Tricyclic usp1 inhibitors and uses thereof

Abstract

The present application relates to the technical field of medicine, and particularly relates to a tricyclic USP1 inhibitor compound, a pharmaceutically acceptable salt, an ester, a deuterium or a stereoisomer thereof, a pharmaceutical composition and preparation containing the compound, the pharmaceutically acceptable salt, the ester, the deuterium or the stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt, the ester, the deuterium or the stereoisomer thereof, and an application of the compound, the pharmaceutically acceptable salt, the ester, the deuterium or the stereoisomer thereof in preparing a medicine for treating and / or preventing a disease mediated by USP1 and related diseases.

Description

Technical Field

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

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

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

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

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

[0006] USP1 inhibitors suppress DNA breakage repair involving PCNA, USP1 / UAF1, and BRCA1 / 2, destabilizing replication forks. Therefore, USP1 inhibitors can have synthetic lethal effects on BRCA1 / 2 mutant (or HRD-positive) cells. Thus, using small molecule inhibitors to suppress USP1 has the potential for treating cancer and other diseases, but it is not yet commercially available or in clinical development. Summary of the Invention

[0007] The purpose of this invention is to provide a tricyclic USP1 inhibitor and its application. The specific technical solution is as follows:

[0008] Option 1: This invention first provides compounds of general formula (I), their pharmaceutically acceptable salts, esters, deuterated derivatives, or stereoisomers thereof:

[0009]

[0010] in,

[0011] Ring A and ring B are independently selected from 5-8 membered heterocyclic groups, 5-8 membered cycloalkyl groups, phenyl groups or 5-8 membered heteroaryl groups that are optionally substituted with one or more Q1 groups;

[0012] R 1 R 2 R 3 Each is independently selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl or 5-12 membered heteroaryl, which are optionally substituted with one or more Q2 groups;

[0013] R 4 Selected from deuterium, hydrogen, carboxyl, cyano, nitro, amino, halogen, C 2-6 alkenyl, C 2-6 The alkynyl group, with the C group optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0014] Each Q1 and each Q2 are independently selected from deuterium, halogen, cyano, carboxyl, hydroxyl, amino, carboxyl, nitro, sulfonamide, and optionally substituted with 1 to 4 substituents Q3. m -C 1-6 Alkyl group, -(L) m -C 2-6 Alkenyl, -(L) m -C 2-6 Alkyne group, -(L) m -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, C 1-6 Alkylaminoyl, C 1-6 Alkyl amide, C 1-6 alkylsulfonyl, C 1-6 Alkylsulfonamide, C 1-6 Alkylaminosulfonyl, -(L) m-6-10 aryl, -(L) m -5-12-membered heteroaryl, -(L) m -3-8 membered cycloalkyl or -(L) m -3-8 membered heterocyclic groups, each Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, -CO-C 1-6 Alkyl-NH2, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0015] Each L is independently selected from -CO-, -O-, -S-, -SO-, -S(O)2-, -NR c -、-CR a R b -;

[0016] Each R a Each R b The C groups are independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, and cyano groups, with the C group optionally deuterated. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Alkylaminoyl, C 1-6 Alkyl amide, C 1-6 Alkylsulfonamide, C 1-6 Alkylaminosulfonyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl or carboxyl C 1-6 alkyl;

[0017] Each R c The C atoms are independently selected from deuterium and hydrogen, respectively, and are optionally deuterated. 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl;

[0018] R 2 Connect L to ring A or ring B;

[0019] Each m and each n are independent integers from 0 to 6.

[0020] Option 1-1: The compound described in Option 1 above, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, wherein,

[0021] R 1 R 2 R 3 Each is independently selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl groups, each optionally substituted with one or more Q2 groups.

[0022] Option 1-2: The compound described in Option 1 above, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, wherein,

[0023] R 1 R 2 R 3 Each is independently selected from 3-10 heterocyclic groups, 6-10 aryl groups, or 5-10 heteroaryl groups that are substituted with 1-4 Q2 groups.

[0024] Schemes 1-3: The compounds described in Scheme 1 above, their pharmaceutically acceptable salts, esters, deuterated derivatives, or stereoisomers thereof, wherein,

[0025] R 1 R 2 R 3 Each is independently selected from 6-10 aryl or 5-10 heteroaryl groups that are substituted with 1-4 Q2 groups.

[0026] Schemes 1-4: The compounds described in Scheme 1 above, their pharmaceutically acceptable salts, esters, deuterated derivatives, or stereoisomers thereof, wherein,

[0027] R 1 R 2 R 3 Each is independently selected from 6-10 aryl groups or 5-10 nitrogen-containing heteroaryl groups that are substituted with 1-3 Q2 groups.

[0028] Option 2: The compound described in any one of Options 1 to 1-3 above, its pharmaceutically acceptable salt, ester, deuterated product, or stereoisomer thereof, wherein,

[0029] Ring A and ring B are each independently selected from 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups that are optionally substituted with one or more Q1 groups;

[0030] R 1R 2 R 3 Each is independently selected from 5-8 membered cycloalkyl, 3-8 membered heterocyclic, phenyl or 5-6 membered heteroaryl groups that are optionally substituted with one or more Q2 groups;

[0031] R 4 Selected from deuterium, hydrogen, cyano, halogen, 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, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0032] Each Q1 and each Q2 are independently selected from deuterium, halogen, cyano, and -(L) groups optionally substituted with 1 to 4 substituents Q3. m -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 group, -(L) m -3-6 membered cycloalkyl or -(L) m -3-6 membered heterocyclic groups, each Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0033] Each L is independently selected from -CO-, -O-, and -NR. c -、-CR a R b -;

[0034] Each R a Each R b The C atoms are independently selected from deuterium, hydrogen, and halogen, and are optionally deuterated. 1-6 Alkyl, C 1-6Alkoxy, 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;

[0035] Each R c The C atoms are independently selected from deuterium and hydrogen, respectively, and are optionally deuterated. 1-6 Alkyl, Halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0036] Each m and each n are independent integers from 0 to 5.

[0037] Option 3: The compound described in any one of Options 1 to 2 above, its pharmaceutically acceptable salt, ester, deuterated product, or stereoisomer thereof, wherein,

[0038] Ring A and ring B are independently selected from 5-membered nitrogen-containing heterocyclic groups or 5-membered nitrogen-containing heteroaryl groups that are substituted by 1 to 4 Q1 groups;

[0039] R 1 R 2 R 3 Each is independently selected from phenyl groups that are substituted with 1-4 Q2 groups or 5-6 membered heteroaryl groups;

[0040] R 4 Selected from deuterium, hydrogen, and C atoms 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;

[0041] Each Q1 and each Q2 are independently selected from deuterium, halogens, and -(L) elements optionally substituted with 1-3 substituents Q3. m -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 1-4Alkyl, carboxyl C 1-4 Alkyl group, -(L) m -3-6 membered cycloalkyl groups, each Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, hydroxyl C 1-4 Alkyl, carboxyl C 1-4 Alkyl, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, C 1-4 Alkoxy, halogenated C 1-4 Alkyl and Halogenated C 1-4 Alkoxy;

[0042] Each L is independently selected from -CR a R b -or -O-;

[0043] 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 or carboxyl C 1-4 alkyl;

[0044] Each R c The C atoms are independently selected from deuterium and hydrogen, respectively, and are optionally deuterated. 1-4 Alkyl, Halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy;

[0045] Each m and each n are independent integers from 0 to 4.

[0046] Option 4: The compound described in any one of Options 1-3 above, its pharmaceutically acceptable salt, ester, deuterated product, or stereoisomer thereof, wherein,

[0047] Ring A and ring B are independently selected from 5-membered nitrogen-containing heterocyclic groups or 5-membered nitrogen-containing heteroaryl groups that are substituted with 1-3 Q1 groups;

[0048] R 1 R 2 R 3The phenyl, furanyl, thiophene, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, 2-pyridonel, 4-pyridonel, pyrimidinyl, pyridazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, imidazo[1,2-c]pyrimidine, imidazo[1,5-c]pyrimidine, and pyrrolo[3,4-c]pyrimidine are selected independently from those substituted with 1 to 3 Q2 groups.

[0049] R 4 Selected from deuterium, hydrogen, trifluoromethyl, trifluoromethoxy, and optionally deuterated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, or difluoromethoxy;

[0050] Each Q1 and each Q2 are independently selected from deuterium, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, and optionally substituted with 1-3 substituents Q3. m -C 1-4 Alkyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, monofluoromethoxy, difluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, -(L) m -3-6-membered cycloalkyl, each Q3 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, cyano, nitro, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl, carboxyethyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

[0051] Each L is independently selected from -CR a R b -;

[0052] Each R a Each R b The compounds are independently selected from deuterium, hydrogen, halogen, and optionally deuterated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, and isopropoxy.

[0053] Each m and each n are independently 0, 1, 2, and 3, respectively.

[0054] Option 5: The compound described in any one of Options 1-4 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein ring A and ring B are independently selected from 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups optionally substituted with 1-4 Q1 groups.

[0055] Scheme 5-1: The compound described in any one of Schemes 1-4 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein ring A and ring B are independently selected from 5-membered heterocyclic groups or 5-membered heteroaryl groups optionally substituted with 1-3 Q1 groups.

[0056] Option 6: The compound described in any one of Options 1 to 5-1 above, its pharmaceutically acceptable salt, ester, deuterated product, or stereoisomer thereof, wherein,

[0057] Ring A and ring B are independently selected from 5-6 member nitrogen-containing heterocyclic groups or 5-6 member nitrogen-containing heteroaryl groups that are substituted with 1-3 Q1 groups.

[0058] Option 6-1: The compound described in any one of Options 1 to 6 above, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, wherein,

[0059] Ring A and ring B are independently selected from 5-membered nitrogen-containing heterocyclic groups or 5-membered nitrogen-containing heteroaryl groups that are substituted with 1 to 3 Q1 groups.

[0060] Option 7: The compound described in any one of Options 1 to 6-1 above, its pharmaceutically acceptable salt, ester, deuterated product, or stereoisomer thereof, wherein,

[0061] Ring A is selected from pyrrole, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, dihydropyrrole, dihydroimidazolyl, dihydropyrazolyl, dihydrotriazolyl, pyrrolidinyl, imidazolyl, and pyrazolylalkyl.

[0062] Ring B is selected from pyrrole, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazole, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, dihydropyrrole, dihydrothiazolyl, dihydroisothiazolyl, dihydrothiadiazolyl, dihydrooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrotriazolyl, pyrroleyl, imidazolyl, and pyrazolylalkyl.

[0063] Option 8: The compound described in any one of Options 1-7 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0064] Cycle B is selected from pyrrole, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, dihydropyrrole, dihydroimidazolyl, dihydropyrazolyl, dihydrothiazolyl, and dihydroisothiazolyl, which are substituted by 1 to 3 Q1 groups.

[0065] Option 9: The compound described in any one of Options 1-8 above, its pharmaceutically acceptable salt, ester, deuterated product, or stereoisomer thereof.

[0066] The tricyclic ring formed by ring B, ring A, and the pyrimidine ring has the following structure:

[0067]

[0068] Each R 1 Each R 4 Each R c The definition is as described in any of the aforementioned technical solutions.

[0069] Scheme 9-1: The compound described in any one of Schemes 1-8 above, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, wherein,

[0070] The tricyclic ring formed by ring B, ring A, and the pyrimidine ring has the following structure:

[0071]

[0072] Each R 1 Each R 4 The definition is as described in any of the aforementioned technical solutions.

[0073] Option 10: The compound described in any one of Options 1 to 9-1 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein R 1 R 2 R 3 Each is independently selected from phenyl groups substituted with 1-4 Q2 groups or 5-6 nitrogen-containing heteroaryl groups.

[0074] Option 11: The compound described in any one of Options 1-10 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0075] R 1 R 2 R 3 The groups are independently selected from phenyl, furanyl, thiophene, pyrrole, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyraz ...yl, pyrazinylyl, pyrazinylyl, pyrazinylyl, pyrazinylyl, pyrazinylylyl, pyrazinylylyl, pyrazinylylylyl, pyrazinylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylyl

[0076] Option 12: The compound described in any one of Options 1-11 above, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, wherein,

[0077] R 1 R 2 R 3 The groups are independently selected from phenyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazole, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl groups, each of which is substituted with 1 to 3 Q2 groups.

[0078] Scheme 12-1: The compound described in any one of Schemes 1 to 12 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0079] R 1 R 3 Each is independently selected from those that can be replaced by 1-3 Q2s.

[0080] Scheme 12-2: The compound described in any one of Schemes 1 to 12-1 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0081] R 1 Selected from those that can be replaced by 1-3 Q2s. Preferably, R 1 Selected from those that can be replaced by 1-3 Q2s.

[0082] Scheme 12-3: The compound described in any one of Schemes 1 to 12-2 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0083] R 3 Selected from those that can be replaced by 1-3 Q2s. Preferably, R 3 Selected from those that can be replaced by 1-3 Q2s. Preferably, R 3 Selected from those that can be replaced by 1-3 Q2s.

[0084] Scheme 13: The compound described in any one of Schemes 1 to 12-3 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, having the structure shown in Formula (II),

[0085]

[0086] X1 and X2 are independently selected from C, N, and CR, respectively. a ;

[0087] X3, X4, and X5 are independently selected from N, S, and CR, respectively. a CR a R b NR c ;

[0088] X6 and X7 are each independently selected from CR a Or N;

[0089] s is an integer selected from 0 to 4;

[0090] The connection methods of X1 and X2, X2 and X3, X3 and X4, X4 and X5, and X1 and X5 are each independently selected from single bonds or double bonds; and among the bonds formed between X1, X2, X3, X4, and X5, no two adjacent bonds can be double bonds at the same time.

[0091] Each L, each R a Each R b Each R c R 1 R 3 R 4 The definitions of each Q2, each Q3, each m, and n are as described in any of the aforementioned technical solutions.

[0092] Scheme 14: The compound described in any one of Schemes 1 to 13 above, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in general formula (III):

[0093]

[0094] Each s is independently selected from integers between 0 and 3;

[0095] X2, X3, X4, X5, each L, each R a Each R b Each R c R 3 R 4 The definitions of each Q2, each Q3, each m, and n are as described in any of the aforementioned technical solutions.

[0096] Scheme 14-1: The compound described in any one of Schemes 1 to 14 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, having the structure shown in general formula (III'):

[0097]

[0098] Among them, R 5 Selected from C that has been replaced by deuterium 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0099] Each s is an independent integer between 0 and 2;

[0100] X2, X3, X4, X5, each L, each R a Each R b Each R c R 3 R 4 The definitions of each Q2, each Q3, each m, and n are as described in any of the aforementioned technical solutions.

[0101] Scheme 14-2: The compound described in Scheme 14-1 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein R 5 Selected from deuterated C 1-6 Alkyl or deuterated C 1-6 Alkyl group.

[0102] Scheme 15: The compound described in any one of Schemes 1 to 14-2 above, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in Formula (IV),

[0103]

[0104] X3 and X4 are independently selected from N or CR. a ;

[0105] X8 and X9 are independently selected from C, N, or CR, respectively. a ;

[0106] s is an integer selected from 0 to 4;

[0107] Each L, each R a Each R b Each R c R 3 R 4 The definitions of each Q2, each Q3, each m, and n are as described in any of the aforementioned technical solutions.

[0108] Scheme 15-1: The compound described in any one of Schemes 1 to 15 above, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in Formula (IV-1),

[0109]

[0110] Among them, R 5 Selected from C that has been replaced by deuterium 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0111] s is an integer selected from 0 to 4;

[0112] X3, X4, X8, X9, each L, each R a Each R b Each R c R 3 R 4 The definitions of each Q2, each Q3, each m, and n are as described in any of the aforementioned technical solutions.

