Tricyclic ubiquitin-specific protease 1 inhibitors and uses thereof

Abstract

The present invention relates to the field of pharmaceutical technology, in particular to a tricyclic ubiquitin-specific protease 1 inhibitor compound, its pharma- ceutically acceptable salt, its ester, its deuterated form or its stereoisomer; pharmaceutical compositions and preparations comprising said compound, its pharma- ceutically acceptable salt, its ester, its deuterated form or its stereoisomer; a method for preparing said compound, its pharma- ceutically acceptable salt, its ester, its deuterated form or its stereoisomer; and the use of said compound, its pharma- ceutically acceptable salt, its ester, its deuterated form or its stereoisomer in the manufacture of a medicament for treating and / or preventing USP1-mediated and related diseases. JPEG2024516447000138.jpg32167

Description

[Technical field]

[0001] The present invention relates to the field of pharmaceutical technology, in particular to a tricyclic ubiquitin-specific protease 1 inhibitor compound, its pharma- ceutically acceptable salt, its ester, its deuterated form or its stereoisomer; pharmaceutical compositions and preparations comprising said compound, its pharma- ceutically acceptable salt, its ester, its deuterated form or its stereoisomer; a method for preparing said compound, its pharma- ceutically acceptable salt, its ester, its deuterated form or its stereoisomer; and the use of said compound, its pharma- ceutically acceptable salt, its ester, its deuterated form or its stereoisomer in the manufacture of a medicament for treating and / or preventing USP1-mediated and related diseases. [Background technology]

[0002] Tumor development and progression involve many related targets. Deubiquitylating enzymes (DUBs) are encoded by over 100 human genes and are divided into six families. Among them, ubiquitin-specific proteases (USPs) are the largest family of DUBs, containing over 50 members. Ubiquitination is a reversible process. DUBs act on the ubiquitin-protease system to bind lysines and UBQs. (Ubiquitin) and affects cell proliferation, cycle, apoptosis, DNA damage response, tumor suppression, development and metastasis.

[0003] USP1 (Ubiquitin specific protease 1) is a member of the USP family and is a cysteine ​​isopeptidase that contains a triplet structure of Cys90, His593, and Asp751. The human USP1 gene was cloned in 1998 and encodes a protein of 785 amino acids. Under normal conditions, USP1 is relatively inactive, but UAF1 (USPl-associated factor 1; WD40, which binds to USP1 and regulates its activity) is a cysteine ​​isopeptidase that is capable of regulating the activity of USP1. (A conserved sequence of 40 amino acids ending with tryptophan and aspartic acid)It is activated by binding to a heterodimeric complex containing a repeat-containing cofactor, where it acts as a deubiquitinase, stabilizes replication forks, and localizes to the cell nucleus.

[0004] USP1 is highly expressed in breast and ovarian cancers, and its expression is increased in other cancers. USP1 overexpression is associated with BRCA1 deficiency in breast and ovarian cancers. 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 anaemia group D2 protein). In TLS, USP1 deubiquitinates PCNA (proliferating cell nuclear antigen). In cell differentiation, USP1 affects the ubiquitination of ID (family of DNA-binding protein inhibitors) to regulate cell proliferation and differentiation.

[0005] These DNA damage response (DDR) pathways are crucial for the repair of DNA damage caused by DNA cross-linking agents such as cisplatin and ultraviolet light. In the TLS pathway, PCNA, which is influenced by USP1, participates in DNA break repair together with USP1 / UAF1 and BRCA1 / 2. After replication forks stall, RAD18-mediated PCNA monoubiquitination promotes PCNA binding to convert replicative polymerases (polδ / ε) to TLS polymerases (e.g., POLK), and after bypassing the foci via TLS polymerases, USP1 further deubiquitinates PCNA, promoting PCNA binding to convert to replicative polymerases. Inhibition of USP1 leads to replication fork instability and is associated with BRCA mutations and synthetic lethality.

[0006] USP1 inhibitors inhibit DNA break repair in which PCNA participates with USP1 / UAF1 and BRCA1 / 2, destabilizing replication forks. Therefore, inhibition of USP1 with small molecule inhibitors may have therapeutic applications in cancer and other diseases, but is not yet commercialized or in clinical development. Summary of the Invention

