with EA, and the organic phase was evaporated to dryness. The residue was separated by column chromatography (SiO2, PE:EA = 85:15) to give 9.0 g of product, with a yield of 31.3%.

[0273] Preparation of methyl 2,4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-bromobenzoate (Int-2)

[0274] Methyl 3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (2.5 g, 7.2 mmol), benzyl bromide (1.5 g, 8.8 mmol), and cesium carbonate (5.0 g, 15.3 mmol) were weighed sequentially and dissolved in DMF (50 mL). After the reaction was completed, the mixture was washed with water, extracted with ethyl acetate, and the organic phase was concentrated. The solution was then subjected to column chromatography (EA:PE = 1:1) to obtain 2.5 g of the target product, with a yield of 79.5%.

[0275] 3. Preparation of (E)-4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-(2-ethoxyvinyl)benzoate (Int-3)

[0276] Methyl 4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-bromobenzoate (2.4 g, 5.5 mmol), tetrakis(triphenylphosphine)palladium (700 mg, 0.61 mmol), potassium carbonate (1.5 g, 10.9 mmol), and (Z)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (1.7 g, 8.6 mmol) were added to 20 mL of dioxane and 5 mL of water. The reaction was carried out under nitrogen at 95 °C for 6 h. After concentration and column chromatography (PE:EA = 70:30), 850 mg of the target product was obtained, with a yield of 36.1%.

[0277] Preparation of methyl 4,4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-(2-oxoethyl)benzoate (Int-4)

[0278] Methyl (E)-4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-(2-ethoxyvinyl)benzoate (850 mg) was dissolved in 15 mL (4 M HCl / Dioxane) and reacted at 50 °C for 3 h. After concentration, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and the organic phase was extracted and concentrated with ethyl acetate to obtain 600 mg of crude product.

[0279] Preparation of methyl 5,4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-(2-hydroxyethyl)benzoate (Int-5)

[0280] Methyl 4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-(2-oxoethyl)benzoate (600 mg, 1.5 mmol) was dissolved in methanol (10 mL), and sodium borohydride (75 mg, 2.0 mmol) was added. The reaction was carried out at 0 °C for 2 h, and LC-MS showed that the reaction was complete. Water (1 mL) was added to the reaction solution, and the mixture was stirred for 0.5 h. The reaction solution was filtered, the filtrate was evaporated to dryness, and the residue was subjected to column chromatography (EA:PE = 50%) to give 350 mg of the target product. The two-step yield was 43.8%.

[0281] Preparation of methyl 6,3-(2-hydroxyethyl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (Int-6)

[0282] Methyl 4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-(2-hydroxyethyl)benzoate (250 mg) was dissolved in 15 mL of methanol, and Pd / C (200 mg) was added. The reaction was carried out at 30 °C under hydrogen atmosphere for 8 h. After filtration, the filtrate was concentrated to obtain 110 mg of the target product, with a yield of 56.6%.

[0283] Preparation of methyl 7,2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline-8-carboxylate (Int-7)

[0284] Methyl 3-(2-hydroxyethyl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (110 mg, 0.35 mmol), triethylamine (110 mg, 1.1 mmol), and MsCl (60 mg, 0.52 mmol) were dissolved in 10 mL of DCM and reacted at 15 °C for 2 hours. The reaction solution was concentrated and subjected to column chromatography (EA:PE = 1:1) to give 25 mg of the target product, with a yield of 24.1%.

[0285] 8. Preparation of (2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline-8-yl)methanol (Int-8)

[0286] 2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline-8-carboxylic acid methyl ester (25 mg, 0.084 mmol) was dissolved in THF (5 mL), and LiAlH4 (10 mg, 0.26 mmol) was added. The reaction was carried out at 15 °C for 1 h, and LC-MS showed that the reaction was complete. The reaction solution was quenched with water, evaporated to dryness, and used directly for the next reaction.

[0287] Preparation of 9,8-(chloromethyl)-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Int-9)

[0288] The crude product from the previous step was dissolved in 5 mL of DCE, and 2 mL of thionyl chloride was added. The reaction was carried out at 50 °C for 1 hour. After concentration, the product was subjected to column chromatography (EA:PE = 1:1) to obtain 10 mg of product, with a two-step yield of 41.3%.

[0289] Preparation of 10.8-((6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Compound 1)

[0290] 8-(chloromethyl)-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (8 mg, 0.028 mmol), 6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (8 mg, 0.029 mmol), potassium carbonate (12 mg, 0.087 mmol), and DMF (5 mL) were weighed sequentially and reacted at 40 °C for 8 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with EA, and the organic phase was evaporated to dryness. The residue was subjected to prep-TLC (SiO2, PE:EA = 1:2, R... f =0.3) Separation yielded 6 mg of product, with a yield of 41.2%.

[0291] Molecular formula: C 26 H 18 D3F3N8O molecular weight: 521.5 LC-MS (m / z): 522.2 (M+H) + )

[0292] 1 H-NMR(400MHz, CDCl3)δ:9.36(s,1H),8.70(s,1H),8.26(s,1H),8.05-8.02(m,1H),7.40-7.37(m,1H),7.35-7.31(m,1H),7. 30-7.21(m,1H),5.73(s,2H),4.11-4.11(m,2H),3.22-3.15(m,2H),1.73-1.63(m,1H),1.30-1.21(m,2H),0.97-0.87(m,2H).

[0293] Preparation Example 2: Preparation of 8-(6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Compound 2)

[0294]

[0295] 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (50 mg, 0.19 mmol), 8-(chloromethyl)-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (60 mg, 0.21 mmol), potassium carbonate (79 mg, 0.57 mmol), and DMF (10 mL) were weighed sequentially. The mixture was reacted at 25 °C for 12 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with EA, and the organic phase was evaporated to dryness. The residue was separated by column chromatography (SiO2, PE:EA = 0:1) to give 30 mg of product, with a yield of 30.5%.

[0296] Molecular formula: C 26 H 21 F3N8O molecular weight: 518.2 LC-MS (m / z): 519.2 (M+H) + )

[0297] 1 H-NMR(400MHz, CDCl3)δ:9.36(s,1H),8.70(s,1H),8.25(s,1H),8.05-8.02(m,1H),7.40-7.37(m,1H),7.35-7.31(m,1H),7.30-7.2 1(m,1H),5.73(s,2H),4.11-4.11(m,2H),3.96(s,3H),3.22-3.15(m,2H),1.73-1.63(m,1H),1.30-1.21(m,2H),0.97-0.87(m,2H).