[0113] Scheme 15-2: The compound described in Scheme 15-1 above, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, wherein R 5 Selected from deuterated C 1-6 Alkyl or deuterated C 1-6 Alkyl group.

[0114] Scheme 15-3: The compounds described in Scheme 15-1 or 15-2 above, their pharmaceutically acceptable salts, esters, deuterated derivatives or their stereoisomers,

[0115] Among them, X3 and X4 are independently selected from N or CH;

[0116] X8 and X9 are independently selected from N, C, or CH, respectively.

[0117] Scheme 16: The compound described in any one of Schemes 1-15 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, having the structure shown in formula (V),

[0118]

[0119] Where s is selected from integers between 0 and 3;

[0120] Each R a Each R b Each R c R 3 R 4 The definitions of each Q2, each Q3, and each m are as described in any of the aforementioned technical solutions.

[0121] Scheme 16-1: The compound described in any one of Schemes 1 to 16 above, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in formula (V-1),

[0122]

[0123] Among them, R 5 Selected from C that has been replaced by deuterium 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0124] Each s is an independent integer between 0 and 2;

[0125] Each R a Each R b Each R c R 3 R 4 The definitions of each Q2, each Q3, and each m are as described in any of the aforementioned technical solutions.

[0126] Scheme 16-2: The compound described in Scheme 16-1 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein R 5 Selected from deuterated C 1-6 Alkyl or deuterated C 1-6 Alkyl group.

[0127] Option 17: The compound described in any one of Options 1 to 16-2 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0128] Each Q1 and each Q2 are independently selected from deuterium, halogens, and C atoms optionally substituted with 1-4 substituents Q3. 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 group, -(L) m -3-6 membered cycloalkyl or -(L) m -3-6 membered heterocyclic groups, each Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkyl group.

[0129] Option 18: The compound described in any one of Options 1-17 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0130] Each Q1 and each Q2 are independently selected from deuterium, halogens, and C atoms optionally substituted with 1-3 substituents Q3. 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, 3-6 membered cycloalkyl, each Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl and Halogenated C 1-4 Alkyl group.

[0131] Option 19: The compound described in any one of Options 1-18 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0132] Each Q1 and each Q2 are independently selected from deuterium, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, and optionally substituted by 1-3 substituents Q3, namely methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, monofluoromethoxy, difluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl. The group Q3 is selected independently from deuterium, fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, cyano, nitro, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0133] Scheme 20: The compound described in any one of Schemes 1-19 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein each L is independently selected from -CR a R b -;

[0134] 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, halogenated C 1-4 Alkyl, Halogenated C1-4 Alkyl group.

[0135] Scheme 21: The compound described in any one of Schemes 1-20 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein each L is independently selected from -CH2-.

[0136] Scheme 22: The compound described in any one of Schemes 1-20 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, having the structure shown in Formula (III-1),

[0137]

[0138] Among them, X3 and X4 are independently selected from N or CR. a ;

[0139] Each L, each R a Each R b Each R c R 3 R 4 The definitions of each Q2, each Q3, each m, n, and each s are as described in any of the aforementioned technical solutions.

[0140] Scheme 22-1: The compound described in any one of Schemes 1 to 22 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, having the structure shown in formula (III-1'),

[0141]

[0142] Among them, R 5 Selected from C that has been replaced by deuterium 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0143] X3 and X4 are independently selected from N or CR. a ; Each L, each R a R 3 R 4 The definitions of each Q2, each Q3, each m, n, and each s are as described in any of the aforementioned technical solutions.

[0144] Scheme 22-2: The compound described in Scheme 22-1 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein R 5 Selected from deuterated C 1-6 Alkyl or deuterated C 1-6 Alkyl group.

[0145] Scheme 23: The compound described in any one of Schemes 1-22 above, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in general formula (III-2):

[0146]

[0147] Among them, X3 and X4 are independently selected from N and CR, respectively. a CR a R b NR c Each s is independently selected from integers between 0 and 3;

[0148] Each Each R can be a single bond or a double bond independently; a Each R b Each R c R 3 R 4 The definitions of each Q2, each Q3, each L, each m, and n are as described in any of the aforementioned technical solutions.

[0149] Scheme 23-1: The compound described in any one of Schemes 1-22 above, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in general formula (III-2'):

[0150]

[0151] Among them, R 5 Selected from C that has been replaced by deuterium 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0152] X3 and X4 are independently selected from N and CR, respectively. a CR a R b NR c Each s is independently selected from integers between 0 and 3;

[0153] Each R a Each R b Each R c R 3 R 4 The definitions of each Q2, each Q3, each L, each m, and n are as described in any of the aforementioned technical solutions.

[0154] Option 24: The compound described in Option 23-1 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein R 5Selected from deuterated C 1-6 Alkyl or deuterated C 1-6 Alkyl group.

[0155] Scheme 25: The compound described in any one of Schemes 1-24 above, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in general formula (VI):

[0156]

[0157] Where s is selected from integers from 0 to 3; X3 and X4 are independently selected from N or CR respectively. a ;

[0158] Each R a R 1 R 3 R 4 The definitions of each Q2, each Q3, each L, each m, and n are as described in any of the aforementioned technical solutions.

[0159] Scheme 25-1: The compound described in any one of Schemes 1-25 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein R 1 R 2 R 3 Each is independently selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl groups, each optionally substituted with one or more Q2 groups.

[0160] Scheme 25-2: The compound described in any one of Schemes 1-25 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein R 1 R 2 R 3 Each is independently selected from 3-10 heterocyclic groups, 6-10 aryl groups, or 5-10 heteroaryl groups that are substituted with 1-4 Q2 groups.

[0161] Scheme 25-3: The compound described in any one of Schemes 1-25 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein R 1 R 2 R 3 Each is independently selected from 6-10 aryl or 5-10 heteroaryl groups that are substituted with 1-4 Q2 groups.

[0162] Scheme 25-4: The compound described in any one of Schemes 1-25 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0163] R 1 R 2 R3 Each is independently selected from 6-10 aryl groups or 5-10 nitrogen-containing heteroaryl groups that are substituted with 1-3 Q2 groups.

[0164] Scheme 25-5: The compound described in any one of Schemes 1 to 25-4 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0165] R 1 Selected from 5-6 substituted heteroaryl groups, preferably 5-6 substituted nitrogen-containing heteroaryl groups.

[0166] Option 26: The compound described in any one of Options 1 to 25-5 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0167] R 1 Selected from 5-6-membered heteroaryl groups substituted with 1-3 Q2s, preferably 5-6-membered nitrogen-containing heteroaryl groups substituted with 1-3 Q2s;

[0168] R 2 Selected from 5-6 membered heteroaryl or phenyl groups substituted with 1-3 Q2 groups;

[0169] R 3 Selected from 5-membered heteroaryl groups substituted with 1-3 Q2s, preferably 5-membered nitrogen-containing heteroaryl groups substituted with 1-3 Q2s;

[0170] R 4 Selected from deuterium, hydrogen, cyano, halogen, 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, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0171] Each Q2 is independently selected from deuterium, halogen, and C, optionally substituted with 1-3 substituents Q3. 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 1-6Alkyl, 3-6 membered cycloalkyl, each Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0172] Each L is independently -CH2-;

[0173] n is an integer between 1 and 3.

[0174] Option 27: The compound described in any one of Options 1-26 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0175] R 1 Selected from phenyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, 2-pyridonel, 4-pyridonel, pyrimidinyl, pyridazinyl, and pyrazinyl;

[0176] R 3 Selected from pyrrole, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl groups, each substituted with 1 to 3 Q2 groups;

[0177] R 4 Selected from deuterium, hydrogen, cyano, halogen, 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 or halogenated C 1-6 Alkoxy;

[0178] Each Q2 is independently selected from deuterium, halogen, and C, optionally substituted with 1-3 substituents Q3. 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, 3-6 membered cycloalkyl, each Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6Alkyl and Halogenated C 1-6 Alkoxy;

[0179] L is -CH2-; n is 1.

[0180] Scheme 27-1: The compound described in any one of Schemes 1-27 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0181] R 1 Selected from those that can be replaced by 1-3 Q2s. Preferably, R 1 Selected from those that can be replaced by 1-3 Q2s.

[0182] Scheme 27-2: The compound described in any one of Schemes 1 to 27-1 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0183] R 3 Selected from those that can be replaced by 1-3 Q2s. Preferably, R 3 Selected from those that can be replaced by 1-3 Q2s.

[0184] Scheme 27-3: The compound described in any one of Schemes 1-27 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0185] R 1 Selected from those that can be replaced by 1-3 Q2s.

[0186] R 3 Selected from those that can be replaced by 1-3 Q2s.

[0187] Scheme 28: The compound described in any one of Schemes 1-13, 17-21, 25-27 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, having the structure shown in general formula (VII):

[0188]

[0189] X3, X4, X 11 Selected independently from N or CR a ;X 10 Selected from N, NR c C, CR a or CRa R b ;

[0190] Each L, each R a Each R b Each R c R 3 R 4 The definitions of each Q2, each Q3, each m, n, and each s are as described in any of the aforementioned technical solutions.

[0191] Option 29: The compound described in Option 28 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein X3 and X4 are independently selected from N or CH; X 11 Selected from N, C, or CH; X 10 Selected from N, NH, C, CH or CH2.

[0192] Option 30: The compound described in any one of Options 1-29 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein,

[0193] X3 and X4 are independently selected from N or CH; n is 1.

[0194] Scheme 31: The compound described in any one of Schemes 1-30 above, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, wherein X3 is CH; X4 is N.

[0195] Scheme 32: The compound described in any one of Schemes 1-31 above, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in general formula (VI),

[0196]

[0197] Among them, X3 and X4 are independently selected from N or CH;

[0198] R 1 Selected from those that can be replaced by 1-3 Q2s.

[0199] R 3 Selected from those that can be replaced by 1-3 Q2s.

[0200] R 4 Selected from deuterium, hydrogen, and C atoms optionally deuterated. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, halogenated C 1-4Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl or halogenated C 1-4 Alkoxy;

[0201] Each Q2 is independently selected from deuterium, halogen, and C, optionally substituted with 1-3 substituents Q3. 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, 3-6 membered cycloalkyl, each Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0202] L stands for -CH2-;

[0203] n is 0, 1, or 2.

[0204] Scheme 33: The compound described in any one of Schemes 1-32 above, its pharmaceutically acceptable salt, ester, deuterated product or its stereoisomer, having the following general formula structure,

[0205]

[0206] X 10 Selected from NR c or CR a R b ;

[0207] Each R a Each R b Each R c Each R 3 Each R 4 The definitions of each Q2, each Q3, each m, and each s are as described in any of the aforementioned technical solutions.

[0208] Scheme 33-1: The compound described in Scheme 33 above, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, wherein,

[0209] X 10 Selected from NR c or CR a R b;

[0210] Each R 3 Each is independently selected from those that can be replaced by 1-3 Q2s.

[0211] Each R 4 Selected from deuterium, hydrogen, cyano, halogen, 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 or halogenated C 1-6 Alkoxy;

[0212] Each Q2 is independently selected from deuterium, halogen, and C, optionally substituted with 1-3 substituents Q3. 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, 3-6 membered cycloalkyl, each Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0213] Each s is independently 0, 1, or 2.

[0214] Option 34: A compound as described in Option 33 or Option 33-1, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, wherein,

[0215] X 10 Selected from N, NH, C, CH or CH2.

[0216] Option 35: A compound as described in any of the preceding options, its pharmaceutically acceptable salt, ester, deuterated form, or stereoisomer thereof, wherein,

[0217] Each R 4 Selected from deuterium, hydrogen, cyano, halogen, and optionally deuterated C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, halogenated C 1-4Alkyl or halogenated C 1-4 Alkoxy;

[0218] Each Q2 is independently selected from deuterium, halogen, and C, optionally substituted with 1-3 substituents Q3. 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 1-64 Alkyl, carboxyl C 1-4 Alkyl, 3-6 membered cycloalkyl, each Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl and Halogenated C 1-4 Alkyl group.

[0219] Scheme 35-1: A compound as described in any of the preceding schemes, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, wherein,

[0220] Each R 4 Selected from deuterium, hydrogen, trifluoromethyl, trifluoromethoxy, and optionally deuterated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, monofluoromethoxy, or difluoromethoxy.

[0221] Each Q2 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, and optionally substituted by 1-3 substituents Q3, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, monofluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclobutyl. Each Q3 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, cyano, nitro, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0222] Scheme 35-2: A compound as described in any of the preceding schemes, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, wherein,

[0223] R 5It is selected from deuterated methoxy, ethoxy, propoxy or isopropoxy, and the number of deuterations is 1, 2, 3 or 4, preferably trideuterated methoxy.

[0224] Scheme 36: Compounds of general formula (I), their pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof:

[0225]

[0226] in,

[0227] Ring A and ring B are independently selected from 5-8 membered heterocyclic groups, 5-8 membered cycloalkyl groups, phenyl groups or 5-8 membered heteroaryl groups that are optionally substituted with one or more Q1 groups;

[0228] R 1 R 2 R 3 Each is independently selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl or 5-12 membered heteroaryl, which are optionally substituted with one or more Q2 groups;

[0229] R 4 Selected from hydrogen, carboxyl, cyano, nitro, amino, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0230] Each Q1 and each Q2 is independently selected from halogen, cyano, carboxyl, hydroxyl, amino, carboxyl, nitro, sulfonamide, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 Alkyl carbonyl, C 1-6 alkoxycarbonyl, C 1-6 Alkylaminoyl, C 1-6 Alkylamide, C 1-6 alkylsulfonyl, C 1-6 Alkylsulfonamide, C 1-6Alkylaminosulfonyl group, optionally substituted with 1-4 substituents Q3-(L) m -C 1-6 Alkyl group, -(L) m -C 2-6 Alkenyl, -(L) m -C 2-6 Alkyne group, -(L) m -C 1-6 Alkoxy group, -(L) m -6-10 aryl, -(L) m -5-12-membered heteroaryl, -(L) m -3-8 membered cycloalkyl or -(L) m -3-8 membered heterocyclic groups, each Q3 is independently selected from carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, -CO-C 1-6 Alkyl-NH2, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0231] Each L is independently selected from -CO-, -O-, -S-, -SO-, -S(O)2-, -NR c -、-CR a R b -;

[0232] Each R a Each R b Each group is independently selected from hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 alkyl)amino, C 1-6 Alkylaminoyl, C 1-6 Alkylamide, C 1-6 Alkylsulfonamide, C 1-6 Alkylaminosulfonyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl;

[0233] Each R c Each is independently selected from hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl;

[0234] R 2 Connect L to ring A or ring B;

[0235] Each m and each n are independent integers from 0 to 6.

[0236] Option 37: The compound described in any of the preceding options, its pharmaceutically acceptable salt, ester, deuterated derivative, or stereoisomer thereof, wherein,

[0237] Ring A and ring B are each independently selected from 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups that are optionally substituted with one or more Q1 groups;

[0238] R 1 R 2 R 3 Each is independently selected from 5-8 membered cycloalkyl, 3-8 membered heterocyclic, phenyl or 5-6 membered heteroaryl groups that are optionally substituted with one or more Q2 groups;

[0239] R 4 Selected from hydrogen, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0240] Each Q1 and each Q2 is independently selected from halogen, cyano, and C. 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl group, optionally substituted with 1-4 substituents Q3-(L) m -C 1-6 Alkyl group, -(L) m-3-6 membered cycloalkyl or -(L) m -3-6 membered heterocyclic groups, each Q3 is independently selected from carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0241] Each L is independently selected from -CO-, -O-, and -NR. c -、-CR a R b -;

[0242] Each R a Each R b Each is independently selected from hydrogen, 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, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl;

[0243] Each R c Each is independently selected from hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0244] Each m and each n are independent integers from 0 to 5.