[0007] The present invention aims to provide a tricyclic ubiquitin-specific protease 1 inhibitor and its use. The specific technical solutions are as follows: Scheme 1: The present invention first provides a compound represented by general formula (I), a pharma- ceutically acceptable salt, ester, deuterated product, or stereoisomer thereof. JPEG0007652935000001.jpg38169 In the formula, X1, X2, X3, and X4 each independently represent N or CR. a is selected from R 1 , R 2 , R 3 are each independently selected from a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, or a 5- to 12-membered heteroaryl group, each of which may be substituted by one or more Q1; R 4 , R 5 are each independently deuterium, hydrogen, a carboxyl group, a cyano group, a nitro group, an amino group, a halogen, or C 2-6 Alkenyl group, C 2-6 Alkynyl groups, optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylamino group, di(C 1-6 Alkyl)amino group, halogenated C 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl group, carboxy C 1-6 Alkyl or halogenated C 1-6 alkoxy groups, Each Q1 is independently selected from deuterium, halogen, cyano, carboxy, hydroxy, amino, nitro, and sulfonylamino groups, and C optionally substituted with 1 to 4 substituents Q2. 1-6 Alkylamino group, di(C 1-6 Alkyl)amino group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl group, carboxy C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, C 1-6 Alkoxycarbonyl group, C 1-6 Alkylaminoacyl group, C 1-6 Alkylamide group, C 1-6 Alkylsulfonyl group, C 1-6 Alkylsulfonylamino group, C 1-6 Alkylaminosulfonyl group, -(L) m -C 1-6 Alkyl group, -(L) m -C 2-6 Alkenyl group, -(L) m -C 2-6 Alkynyl group, -(L) m -C 1-6 Alkoxy group, -(L) m -6-10 membered aryl group, -(L) m -5-12 membered heteroaryl group, -(L) m -3-8 membered cycloalkyl group or -(L) m -3-8 membered heterocyclyl groups, each Q2 is independently selected from deuterium, halogen, carboxyl group, hydroxyl group, cyano group, nitro group, amino group, C 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, carboxy C 1-6 Alkyl group, C 1-6 Alkylamino group, di(C 1-6 Alkyl)amino group, -CO-C 1-6 Alkylene-NH2, -CO-C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl and halogenated C1-6 alkoxy groups, L is independently -CO-, -O-, -S-, -SO-, -S(O)2-, or -NR c -, -CR a R b - selected from Each R a , each R b are each independently deuterium, hydrogen, halogen, amino group, hydroxyl group, carboxyl group, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups, optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylamino group, di(C 1-6 alkyl)amino group, C 1-6 Alkylaminoacyl group, C 1-6 Alkylamide group, C 1-6 Alkylsulfonylamino group, C 1-6 Alkylaminosulfonyl group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl group, carboxy C 1-6 alkyl group; Each R c are each independently deuterium, hydrogen, or optionally deuterated C 1-6 Alkyl groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl group, carboxy C 1-6 alkyl groups, each m is independently an integer from 0 to 3; Each n is independently an integer from 0 to 6.

[0008] Scheme 2: In the compound according to Scheme 1, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, X1, X2, X3, and X4 each independently represent N or CR. a is selected from R 1 , R 2 , R 3 are each independently selected from a 5- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, each of which may be substituted by one or more Q1; R 4 , R 5 are each independently deuterium, hydrogen, a cyano group, a halogen, or an optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylamino group, di(C 1-6 Alkyl)amino group, halogenated C 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl group, carboxy C 1-6 Alkyl or halogenated C 1-6 alkoxy groups, Each Q1 is independently selected from deuterium, halogen, cyano, and C optionally substituted with 1 to 4 substituents Q2. 1-6 Alkoxy group, C 1-6 Alkylamino group, di(C 1-6 Alkyl)amino group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl group, carboxy C 1-6 Alkyl group, -(L) m -C 1-6 Alkyl group, -(L) m -3-6 membered cycloalkyl group or -(L) m -3-6 membered heterocyclyl groups, each Q2 is independently selected from deuterium, halogen, carboxyl group, hydroxyl group, cyano group, nitro group, amino group, C 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, carboxy C 1-6 Alkyl group, C 1-6Alkylamino group, di(C 1-6 alkyl)amino group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl and halogenated C 1-6 alkoxy groups, Each L is independently -CO-, -O-, or -NR c -, -CR a R b - selected from Each R a and each R b are each independently deuterium, hydrogen, or optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylamino group, di(C 1-6 Alkyl)amino group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl group, carboxy C 1-6 alkyl groups, Each R c are each independently deuterium, hydrogen, or optionally deuterated C 1-6 Alkyl groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 alkoxy groups, each m is independently an integer from 0 to 2; Each n is independently an integer from 0 to 5.