[0298] Preparation Example 3: Preparation of 8-((6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1H-pyrazol[3,4-d]pyrimidin-1-yl)methyl)-5-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Compound 3)

[0299]

[0300] Preparation of methyl 1,3-bromo-4-carboxybenzoate (Int-10)

[0301] Potassium carbonate (57.9 g, 419.0 mmol) and methyl iodide (32.7 g, 230.4 mmol) were added sequentially to a DMF (700 mL) solution of 3-bromo-4-carboxybenzoic acid (48.0 g, 209.6 mmol). The reaction was carried out at 25 °C for 5 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with EA, and the organic phase was evaporated to dryness to obtain 51.0 g of crude product.

[0302] Preparation of methyl 2,3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (Int-11)

[0303] Sodium acetate (20.2 g, 246.3 mmol) was added to an aqueous solution (150 mL) of 3,3-dibromo-1,1,1-trifluoropropane-2-one (33.3 g, 123.4 mmol). The reaction was carried out at 100 °C for 1 h, then cooled to 0 °C. Methanol (300 mL), methyl 3-bromo-4-carboxybenzoate (20.0 g, 82.3 mmol), and ammonia (150 mL) were added to the reaction solution. The reaction was carried out at 25 °C for 1 h, then heated to 100 °C for 3 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with EA, and the organic phase was evaporated to dryness. The residue was separated by column chromatography (SiO2, PE:EA = 85:15) to give 9.0 g of product, with a yield of 31.3%.

[0304] Preparation of methyl 3,5-hydroxy-5-methyl-2-(trifluoromethyl)-5,6-dihydroimidazole[2,1-a]isoquinoline-8-carboxylate (Int-12)

[0305] 2.0 g (5.7 mmol) of methyl 3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate, 18.3 g (57.0 mmol) of tributyl(methoxy)tin, 5.7 g (56.9 mmol) of propen-1-en-2-acetate, 128 mg (0.57 mmol) of palladium acetate, 174 mg (0.57 mmol) of tri-o-tolylphosphine, and 30 mL of toluene were weighed sequentially. The mixture was purged with nitrogen three times and reacted in a sealed tube at 100 °C for 24 h. The reaction was confirmed to be complete by LC-MS. The reaction solution was evaporated to dryness, and the residue was separated by column chromatography (SiO2, PE:EA = 90:10-85:15) to give 890 mg of product, with a yield of 47.6%.

[0306] Preparation of methyl 4,5-methyl-2-(trifluoromethyl)imidazolium[2,1-a]isoquinoline-8-carboxylic acid (Int-13)

[0307] A solution of methyl 5-hydroxy-5-methyl-2-(trifluoromethyl)-5,6-dihydroimidazole[2,1-a]isoquinoline-8-carboxylic acid (890 mg, 2.7 mmol) in dioxane (5 mL) was added to a solution of HCl / dioxane (4 M, 15 mL, 60.0 mmol). The reaction was carried out at 100 °C for 5 h, and LC-MS showed that the reaction was complete. The reaction solution was evaporated to dryness, the residue was diluted with DCM, washed with saturated sodium bicarbonate solution, the organic phase was evaporated to dryness, and the residue was separated by column chromatography (SiO2, PE:EA = 90:10-82:18) to give 530 mg of product, with a yield of 63.0%.

[0308] Preparation of methyl 5,5-methyl-2-(trifluoromethyl)-5,6-dihydroimidazole[2,1-a]isoquinoline-8-carboxylate (Int-14)

[0309] Palladium / carbon (1.0 g) was added to a methanol (30 mL) solution of methyl 5-methyl-2-(trifluoromethyl)imidazolium[2,1-a]isoquinoline-8-carboxylic acid (530 mg, 1.7 mmol), and the reaction was carried out at 35 °C for 13 h. The reaction solution was filtered, evaporated to dryness, and the residue was separated by column chromatography (SiO2, PE:EA = 10:1-5:1) to give 150 mg of product, yield 28.1%.

[0310] 6. Preparation of (5-methyl-2-(trifluoromethyl)-5,6-dihydroimidazol[2,1-a]isoquinoline-8-yl)methanol (Int-15)

[0311] At 10°C, lithium aluminum hydride (140 mg, 3.7 mmol) was added to a tetrahydrofuran (5 mL) solution of methyl 5-methyl-2-(trifluoromethyl)-5,6-dihydroimidazole[2,1-a]isoquinoline-8-carboxylic acid ester (140 mg, 0.45 mmol). The reaction was carried out at 10°C for 1 h, and LC-MS showed that the reaction was complete. Water (1 mL) was added to the reaction solution, and the mixture was stirred for 0.5 h. The reaction solution was filtered and evaporated to dryness to obtain 130 mg of crude product.

[0312] Preparation of 7,8-(chloromethyl)-5-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Int-16)

[0313] To a solution of (5-methyl-2-(trifluoromethyl)-5,6-dihydroimidazolium[2,1-a]isoquinoline-8-yl)methanol (120 mg crude) in 1,2-dichloroethane (10 mL), 2 mL of thionyl chloride was added. The mixture was reacted at 50 °C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was evaporated to dryness, and the residue was diluted with EA, washed with saturated sodium bicarbonate aqueous solution, and the organic phase was evaporated to dryness. The residue was then analyzed by prep-TLC (SiO2, PE:EA = 3:1, R... f =0.4) Separate to obtain 100mg of product.

[0314] Preparation of 8,6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Int-17)

[0315] 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.0 g, 4.2 mmol), (4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)boronic acid (1.2 g, 6.1 mmol), XPhos-Pd-G2 (330 mg, 0.42 mmol), XPhos (200 mg, 0.42 mmol), potassium phosphate (2.7 g, 12.7 mmol), dioxane (30 mL), and water (5 mL) were weighed sequentially. The mixture was reacted at 90 °C for 4 h, and LC-MS showed that the reaction was complete. The reaction solution was evaporated to dryness, and the residue was separated by column chromatography (SiO2, PE:EA = 3:1-1:1) to give 1.3 g of product, with a yield of 87.3%.

[0316] Preparation of 9,6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (Int-18)

[0317] 6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.2 g, 3.4 mmol) was dissolved in trifluoroacetic acid (20 mL) and reacted at 25 °C for 5 h. The reaction was completed by LC-MS. The reaction solution was evaporated to dryness, the residue was diluted with DCM, washed with saturated sodium bicarbonate solution, and the organic phase was evaporated to dryness. The residue was separated by column chromatography (SiO2, PE:EA = 3:1-1:1) to give 700 mg of product, with a yield of 76.4%.