[0245] Option 38: The compound described in any of the preceding options, its pharmaceutically acceptable salt, ester, deuterated derivative, or stereoisomer thereof, wherein,

[0246] Ring A and ring B are independently selected from 5-membered nitrogen-containing heterocyclic groups or 5-membered nitrogen-containing heteroaryl groups that are substituted by 1 to 4 Q1 groups;

[0247] R 1 R 2 R 3 Each is independently selected from phenyl groups that are substituted with 1-4 Q2 groups or 5-6 membered heteroaryl groups;

[0248] R 4 Selected from hydrogen, C 1-4 Alkyl, C1-4 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;

[0249] Each Q1 and each Q2 is independently selected from halogens, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl group, optionally substituted with 1-3 substituents Q3-(L) m -C 1-4 Alkyl group, -(L) m -3-6 membered cycloalkyl, each Q3 is independently selected from carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, hydroxyl C 1-4 Alkyl, carboxyl C 1-4 Alkyl, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, C 1-4 Alkoxy, halogenated C 1-4 Alkyl and Halogenated C 1-4 Alkoxy;

[0250] Each L is independently selected from -CR a R b -or -O-;

[0251] Each R a Each R b Each is independently selected from hydrogen, 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, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 alkyl;

[0252] Each R c Each is independently selected from hydrogen, C 1-4 Alkyl, Halogenated C 1-4Alkyl, Halogenated C 1-4 Alkoxy;

[0253] Each m and each n are independent integers from 0 to 4.

[0254] Option 39: The compound described in any of the preceding options, its pharmaceutically acceptable salt, ester, deuterated derivative, or stereoisomer thereof, wherein,

[0255] Ring A and ring B are independently selected from 5-membered nitrogen-containing heterocyclic groups or 5-membered nitrogen-containing heteroaryl groups that are substituted with 1-3 Q1 groups;

[0256] R 1 R 2 R 3 The phenyl, furanyl, thiophene, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, 2-pyridonel, 4-pyridonel, pyrimidinyl, pyridazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, imidazo[1,2-c]pyrimidine, imidazo[1,5-c]pyrimidine, and pyrrolo[3,4-c]pyrimidine are selected independently from those substituted with 1 to 3 Q2 groups.

[0257] R 4 Selected from hydrogen, 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, trifluoromethoxy;

[0258] Each Q1 and each Q2 is independently selected from fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, optionally substituted by 1-3 substituents Q3. m -C 1-4 Alkyl group, -(L) m-3-6-membered cycloalkyl, each Q3 is independently selected from carboxyl, hydroxyl, cyano, nitro, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl, carboxyethyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

[0259] Each L is independently selected from -CR a R b -;

[0260] Each R a Each R b Each of the following is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, and isopropoxy;

[0261] Each m and each n are independently 0, 1, 2, and 3, respectively.

[0262] Scheme 40: The compound described in any of the preceding schemes, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in formula (II),

[0263]

[0264] X1 and X2 are independently selected from C, N, and CR, respectively. a ;

[0265] X3, X4, and X5 are independently selected from N, S, and CR, respectively. a CR a R b NR c ;

[0266] X6 and X7 are each independently selected from CR a Or N;

[0267] s is an integer selected from 0 to 4;

[0268] The connection methods of X1 and X2, X2 and X3, X3 and X4, X4 and X5, and X1 and X5 are each independently selected from single bonds or double bonds; and among the bonds formed between X1, X2, X3, X4, and X5, no two adjacent bonds can be double bonds at the same time.

[0269] Each L, each R a Each R b Each R c R 1 R 3 R 4The definitions of each Q2, each Q3, each m, and n are as described in any of the aforementioned technical solutions.

[0270] Scheme 41: The compound described in any of the preceding schemes, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in general formula (III):

[0271]

[0272] in,

[0273] Each s is independently selected from integers between 0 and 3;

[0274] X2, X3, X4, X5, each L, each R a Each R b Each R c R 3 R 4 The definitions of each Q2, each Q3, each m, and n are as described in any of the aforementioned technical solutions.

[0275] Scheme 42: The compound described in any of the preceding schemes, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in formula (III-1),

[0276]

[0277] Among them, X3 and X4 are independently selected from N or CR. a ;

[0278] Each L, each R a Each R b Each R c R 3 R 4 The definitions of each Q2, each Q3, each m, n, and each s are as described in any of the aforementioned technical solutions.

[0279] Scheme 43: The compound described in any of the preceding schemes, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in general formula (III-2):

[0280]

[0281] Among them, X3 and X4 are independently selected from N and CR, respectively. a CR a R b NR c ;

[0282] Each s is independently selected from integers between 0 and 3;

[0283] Each R a Each R b Each R c R 3 R 4 The definitions of each Q2, each Q3, each L, each m, and n are as described in any of the aforementioned technical solutions.

[0284] Option 44: The compound described in any of the preceding options, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, wherein the tricyclic ring formed by ring B, ring A together with the pyrimidine ring has the following structure:

[0285]

[0286] Each R 1 Each R 4 The definition is as described in any of the aforementioned technical solutions.

[0287] Scheme 45: The compound described in any of the preceding schemes, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in general formula (VI):

[0288]

[0289] s is selected from integers from 0 to 3; X3 and X4 are independently selected from N or CR respectively. a ;

[0290] Each R a R 1 R 3 R 4 The definitions of each Q2, each Q3, each L, each m, and n are as described in any of the aforementioned technical solutions.

[0291] Option 46: The compound described in any of the preceding options, its pharmaceutically acceptable salt, ester, deuterated derivative, or stereoisomer thereof, wherein,

[0292] R 1 R 2 R 3 Each is independently selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl groups, each optionally substituted with one or more Q2 groups.

[0293] Option 47: The compound described in any of the preceding options, its pharmaceutically acceptable salt, ester, deuterated derivative, or stereoisomer thereof, wherein R 1 R 2 R 3Each is independently selected from 3-10 heterocyclic groups, 6-10 aryl groups, or 5-10 heteroaryl groups that are substituted with 1-4 Q2 groups.

[0294] Option 48: The compound described in any of the preceding options, its pharmaceutically acceptable salt, ester, deuterated derivative, or stereoisomer thereof, wherein R 1 R 2 R 3 Each is independently selected from 6-10 aryl or 5-10 heteroaryl groups that are substituted with 1-4 Q2 groups.

[0295] Option 49: The compound described in any of the preceding options, its pharmaceutically acceptable salt, ester, deuterated derivative, or stereoisomer thereof, wherein,

[0296] R 1 R 2 R 3 Each is independently selected from 6-10 aryl groups or 5-10 nitrogen-containing heteroaryl groups that are substituted with 1-3 Q2 groups.

[0297] Option 50: The compound described in any of the preceding options, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, wherein R 1 Selected from 5-6 substituted heteroaryl groups, preferably 5-6 substituted nitrogen-containing heteroaryl groups.

[0298] Option 51: The compound described in any of the preceding options, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, wherein R 1 Selected from 5-6-membered heteroaryl groups substituted with 1-3 Q2s, preferably 5-6-membered nitrogen-containing heteroaryl groups substituted with 1-3 Q2s;

[0299] R 2 Selected from 5-6 membered heteroaryl or phenyl groups substituted with 1-3 Q2 groups;

[0300] R 3 Selected from 5-membered heteroaryl groups substituted with 1-3 Q2s, preferably 5-membered nitrogen-containing heteroaryl groups substituted with 1-3 Q2s;

[0301] R 4 Selected from hydrogen, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or halogenated C 1-6Alkoxy;

[0302] Each Q2 is independently selected from halogens, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl groups, optionally substituted with 1-3 substituents Q3 1-6 Alkyl, 3-6 membered cycloalkyl, each Q3 is independently selected from carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0303] Each L is independently -CH2-;

[0304] n is an integer between 1 and 3.

[0305] Option 52: The compound described in any of the preceding options, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, wherein R 1 Selected from phenyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, 2-pyridonel, 4-pyridonel, pyrimidinyl, pyridazinyl, and pyrazinyl;

[0306] R 3 Selected from pyrrole, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl groups, each substituted with 1-3 Q2 groups; R 4 Selected from hydrogen, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0307] Each Q2 is independently selected from halogens, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C1-6 Alkyl, carboxyl C 1-6 Alkyl groups, optionally substituted with 1-3 substituents Q3 1-6 Alkyl, 3-6 membered cycloalkyl, each Q3 is independently selected from carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0308] L is -CH2-; n is 1.

[0309] Option 53: The compound described in any of the preceding options, its pharmaceutically acceptable salt, ester, deuterated derivative, or stereoisomer thereof, wherein,

[0310] R 1 Selected from those that can be replaced by 1-3 Q2s. Preferably, R 1 Selected from those that can be replaced by 1-3 Q2s.

[0311] Option 54: The compound described in any of the preceding options, its pharmaceutically acceptable salt, ester, deuterated derivative, or stereoisomer thereof, wherein,

[0312] R 3 Selected from those that can be replaced by 1-3 Q2s. Preferably, R 3 Selected from those that can be replaced by 1-3 Q2s.

[0313] 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.

[0314] In some embodiments of the present invention, the structures of the compounds of the aforementioned general formula (I), their pharmaceutically acceptable salts, esters, deuterated derivatives, or stereoisomers thereof are shown in Table 1:

[0315] Table 1

[0316]

[0317]

[0318]

[0319]

[0320]

[0321] This invention provides an intermediate for preparing the compound of general formula (II), having the following structure:

[0322]

[0323] Wherein, G is a halogen; R 3 R 4 X1, X2, X3, X4, X5, X6, X7, each R a Each R b Each R c The definitions of each Q2, each Q3, each L, each m, n, and s are as defined in any of the aforementioned technical solutions.

[0324] The present invention also provides an intermediate for preparing the compound of general formula (III), having the following structure:

[0325]

[0326] Wherein, G is a halogen; R 3 R 4 X2, X3, X4, X5, each R a Each R b Each R c The definitions of each Q2, each Q3, each L, each m, n, and s are as defined in any of the aforementioned technical solutions.

[0327] This invention provides an intermediate for preparing compounds of general formula (VI), having the following structure:

[0328]

[0329] Wherein, G is a halogen; R 3 R 4 X3, X4, each R a The definitions of each Q2, each Q3, each L, each m, n, and s are as defined in any of the aforementioned technical solutions.

[0330] The "pharmaceutically acceptable salt" as described in this invention refers to the addition salt of pharmaceutically usable acids and bases, such as metal salts, ammonium salts, salts formed with organic acids, salts formed with organic bases, salts formed with inorganic acids, and salts formed with acidic or basic amino acids.

[0331] The term "ester" as used in this invention refers to a pharmaceutically acceptable ester, particularly esters that are hydrolyzed in vivo and include esters that readily decompose in the human body, leaving behind a parent compound (the compound of general formula (I)) or its salt. The term "ester" as used in this invention may, for example, be selected from the following group: (1) carboxylic acid esters obtained by esterification with carboxylic acid compounds, wherein the non-carbonyl portion of the carboxylic acid compound is selected, for example, C 1-20 Straight-chain or branched alkyl groups, C 1-12 Straight-chain or branched alkyl groups, C 1-8 Straight-chain or branched alkyl groups, C 1-6 Straight-chain or branched alkyl groups (e.g., methyl, ethyl, n-propyl, tert-butyl, or n-butyl), C 1-6 Alkoxy C 1-6 Alkyl (e.g., methoxymethyl), C 6-10 Aryl C 1-6 Alkyl (e.g., benzyl), C 6-10 Aryloxy C 1-6 Alkyl (e.g., phenoxymethyl), C 6-10 Aryl (e.g., phenyl, optionally replaced by, for example, halogen, C) 1-4 Alkyl or C 1-4 (1) Alkoxy or amino substituted; (2) sulfonates, such as alkylsulfonyl or aralkylsulfonyl (e.g., methylsulfonyl); (3) amino acid esters (e.g., L-valine or L-isoleucyl); and (4) mono-, di-, or triphosphate esters, etc.; (5) esters obtained by esterification with alcohols, wherein the non-hydroxyl portion of the alcohol is selected from, for example, C 1-20 Straight-chain or branched alkyl groups, C 1-12 Straight-chain or branched alkyl groups, C 1-8 Straight-chain or branched alkyl groups, C 1-6 Straight-chain or branched alkyl groups (e.g., methyl, ethyl, n-propyl, tert-butyl, or n-butyl), C 1-6 Alkoxy C 1-6 Alkyl (e.g., methoxymethyl), C 6-10 Aryl C 1-6 Alkyl (e.g., benzyl), C 6-10 Aryloxy C 1-6 Alkyl (e.g., phenoxymethyl), C 6-10 Aryl (e.g., phenyl, optionally replaced by, for example, halogen, C) 1-4 Alkyl or C 1-4 (alkoxy or amino substitution).

[0332] 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.

[0333] The present invention also provides a pharmaceutical composition comprising a compound represented by the aforementioned general formulas (I) to (VII), a pharmaceutically acceptable salt, ester, deuterated form or stereoisomer thereof, and one or more second therapeutic agents, optionally, the pharmaceutical composition further comprising one or more pharmaceutical carriers and / or diluents.

[0334] The present invention also provides a pharmaceutical preparation comprising a compound represented by the aforementioned general formulas (I) to (VII), a pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, and one or more pharmaceutical carriers and / or diluents; the pharmaceutical preparation being any clinically or pharmaceutically acceptable dosage form.

[0335] 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.

[0336] 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.

[0337] The present invention also provides the use of the compounds represented by the aforementioned general formulas (I) to (VII), their pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof, the aforementioned pharmaceutical preparations or the aforementioned pharmaceutical compositions in the preparation of medicaments for the treatment and / or prevention of USP1-mediated diseases and related diseases; wherein the USP1-mediated diseases and related diseases are selected from cancer or benign tumors.

[0338] The present invention also provides the use of the compounds represented by the aforementioned general formulas (I) to (VII), their pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof, the aforementioned pharmaceutical preparations or the aforementioned pharmaceutical compositions in the treatment and / or prevention of USP1-mediated diseases and related diseases; wherein the USP1-mediated diseases and related diseases are selected from cancer or benign tumors.

[0339] The present invention also provides a method for treating a disease, the method comprising administering to a patient in need a therapeutically effective amount of a compound represented by the aforementioned general formulas (I) to (VII), a pharmaceutically acceptable salt, ester, deuterated form thereof or a stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition, wherein the disease is a USP1-mediated disease or related disease; the USP1-mediated disease or related disease is selected from cancer or benign tumors.

[0340] 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.

[0341] 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.

[0342] The "halogen" mentioned in this invention refers to fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred.

[0343] 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.

[0344] 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.

[0345] 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, C3-4 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.

[0346] The "C" described in this invention 2-6 "Alkenyl" refers to a straight-chain, branched, or cyclic alkenyl group containing at least one double bond and having 2-6 carbon atoms, including, for example, "C". 2-5 "alkenyl", "C" 2-4 "alkenyl", "C" 2-3 "Alkenyl", etc., specific examples include but are not limited to: vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl -1-pentenyl, 1-methyl-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-1-butenyl, 2-ethyl-1-butenyl, 2-ethyl-3-butenyl, etc.

[0347] The "C" described in this invention 2-6 "Alkyne group" refers to a straight-chain or branched alkynyl group containing 2-8 carbon atoms with a triple bond, including, for example, "C". 2-5 "Alkyne", "C" 2-4 "Alkyne", "C" 2-3 "Alynyl", etc., specific examples include but are not limited to: ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1,1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, etc.

[0348] The “C” mentioned in this article 1-6Alkoxy, 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" is a group formed in the alkyl-OC(O)- manner. 1-6 The definition of "alkyl" is as described above.

[0349] 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 a carbonyl group of C10 and C20. 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" is a group formed in the alkyl-OC(O)- manner. 1-4 The definition of "alkyl" is as described above.

[0350] 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.

[0351] 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.

[0352] The “3-12 membered cycloalkyl” mentioned in this invention refers to a saturated or partially saturated cycloalkyl group containing 3-12 carbon atoms that is not aromatic, including “monocycloalkyl” and “fused cycloalkyl”.