[0009] Scheme 3: In the compound according to Scheme 1 or 2, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof or a stereoisomer thereof, X1, X2, X3, and X4 are each independently N; R 1 , R 2 , R 3 are each independently selected from a phenyl group or a 5- to 6-membered heteroaryl group optionally substituted with 1 to 4 Q1; R 4 , R 5are each independently deuterium, hydrogen, or optionally deuterated C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Alkylamino group, di(C 1-4 Alkyl)amino group, halogenated C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, amino C 1-4 Alkyl group, carboxy C 1-4 Alkyl or halogenated C 1-4 alkoxy groups, Each Q1 is independently selected from the group consisting of deuterium, halogen, and C, which may be substituted with 1 to 3 substituents Q2. 1-4 Alkoxy group, C 1-4 Alkylamino group, di(C 1-4 Alkyl)amino group, halogenated C 1-4 Alkyl groups, halogenated C 1-4 Alkoxy group, hydroxy C 1-4 Alkyl group, amino C 1-4 Alkyl group, carboxy C 1-4 Alkyl group, -(L) m -C 1-4 Alkyl group, -(L) m Each Q2 is independently selected from the group consisting of deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, carboxy C 1-4 Alkyl group, C 1-4 Alkylamino group, di(C 1-4 alkyl)amino group, C 1-4 Alkoxy groups, halogenated C 1-4 Alkyl and halogenated C 1-4 alkoxy groups, Each L is independently -CR a R b - or -O-, Each R a and each R b are each independently deuterium, hydrogen, or optionally deuterated C 1-4 Alkyl group, C 1-4Alkoxy group, C 1-4 Alkylamino group, di(C 1-4 Alkyl)amino group, halogenated C 1-4 Alkyl groups, halogenated C 1-4 Alkoxy group, hydroxy C 1-4 Alkyl group, amino C 1-4 Alkyl group, carboxy C 1-4 alkyl groups, Each R c are each independently deuterium, hydrogen, or optionally deuterated C 1-4 Alkyl groups, halogenated C 1-4 Alkyl groups, halogenated C 1-4 alkoxy groups, each m is independently an integer from 0 to 2; Each n is independently an integer from 0 to 4.

[0010] Scheme 4: A compound according to any one of the above schemes, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, X1, X2, X3, and X4 are each independently N; R 1 , R 2 , R 3 are each independently selected from a phenyl group, a furyl group, a thienyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, an imidazolyl group, a pyrazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a pyridyl group, a 2-pyridonyl group, a 4-pyridonyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a 1,2,3-triazinyl group, a 1,3,5-triazinyl group, and a 1,2,4,5-tetrazinyl group, each of which may be substituted by 1 to 3 Q1; R 4 , R 5are each independently selected from deuterium, hydrogen, an optionally deuterated methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a methylamino group, a dimethylamino group, a monofluoromethyl group, a difluoromethyl group, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, an aminomethyl group, a carboxymethyl group, a carboxyethyl group, and a trifluoromethoxy group; Each Q1 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, a methoxy group optionally substituted by 1 to 3 substituents Q2, an ethoxy group, a propoxy group, an isopropoxy group, a methylamino group, a dimethylamino group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, an aminomethyl group, a carboxymethyl group, a carboxyethyl group, -(L) m -C 1-4 Alkyl group, -(L) m each Q2 is independently selected from deuterium, a halogen, a carboxy group, a hydroxy group, a cyano group, a nitro group, an amino group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, a carboxymethyl group, a carboxyethyl group, a methylamino group, a dimethylamino group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group; Each L is independently -CR a R b - and Each R a and each R bare each independently selected from deuterium, hydrogen, an optionally deuterated methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group; each m is independently selected from 0, 1, and 2; Each n is independently selected from 0, 1, 2, and 3.

[0011] Scheme 5: A compound according to any one of the above schemes, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, R 1 , R 2 , R 3 are each independently selected from a phenyl group or a 5- to 6-membered nitrogen-containing heteroaryl group optionally substituted with 1 to 4 Q1.

[0012] Scheme 6: A compound according to any one of the above schemes, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, R 1 , R 2 , R 3 are each independently selected from a phenyl group, a furyl group, a thienyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, and a pyrazinyl group, each of which may be substituted by 1 to 3 Q1.

[0013] Scheme 7: In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product or its stereoisomer, R 1 , R 2 , R 3are each independently selected from a phenyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, and a pyrazinyl group, each of which may be substituted by 1 to 3 Q1.

[0014] Scheme 7-1: A compound according to any one of the above schemes, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, R 1 , R 2 , R 3 are each independently selected from a phenyl group, a pyrimidinyl group, a pyridyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, a pyridazinyl group, and a pyrazinyl group, each of which may be substituted with 1 to 3 Q1.

[0015] Scheme 7-2: In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product, or its stereoisomer, R 1 , R 3 are each independently optionally substituted with 1 to 3 Q1. JPEG0007652935000002.jpg36168 is selected.