[0318] Preparation of 10.8-((6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1H-pyrazol[3,4-d]pyrimidin-1-yl)methyl)-5-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Compound 3)

[0319] 6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (90 mg, 0.33 mmol), 8-(chloromethyl)-5-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (100 mg, 0.33 mmol), potassium carbonate (137 mg, 0.99 mmol), and DMF (5 mL) were weighed sequentially and reacted at 40 °C for 8 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with EA, and the organic phase was evaporated to dryness. The residue was subjected to prep-TLC (SiO2, PE:EA = 1:2, R... f =0.3) Separation yielded 70 mg of product, with a yield of 39.3%.

[0320] Molecular formula: C 27 H20 D3F3N8O molecular weight: 535.5 LC-MS (m / z): 536.3 (M+H) + )

[0321] 1 H-NMR(400MHz, CDCl3)δ:9.36(s,1H),8.70(s,1H),8.26(s,1H),8.05-8.02(m,1H),7.40-7.37( m,1H),7.35-7.31(m,2H),5.73(s,2H),4.41-4.35(m,1H),3.22-3.15(m,1H),2.95-2.88(m,1H) ,1.73-1.63(m,1H),1.55-1.52(m,3H),1.30-1.21(m,2H),0.97-0.87(m,2H). Preparation Example 4: Preparation of 8-(6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazol[3,4-d]pyrimidin-1-yl)methyl)-5-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Compound 4)

[0322]

[0323] 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (40 mg, 0.15 mmol), 8-(chloromethyl)-5-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (50 mg, 0.17 mmol), potassium carbonate (62 mg, 0.45 mmol), and DMF (5 mL) were weighed sequentially and reacted at 70 °C for 3 h. LC-MS showed that the reaction was complete. The reaction solution was filtered, evaporated to dryness, and the residue was separated by column chromatography (SiO2, PE:EA = 80:20-40:60) to obtain 30 mg of the target product, with a yield of 37.7%.

[0324] Molecular formula: C 27 H 23 F3N8O molecular weight: 532.5 LC-MS (m / z): 533.2 (M+H) + )

[0325] 1H-NMR(400MHz, CDCl3)δ:9.36(s,1H),8.70(s,1H),8.26(s,1H),8.05-8.02(m,1H),7.40-7.20(m,3H),5.73(s,2H),4.41-4.35(m,1 H),3.96(s,3H),3.22-3.15(m,1H),2.95-2.88(m,1H),1.73-1.63(m,1H),1.56-1.52(m,3H),1.32-1.21(m,2H),0.98-0.87(m,2H).

[0326] Preparation Example 5: Preparation of 8-((6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Compound 5)

[0327]

[0328] 1. Preparation of (3-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline-8-yl)methanol (Int-19)

[0329] Methyl 3-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline-8-carboxylic acid (45 mg, 0.15 mmol) was dissolved in THF (5 mL), and lithium aluminum hydride (20 mg, 58.2 mmol) was added. The reaction was carried out at 100 °C for 1 hour, cooled to 25 °C, and 3,3-dibromo-1,1,1-trifluoroprop-2-one (9.0 g, 0.53 mmol) was added. The reaction was carried out at 20 °C for 1 hour. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was collected, concentrated, and used directly in the next reaction.

[0330] Preparation of 2,8-(chloromethyl)-3-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Int-20)

[0331] The crude product from the previous step was dissolved in 2 mL of 1,2-dichloroethane, and thionyl chloride was added. The reaction was carried out at 50 °C for 1 hour. After the reaction was completed, the product was concentrated, the pH was adjusted to 7 with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was concentrated. The residue was subjected to column chromatography (EA:PE = 1:3) to give 30 mg of the target compound. The two-step yield was 68.9%.

[0332] Preparation of 3,8-((6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Compound 5)

[0333] 8-(chloromethyl)-3-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (20 mg, 0.070 mmol) was dissolved in DMF (5 mL), and 6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (22 mg, 0.081 mmol) and potassium carbonate (40 mg, 0.29 mmol) were added. After the addition was complete, the reaction was carried out at 50 °C for 5 hours. After washing with water, the mixture was extracted with EA, the organic phase was evaporated to dryness, and purified by silica gel column chromatography (PE:EA = 2:1) to obtain 18 mg of the target compound, with a yield of 49.5%.

[0334] Molecular formula: C 26 H 18 F3D 38 N8O molecular weight: 521.5 LC-MS (M / e): 522.2 (M+H) + )

[0335] 1 H-NMR (400MHz, DMSO) δ: 9.36 (s, 1H), 8.70 (s, 1H), 8.26 (s, 1H), 8.02-8.0 (d, J = 7.92, 1H), 7.41-7.40 (m, 1H), 7.43-7.40 (m, 1 H),7.28(s,1H),5.74(s,2H),4.24-4.20(m,2H),3.23-3.18(m,2H),1.81-1.67(m,1H),1.32-1.29(m,2H),0.91-0.94(m,2H).

[0336] Preparation Example 6: Preparation of 8-(6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Compound 9)

[0337]

[0338] Preparation of methyl 1,4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-bromobenzoate (Int-21)

[0339] Methyl 3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (1.0 g, 2.9 mmol) was dissolved in 30 mL of DMF, and 3-bromopropene (400 mg, 3.3 mmol) and cesium carbonate (1.9 g, 5.8 mmol) were added. The reaction was carried out at 30 °C for 1 h. After concentration, 850 mg of the target product was obtained, with a yield of 76.2%.

[0340] Preparation of methyl 2,6-methyl-2-(trifluoromethyl)imidazo[2,1-a]isoquinoline-8-carboxylic acid (Int-22)

[0341] Methyl 4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-bromobenzoate (700 mg, 1.8 mmol) was dissolved in 5 mL of DMF, and sodium acetate (350 mg, 4.3 mmol) and palladium dichloride bis(triphenylphosphine) (125 mg, 1.8 mmol) were added. The system was reacted in N2 at 110 °C for 2 h. After the reaction was completed, the product was concentrated and subjected to column chromatography (EA:PE = 15%) to obtain 380 mg of crude product.

[0342] Preparation of methyl 3,6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline-8-carboxylic acid (Int-23)

[0343] 270 mg of methyl 6-methyl-2-(trifluoromethyl)imidazo[2,1-a]isoquinoline-8-carboxylic acid was dissolved in 10 mL of methanol, and 270 mg of Pd / C was added. The mixture was reacted at 50 °C for 5 h. After the reaction was completed, the product was concentrated and subjected to column chromatography (EA:PE = 30%) to obtain 150 mg of the target product.