[0353] The term "monocycloalkyl" as used in this invention refers to a saturated or partially saturated monocycloalkyl group that is non-aromatic, including "3-8 membered saturated cycloalkyl" and "3-8 membered partially saturated cycloalkyl"; preferably "3-4 membered cycloalkyl", "3-5 membered cycloalkyl", "3-6 membered cycloalkyl", "3-7 membered cycloalkyl", "4-5 membered cycloalkyl", "4-6 membered cycloalkyl", "4-7 membered cycloalkyl", "4-8 membered cycloalkyl", "5-6 membered cycloalkyl", "5-7 membered cycloalkyl", "5-8 membered cycloalkyl", "6-7 membered cycloalkyl", "5-8 ... Cycloalkyl, 6-8 membered cycloalkyl, 7-8 membered cycloalkyl, 3-6 membered saturated cycloalkyl, 4-7 membered saturated cycloalkyl, 4-8 membered saturated cycloalkyl, 5-8 membered saturated cycloalkyl, 5-7 membered saturated cycloalkyl, 5-6 membered saturated cycloalkyl, 3-6 membered partially saturated cycloalkyl, 4-7 membered partially saturated cycloalkyl, 4-8 membered partially saturated cycloalkyl, 5-8 membered partially saturated cycloalkyl, 5-7 membered partially saturated cycloalkyl, 5-6 membered partially saturated cycloalkyl, etc. Specific examples of the "3-8 saturated cycloalkyl group" include, but are not limited to: cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane (cycloheptyl), cyclooctane (cyclooctyl), etc.; specific examples of the "3-8 partially saturated cycloalkyl group" include, but are not limited to: cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1,3-diene, cyclohex-1,4-diene, cycloheptenyl, cycloheptenyl-1,3-diene, cycloheptenyl-1,4-diene, cycloheptenyl-1,3,5-trienyl, cyclooctenyl, cyclooctyl-1,3-diene, cyclooctyl-1,4-diene, cyclooctyl-1,5-diene, cyclooctyl-1,3,5-trienyl, cyclooctatetraenyl, etc.

[0354] The "fused cycloalkyl" of this invention refers to a saturated or partially saturated non-aromatic cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms. One ring in the fused ring may be an aromatic ring, but the fused ring as a whole does not possess aromaticity. Its fusion mode can be: 5-6 membered cycloalkyl and 5-6 membered cycloalkyl, benzo5-6 membered cycloalkyl, benzo5-6 membered 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.

[0355] The "3-12 membered heterocyclic group" described in this invention refers to a saturated or partially saturated monocyclic or fused-ring group containing at least one heteroatom (e.g., 1, 2, 3, 4, or 5) and having 3-12 ring atoms, and lacking aromaticity. The heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom. Optionally, the ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the ring structure can be substituted with oxygen. The "3-12 membered heterocyclic group" described in this invention includes "3-12 membered saturated heterocyclic groups" and "3-12 membered partially saturated heterocyclic groups." Preferably, the "3-12 membered heterocyclic group" described in this invention contains 1-3 heteroatoms; preferably, the "3-12 membered heterocyclic group" described in this invention contains 1-2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and / or oxygen atoms; preferably, the "3-12 membered heterocyclic group" described in this invention contains 1-2 nitrogen atoms. The “3-12 membered heterocyclic group” is preferably a “3-10 membered heterocyclic group”, a “3-8 membered heterocyclic group”, a “4-8 membered heterocyclic group”, a “3-6 membered heterocyclic group”, a “3-6 membered saturated heterocyclic group”, a “3-6 membered nitrogen-containing heterocyclic group”, a “3-6 membered saturated nitrogen-containing heterocyclic group”, a “5-6 membered heterocyclic group”, or a “5-6 membered saturated heterocyclic group”.Specific examples of “3-12 membered heterocyclic 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, tetrahydropyranyl, dihydropyrroleyl, pyrroleyl, imidazolyl, 4,5-dihydroimidazolyl, pyrazolyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisooxazolyl, 2,3-dihydroisooxazolyl, 2H-1,2-oxazolyl Azinyl, 6H-1,3-oxazinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-one, 3,4-dihydro-2H-pyranyl, pyrrolidinylcyclopropyl, cyclopentylaziryl, pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, pyrrolidinylmorpholinyl, piperidinylmorpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzoimidazoalkyl, benzooxazolidinyl, benzothiazoalkyl, benzoisooxazolidinyl, benzoisothiazoalkyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzotetrahydropyranyl, pyridinylcyclopentyl, pyrrolidinyl Pyridocyclohexyl, pyridotetrahydrofuranyl, pyridopyrrolidinyl, pyridoimidazolidinyl, pyridooxazolyl, pyridothiazolidinyl, pyridoisooxazolyl, pyridoisothiazolidinyl, pyridopiperidinyl, pyridomorpholinyl, pyridopiperazinyl, pyridotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidotetrahydrofuranyl, pyrimidopyrrolidinyl, pyrimidoimidazolidinyl, pyrimidooxazolyl, pyrimidoisooxazolyl, pyrimidoisothiazolidinyl, pyrimidopiperidinyl, pyrimidomorpholinyl, pyrimidopiperazinyl, pyrimidotetrahydropyranyl; tetrahydroimidazo[4,5-c]pyridinyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxolinyl, 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- Thiophene[3,4-d]imidazolyl, 4,6-dihydro-1H-pyrrolo[3,4-d]imidazolyl, octahydro-benzo[d]imidazolyl, decahydroquinolinyl, hexahydrothieneno[imidazolyl, hexahydrofuran[imidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopenten[c]pyrrolel, 4H-1,3-benzoxazinyl, etc.

[0356] 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”.

[0357] 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.

[0358] 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.

[0359] 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".

[0360] 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.

[0361] 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.

[0362] The phrase "optionally replaced by..." as described in this invention includes both "replaced" and "not replaced".

[0363] The present invention Selected from single or double bonds.

[0364] Unless otherwise specified, any atom in the compounds of this application may represent any stable isotope of that atom. Unless otherwise specified, when a position in the structure is defined as H, i.e., hydrogen (Hl), that position contains only naturally occurring isotopes. Similarly, unless otherwise specified, when a position in the structure is defined as D, i.e., deuterium (H₂), that position contains an isotope amount at least 3340 times greater than the amount of naturally occurring isotopes (0.015%) (i.e., at least 50.1% deuterium isotopes). When one or more positions in the structure of the compounds of this application are defined as D, i.e., deuterium (H₂), the content of the compound shown in that structure may be at least 52.5%, at least 60%, at least 67.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98.5%, at least 99%, or at least 99.5%.

[0365] The deuteration rate of the compounds in this application refers to the ratio of the content of the labeled synthetic isotope to the amount of the naturally occurring isotope. The deuteration rate of each specified deuterium atom in the compounds in this application may be at least 3500 times (52.5%), at least 4000 times (60%), at least 4500 times (67.5%), at least 5000 times (75%), at least 5500 times (82.5%), at least 6000 times (90%), at least 6333.3 times (95%), at least 6466.7 times (97%), at least 6566.7 times (98.5%), at least 6600 times (99%), and at least 6633.3 times (99.5%).

[0366] In this application, isotopes refer to compounds that differ only in their isotopic composition in terms of chemical structure. The deuterium-containing compounds at specific positions in this application will also contain very small amounts of hydrogen isotopes at those positions. The amount of hydrogen isotopes at the deuterated positions in the deuterated compounds of this application depends on many factors, including the deuterotopic purity of the deuterating reagent (D₂O, D₂, NaBD₄, L₁AID₄, etc.) and the effectiveness of the deuterotope synthesis method. However, as mentioned above, the total amount of hydrogen isotopes at such deuterated positions will be less than 49.9%. The total amount of hydrogen isotopes at the deuterated positions in the deuterated compounds of this application will be less than 47.5%, 40%, 32.5%, 25%, 17.5%, 10%, 5%, 3%, 1%, or 0.5%.

[0367] In this application, any atom not designated as deuterium exists at its natural isotopic abundance.

[0368] In this invention, "deuteration" refers to the substitution of one or more hydrogen atoms on a deuterated group by one or more deuterium atoms. This can be partial or complete deuteration. For example, a deuterated compound may contain only one deuterium atom. In some embodiments, the deuterated compound contains only two deuterium atoms. In some embodiments, the deuterated compound contains only three deuterium atoms. In some embodiments, the deuterated compound contains four deuterium atoms.

[0369] The "optionally deuterated" in this invention includes two cases: the group is deuterated and the group is not deuterated, wherein "deuterated" is as defined above.

[0370] 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.

[0371] Beneficial effects of the invention

[0372] (1) The compounds of the present invention, their pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof have excellent USP1 inhibitory activity and can treat and / or prevent USP1-mediated diseases and related diseases.

[0373] (2) The compounds of the present invention, their pharmaceutically acceptable salts, esters, deuterated derivatives or their stereoisomers have good pharmacokinetic properties, longer duration of action and high bioavailability;

[0374] (3) The compounds of the present invention, their pharmaceutically acceptable salts, esters, deuterated derivatives or their stereoisomers have good safety;

[0375] (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.

[0376] 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.

[0377] Experimental Example 1: In vitro enzymatic activity of the compounds of the present invention

[0378] Test sample: The compounds synthesized in the embodiments of the present invention have the structural formula shown in Table 1.

[0379] Experimental reagents:

[0380]

[0381] Laboratory consumables:

[0382] Consumables Vendor Cat No. 384-Well plate Perkin Elmer 6007279

[0383] Experimental Method 1:

[0384] 1. Compound dilution

[0385] 1) The compound of the present invention was prepared to 10 mM using DMSO as a test stock solution.

[0386] 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.

[0387] 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%.

[0388] 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.

[0389] 2. Enzyme reaction experiment

[0390] 1) Prepare the enzyme solution in 1× test buffer.

[0391] 2) Add Ubiquitin Rhodamine 110 Protein,CF(Ub-Rho) to 1× test buffer to prepare substrate solution.

[0392] 3) Transfer 10 μL of enzyme solution and 1× reaction buffer to a 384-well plate.

[0393] 4) Incubate at room temperature for 15 minutes.

[0394] 5) Add 10 μL of substrate solution to each well to start the reaction, centrifuge for 30 s, and shake for 30 s.

[0395] 3. Result Detection

[0396] 1) Read the plate on a SpectraMax Paradigm for 30 minutes, with an excitation wavelength of 480nm and an emission wavelength of 540nm.

[0397] 2) Collect data from SpectraMax Paradigm.

[0398] 4. Data Analysis

[0399] The inhibition rate (%inh) is calculated using the following formula:

[0400]

[0401] Where Max represents the luminescence signal intensity of the positive control well without the addition of the compound;

[0402] Min represents the luminescence signal intensity of the negative control well without enzyme addition;

[0403] Signal indicates the intensity of the luminescence signal of the test compound;

[0404] IC is calculated using the following formula. 50 :

[0405]

[0406] Where Y represents: %inhibition;

[0407] X represents the concentration of the compound.

[0408] Experimental results:

[0409] Table 2. Inhibitory activity of the compounds of the present invention against USP-1

[0410]

[0411] 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.

[0412] Experimental Method Two:

[0413] In the enzyme reaction experiment, the room temperature incubation time was changed to 60 min, while other conditions remained the same as in Experimental Method 1. The following test results were obtained:

[0414] Table 3 Inhibitory activity of the compounds of the present invention against USP-1

[0415]

[0416]

[0417] 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.

[0418] Experimental Example 2: In vitro cellular inhibitory activity of the compounds of the present invention

[0419] Test substances: Some compounds of this invention, whose chemical names and structures are given in the preparation examples.

[0420] The cell lines used in the following experiments are as follows: MDA-MB-436: human breast cancer cells.

[0421] Experimental Method 1 (CelltiterGlo assay)

[0422] 1. Prepare cells

[0423] 1.1 Cell Culture:

[0424] All cells were adherent cells, and the culture medium was DMEM + 10% FBS + 1% ITS-G + 16 μg / ml glutathione. The cells were tested during the logarithmic growth phase.

[0425] 1.2 Preparation of cell suspension:

[0426] 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.

[0427]

[0428] 2. Preparation of test compounds

[0429] 2.1 Prepare DMSO stock solutions for the test compounds, with a stock solution concentration of 10 mM for each test compound.

[0430] 2.2 Preparation of working stock solution for test compounds

[0431] The 10 mM stock solution of the test compound was serially diluted 3-fold with DMSO to obtain 8 concentrations. Then, 2 μL of each serially diluted compound with DMSO was added to 198 μL of culture medium to prepare the working stock solution of the test compound (the compound concentration was 10 times the final concentration, with the highest concentration being 100 μM).

[0432] 2.3 Compound Treatment

[0433] 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.

[0434] The final concentrations of the tested compounds were: 10000.00 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, and 4.57 nM.

[0435] 2.4 Setting of reference holes

[0436] Solvent control: 0.1% DMSO.

[0437] Blank control: 96-well plate readings at 0h after drug administration.

[0438] 2.5 Place the 96-well plate in a 37°C, 5% CO2 cell culture incubator and culture for 7 days.

[0439] 3. Testing

[0440] Melt the CTG reagent and equilibrate the 96-well plate to room temperature for 30 minutes. Add 60 μL of reagent (Celltiter Gloassay kit) to each well, shake for 2 minutes to mix (protect from light), and incubate at room temperature for 20 minutes (protect from light). Read the light signal value using a multi-mode microplate reader.

[0441] 4. Data Processing

[0442] 1) Inhibition rate (%) = (DMSO solvent control well reading – test sample well reading) / (DMSO solvent control well reading – blank control well reading) × 100%;

[0443] 2) Plot the graph to obtain the curve and IC. 50 .

[0444] Experimental Results and Conclusions

[0445] Table 4. In vitro cellular activities (IC50) of the compounds of this invention. 50 ,nM)

[0446]

[0447] Experimental Method Two:

[0448] The cell number was changed to 3000 cells / well, and other conditions remained the same as in Experimental Method 1. The following test results were obtained:

[0449] Table 5. In vitro cellular activities (IC50) of the compounds of this invention. 50 ,nM)

[0450]

[0451] Using the above experimental methods, the inhibitory activity of other specific compounds in Table 1 of this application against MDA-MB-436 cells was further tested, and they all showed good inhibitory activity against MDA-MB-436 cells.

[0452] The experimental results above show that the compound of the present invention can effectively inhibit the proliferation of MDA-MB-436 cells, indicating that the compound of the present invention has the potential for clinical application in treating cancerous diseases caused by BRCA1 gene mutations.

[0453] Experimental Method 3:

[0454] The number of cells inoculated was changed to 3000 cells / well.

[0455] The 10 mM stock solution of the test compound was serially diluted 3-fold with DMSO to obtain a total of 9 concentrations.

[0456] 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.

[0457] Under the same conditions as in Experimental Method 1, the IC50 of compound 30 against the inhibitory activity of MDA-MB-436 cells was obtained. 50 The value is less than 200 nM.

[0458] Experimental Example 3: In vitro cellular inhibitory activity of the compounds of the present invention (II)

[0459] Test substances: Some compounds of this invention, whose chemical names and structures are given in the preparation examples.

[0460] The cell lines used in the following experiments are as follows: Caov-3: Homologous recombination repair deficient (HRD+) human ovarian cancer cells.

[0461] Experimental Method 1 (CelltiterGlo assay)

[0462] 1. Prepare cells

[0463] 1.1 Cell Culture:

[0464] All cells were adherent cells. The Caov-3 cells were cultured in DMEM + 10% FBS, and the cells were tested during the logarithmic growth phase.

[0465] 1.2 Preparation of cell suspension:

[0466] 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.

[0467] Table 6 Cell Seeding Number

[0468]

[0469]

[0470] 2. Preparation of test compounds

[0471] 2.1 Prepare DMSO stock solutions for the test compounds, with a stock solution concentration of 10 mM for each test compound.

[0472] 2.2 Preparation of working stock solution for test compounds

[0473] The 10 mM stock solution of the test compound was serially diluted 3-fold with DMSO to obtain 8 concentrations. Then, 2 μL of each serially diluted compound with DMSO was added to 198 μL of culture medium to prepare the working stock solution of the test compound (the compound concentration was 10 times the final concentration, with the highest concentration being 100 μM).

[0474] 2.3 Compound Treatment

[0475] 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.

[0476] The final concentrations of the tested compounds were: 10000.00 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, and 4.57 nM.

[0477] 2.4 Setting of reference holes

[0478] Solvent control: 0.1% DMSO.

[0479] Blank control: 96-well plate readings at 0 h after drug administration.

[0480] 2.5 Place the 96-well plate in a 37°C, 5% CO2 cell culture incubator and culture for 7 days.

[0481] 3. Testing

[0482] Melt the CTG reagent and equilibrate the 96-well plate to room temperature for 30 minutes. Add 60 μL of reagent (Celltiter Gloassay kit) to each well, shake for 2 minutes to mix (protect from light), and incubate at room temperature for 20 minutes (protect from light). Read the light signal value using a multi-mode microplate reader.

[0483] 4. Data Processing

[0484] 1) Inhibition rate (%) = (DMSO solvent control well reading – test sample well reading) / (DMSO solvent control well reading – blank control well reading) × 100%;

[0485] 2) Input the data into GraphPad Prism to plot the curve and obtain the IC. 50 .

[0486] Experimental Results and Conclusions

[0487] IC50 of the inhibitory activity of compounds 9, 18, 23, 24, 26, 27, 29, 2-1, and 27-1 on Caov-3 cells 50 The value is 1-500 nM, indicating that the compound of the present invention can effectively inhibit the proliferation of Caov-3 cells and has the potential for clinical application in treating HRD-positive (homologous recombination defect) cancer.

[0488] Experimental Method Two:

[0489] The 10 mM stock solution of the test compound was serially diluted 3-fold with DMSO to obtain a total of 9 concentrations.

[0490] 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.

[0491] Under the same conditions as in Experimental Method 1, the IC50 of compound 30 against Caov-3 cells was obtained. 50 The value is less than 200 nM.

[0492] Experimental Example 4: Pharmacokinetic Experiment of the Compound of the Present Invention

[0493] 1. Test sample

[0494] The preparation of the compounds in the embodiments of this invention is described in the examples in this application specification.

[0495]

[0496] 2. Preparation of test solution

[0497] (1) Intravenous bolus injection (iv): Take 2.44 mg of compound 9, add 0.0709 ml of DMSO, dissolve by sonication, then add 2.293 ml of 28% HP-β-CD solution, vortex to mix, and a colorless and transparent solution with a concentration of 1 mg / ml is obtained.

[0498] (2) Oral administration (po): Take 3.25 mg of compound 9, place it in a tissue homogenizer, add an appropriate amount of solvent 2% HPC + 0.1% Tween 80 and homogenize. Transfer the homogenizer to a glass bottle and clean it with solvent in small amounts several times. Transfer the cleaning solution to the glass bottle as well. Add a total of 3.149 ml of solvent and mix well to obtain a homogeneous suspension with a final concentration of 1 mg / mL.

[0499] 3. Experimental Methods

[0500] (1) Administration

[0501] The test sample was administered via intravenous bolus injection (iv), with a dose of 5 mg / kg and an administration volume of 5 ml / kg.

[0502] Oral administration (po), the dosage is 10 mg / kg, and the administration volume is 10 ml / kg.

[0503] (2) Blood collection

[0504] Blood samples were collected from the tail vein at 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after drug administration. Approximately 100 μl of whole blood was collected at each time point. The plasma was separated by centrifugation at 8000 rpm for 6 minutes and then stored at -80°C.

[0505] (3) Plasma sample analysis

[0506] Protein precipitation method was used: 20 μl of plasma was added to a 96-well deep plate, 200 μl of internal standard solution was added, vortexed for 10 min, then centrifuged at 4000 rpm for 20 min, 100 μl of supernatant was taken, 100 μL of water was added, and vortexed for 3 min; LC-MS / MS analysis was performed.

[0507] 4. Experimental Results and Conclusions

[0508] Experimental data show that the compounds of the present invention, when administered intravenously or orally, have high exposure levels, suitable half-lives and clearance rates in vivo, exhibiting good pharmacokinetic properties. For example, the bioavailability of compound 9 is over 50%, showing great promise for clinical application. Detailed Implementation

[0509] 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 embodiments 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.

[0510] The abbreviations used in the following experiments have the following meanings:

[0511] Xphos-Pd-G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); TEA: triethylamine; DMAP: 4-dimethylaminopyridine; EA: ethyl acetate; PE: petroleum ether;

[0512] DCM: Dichloromethane; THF: Tetrahydrofuran; DMSO: Dimethyl sulfoxide;

[0513] EDCI: 1-Ethyl-3-(3-dimethylpropylamine)carbodiimide; DIEA: N,N-diisopropylethylamine

[0514] Xphos: 2-Dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; DDQ: 2,3-Dichloro-5,6-dicyano-p-benzoquinone

[0515] Example 1: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[2,1-f]purine (Compound 1)

[0516] (1) Preparation of 2-isothiocyanate-1,1-dimethoxyethane

[0517]

[0518] 2,2-Dimethoxyethane-1-amine (5 g, 48 mmol) was dissolved in ethanol (15 mL), and TEA (4.8 g, 48 mmol) was dissolved in CS2 (36 g, 480 mmol). These solutions were added to the above reaction solution, and the mixture was reacted at 15 °C for 30 min. The temperature was then lowered to 0 °C. (Boc)2O (10 g, 46 mmol) and DMAP (59 mg, 0.48 mmol) were dissolved in ethanol (30 mL) and added to the above reaction solution. The mixture was heated to 15 °C and reacted for 2.5 h. After the reaction was completed, the mixture was evaporated to dryness to obtain 6.8 g of the product, with a yield of 97%.

[0519] (2) Preparation of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl nitrile

[0520]

[0521] 3,3-Dibromo-1,1,1-trifluoropropane-2-one (15 g, 55.6 mmol) was dissolved in water (24 mL), and AcONa (4.1 g, 50 mmol) was added. The mixture was reacted at 100 °C for 1 h, cooled to 15 °C, and a methanol solution of 4-formylbenzylnitrile (6.6 g, 50.3 mmol) (240 mL) and ammonia (48 mL) were added. The mixture was reacted at 15 °C for 40 min, and then heated to 100 °C for 2 h. After the reaction was complete, EA and saturated NaOH solution were added for extraction three times. The organic phase was dried, filtered, and evaporated to dryness. The product was then separated by normal phase preparative separation (PE:EA = 3:1) to obtain 8.3 g of product, with a yield of 69.7%.

[0522] (3) Preparation of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl nitrile

[0523]

[0524] 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl nitrile (8 g, 33.8 mmol) was dissolved in THF (80 mL), and NaH (60%, 1.7 g, 42.5 mmol) was added at 0 °C and reacted for 1 h. Then CH3I (6 g, 42.2 mmol) was added, and the reaction was continued at 0 °C for 2.5 h. After the reaction was complete, EA and saturated NaCl solution were added to the reaction solution for extraction three times by separation. The organic phase was dried, filtered, and evaporated to dryness. The product was then separated by normal phase preparative separation (PE:EA = 3:1) to obtain 7.5 g of product, with a yield of 88.5%.

[0525] (4) Preparation of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methylamine

[0526]

[0527] 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl nitrile (7.4 g, 29.5 mmol) was dissolved in EA (70 mL), ammonia (2 mL) and Raney nickel (8 g) were added, and the mixture was reacted at 15 °C under H2 for 2 h. After the reaction was completed, the mixture was filtered, the filtrate was evaporated to dryness, and the product was separated by normal phase preparative chromatography (DCM:MeOH:TEA = 100:10:1) to obtain 3 g of product, with a yield of 40%.

[0528] (5) Preparation of 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-nitropyrimidine-4-amine

[0529]

[0530] (9.3 g, 36.5 mmol) methylamine was dissolved in THF (100 mL), and DIEA (12 g, 92.9 mmol) was added. A THF solution of 2,4-dichloro-5-nitropyrimidine (8.4 g, 44 mmol) was added at -78 °C, and the reaction was carried out at -78 °C for 1 h. After the reaction was complete, EA and water were added for three hydration extractions. The organic phase was dried, filtered, and evaporated to dryness. The product was then separated by normal phase preparative separation (PE:EA = 3:1 to 1:1) to obtain 12.4 g of product, with a yield of 82.6%.

[0531] (6)2-Chloro-N 4 Preparation of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidine-4,5-diamine

[0532]

[0533] 12.3 g (30 mmol) of 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-nitropyrimidine-4-amine was dissolved in a mixed solvent of THF (60 mL), ethanol (60 mL), and water (20 mL). Fe (10.1 g, 180 mmol) and NH4Cl (3.2 g, 60 mmol) were added, and the reaction was carried out at 85 °C for 1 h. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness and then subjected to normal-phase preparative separation (PE:EA = 1:6) to obtain 7.8 g of the product, with a yield of 68.4%.

[0534] (7) 4'-Cyclopropyl-6'-Methoxy-N 4Preparation of -(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[2,5'-bipyrimidine]-4,5-diamine

[0535]

[0536] 2-chloro-N 4 -(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidine-4,5-diamine (2 g, 5.2 mmol) was dissolved in 1,4-dioxane (20 mL), and (4-cyclopropyl-6-methoxypyrimidine-5-yl)boronic acid (1.3 g, 6.7 mmol), Xphos-Pd-G2 (393 mg, 0.5 mmol), Xphos (495 mg, 1.04 mmol), K3PO4 (1.7 g, 7.8 mmol), and water (2 mL) were added. The mixture was reacted under N2 protection at 100 °C for 4 h in a microwave oven. After the reaction was completed, the solvent was evaporated, and the crude product was obtained by normal-phase preparative separation (DCM:MeOH = 20:1). The crude product was then obtained by reverse-phase preparative separation (water:methanol = 1:3) to give 630 mg of the product, with a yield of 24%.

[0537] (8) Preparation of 1-(4'-cyclopropyl-6'-methoxy-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-[2,5'-bipyrimidin]-5-yl)-3-(2,2-dimethoxyethyl)thiourea

[0538]

[0539] 4'-cyclopropyl-6'-methoxy-N 4 -(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[2,5'-bipyrimidine]-4,5-diamine (580 mg, 1.2 mmol) was dissolved in DMSO (10 mL), and 2-isothiocyanate-1,1-dimethoxyethane (265 mg, 1.8 mmol) was added. The reaction was carried out at 80 °C for 4 h. After the reaction was completed, the reaction solution was used directly for the next step.

[0540] (9) Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(2,2-dimethoxyethyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine-8-amine

[0541]

[0542] Add EDCI (346 mg, 1.8 mmol) and DIEA (232 mg, 1.8 mmol) to the reaction solution from the previous step, and react at 80 °C for 20 h. After the reaction is complete, add EA and water to the reaction solution for three liquid-liquid extractions. Dry the organic phase, filter, and evaporate to dryness. Then, perform normal phase preparative separation (PE:EA = 1:1, DCM:MeOH = 20:1) to obtain 800 mg of crude product.

[0543] (10) Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[2,1-f]purine

[0544]

[0545] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(2,2-dimethoxyethyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine-8-amine (780 mg crude) was dissolved in TFA (10 mL) and reacted at 80 °C for 7 h. After the reaction was completed, the product was directly evaporated to dryness, and the pH was adjusted to 8-9 with saturated NaHCO3 solution. DCM and water were added and extracted three times. The organic phase was evaporated to dryness, and the product was separated by normal phase preparative separation (DCM:MeOH = 40:1) to obtain 54 mg of pure product and 30 mg of crude product.

[0546] Molecular formula: C 27 H 22 F3N9O molecular weight: 545.5 LC-MS (M / e): 545.2 (M+H) + )

[0547] 1 H-NMR (400MHz, CDCl3) δ: 9.24 (s, 1H), 8.70 (s, 1H), 7.90-7.92 (m, 2H), 7.68-7.70 (d, J = 8.0Hz, 2H), 7.56-7.58 (d, J =8Hz,2H),7.20-7.21(d,J=4Hz,1H),5.51(s,2H),3.87(s,3H),3.75(s,3H),2.75(m,1H),1.06(m,2H),1.85(m,2H).

[0548] Example 2 Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine (Compound 2)

[0549] (1) Preparation of 2-chloro-8-(chloromethyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine

[0550]

[0551] 2-Chloro-N-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidine-4,5-diamine (3.0 g, 8 mmol) was dissolved in acetonitrile (50 mL), and p-toluenesulfonic acid (300 mg, 1.74 mmol) and 2-chloro-1,1,1-triethoxyethane (12.0 g, 77.6 mmol) were added. The reaction was carried out at 130 °C for 1.5 h. After the reaction was completed, the product was concentrated and separated by normal phase preparative chromatography (EA:PE = 60%) to give 850 mg of product, with a yield of 24.1%.

[0552] (2) Preparation of (2-chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purin-8-yl)methylamine

[0553]

[0554] 2-Chloro-8-(chloromethyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine (850 mg) was dissolved in 10 mL of ammonia-isopropanol solution and reacted at 80 °C for 3.0 h. After the reaction was completed, the solvent was evaporated and the product was separated by normal phase preparation (MeOH:DCM = 15%) to obtain 380 mg of product, with a yield of 46.8%.

[0555] (3) Preparation of N-((2-chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purin-8-yl)methyl)formamide

[0556]

[0557] At 20°C, 5.0 mL of formic acid was added dropwise to 5 mL of acetic anhydride solution and stirred for 1.0 h. Then, 380 mg of (2-chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine-8-yl)methylamine was added to the above solution, and the reaction was carried out at 25°C for 1.0 h. After the reaction was completed, the solution was concentrated and used directly in the next step.

[0558] (4) Preparation of 2-chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazo[5,1-f]purine

[0559]

[0560] The crude product from the previous step was added to POCl3 (5.0 mL) and reacted at 100 °C for 2.0 h. After the reaction was completed, the product was concentrated and dissolved in 10 mL of ethyl acetate. The pH was then adjusted to 7 with saturated sodium carbonate solution. The product was extracted three times with EA and water. The organic phase was dried, filtered, and evaporated to dryness. The product was then separated by normal phase preparation (DCM:MeOH = 10:1) to obtain 200 mg of product. The yield of the two steps was 51.4%.

[0561] (5) Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine

[0562]

[0563] 2-Chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazo[5,1-f]purine (200 mg, 0.46 mmol) was dissolved in 1,4-dioxane (15.0 mL), and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (120.0 mg, 0.62 mmol), Xphos-Pd-G2 (130.0 mg, 0.17 mmol), Xphos (70.0 mg, 0.15 mmol), K3PO4 (120.0 mg, 0.57 mmol), and water (1.5 mL) were added. The mixture was reacted at 90 °C for 1.5 h under N2 protection. After the reaction was completed, the solvent was evaporated, and the product was separated by normal phase preparation (DCM:MeOH = 10:1) to give 110 mg of product, with a yield of 43.5%.

[0564] Molecular formula: C 27 H 22 F3N9O molecular weight: 545.5 LC-MS (M / e): 545.2 (M+H) + )

[0565] 1 H-NMR (400MHz, CDCl3) δ: 9.00 (s, 1H), 8.70 (s, 1H), 8.07 (s, 1H), 7.68-7.70 (d, J = 8.0Hz, 2H), 7.56-7.58 (d, J = 8Hz, 2H), 7 .28(s,1H),6.57(s,1H),5.43(s,2H),4.15(s,3H),3.77(s,3H),1.78-1.70(m,1H),1.45-1.35(m,2H)1.35-1.45(m,2H).