[0344] 4. Preparation of (6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline-8-yl)methanol (Int-24)

[0345] Methyl 6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline-8-carboxylic acid (140 mg, 0.45 mmol) was dissolved in 10 mL of THF, and LiAlH4 (30 mg, 0.79 mmol) was added. The reaction was carried out at 25 °C for 2.0 h. After the reaction was completed, the mixture was quenched with water and concentrated for use in the next step.

[0346] Preparation of 5,8-(chloromethyl)-6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Int-25)

[0347] The crude product from the previous step was dissolved in 10 mL of 1,2-dichloroethane, and 3 mL of thionyl chloride was added. The mixture was heated to 50 °C and reacted for 1 hour. After concentration, the pH was adjusted to 7 with saturated sodium bicarbonate solution. The product was extracted with ethyl acetate and separated. The organic phase was concentrated, and the residue was subjected to column chromatography (EA:PE = 40%) to obtain 100 mg of the target product. The yield of the two steps was 73.7%.

[0348] Preparation of 6,8-(6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Compound 8)

[0349] 8-(chloromethyl)-6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (40 mg, 0.13 mmol) was dissolved in 10 mL of DMF, and potassium carbonate (40 mg, 0.29 mmol) and 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (40 mg, 0.15 mmol) were added. The system was reacted at 60 °C for 5.0 h. After the reaction was completed, the product was concentrated and subjected to column chromatography (EA:PE = 70%) to obtain the crude target compound. Then, reversed-phase column chromatography (MeOH:H2O) was performed to obtain 20 mg of the target product, with a yield of 28.2%.

[0350] Molecular formula: C 27 H 23 F3N8O molecular weight: 532.5 LC-MS (M / e): 533.2 (M+H) + )

[0351] 1 H-NMR(400MHz,DMSO)δ:9.36(s,1H),8.71(s,1H),8.25(s,1H),8.08-8.01(m,1H),7.40-7.30(m,2H),7.28(s,1H)5.75(s,2H), 3.98(s,3H),3.97-3.90(m,1H)3.31-3.28(m,1H),2.09-1.98(m,1H),1.78-1.62(m,1H),1.39-1.22(m,4H),0.98-0.96(m,3H).

[0352] Preparation Example 7: Preparation of 9-(6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazol[1,2-a]azapyrrolidone (Compound 10)

[0353]

[0354] 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (50 mg, 0.19 mmol), 9-(chloromethyl)-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyridine (63 mg, 0.21 mmol), potassium carbonate (79 mg, 0.57 mmol), and DMF (5 mL) were weighed sequentially. The mixture was reacted at 50 °C for 6 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with EA, and the organic phase was evaporated to dryness. The residue was separated by column chromatography (SiO2, PE:EA = 0:1) to give 30 mg of product, with a yield of 26.8%.

[0355] Molecular formula: C 27 H 23 F3N8O molecular weight: 532.2 LC-MS (m / z): 533.2 (M+H) + )

[0356] 1 H-NMR (400MHz, DMSO-d6)δ:9.47(s,1H),8.69(s,1H),8.49(s,1H),7.93(s,1H),7.61(d,J=7.9Hz,1H),7.30(s,1H),7.23(d,J=7.9Hz,1H),5 .71(s,2H),4.12-3.98(m,2H),3.83(s,3H),2.78-2.59(m,2H),2.41- 2.19(m,2H),1.78-1.53(m,1H),1.29-1.01(m,2H),0.97-0.80(m,2H).

[0357] Preparation Example 8: Preparation of Compound 11 from 9-(6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyrrolidone

[0358]

[0359] 9-(chloromethyl)-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyridine (40 mg, 0.13 mmol) was dissolved in 10 mL of DMF, and potassium carbonate (40 mg, 0.29 mmol) and 6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (40 mg, 0.15 mmol) were added. The reaction was carried out at 60 °C for 5.0 h. After concentration and column chromatography (EA:PE = 70%), 55 mg of the target product was obtained, yield: 77.2%.

[0360] Molecular formula: C 27 H 20 D3F3N8O molecular weight: 535.5 LC-MS (M / e): 536.2 (M+H) + )

[0361] 1 H-NMR (400MHz, DMSO) δ: 9.50 (s, 1H), 8.71 (s, 1H), 8.51 (s, 1H), 7.96 (s, 1H), 7.64-7.62 (d, J = 7.9, 1H), 7.32-7.25 (m, 2H), 5. 73(s,2H),3.97-3.94(m,2H),2.64-2.62(m,2H),2.22-2.21(m,2H),2.09-1.98(m,1H),1.29-1.22(m,2H),0.98-0.96(m,2H).

[0362] Preparation Example 9: Preparation of 8-(6-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1H-pyrazol[3,4-d]pyrimidin-1-yl)methyl)-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Compound 12)

[0363]

[0364] Preparation of 1,6-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Int-27)

[0365] 6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.2 g, 5.0 mmol) was dissolved in dioxane (20 mL) and water (4 mL). 4-Cyclopropyl-6-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran-2-yl)pyrimidine (1.3 g, 5.7 mmol), tetraphenylphosphine palladium (600 mg, 0.51 mmol), and sodium carbonate (1.1 g, 10.4 mmol) were added. The system was reacted at 90 °C for 5 h under a nitrogen atmosphere. After the reaction was complete, the product was concentrated and subjected to column chromatography (EA:PE = 20%) to obtain 750 mg of the target product, with a yield of 38.4%.

[0366] Preparation of 2,6-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (Int-28)

[0367] 720 mg of 6-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine was dissolved in 20 mL of TFA and reacted at 25 °C for 3 h. The solution was concentrated, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. After concentration and column chromatography of the residue (EA:PE = 70%), 300 mg of the target product was obtained, with a yield of 53.2%. Preparation of 3,8-(6-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Compound 12)

[0368] 8-(chloromethyl)-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (100 mg, 0.35 mmol) was dissolved in 10 mL of DMF, and potassium carbonate (90 mg, 0.65 mmol) and 6-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (90 mg, 0.30 mmol) were added. The reaction mixture was reacted at 60 °C for 5.0 h. After the reaction was completed, the product was concentrated and subjected to column chromatography (EA:PE = 65%) to obtain 58 mg of the target product, yield: 35.4%.

[0369] Molecular formula: C 26 H 19 F5N8O molecular weight: 554.5 LC-MS (M / e): 555.2 (M+H) + )

[0370] 1H-NMR(400MHz,DMSO-d6)δ:9.36(s,1H),8.73(s,1H),8.27(s,1H),8.06-8.04(m,1H),7.80-7.40(m,2H),7.28-7.27 (m,2H),5.75(s,2H),4.20-4.16(m,2H),3.16-3.14(m,2H),1.90-1.89(m,1H),1.41-1.31(m,2H),1.01-1.00(m,2H).

[0371] Preparation Example 10: Preparation of 8-(6-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (Compound 13)

[0372]

[0373] 6-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (30 mg, 0.099 mmol), 8-(chloromethyl)-5-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (30 mg, 0.10 mmol), potassium carbonate (41 mg, 0.30 mmol), and DMF (5 mL) were weighed sequentially. The mixture was reacted at 50 °C for 3 h. The reaction was completed by LC-MS. The reaction solution was filtered, evaporated to dryness, and the residue was separated by column chromatography (SiO2, PE:EA = 80:20-40:60) to obtain 20 mg of the target product, with a yield of 35.3%.

[0374] Molecular formula: C 27 H 21 F5N8O molecular weight: 568.5 LC-MS (m / z): 569.2 (M+H) + )

[0375] 1 H-NMR(400MHz, CDCl3)δ:9.37(s,1H),8.73(s,1H),8.27(s,1H),8.05-8.02(m,1H),7.83-7.24(m,4H),5.73(s,2H),4.44-4. 35(m,1H),3.25-3.15(m,1H),2.95-2.85(m,1H),1.90-1.70(m,1H),1.56-1.52(m,3H),1.32-1.20(m,2H),0.99-0.87(m,2H).

[0376] Preparation Example 11: Preparation of 9-(6-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyrrolidone (Compound 14)

[0377]

[0378] Preparation of methyl 1,3-allyl-4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (Int-29)

[0379] Methyl 4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-bromobenzoate (1.1 g, 2.5 mmol) was dissolved in 1,4-dioxane (30 mL) and water (2 mL). Then, 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxoborane (450 mg, 2.7 mmol), tetrakis(triphenylphosphine)palladium (300 mg, 0.26 mmol), and sodium carbonate (600 mg, 5.7 mmol) were added. The system was reacted at 85 °C for 5 h under a nitrogen atmosphere. After the reaction was complete, the product was concentrated and subjected to column chromatography (EA:PE = 20%) to obtain 850 mg of the target product, with a yield of 84.7%.

[0380] Preparation of methyl 2,4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-(3-hydroxypropyl)benzoate (Int-30)

[0381] Methyl 3-allyl-4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (850 mg, 2.1 mmol) was dissolved in THF (20 mL), and 1 M BH3 / THF (6.5 mL) was added. The reaction was carried out at 30 °C for 5 h. After the reaction was completed, 5 mL of hydrogen peroxide was added, and the solution was concentrated and subjected to column chromatography (EA:PE = 50%) to obtain 600 mg of the target product, with a yield of 67.5%.

[0382] Preparation of methyl 3,3-(3-hydroxypropyl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (Int-31)

[0383] Methyl 4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-(3-hydroxypropyl)benzoate (550 mg) was dissolved in 10 mL of methanol, and Pt / C (550 mg) was added. The reaction was carried out in H2 at 30 °C for 2.0 h. After the reaction was completed, the mixture was filtered and concentrated to obtain 400 mg of the target product, with a yield of 92.7%.

[0384] Preparation of methyl 4,3-(3-((methanesulfonyl)oxy)propyl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (Int-32)

[0385] Methyl 3-(3-hydroxypropyl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (350 mg, 1.1 mmol) was dissolved in 10 mL of acetonitrile, and potassium carbonate (300 mg, 2.2 mmol) and MsCl (210 mg, 1.8 mmol) were added. The mixture was reacted at 30 °C for 2 h, then concentrated, and the crude product was used directly in the next step of the reaction.

[0386] Preparation of methyl 5,2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyro-9-carboxylic acid (Int-33)

[0387] Methyl 3-(3-((methanesulfonyl)oxy)propyl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (the crude product from the previous step) was dissolved in 15 mL of THF, and 60% NaH (70 mg, 1.8 mmol) was added. The system was reacted at 25 °C for 2.0 h. After the reaction was completed, the product was concentrated and subjected to column chromatography (EA:PE = 35%) to obtain 260 mg of the target product. The two-step yield was 78.6%.

[0388] 6. Preparation of (2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azaphene-9-yl)methanol (Int-34)

[0389] Methyl 2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyro-9-carboxylic acid (230 mg, 0.74 mmol) was dissolved in 20 mL of THF, and LiAlH4 (70 mg, 1.8 mmol) was added. The reaction was carried out at 25 °C for 2.0 h. After the reaction was completed, the mixture was quenched with water, concentrated, and used directly in the next reaction step.

[0390] Preparation of 7,9-(chloromethyl)-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyrrolidone (Int-26)

[0391] The crude product from the previous step was dissolved in 20 mL of 1,2-dichloroethane, and 3 mL of thionyl chloride was added. The mixture was then heated to 50 °C and reacted for 1 hour. After concentration, the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was concentrated. The residue was subjected to column chromatography (EA:PE = 25%) to obtain 150 mg of the target product. The two-step yield was 67.3%.

[0392] Preparation of 8.9-(6-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyrrolidone (Compound 14)

[0393] 9-(chloromethyl)-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyridine (20 mg, 0.067 mmol) was dissolved in 10 mL of DMF, and potassium carbonate (20 mg, 0.14 mmol) and 6-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (20 mg, 0.066 mmol) were added. The reaction was carried out at 60 °C for 5.0 h. The system was concentrated and subjected to column chromatography (EA:PE = 80%) to give 15 mg of the target product, yield: 40.1%.

[0394] Molecular formula: C 27 H 21 F5N8O molecular weight: 568.5 LC-MS (M / e): 569.2 (M+H) + )

[0395] 1 H-NMR(400MHz,DMSO)δ:9.55(s,1H),8.42(s,1H),8.55(s,1H),8.00-7.61(m,3H),7.30-7.28(m,2H),5.75(s,2H), 3.97-3.94(m,2H),2.64-2.62(m,2H),2.22-2.21(m,2H),2.09-1.98(m,1H),1.29-1.22(m,2H),0.98-0.96(m,2H).