[0566] Example 3 Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine (Compound 18)

[0567] (1) Preparation of 6-cyclopropylpyrimidine-4-ol

[0568]

[0569] Sodium methoxide (53 g, 981.5 mmol) was added in portions to a methanol (500 mL) solution of formamidine acetate (29 g, 278.6 mmol) and methyl 3-cyclopropyl-3-oxopropionate (20 g, 140.6 mmol). The reaction was carried out at 25 °C for 48 h. TLC (PE:EA = 1:1) showed a small amount of methyl 3-cyclopropyl-3-oxopropionate remaining. The pH of the reaction solution was adjusted to 7 with acetic acid, and the solution was evaporated to dryness. The residue was separated by column chromatography (SiO2, PE:EA = 3:1-1:1-0:1) to give 12 g of product, with a yield of 63%.

[0570] (2) Preparation of 5-bromo-6-cyclopropylpyrimidine-4-ol

[0571]

[0572] At 25°C, liquid bromine (14 g, 88 mmol) was added dropwise to a solution of 6-cyclopropylpyrimidin-4-ol (10 g, 73 mmol) in acetic acid (50 mL). The reaction was carried out at 25°C for 1 h. TLC (PE:EA = 1:1) showed that the reaction was complete. The reaction solution was evaporated to dryness, and the residue was separated by column chromatography (SiO2, DCM:MeOH = 100:0-95:5) to obtain 16 g of crude product. The crude product was then slurried with pure ethyl acetate to obtain 15 g of product, with a yield of 95%.

[0573] (3) Preparation of 5-bromo-4-cyclopropyl-6-(difluoromethoxy)pyrimidine

[0574]

[0575] Sodium hydride (60%, 840 mg, 21 mmol) was added in portions to a suspension of 5-bromo-6-cyclopropylpyrimidin-4-ol (1.5 g, 7 mmol) in acetonitrile (50 mL) at 25 °C. The reaction was carried out at 25 °C for 0.5 h. Then, 2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.1 g, 11.8 mmol) was added, and the reaction was carried out at 25 °C for 15 h. TLC (PE:EA = 1:1) showed a small amount of 5-bromo-6-cyclopropylpyrimidin-4-ol remaining. The reaction solution was quenched with water, extracted with ethyl acetate, dried over an evaporator, and the residue was separated by column chromatography (SiO2, PE:EA = 10:1-6:1) to give 500 mg of product, with a yield of 27%.

[0576] (4) Preparation of 4-cyclopropyl-6-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyrimidine

[0577]

[0578] 5-Bromo-4-cyclopropyl-6-(difluoromethoxy)pyrimidine (100 mg, 0.38 mmol), pinacol diboronate (192 mg, 0.76 mmol), Pd(dppf)Cl2 (28 mg, 0.038 mmol), potassium acetate (111 mg, 1.13 mmol), and dioxane (4 mL) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times and reacted at 95 °C for 5 h. LC-MS showed the formation of the target product. The reaction solution was diluted with ethyl acetate, filtered, and the filtrate was evaporated to dryness. The residue was separated by preparative thin-layer chromatography (SiO2, PE:EA = 1:1, Rf ~ 0.8) to obtain 70 mg of crude product.

[0579] (5) Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine

[0580]

[0581] Add the following to the reaction flask sequentially: 4-cyclopropyl-6-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)pyrimidine (70 mg, crude), 2-chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazo[5,1-f]purine (40 mg), potassium phosphate (60 mg), Xphos-Pd-G2 (10 mg), and X... Phosphine (8 mg), dioxane (3 mL), and water (0.5 mL) were added, and the mixture was purged with nitrogen three times. The reaction was carried out at 90 °C for 2 h. LC-MS showed that the reaction was complete. The reaction solution was filtered, and the filtrate was evaporated to dryness. The residue was first separated by preparative thin-layer chromatography (SiO2, DCM:MeOH = 20:1, Rf ~ 0.4), and then separated by reversed-phase column chromatography (C18, water:methanol = 90:10-30:70) to obtain 9.65 mg of product. The two-step yield was 4%.

[0582] Molecular formula: C 27 H 20 F5N9O molecular weight: 581.5 LC-MS (m / z): 582.1 (M+H) + )

[0583] 1 H-NMR(400MHz, CDCl3)δ:8.99(s,1H),8.71(s,1H),8.07(s,1H),7.76-7.35(m,5H),7.31(s,1H), 6.64(s,1H),5.37(s,2H),3.74(s,3H),2.03-1.92(m,1H),1.36-1.30(m,2H),1.08-0.90(m,2H).

[0584] Example 4 Preparation of 2-(4-cyclopropyl-6-ethoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazo[5,1-f]purine (Compound 19)

[0585] (1) Preparation of 5-bromo-4-chloro-6-cyclopropylpyrimidine

[0586]

[0587] 5-Bromo-6-cyclopropylpyrimidine-4-ol (1.3 g, 6.0 mmol) was dissolved in phosphorus oxychloride (10 mL) and reacted at 90 °C for 2 h. After the reaction was complete, it was used directly in the next step.

[0588] (2) Preparation of 5-bromo-4-cyclopropyl-6-ethoxypyrimidine

[0589]

[0590] Anhydrous ethanol (15 mL) was added to the reaction solution of 5-bromo-4-chloro-6-cyclopropylpyrimidine at 0 °C, and the reaction was carried out at 60 °C for 1 h. After the reaction was completed, the solvent was evaporated, the pH was adjusted to about 8 with saturated sodium bicarbonate solution, and the product was extracted with ethyl acetate (50 mL). The product was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 20:1) to give 1.0 g of product. The two-step yield was 68.1%.

[0591] (3) Preparation of (4-cyclopropyl-6-ethoxypyrimidin-5-yl)boronic acid

[0592]

[0593] 5-Bromo-4-cyclopropyl-6-ethoxypyrimidine (200 mg, 0.82 mmol) and triisopropyl borate (216 mg, 1.1 mmol) were dissolved in tetrahydrofuran (7 mL), cooled to -78 °C, and n-butyllithium (2.5 M) (0.46 mL) was added dropwise. The reaction was carried out at -78 °C for 2 hours. The pH was adjusted to 5-6 with 3 M hydrochloric acid, and then adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (20 mL), concentrated, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to give 80 mg of the product, with a yield of 46.7%.

[0594] (4) Preparation of 2-(4-cyclopropyl-6-ethoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazo[5,1-f]purine

[0595]

[0596] 2-Chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazo[5,1-f]purine (70 mg, 0.16 mmol) was dissolved in 1,4-dioxane (12 mL) and water (3 mL), and (4-cyclopropyl-6-ethoxypyrimidin-5-yl)boronic acid (35 mg, 0.17 mmol), Xphos-Pd-G2 (14 mg, 0.018 mmol), Xphos (18 mg, 0.038 mmol), and K3PO4 (39 mg, 0.18 mmol) were added. Under N2 protection, the reaction was carried out at 90℃ for 3 hours. After the reaction was completed, the product was extracted with water (20 mL) and ethyl acetate (30 mL), concentrated, and the crude product was purified by preparative silica gel plate (DCM:MeOH = 17:1) to obtain 60 mg of product. The product was then purified by C18 column (methanol / water = 0-70%) to obtain 14 mg of product, with a yield of 15.4%.

[0597] Molecular formula: C 28 H24 F3N9O molecular weight: 559.6 LC-MS (M / e): 560.2 (M+H) + )

[0598] 1 H-NMR (400MHz, CDCl3) δ: 9.00 (s, 1H), 8.67 (s, 1H), 8.07 (s, 1H), 7.72-7.60 (d, J = 6.4Hz, 2H), 7.56-7.50 (d, J = 6.4Hz, 2H), 7.3 2(s,1H),6.57(s,1H),5.43(s,2H),4.55-4.40(m,2H),3.79(s,3H),1.78-1.70(m,1H),1.41-1.23(m,5H),0.95-0.87(m,2H).

[0599] Example 5 Preparation of 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-[1,2,4]triazolyl[3,4-f]purine (Compound 9)

[0600] (1) Preparation of 2-chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purine-8-thione

[0601]

[0602] 2-chloro-N 4 -(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidine-4,5-diamine (1.6 g, 4.2 mmol), imidazole (569 mg, 8.36 mmol), and S-CDI (1.49 g, 8.36 mmol) were added to DCM (40 mL), and the system was reacted at 25 °C for 2 hours. A solid precipitated from the system, which was then filtered under reduced pressure. The filter cake was washed with DCM (5 mL × 2) and dried to give the target compound (1.7 g, yield 95.3%).

[0603] (2) Preparation of 2,8-dichloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine

[0604]

[0605] 1.5 g (3.5 mmol) of 2-chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purine-8-thione (2.5 g, 3.5 mmol) was added to a mixed solution of thionyl chloride (2.1 g, 17.6 mmol) and acetonitrile (20 mL), and the reaction was carried out at 80 °C for 3 hours. The temperature was lowered to 25 °C, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (DCM:MeOH = 30:1) to give 600 mg of the target compound in pure form and 700 mg of the crude product.

[0606] (3) Preparation of 2-chloro-8-hydrazino-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine

[0607]

[0608] Hydrazine hydrate (80%, 367 mg, 5.8 mmol) was added to 15 mL of THF containing 2,8-dichloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine (500 mg, 1.2 mmol), and the reaction was carried out at 25 °C for 3 hours. The temperature was lowered to 25 °C, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (DCM:MeOH = 10:1) to give 400 mg of the target compound, yield: 78.8%.

[0609] (4) Preparation of 7-chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-[1,2,4]triazolyl[3,4-f]purine

[0610]

[0611] 2-Chloro-8-hydrazino-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine (350 mg, 0.83 mmol), triethyl orthoformate (1.2 g, 8.4 mmol), and formic acid (38 mg, 0.83 mmol) were added to 1,4-dioxane (15 mL), and the reaction was carried out at 110 °C for 3 hours. The temperature was lowered to 25 °C, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (DCM:MeOH = 20:1) to give 240 mg of the target compound, yield: 66.8%.

[0612] (5) Preparation of 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-[1,2,4]triazolyl[3,4-f]purine

[0613]

[0614] 7-chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-[1,2,4]triazolyl[3,4-f]purine (120 mg, 0.28 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (54 mg, 0.28 mmol), XPhos Pd G2 (22 mg, 0.028 mmol), XPhos (27 mg, 0.057 mmol), and potassium phosphate (178 mg, 0.84 mmol) were added to a system containing 1,4-dioxane (12 mL) and water (2 mL), and reacted at 90 °C for 2 hours under nitrogen atmosphere. The temperature was lowered to 25°C, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (DCM:MeOH = 25:1) to obtain 75 mg of crude target compound. Then, it was purified by C18 reverse purification (water:methanol = 3:7) to obtain 35 mg of target compound, with a yield of 22.9%.

[0615] Molecular formula: C 26 H 21 F3N 10 Molecular weight: 546.5 LC-MS (M / e): 547.1 (M+H) + )

[0616] 1 H-NMR (400MHz, CDCl3) δ: 9.08 (s, 1H), 8.76 (s, 1H), 8.72 (s, 1H), 7.78 (d, J = 8.0Hz, 2H), 7.63 (d, J = 8.0Hz, 2H), 7.31(s,1H),5.59(s,2H),3.97(s,3H),3.75(s,3H),1.75-1.68(m,1H),1.32-1.28(m,2H),0.96-0.92(m,2H).

[0617] Example 6 Preparation of 2-(4-cyclopropylpyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazo[5,1-f]purine (Compound 20)

[0618] (1) Preparation of 5-bromo-4-cyclopropylpyrimidine

[0619]

[0620] Cyclopropylmagnesium bromide (26.5 mL) was added dropwise to a THF (60 mL) solution of 5-bromopyrimidine (4 g, 25.2 mmol) at 0 °C, and the reaction was carried out at 30 °C for 1 h. Then, DDQ (5.7 g, 25.2 mmol) was added, and the reaction was carried out at 30 °C for 6 h. The product was then separated by normal-phase preparative chromatography (ethyl acetate / petroleum ether = 5%–10%) to give 1.2 g, yield 24%.

[0621] (2) Preparation of 4-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyrimidine

[0622]

[0623] 5-Bromo-4-cyclopropylpyrimidine (1.1 g, 5.5 mmol), bis(boron) (2.1 g, 8.3 mmol), and potassium acetate (1.1 g, 5.5 mmol) were added.

[0624] A solution of 1,4-dioxane (20 ml) containing 11.1 mmol of Pd(dppf)Cl2 (402 mg, 0.55 mmol) was reacted at 100 °C for 4 h under nitrogen protection. The product was then separated by normal phase preparation (ethyl acetate / petroleum ether = 10%-20%) to obtain 1.1 g, with a yield of 81.2%.

[0625] (3) Preparation of 2-(4-cyclopropylpyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazo[5,1-f]purine

[0626]

[0627] 2-Chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine (177 mg, 0.41 mmol) was dissolved in 1,4-dioxane (8 mL), and 4-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrimidine (100 mg, 0.41 mmol), Xphos-Pd-G2 (31.4 mg, 0.04 mmol), Xphos (38.1 mg, 0.08 mmol), K3PO4 (131.6 mg, 0.6 mmol), and water (2 mL) were added. The mixture was reacted at 10 °C for 3 h under N2 protection. After the reaction was completed, the solvent was evaporated, and the product was separated by reverse phase preparation (acetonitrile / water = 0-50%) to give 16 mg, with a yield of 7.6%.

[0628] Molecular formula: C 26 H 20 F3N9 molecular weight: 515.5 LC-MS (M / e): 516.2 (M+H) +)

[0629] 1 H-NMR(400MHz, CDCl3)δ:9.17(s,1H),9.14(s,1H),9.06(s,1H),8.09(s,1H),7.68-7.66(d,2H),7.56-7.53(d,2 H),7.32(s,1H),6.61(s,1H),5.44(s,2H),3.77(s,3H),3.09-3.05(m,1H),1.39-1.37(m,2H),1.16-1.10(m.2H).

[0630] Example 7 Preparation of 2-(4-cyclopropyl-6-(trifluoromethyl)pyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine (Compound 21)

[0631] (1) Preparation of 4-cyclopropyl-6-(trifluoromethyl)pyrimidine

[0632]

[0633] 4-Chloro-6-(trifluoromethyl)pyrimidine (12.0 g, 65.8 mmol) and cyclopropylboronic acid (14.1 g, 164.1 mmol) were dissolved in 1,4-dioxane (300 mL), and [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (2.4 g, 3.3 mmol), potassium phosphate (41.5 g, 195.5 mmol), and silver oxide (7.6 g, 32.8 mmol) were added. The reaction was carried out at 100 °C for 4 h under nitrogen protection. After the reaction was completed, the solution was concentrated and purified by silica gel column chromatography (n-heptane:ethyl acetate = 15:1) to give 2.3 g of the product, with a yield of 18.6%.

[0634] (2) Preparation of 5-bromo-4-cyclopropyl-6-(trifluoromethyl)pyrimidine

[0635]

[0636] 4-Cyclopropyl-6-(trifluoromethyl)pyrimidine (2.3 g, 12.2 mmol) was dissolved in anhydrous ethanol (50 mL), cooled to -10 °C, and bromine (7.8 g, 48.8 mmol) was added dropwise. The reaction was carried out at 30 °C for 16 h. After the reaction was completed, the pH was adjusted to about 8 with saturated sodium bicarbonate solution, and the product was extracted with dichloromethane (150 mL). The product was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 20:1) to give 1.0 g of product, with a yield of 30.6%.