[0396] Preparation Example 12: Preparation of 9-(6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolyl[3,4-d]pyrimidin-1-yl)methyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyrrolidone (Compound 16)

[0397]

[0398] Preparation of methyl 1,4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-bromobenzoate (Int-35)

[0399] 7.0 g (20.2 mmol) of methyl 3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate, 4.1 g (24.2 mmol) of benzyl bromide, and 13.2 g (40.4 mmol) of cesium carbonate were weighed and dissolved in DMF (50 mL). The mixture was reacted at 25 °C for 1 h. After the reaction was completed, the mixture was washed with water, extracted with ethyl acetate, and the organic phase was concentrated. The solution was then subjected to column chromatography (EA:PE = 1:1) to obtain 5.0 g of the target product, with a yield of 56.4%. 2. Preparation of methyl 4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-(3-hydroxybut-1-yn-1-yl)benzoate (Int-36)

[0400] Methyl 4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-bromobenzoate (2.0 g, 4.6 mmol), palladium dichloride bis(triphenylphosphine) (646 mg, 0.92 mmol), cuprous iodide (876 mg, 4.6 mmol), triethylamine (5 mL), and 3-butyn-2-ol (483 mg, 6.9 mmol) were added to 50 mL of dioxane and reacted at 100 °C under nitrogen for 12 h. After the reaction was completed, the product was concentrated and subjected to column chromatography (PE:EA = 1:1) to obtain 700 mg of the target product, with a yield of 35.5%.

[0401] Preparation of methyl 3,3-(3-hydroxybutyl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (Int-37)

[0402] Methyl 4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-(3-hydroxybut-1-yn-1-yl)benzoate (700 mg, 1.6 mmol) was dissolved in methanol (20 mL), and Pd / C (700 mg) was added. The reaction was carried out at 25 °C for 12 h. After filtration through diatomaceous earth, the product was concentrated and subjected to column chromatography (SiO2, PE:EA = 1:1) to obtain 200 mg of the target product, with a yield of 36.5%.

[0403] Preparation of methyl 4,3-(3-(methylsulfonyl)oxy)butyl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (Int-38)

[0404] Cesium carbonate (567 mg, 1.7 mmol) and methanesulfonyl chloride (100 mg, 0.87 mmol) were added to a tetrahydrofuran (20 mL) solution of methyl 3-(3-hydroxybutyl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (200 mg, 0.58 mmol). The reaction was carried out at 25 °C for 2 h. LC-MS showed that the reaction was complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was collected and evaporated to dryness to obtain 300 mg of crude product, which was directly used in the next step of the reaction.

[0405] Preparation of methyl 5,5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazole[1,2-a]azapyro-9-carboxylic acid (Int-39)

[0406] Sodium hydride (192 mg) was added to a solution of methyl 3-(3-(methylsulfonyl)oxy)butyl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (300 mg, crude) in tetrahydrofuran (20 mL), and the reaction was carried out at 70 °C for 1 h. The reaction mixture was evaporated to dryness and subjected to column chromatography (SiO2, PE:EA = 3:1) to give 100 mg of the target product, with a two-step yield of 53.2%.

[0407] 6. Preparation of (5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azaphen-9-yl)methanol (Int-40)

[0408] 100 mg (0.29 mol) of methyl 5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazole[1,2-a]azapyro-9-carboxylic acid ester was dissolved in 10 mL of THF, and LiAlH4 (33 mg, 0.87 mmol) was added. The reaction was carried out at 25 °C for 30 min. LC-MS showed that the reaction was complete. The reaction solution was quenched with water, evaporated to dryness, and used directly for the next step of the reaction.

[0409] Preparation of 7,9-(chloromethyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyrrolidone (Int-41)

[0410] The crude product from the previous step was dissolved in 5 mL of DCE, and 2 mL of thionyl chloride was added. The reaction was carried out at 50 °C for 1 hour. After concentration, the system was subjected to column chromatography (EA:PE = 4:3) to obtain 66 mg of the target product, with a two-step yield of 72.5%.

[0411] Preparation of 8,9-(6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolyl[3,4-d]pyrimidin-1-yl)methyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyrrolidone (Compound 16)

[0412] 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (35 mg, 0.13 mmol), 9-(chloromethyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]aza-heterocyclic (44 mg, 0.14 mmol), and potassium carbonate (54 mg, 0.39 mmol) were weighed sequentially and added to DMF (5 mL). The reaction was carried out at 50 °C for 6 h, and LC-MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with EA, and the organic phase was evaporated to dryness. The residue was separated by column chromatography (SiO2, PE:EA = 0:1) to give 35 mg of product, with a yield of 49.2%.

[0413] Molecular formula: C 28 H 25 F3N8O molecular weight: 546.2 LC-MS (m / z): 547.2 (M+H) + )

[0414] 1 H-NMR(400MHz,DMSO-d6)δ:9.51(s,1H),8.71(s,1H),8.52(s,1H),7.96(s,1H),7.62 (d,J=7.9Hz,1H),7.32(s,1H),7.25(d,J=7.9Hz,1H),5.74(s,2H),4.12-3.98(m,1H) ,3.86(s,3H),2.86-2.67(m,1H),2.52-2.41(m,1H),2.38-2.28(m,1H),2.09-1.95(m ,1H),1.78-1.53(m,1H),1.44(d,J=6.6Hz,3H),1.29-1.01(m,2H),0.97-0.80(m,2H).

[0415] Preparation Example 13: Preparation of (R)-9-(6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolyl[3,4-d]pyrimidin-1-yl)methyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyrrolidone (Compound 16-1)

[0416] Preparation of (S)-9-(6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolyl[3,4-d]pyrimidin-1-yl)methyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyrrolidone (Compound 16-2)

[0417] Compounds 16-1 and 16-2 were prepared by using (S)-3-butyn-2-ol and (R)-3-butyn-2-ol as raw materials, respectively, in the same or similar manner as in Preparation Example 13.

[0418]

[0419] Preparation Example 14: Preparation of 9-(6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyrrolidone (Compound 17)

[0420]

[0421] 6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (50 mg, 0.18 mmol), 9-(chloromethyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyridine (63 mg, 0.20 mmol), and potassium carbonate (75 mg, 0.54 mmol) were weighed sequentially and added to DMF (5 mL). The reaction was carried out at 50 °C for 6 h, and LC-MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with EA, and the organic phase was evaporated to dryness. The residue was separated by column chromatography (SiO2, PE:EA = 0:1) to obtain 40 mg of the target product, with a yield of 40.5%.

[0422] Molecular formula: C 28 H 22 D3F3N8O molecular weight: 549.2 LC-MS (m / z): 550.2 (M+H) + )

[0423] 1 H-NMR(400MHz,DMSO-d6)δ:9.53(s,1H),8.73(s,1H),8.54(s,1H),7.94(s,1H),7 .61(d,J=7.9Hz,1H),7.30(s,1H),7.25(d,J=7.9Hz,1H),5.73(s,2H),4.12-3.98( m,1H),2.86-2.67(m,1H),2.52-2.41(m,1H),2.38-2.28(m,1H),2.09-1.95(m,1H ),1.78-1.53(m,1H),1.44(d,J=6.6Hz,3H),1.29-1.01(m,2H),0.97-0.80(m,2H).

[0424] Preparation Example 15: Preparation of 9-(6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazaprodone (Compound 18)

[0425]

[0426] Preparation of methyl 1,3-fluoro-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (Int-42)

[0427] Sodium acetate (1.4 g, 16.5 mmol) was added to a water (10 mL) solution of 3,3-dibromo-1,1,1-trifluoropropane-2-one (2.2 g, 8.3 mmol), and the reaction was carried out at 100 °C for 1 h. The temperature was then lowered to 0 °C, and methanol (20 mL), methyl 3-fluoro-4-carboxybenzoate (1.0 g, 5.5 mmol), and ammonia (10 mL) were added to the reaction solution. The reaction was carried out at 25 °C for 1 h, and then at 100 °C for 3 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with EA, and the organic phase was evaporated to dryness. The residue was separated by column chromatography (SiO2, PE:EA = 85:15) to give 821 mg of product, with a yield of 51.8%.

[0428] Preparation of methyl 2,4-(1-(2-(tert-butyldimethylsilyl)oxy)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (Int-43)

[0429] 3-fluoro-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (800 mg, 2.8 mmol), (2-bromoethoxy)tert-butyldimethylsilane (1.0 g, 4.2 mmol), and cesium carbonate (2.7 g, 8.4 mmol) were weighed and dissolved in DMF (15 mL). The mixture was reacted at 50 °C for 6 h. After the reaction was completed, the organic phase was washed with water, extracted with ethyl acetate, concentrated, and subjected to column chromatography (SiO2, EA:PE = 1:10) to obtain 560 mg of the target product, with a yield of 50.0%.

[0430] Preparation of methyl 3,4-(1-(2-hydroxyethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (Int-44)

[0431] Methyl 4-(1-(2-(tert-butyldimethylsilyl)oxy)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (560 mg, 1.4 mmol) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (4.2 mL, 4.2 mmol) was added. The reaction was carried out at 25 °C for 30 min. After concentration and column chromatography (SiO2, PE:EA = 1:1), 270 mg of the target product was obtained, with a yield of 58.1%.

[0432] Preparation of methyl 4,2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazapyro-9-carboxylic acid (Int-45)

[0433] Methyl 4-(1-(2-hydroxyethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (270 mg) was dissolved in DMF (20 mL), and cesium carbonate (782 mg, 2.4 mmol) was added. The reaction was carried out at 50 °C for 3 h, and LC-MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with EA, the organic phase was evaporated to dryness, and column chromatography (SiO2, PE:EA = 3:1) was performed to give 140 mg of the target product, with a yield of 55.4%.

[0434] 5. Preparation of (2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazon-9-yl)methanol (Int-46)

[0435] 140 mg (0.45 mmol) of methyl 2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazole[1,2-d][1,4]oxazapyrrolidone-9-carboxylic acid was dissolved in 10 mL of THF, and LiAlH4 (53 mg, 1.4 mmol) was added. The reaction was carried out at 25 °C for 15 min, and LC-MS showed that the reaction was complete. The reaction solution was quenched with water, evaporated to dryness, and used directly for the next reaction.

[0436] Preparation of 6,9-(chloromethyl)-2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazazole (Int-47)

[0437] The crude product from the previous step was dissolved in 5 mL of DCE, and 2 mL of thionyl chloride was added. The reaction was carried out at 50 °C for 1 hour. After concentration, the product was obtained by column chromatography (SiO2, EA:PE = 1:1) to yield 66 mg of the target product.

[0438] Preparation of 7,9-(6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazazepine (Compound 18)

[0439] 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine (54 mg, 0.20 mmol), 9-(chloromethyl)-2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazapyrrolizidine (66 mg, 0.22 mmol), potassium carbonate (83 mg, 0.60 mmol), and DMF (10 mL) were weighed sequentially and reacted at 50 °C for 12 h. The reaction was completed by LC-MS. The reaction solution was diluted with water, extracted with EA, and the organic phase was evaporated to dryness. The residue was separated by column chromatography (SiO2, PE:EA = 0:1) to obtain 43 mg of the target product, with a yield of 40.2%.

[0440] Molecular formula: C 26 H 21 F3N8O2 molecular weight: 534.2 LC-MS (m / z): 535.2 (M+H) + )

[0441] 1 H-NMR (400MHz, DMSO-d6)δ:9.51(s,1H),8.72(s,1H),8.51(s,1H),8.28(d,J=8.3Hz,1H),7.96(s,1H),7.07(d,J=8.4 Hz,1H),6.93(s,1H),5.70(s,2H),4.44(s,4H),3.86(s,3H),1.73-1.63(m,1H),1.30-1.21(m,2H),0.97-0.87(m,2H).

[0442] Preparation Example 16: Preparation of 9-(6-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyrrolidone (Compound 19)

[0443]

[0444] Preparation of 1,9-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyrrolidone (Int-48)

[0445] 6-Chloro-1H-pyrazolo[3,4-d]pyrimidine (86 mg, 0.56 mmol), 9-(chloromethyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyridine (150 mg, 0.48 mmol), and potassium carbonate (193 mg, 1.4 mmol) were weighed sequentially and added to DMF (10 mL). The reaction was carried out at 50 °C for 6 h, and LC-MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with EA, and the organic phase was evaporated to dryness. The residue was separated by column chromatography (SiO2, PE:EA = 0:1) to obtain 75 mg of the target product, with a yield of 36.2%. Preparation of 2,9-(6-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyrrolidone

[0446] To a solution of 9-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapyridine (75 mg, 0.17 mmol) in 1,4-dioxane (10 mL), 4-cyclopropyl-6-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran-2-yl)pyrimidine (93 mg, 0.30 mmol), XPhosPdG2 (20 mg, 0.025 mmol), XPhos (12 mg, 0.025 mmol), potassium phosphate (159 mg, 0.75 mmol), and water (2 mL) were added. The reaction was carried out at 100 °C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS until it ended. The reaction solution was evaporated to dryness and separated by column chromatography (SiO2, PE:EA = 0:1) to obtain 30 mg of the target product, with a yield of 30.3%.

[0447] Molecular formula: C 28 H 23 F5N8O molecular weight: 582.2 LC-MS (m / z): 583.2 (M+H) + )

[0448] 1H-NMR(400MHz,DMSO-d6)δ:9.55(s,1H),8.84(s,1H),8.54(s,1H),7.93(s,1H),7.8 1(t,J=71.6Hz,1H),7.62(d,J=7.9Hz,1H),7.35-7.25(m,2H),5.74(s,2H),4.12-3. 98(m,1H),2.86-2.67(m,1H),2.52-2.41(m,1H),2.38-2.28(m,1H),2.09-1.95(m,1 H),1.78-1.53(m,1H),1.44(d,J=6.6Hz,3H),1.29-1.01(m,2H),0.97-0.80(m,2H).