[0637] (3) Preparation of 4-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-6-(trifluoromethyl)pyrimidine

[0638]

[0639] 5-Bromo-4-cyclopropyl-6-(trifluoromethyl)pyrimidine (350 mg, 1.3 mmol) and bis-pinacol boronic acid ester (500 mg, 2.0 mmol) were dissolved in 1,4-dioxane (10 mL), and tetra(triphenylphosphine)palladium (150 mg, 0.13 mmol) and potassium acetate (390 mg, 4.0 mmol) were added. The reaction was carried out at 100 °C for 16 h under nitrogen protection. After the reaction was completed, the solution was concentrated and purified by silica gel column chromatography (n-heptane:ethyl acetate = 10:1) to give 250 mg of crude product.

[0640] (4) Preparation of 2-(4-cyclopropyl-6-(trifluoromethyl)pyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine

[0641]

[0642] 2-Chloro-9-(4-(1-(4-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazo[5,1-f]purine (50 mg, 0.12 mmol) was dissolved in 1,4-dioxane (12 mL) and water (3 mL). 4-Cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)-6-(trifluoromethyl)pyrimidine (100 mg, crude), tetra(triphenylphosphine)palladium (15 mg, 0.013 mmol), and sodium carbonate (38 mg, 0.36 mmol) were added. The reaction was carried out at 90 °C for 3 h under nitrogen protection. After the reaction was complete, the mixture was filtered, concentrated, and purified using preparative silica gel filtration (DCM:MeOH = 14:1) to obtain 15 mg of the product. This product was then purified by high-pressure preparative liquid chromatography (methanol / water = 0-90%) to obtain 1.3 mg of the product.

[0643] Molecular formula: C 27 H 19 F6N9 molecular weight: 583.5 LC-MS (M / e): 584.2 (M+H) + )

[0644] 1H-NMR (400MHz, CDCl3) δ: 9.21 (s, 1H), 8.99 (s, 1H), 8.09 (s, 1H), 7.65 (d, J = 6.4Hz, 2H), 7.52 (d, J = 6.4Hz, 2H), 7.33(s,1H),6.64(s,1H),5.40(s,2H),3.76(s,3H),1.82-1.70(m,1H),1.45-1.33(m,2H),1.15-1.04(m,2H).

[0645] Example 8 Preparation of 2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine (Compound 23)

[0646] (1) Preparation of 1-isopropyl-4-methyl-1H-pyrazole

[0647]

[0648] 4-Methyl-1H-pyrazole (4.0 g, 48.7 mmol) was dissolved in tetrahydrofuran (55 mL). 60% NaH (2.2 g, 55.0 mmol) was added in portions to this solution at 0 °C. After the addition was complete, the reaction was stirred at 25 °C for 1 h. Iodopropane (10.0 g, 58.8 mmol) was added, and the reaction was placed in a sealed tube and reacted at 100 °C for 2.0 h. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated and subjected to column chromatography (SiO2, ethyl acetate: petroleum ether = 30%) to give 5.0 g of the target product, with a yield of 82.6%.

[0649] (2) Preparation of 1-isopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl)-1H-pyrazole

[0650]

[0651] 1-Isopropyl-4-methyl-1H-pyrazole (200 mg, 1.6 mmol) was dissolved in tetrahydrofuran (10 mL), and n-BuLi (1.3 mL, 3.3 mmol) was added at 0 °C. After stirring for 1.0 h, the system was cooled to -78 °C, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxorane (300 mg, 1.6 mmol) was added dropwise. After the addition was complete, the mixture was stirred for 1.0 h, then heated to 25 °C and stirred for another 3.0 h. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated. The residue was subjected to column chromatography (SiO2, ethyl acetate: petroleum ether = 30%) to give 85 mg of the product, with a yield of 21.1%.

[0652] (3) Preparation of 2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine

[0653]

[0654] 2-Chloro-9-(4-(1-(-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazo[5,1-f]purine (110 mg, 0.25 mmol) was dissolved in 1,4-dioxane (15 mL) and water (3 mL), and 1-isopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole (60 mg) was added. The reaction mixture consisted of 25 mg (0.24 mmol), XPhos-Pd-G2 (25 mg, 0.03 mmol), XPhos (15 mg, 0.03 mmol), and potassium phosphate (110 mg, 0.52 mmol). The reaction was carried out under N2 protection at 95 °C for 2.0 h. After the reaction was complete, the mixture was filtered, concentrated, and purified by column chromatography (SiO2, dichloromethane:methanol = 15:1) to give 16 mg of product, with a yield of 12.8%.

[0655] Molecular formula: C 26 H 24 F3N9 molecular weight: 519.5 LC-MS (M / e): 520.2 (M+H) + )

[0656] 1 H-NMR (400MHz, CDCl3) δ: 8.95 (s, 1H), 9.05 (s, 1H), 7.65-7.62 (m, 2H), 7.55 (d, J = 8.4Hz, 2H), 7.48 (s, 1H) ),7.32(s,1H),6.57(s,1H)5.56-5.54(m,1H),5.43(s,2H),3.76(s,3H),2.37(s,3H),1.59-1.55(m,6H).

[0657] Example 9 Preparation of 2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-imidazol[5,1-f]purine (Compound 24)

[0658] (1) Preparation of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol

[0659]

[0660] Methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate (4.0 g, 14.1 mmol) was dissolved in tetrahydrofuran (50 mL). Diisobutylaluminum hydride (1.5 M, 30 mL, 45.0 mmol) was added in portions to this solution at 25 °C. After the addition was complete, the reaction was stirred at 30 °C for 2.0 h, quenched with water, extracted with ethyl acetate, and the organic phase was concentrated and subjected to column chromatography (silica, ethyl acetate: petroleum ether = 30%) to give 3.5 g of the target product, with a yield of 97.1%.

[0661] (2) Preparation of 1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole

[0662]

[0663] (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (3.5 g, 13.6 mmol) was dissolved in 1,2-dichloroethane (30 mL), and thionyl chloride (8.1 g, 68.1 mmol) was added. The system was stirred at 70 °C for 1.0 h, concentrated, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was concentrated to obtain the crude product, which was directly used in the next reaction.

[0664] (3) Preparation of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamine

[0665]

[0666] The crude product from the previous step was dissolved in 30 mL of ethanol and 30 mL of ammonia water, and reacted at 70 °C for 1.0 h in a sealed tube. After concentration, the product was obtained by column chromatography (silica, methanol: dichloromethane = 10%), yielding 3.0 g of the target product. The two-step yield was 86.1%.

[0667] (4) Preparation of 2-chloro-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-5-nitropyrimidine-4-amine

[0668]

[0669] 2,4-Dichloro-5-nitropyrimidine (2.3 g, 11.8 mmol) and DIEA (1.6 g, 12.4 mmol) were dissolved in tetrahydrofuran (50 mL). The system was then subjected to the addition of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamine (3.0 g, 11.8 mmol) at -78 °C. The reaction was allowed to proceed for 1.5 h. After concentration and column chromatography (silica, ethyl acetate: petroleum ether = 60%-80%), 3.5 g of the target product was obtained, with a yield of 72.1%.

[0670] (5) 2-Chloro-N 4 Preparation of 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrimidine-4,5-diamine

[0671]

[0672] 2-Chloro-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-5-nitropyrimidine-4-amine (3.5 g, 8.5 mmol) and iron powder (2.4 g, 42.9 mmol) were dissolved in 10 mL of acetic acid, 10 mL of ethanol, and 10 mL of water. The mixture was reacted at 75 °C for 1.0 h, filtered, concentrated, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was concentrated and subjected to column chromatography (silica, ethyl acetate: petroleum ether = 80%-100%) to give 2.8 g of the target product, with a yield of 86.3%.

[0673] (6) Preparation of 2-chloro-8-(chloromethyl)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-purine

[0674]

[0675] 2-Chloro-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-5-nitropyrimidine-4-amine (2.8 g, 7.3 mmol), 2-chloro-1,1,1-trimethoxyethane (6.0 g, 38.8 mmol), and p-toluenesulfonic acid (600 mg, 3.5 mmol) were dissolved in 50 mL of dioxane and reacted at 120 °C for 10 h. After concentration and column chromatography (silica, ethyl acetate: petroleum ether = 60%-80%), 1.5 g of the target product was obtained, with a yield of 46.5%.

[0676] (7) Preparation of 2-chloro-8-(methylamine)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-purine

[0677]

[0678] 1.4 g (3.2 mmol) of 2-chloro-8-(chloromethyl)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-purine was dissolved in 20 mL of NH3 / isopropanol solution and reacted at 70 °C for 1.0 h after sealing. The product was concentrated and subjected to column chromatography (silica, methanol:dichloromethane = 10%) to give 1.0 g of the target product, with a yield of 74.1%.

[0679] (8) Preparation of N-((2-chloro-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-purin-8-yl)methyl)formamide

[0680]

[0681] Add 10 mL of formic acid to 10 mL of acetic anhydride and react at 25 °C for 1.0 h. Then add 2-chloro-8-(methylamine)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-purine (900 mg, 2.1 mmol) and continue the reaction for another 1.0 h. Concentrate the product and use the crude product directly in the next step of the reaction.

[0682] (9) Preparation of 2-chloro-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-imidazo[5,1-f]purine

[0683]

[0684] The crude product from the previous step was dissolved in 10 mL of phosphorus oxychloride and reacted at 110 °C for 3.0 h. The mixture was concentrated, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and the product was extracted with ethyl acetate. The organic phase was concentrated and subjected to column chromatography (silica, methanol: dichloromethane = 10%) to obtain 500 mg of the target product. The two-step yield was 54.2%.

[0685] (10) Preparation of 2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-imidazol[5,1-f]purine

[0686]

[0687] 2-Chloro-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-imidazo[5,1-f]purine (440 mg, 1.0 mmol) was dissolved in 1,4-dioxane (40 mL) and water (5 mL), and 1-isopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl)-1H-pyrazol (240 mg, 1.0 mmol), XPhos-Pd-G2 (100 mg, 0.12 mmol), XPhos (60 mg, 0.13 mmol) and potassium phosphate (450 mg, 2.1 mmol) were added. Under nitrogen protection, the reaction was carried out at 95°C for 2.0 h. After the reaction was completed, the mixture was filtered, concentrated, and purified by column chromatography (silica, dichloromethane:methanol = 15:1) to obtain 56 mg of product, with a yield of 10.8%.

[0688] Molecular formula: C 26 H 24 F3N9 molecular weight: 519.5 LC-MS (M / e): 520.2 (M+H) + )

[0689] 1 H-NMR(400MHz, CDCl3)δ:9.47(s,1H),8.05(s,1H),7.65-7.62(m,2H),7.55-7.53(m,3H),6.60(s ,1H),6.45(s,1H),5.56-5.54(m,1H),5.43(s,2H),2.48(s,3H),2.46(s,3H),1.59-1.55(m,6H).

[0690] Example 10 Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine (Compound 26)

[0691] (1) Preparation of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile

[0692]

[0693] Sodium acetate (177.0 g, 2.2 mol) was added to an aqueous solution (285 mL) of 291.0 g, 1.1 mol of 3,3-dibromo-1,1,1-trifluoropropane-2-one. The reaction was carried out at 100 °C for 1 h, then cooled to 0 °C. Methanol (475 mL), 4-formylbenzonitrile (95.0 g, 0.72 mol), and ammonia (285 mL) were added sequentially. The reaction was carried out at 25 °C for 1 h, then increased to 100 °C for 5 h. LC-MS showed that the reaction was complete. The reaction solution was poured into a large amount of water, filtered, the filter cake was washed with water, and dried to obtain a crude product. This crude product was pulped with PE / EA (5:1), filtered, and dried to obtain 120.0 g of product, with a yield of 69.8%.

[0694] (2) Preparation of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile

[0695]

[0696] To a DMF (200 mL) solution of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (25.0 g, 105.4 mmol), cesium carbonate (51.5 g, 158.1 mmol) and 2-iodopropane (53.8 g, 316.5 mmol) were added. The reaction was carried out at 130 °C for 11 h. LC-MS showed a small amount of starting material remaining. 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 = 6:1-5:1) to give 14.0 g of product, with a yield of 47.6%.

[0697] (3) Preparation of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methylamine

[0698]

[0699] At 0°C, 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (40 g, 143.2 mmol) was added in portions to a suspension of lithium aluminum hydride (16.3 g, 429.5 mmol) in tetrahydrofuran (500 mL). The mixture was reacted at 25°C for 2 h. LC-MS showed that the reaction was complete. At 0°C, water (16 mL) and 10% sodium hydroxide solution (32 mL) were added dropwise to the reaction solution. The mixture was stirred at 25°C for 1 h. Diatomaceous earth was then added and stirred for 10 min. The mixture was filtered, and the filtrate was evaporated to dryness to obtain 41.5 g of crude product.

[0700] (4) Preparation of 2-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-nitropyrimidine-4-amine

[0701]

[0702] At -78°C, DIEA (27.4 g, 212.1 mmol) and (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methylamine (40.0 g, 141.2 mmol) in tetrahydrofuran (100 mL) were added sequentially to a solution of 2,4-dichloro-5-nitropyrimidine (28.8 g, 148.5 mmol) in tetrahydrofuran (500 mL). The reaction was carried out at -78°C for 3 h. LC-MS showed that the reaction was complete. The reaction solution was filtered, and the filtrate was evaporated to dryness to obtain 70.0 g of crude product.

[0703] (5) 2-Chloro-N 4 Preparation of -(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidine-4,5-diamine

[0704]

[0705] Iron powder (44.5 g, 0.79 mol), ammonium chloride (42.5 g, 0.79 mol), and water (200 mL) were added sequentially to an ethanol (1.0 L) suspension of 2-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-nitropyrimidine-4-amine (70.0 g crude product). The mixture was reacted at 80 °C for 4 h. LC-MS showed that the reaction was complete. The reaction solution was filtered, the filtrate was evaporated to dryness, and the residue was slurried with DCM / MeOH (10:1), filtered, and the filtrate was evaporated to dryness to obtain 69.0 g of crude product.

[0706] (6) Preparation of 2-chloro-8-(chloromethyl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine

[0707]

[0708] Weigh out 2-chloro-N in sequence 4 -(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidine-4,5-diamine (69.0 g crude), 2-chloro-1,1,1-trimethoxyethane (129.8 g, 0.84 mol), p-toluenesulfonic acid (2.9 g, 16.8 mmol), and dioxane (500 mL) were reacted at 120 °C for 20 h. 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 = 4:1-2:1) to give 31.0 g of product. The four-step yield was 46.1%.

[0709] (7) Preparation of (2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine-8-yl)methylamine

[0710]

[0711] 2-Chloro-8-(chloromethyl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine (21.0 g, 44.7 mmol) was added to a solution of ammonia in isopropanol (2 M, 300 mL, 600.0 mmol), and the reaction was carried out at 70 °C for 4 h. LC-MS showed that the reaction was complete. The reaction solution was evaporated to dryness to give 20.0 g of crude product.

[0712] (8) Preparation of 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine

[0713]

[0714] Acetic anhydride (100 mL) was added to formic acid (100 mL), and the mixture was reacted at 30 °C for 1 h. This mixture was then added to (2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purin-8-yl)methylamine (20.0 g crude product), and the mixture was reacted at 30 °C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was evaporated to dryness to obtain the crude product. Phosphorus oxychloride (200 mL) was added to this crude product, and the mixture was reacted at 110 °C for 2 h. LC-MS showed that the reaction was complete. The reaction solution was evaporated to dryness to obtain the crude product. The residue was diluted with water, and the pH was adjusted to neutral with sodium bicarbonate. The mixture was extracted with DCM, and the organic phase was evaporated to dryness to obtain the crude product. The residue was separated by column chromatography (SiO2, DCM:MeOH = 98:2-96:2) to obtain 11.0 g crude product. This crude product was pulped with EA, filtered, and dried to obtain 3.4 g solid. The two-step yield was 16.5%.

[0715] (9) Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine

[0716]

[0717] Add 4-cyclopropyl-6-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyrimidine (650 mg, crude), 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine (400 mg, 0.87 mmol), potassium phosphate (554 mg, 2.6 mmol), and XPos-Pd-G2 (68 mg, crude) sequentially to the reaction flask. 0.086 mmol), XPhos (41 mg, 0.086 mmol), dioxane (20 mL) and water (4 mL), purged with nitrogen three times, reacted at 90 °C for 2 h, and LC-MS showed that the reaction was complete. The reaction solution was filtered, the filtrate was evaporated to dryness, and the residue was first separated by column chromatography (SiO2, DCM:MeOH = 98:2-96:4) and then by reversed-phase column chromatography (C18, water:methanol = 80:20-40:60) to obtain 224 mg of product, with a yield of 42.2%.

[0718] Molecular formula: C 29 H 24 F5N9O molecular weight: 609.6 LC-MS (m / z): 610.2 (M+H) + )

[0719] 1 H-NMR(400MHz, CDCl3)δ:8.99(s,1H),8.71(s,1H),8.07(s,1H),7.76-7.54(m,6H),6.67(s,1H),5.41( s,2H),4.53-4.49(m,1H),1.98-1.94(m,1H),1.46-1.43(m,6H),1.36-1.30(m,2H),1.08-1.02(m,2H).

[0720] Example 11 Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine (Compound 27)

[0721]

[0722] Add (4-cyclopropyl-6-methoxypyrimidin-5-yl)boric acid (260 mg crude), 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine (400 mg, 0.87 mmol), potassium phosphate (554 mg, 2.6 mmol), XPhos-Pd-G2 (68 mg, 0.086 mmol), XPh OS (41 mg, 0.086 mmol), dioxane (20 mL), and water (4 mL) were added. The mixture was purged with nitrogen three times and reacted at 90 °C for 2 h. LC-MS showed that the reaction was complete. The reaction solution was filtered, and the filtrate was evaporated to dryness. The residue was first separated by column chromatography (SiO2, DCM:MeOH = 98:2-96:4) and then by reversed-phase column chromatography (C18, water:methanol = 80:20-40:60) to obtain 352 mg of product, with a yield of 70.6%.

[0723] Molecular formula: C 29 H 26 F3N9O molecular weight: 573.6 LC-MS (m / z): 574.3 (M+H) + )

[0724] 1 H-NMR(400MHz, CDCl3)δ:9.00(s,1H),8.69(s,1H),8.08(s,1H),7.56-7.54(m,4H),7.43(s,1H),6.60(s,1H),5.42( s,2H),4.54-4.49(m,1H),3.96(s,3H),1.78-1.724(m,1H),1.46-1.43(m,6H),1.29-1.25(m,2H),0.95-0.90(m,2H).

[0725] Example 12 Preparation of 9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-9H-imidazol[5,1-f]purine (Compound 29)

[0726]

[0727] Add 1-isopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl)-1H-pyrazole (85 mg, 0.34 mmol), 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine (150 mg, 0.33 mmol), and potassium phosphate (150 mg, 0.71 mmol) sequentially to the reaction flask. The reaction mixture consisted of 15 mg (1 mol), XPhos-Pd-G2 (24 mg, 0.031 mmol), XPhos (15 mg, 0.031 mmol), dioxane (20 mL), and water (4 mL). The mixture was purged with nitrogen three times and reacted at 95 °C for 2.5 h. LC-MS showed that the reaction was complete. The reaction solution was filtered, the filtrate was evaporated to dryness, and the residue was separated by column chromatography (SiO2, DCM:MeOH = 10:1) to obtain 30 mg of product, with a yield of 16.8%.

[0728] Molecular formula: C 28 H 28 F3N9 molecular weight: 547.6 LC-MS (m / z): 548.3 (M+H) + )

[0729] 1 H-NMR(400MHz, CDCl3)δ:8.95(s,1H),8.05(s,1H),7.56-7.54(m,4H),7.51-7.43(s,2H),6.60(s,1 H),5.56(t,1H),5.41(s,2H),4.55-4.52(m,1H),2.36(s,3H),1.65-1.60(m,6H),1.52-1.48(m,6H).

[0730] Example 13 Preparation of 7-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-[1,2,4]triazolo[3,4-f]purine (Compound 30)

[0731]

[0732] 7-chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-[1,2,4]triazolo[3,4-f]purine (80 mg, 0.18 mmol), 4-cyclopropyl-6-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrimidine (481 mg, 0.54 mmol, 35%), XPhosPd G2 (14 mg, 0.018 mmol), XPhos (17 mg, 0.036 mmol), and potassium phosphate (115 mg, 0.54 mmol, 35%) were dissolved in 1,4-dioxane / water (6 / 1 = 30 / 5 mL). After nitrogen purging, the mixture was heated to 90 °C and stirred for 2 hours. After the reaction was complete as detected by LC-MS, water (50 mL) and ethyl acetate (50 mL × 3) were added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography (EA:PE = 1:1). The organic phase was concentrated to give the target compound (20 mg, yield 19.0%).

[0733] Molecular formula: C 26 H 19 F5N 10 Molecular weight: 582.2 LC-MS (M / e): 583.2 (M+H) + )

[0734] 1 H-NMR(400MHz,CD3OD)δ:9.29(s,1H),9.15(s,1H),8.72(s,1H),7.86-7.72(m,2H),7.68-7.64(m,2H),7. 62-7.50(m,2H),5.61(s,2H),3.74-3.64(m,3H),1.93-1.89(m,1H),1.27-1.23(m,2H),1.02-0.89(m,2H).

[0735] Example 14 Preparation of 2-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine (Compound 2-1)

[0736] (1) Preparation of 5-bromo-4-chloro-6-cyclopropylpyrimidine

[0737]

[0738] 5-Bromo-6-cyclopropylpyrimidin-4-ol (200 mg, 0.93 mmol) was dissolved in phosphorus oxychloride (3 mL) and reacted at 90 °C for 0.5 h. After the reaction was complete, it was used directly in the next step.

[0739] (2) Preparation of 5-bromo-4-cyclopropyl-6-(methoxy-d3)pyrimidine

[0740]

[0741] At 0°C, deuterated methanol (4 mL) was added to the reaction solution of 5-bromo-4-chloro-6-cyclopropylpyrimidine, and the reaction was carried out at 60°C for 2 h. After the reaction was completed, the solvent was evaporated, the pH was adjusted to about 8 with saturated sodium bicarbonate solution, and the product was extracted with ethyl acetate (20 mL). The crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 15:1) to obtain 1.0 g of product.

[0742] (3) Preparation of 4-cyclopropyl-6-(methoxy-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyrimidine

[0743]

[0744] 5-Bromo-4-cyclopropyl-6-(methoxy-d3)pyrimidine (70 mg, 0.30 mmol) and pinacol diboronate (153 mg, 0.60 mmol) were dissolved in 1,4-dioxane (5 mL), and tetrakis(triphenylphosphine palladium) (35 mg, 0.030 mmol) and potassium acetate (90 mg, 0.92 mmol) were added. The reaction was carried out at 100 °C for 16 h under N2 protection. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 10:1) to give 150 mg of crude product.

[0745] (4) Preparation of 2-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine

[0746]

[0747] 2-Chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazo[5,1-f]purine (80 mg, 0.19 mmol) and 4-cyclopropyl-6-(methoxy-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyrimidine (150 mg, crude) were dissolved in 1,4-dioxane (7 mL) and water (2 mL). Xphos-Pd-G2 (16 mg, 0.020 mmol), Xphos (20 mg, 0.042 mmol), and K3PO4 (44 mg, 0.21 mmol) were added. The reaction was carried out at 90 °C for 4 h under N2 protection. After the reaction was completed, the solution was concentrated and purified by silica gel column chromatography (DCM:MeOH = 14:1) to give 36 mg of product.

[0748] Molecular formula: C 27 H 19 D3F3N9O molecular weight: 548.5 LC-MS (M / e): 549.2 (M+H) + )

[0749] 1 H-NMR (400MHz, CDCl3) δ: 9.00 (s, 1H), 8.69 (s, 1H), 8.07 (s, 1H), 7.65 (d, J = 8.4Hz, 2H), 7.55 (d, J = 8.0Hz, 2H) ,7.33(s,1H),6.57(s,1H),5.40(s,2H)3.76(s,3H),1.82-1.70(m,1H),1.35-1.20(m,2H),0.99-0.87(m,2H).

[0750] Example 15 Preparation of 2-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine (Compound 27-1)

[0751]

[0752] Add the following to the reaction flask in sequence: (4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)boronic acid (200 mg, 1.0 mmol), 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazol[5,1-f]purine (400 mg, 0.87 mmol), potassium phosphate (554 mg, 2.6 mmol), and XPos-Pd-G2 (68 mg, 0.086 mmol). XPhos (41 mg, 0.086 mmol), dioxane (20 mL), and water (4 mL) were added. The mixture was purged with nitrogen three times and reacted at 90 °C for 2 h. LC-MS showed that the reaction was complete. The reaction solution was filtered, and the filtrate was evaporated to dryness. The residue was first separated by column chromatography (SiO2, DCM:MeOH = 98:2-96:4) and then by reversed-phase column chromatography (C18, water:methanol = 80:20-40:60) to obtain 250 mg of product, with a yield of 50.0%.

[0753] Molecular formula: C 29 H 23 D3F3N9O molecular weight: 576.2 LC-MS (m / z): 577.2 (M+H) + )

[0754] 1 H-NMR(400MHz, CDCl3)δ:9.00(s,1H),8.69(s,1H),8.08(s,1H),7.56-7.54(m,4H),7.43(s,1H),6.60(s,1H), 5.42(s,2H),4.54-4.49(m,1H),1.78-1.724(m,1H),1.46-1.43(m,6H),1.29-1.25(m,2H),0.95-0.90(m,2H).

[0755] The compounds shown in the following table were prepared using the same or similar methods as those used in the above examples:

[0756]

[0757] 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. Compounds of general formula (VI), their pharmaceutically acceptable salts or deuterated derivatives, Expression (VI) in, X3 and X4 are independently selected from N or CR. a ; R 1 Selected from phenyl groups substituted with 1-4 Q2 groups or 5-6 membered heteroaryl groups; R 3 Selected from pyrrole, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl groups, each substituted with 1 to 3 Q2 groups; R 4 Selected from deuterium, hydrogen, carboxyl, cyano, nitro, amino, halogen, 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, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or halogenated C 1-6 Alkoxy; Each Q2 is independently selected from deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, sulfonamide, and optionally substituted with 1-4 substituents Q3. m -C 1-6 Alkyl group, -(L) m -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 group, -(L) m -3-8 membered cycloalkyl or -(L) m -3-8 membered heterocyclic groups, each Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, -CO-C 1-6 Alkyl-NH2, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy; Each L is independently selected from -CR a R b -; Each R a Each R b The C groups are independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, and cyano groups, with the C group optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, 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 or carboxyl C 1-6 alkyl; s is an integer selected from 0 to 3; Each m and each n are independently 0, 1, 2, and 3, respectively.

2. The compound of claim 1, its pharmaceutically acceptable salt or deuterated derivative, in, X3 and X4 are independently selected from N or CR. a ; R 1 Selected from phenyl groups substituted with 1-4 Q2 groups or 5-6 membered heteroaryl groups; R 3 Selected from pyrrole, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl groups, each substituted with 1 to 3 Q2 groups; R 4 Selected from deuterium, hydrogen, cyano, halogen, 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, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or halogenated C 1-6 Alkoxy; Each Q2 is independently selected from deuterium, halogen, cyano, and optionally substituted with 1-4 Q3 substituents (-(L)). m -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 group, -(L) m -3-6 membered cycloalkyl or -(L) m -3-6 membered heterocyclic groups, each Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy; Each L is independently selected from -CR a R b -; Each R a Each R b The C atoms are independently selected from deuterium, hydrogen, and halogen, and are optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl; s is an integer selected from 0 to 3; Each m and each n are independently 0, 1, 2, and 3, respectively.

3. The compound as described in claim 1 or 2, its pharmaceutically acceptable salt or deuterated derivative, in, X3 and X4 are independently selected from N or CR. a ; R 1 Selected from phenyl, furanyl, thiophene, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, 2-pyridonel, 4-pyridonel, pyrimidinyl, pyridazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetraazinyl; R 3 Selected from pyrrole, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl groups, each substituted with 1 to 3 Q2 groups; R 4 Selected from deuterium, hydrogen, trifluoromethyl, trifluoromethoxy, and optionally deuterated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, or difluoromethoxy; Each Q2 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, and optionally substituted with 1-3 substituents Q3 (-(L)). m -C 1-4 Alkyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, monofluoromethoxy, difluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, -(L) m -3-6-membered cycloalkyl, each Q3 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, cyano, nitro, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl, carboxyethyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy; Each L is independently selected from -CR a R b -; Each R a Each R b Each 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, and isopropoxy. s is an integer selected from 0 to 3; Each m and each n are independently 0, 1, 2, and 3, respectively.

4. The compound of claim 1, its pharmaceutically acceptable salt or deuterated derivative, wherein, X3 and X4 are each independently selected from N or CH; R 1 Selected from phenyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, 2-pyridonel, 4-pyridonel, pyrimidinyl, pyridazinyl, and pyrazinyl; R 3 Selected from pyrrole, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl groups, each substituted with 1 to 3 Q2 groups; R 4 Selected from deuterium, hydrogen, cyano, halogen, 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 or halogenated C 1-6 Alkoxy; Each Q2 is independently selected from deuterium, halogen, and C, optionally substituted with 1-3 substituents Q3. 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, 3-6 membered cycloalkyl, each Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy; L stands for -CH2-; n is 1.

5. The compound of claim 4, its pharmaceutically acceptable salt or deuterated derivative, wherein, R 1 Selected from those that can be replaced by 1-3 Q2s. , , , , , , , , , , ; R 3 Selected from those that can be replaced by 1-3 Q2s. , , , , , , , , ; Each Q2 is independently selected from deuterium, halogen, and C, optionally substituted with 1-3 substituents Q3. 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, 3-6 membered cycloalkyl, each Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkyl group.

6. The compound of claim 1, its pharmaceutically acceptable salt or deuterated derivative, having the following general formula structure, Formula (V) or Equation (VII-1) X 10 Selected from NR c or CR a R b ; Each R c The C atoms are independently selected from deuterium and hydrogen, respectively, and are optionally deuterated. 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl; Each R 3 Each R 4 The definitions of each Q2 and each s are as described in claim 1.

7. The compound of claim 1, its pharmaceutically acceptable salt or deuterated derivative, having the structure shown in formula (V-1), Equation (V-1) in, R 5 Selected from C that has been replaced by deuterium 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy; Each s is an independent integer between 0 and 2; R 3 R 4 Each Q2 is defined as described in claim 1.

8. The following compounds, their pharmaceutically acceptable salts or deuterated derivatives:

9. A pharmaceutical preparation comprising the compound of any one of claims 1-8, a pharmaceutically acceptable salt or deuterated form thereof, and one or more pharmaceutical carriers and / or diluents; said pharmaceutical preparation being any clinically or pharmaceutically acceptable dosage form.

10. A pharmaceutical composition comprising the compound of any one of claims 1-8, a pharmaceutically acceptable salt or deuterated form thereof, and one or more second therapeutic agents; optionally, the pharmaceutical composition further comprising one or more pharmaceutical carriers and / or diluents.

11. Use of the compound of any one of claims 1-8, its pharmaceutically acceptable salt, deuterated form, or pharmaceutical formulation of claim 9, or pharmaceutical composition of claim 10, in the preparation of a medicament for the treatment and / or prevention of USP1-mediated diseases and related diseases.

12. Prepare an intermediate of the compound shown in general formula (VI) having the following structure: (WE') in, G is a halogen; R 3 R 4 The definitions of X3, X4, each Q2, each L, n, and s are as defined in any one of the preceding claims 1-8.

Images