[0449] The compounds shown in the following table were prepared using the same or similar methods as those used in the preparation examples above:

[0450]

[0451] 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, ring A is selected from pyrimidinyl optionally substituted with 1-3 Q1; ring B is selected from imidazolyl optionally substituted with 1-3 Q2; m is 1, 2, 3; n is 1; each t is independently selected from 0, 1, or 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, ring A is selected from pyrimidinyl optionally substituted with 1-3 Q1; ring B is selected from imidazolyl optionally substituted with 1-3 Q2; m is 1, 2, 3; n is 1; each t is independently selected from 0, 1, or 2. X 3 , X 4 , X 5 are each independently selected from CR a ; X 6 selected from C; X 7 selected from N; 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein, ring A is selected from pyrimidinyl optionally substituted with 1-3 Q1; ring B is selected from imidazolyl optionally substituted with 1-3 Q2; m is 1, 2, or 3; each t is independently selected from 0 or 1.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, ring A is selected from pyrimidinyl optionally substituted with 1-3 Q1; ring B is selected from imidazolyl optionally substituted with 1-3 Q2; m is 1, 2, or 3; n is 1; each t is independently selected from 0 or 1. 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, 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; each L is independently selected from -CR a R b -; Each Y is independently selected from -CR a R b -、-NR c -or -O-; Each Q1 and each Q2 is independently selected from deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and 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, 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 group, -(CH2) t -3-6 membered cycloalkyl; each R a , each R b is independently selected from the group consisting of 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; each R is independently selected from the group consisting of deuterium, hydrogen, C c is independently selected from the group consisting of deuterium, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, 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; 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein, ring A is selected from pyrimidinyl optionally substituted with 1-3 Q1; ring B is selected from imidazolyl optionally substituted with 1-3 Q2; m is 1, 2, or 3; n is 1; each t is independently selected from 0 or 1.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II-1), wherein, ring A is selected from pyrimidinyl optionally substituted with 1-3 Q1; ring B is selected from imidazolyl optionally substituted with 1-3 Q2; m is 1, 2, or 3; n is 1; each t is independently selected from 0 or 1; s is selected from 1, 2, or 3.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II-3), wherein, ring A is selected from pyrimidinyl optionally substituted with 1-3 Q1; ring B is selected from imidazolyl optionally substituted with 1-3 Q2; m is 1, 2, or 3; n is 1; each t is independently selected from 0 or 1; s, q are independently selected from 1, 2, or 3. is a single bond.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II-3), wherein, ring A is selected from pyrimidinyl optionally substituted with 1-3 Q1; ring B is selected from imidazolyl optionally substituted with 1-3 Q2; m is 1, 2, or 3; n is 1; each t is independently selected from 0 or 1; s, q are independently selected from 1, 2, or 3. X 3 , X 4 , X 5 are each independently selected from CR a ; X 6 selected from C; X 7 selected from N; 9. A pharmaceutical preparation comprising a compound of any one of claims 1-8, 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.

10. A pharmaceutical composition comprising a compound of any one of claims 1-8, 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. 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, 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; each L is independently selected from -CR a R b -; each Y is independently selected from -CR a R b -, -NR c -, -O-; Each Q1 and each Q2 is independently selected from deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and optionally deuterated C. 1-4 Alkyl, C 1-4 Alkoxy, 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, carboxyl C 1-4 Alkyl, C 1-4 alkyl carbonyl, C 1-4 Alkoxycarbonyl group, -(CH2) t -3-6 membered cycloalkyl; 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, 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; each R is independently selected from the group consisting of deuterium, hydrogen, C1-6alkyl, c are each independently selected from the group consisting of deuterium, hydrogen, C1-6alkyl, 1-4 alkyl, C1-6alkoxy, halo, 1-4 alkyl, C1-6alkoxy, halo, 1-4 alkyl, C1-6alkoxy, halo, 1-4 alkyl, C1-6alkoxy, halo, The USP1-mediated disease and related diseases are selected from cancer or benign tumor. ​ ​ is a single bond. ​ X 3 , X 4 , X 5 are each independently selected from CR a ; X 6 selected from C; X 7 selected from N; ​ ​ 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, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy, optionally substituted with deuterium; each L is independently selected from -CR a R b -; each Y is independently selected from -CR a R b -, -NR c - or -O-; each Q1and each Q2are each independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, -(CH2) t - cyclopropyl, -(CH2) t - cyclobutyl, -(CH2) t - cyclopentyl, -(CH2) t - cyclohexyl; each R a , each R b is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy, optionally substituted with deuterium; Each R c Each of the following is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy; ​ ​ is a single bond. ​ R 1 , R 2 are each independently selected from deuterium, hydrogen, halogen, C 1-4 alkyl optionally substituted with deuterium, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, carboxy C 1-4 alkyl, or halogenated C 1-4 alkoxy; Ring A, Ring B, X 3 , X 4 , X 5 , X 6 , X 7 , L, Y, Q1, Q2, m, n, R a , R b , R c , t, as defined in claim 1. ​ 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, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy, optionally substituted with deuterium. ​ wherein X 3 , X 4 , X 5 are each independently selected from CR a ; X 6 selected from C; X 7 selected from N; ​ ​ each L is independently selected from -CR a R b -; each Y is independently selected from -CR a R b -, -NR c - or -O-; each Q1and each Q2are each independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, -(CH2) t - cyclopropyl, -(CH2) t - cyclobutyl, -(CH2) t - cyclopentyl or -(CH2) t - cyclohexyl; each R a , each R b is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy, optionally substituted with deuterium; Each R c The compounds are independently selected from deuterium, hydrogen, and optionally deuterated methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy. ​ ​ ​ is a single bond. ​ wherein (L) n selected from -CR a R b -; (Y) m selected from -CR a R b -CR a R b -, -CR a R b -CR a R b -CR a R b -, -NR c -CR a R b -CR a R b -, -CR a R b -CR a R b -NR c -, -O-CR a R b -CR a R b -, -CR a R b -O-CR a R b -, -CR a R b -NR c -CR a R b -, or -CR a R b -CR a R b -O-; ​ X 3 , X 4 , X 5 , Q1, Q2, R a , R b , R c are as defined in claim 1. ​ ​ ​ ​ 11. Use of a compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof or a pharmaceutical preparation of claim 9 or a pharmaceutical composition of claim 10 for the manufacture of a medicament for the treatment and / or prevention of a USP1 mediated disease and related diseases; wherein, ​

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