[0016] Scheme 7-3: In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product, or its stereoisomer, R 1 may be substituted with 1-3 Q1 JPEG0007652935000003.jpg30168, preferably R 1 may be substituted with 1-3 Q1 Selected from JPEG0007652935000004.jpg17168.

[0017] Scheme 7-4: In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product, or its stereoisomer, R 3 may be substituted with 1-3 Q1 JPEG0007652935000005.jpg34168, preferably R 3 may be substituted with 1-3 Q1 JPEG0007652935000006.jpg18168, preferably R 3 may be substituted with 1-3 Q1 Selected from JPEG0007652935000007.jpg17168.

[0018] Scheme 7-5: In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product, or its stereoisomer, R 2 is selected from a phenyl group or a pyridyl group optionally substituted with 1 to 3 Q1.

[0019] Scheme 8: A compound according to any one of the above schemes having a structure represented by formula (II), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000008.jpg32168In formula, each L, each R a , each R b , each R c , R 1 , R 2 , R 3 The definitions of Q1, Q2, m, and n are the same as in any one of the schemes described above.

[0020] Scheme 8-1: A compound according to any one of the above schemes having a structure represented by formula (II-1), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000009.jpg32168In formula, each L, each Ra , each R b , each R c , R 1 , R 2 , R 3 , R 4 , R 5 The definitions of Q1, Q2, m, and n are the same as in any one of the schemes described above.

[0021] Scheme 9: A compound according to any one of the above schemes having a structure represented by general formula (III), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000010.jpg35168 In the formula, Y1, Y2, Y3, Y4, and Y6 each independently represent N, C, or CR. a is selected from Y5 and Y7 each independently represent N or NR c , C, C.R. a R b or CR a is selected from -- and are each independently selected from a single bond or a double bond, and two adjacent bonds may not simultaneously be double bonds; each s is independently selected from an integer of 0 to 2; Each Q1, m, each L, each R a , each R b , each R c The definition of is the same as in any one of the schemes above.

[0022] Scheme 9-1: A compound according to any one of the above schemes having a structure represented by general formula (III-1), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000011.jpg35168 In the formula, Y1, Y2, Y3, Y4, and Y6 each independently represent N, C, or CR. a is selected from Y5 and Y7 each independently represent N or NR c , C, C.R. a R b or CRa is selected from -- and - is independently selected from a single bond or a double bond, and two adjacent bonds may not simultaneously be double bonds; each s is independently selected from an integer of 0 to 3; Each Q1, m, each L, each R a , each R b , each R c , R 4 , R 5 The definition of is the same as in any one of the schemes above.

[0023] Scheme 9-2: A compound according to any one of the above schemes having a structure represented by general formula (III-1'), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof or a stereoisomer thereof. JPEG0007652935000012.jpg35168In formula, R 6 is hydrogen, optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 alkoxy groups, Y1, Y2, Y3, Y4, and Y6 each independently represent N, C, or CR. a is selected from Y5 and Y7 each independently represent N or NR c , C, C.R. a R b or CR a is selected from -- and are each independently selected from a single bond or a double bond, and two adjacent bonds may not simultaneously be double bonds; each s is independently selected from an integer of 0 to 3; Each Q1, m, each L, each R a , each R b , each R c , R 4 , R 5 The definition of is the same as in any one of the schemes above.

[0024] Scheme 9-3: In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product, or its stereoisomer, R 6 is hydrogen, deuterated C 1-6 Alkyl group or deuterated C 1-6 The alkoxy group is selected from the group consisting of aryl, ... and aryl groups.

[0025] Scheme 9-4: In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product, or its stereoisomer, Y1, Y2, Y3, Y4, and Y6 are each independently selected from N, C, or CH; Y5, Y7 are each independently selected from N, NH, C, CH2, or CH.

[0026] Scheme 9-5: In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product, or its stereoisomer, JPEG0007652935000013.jpg14168 has the following structure: Selected from JPEG0007652935000014.jpg14168.

[0027] Scheme 9-6: In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product, or its stereoisomer, JPEG0007652935000015.jpg11168 has the following structure: Selected from JPEG0007652935000016.jpg16168.

[0028] Scheme 10: A compound according to any one of the above schemes having the structure represented by (IV), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000017.jpg35168, where Q1 and m are defined as in any one of the above schemes, -- and are each independently selected from a single bond or a double bond, and two adjacent bonds may not simultaneously be double bonds; The definitions of Y1, Y2, Y5, Y6, Y7, and each s are the same as in any one of the above-mentioned schemes.

[0029] Scheme 10-1: A compound according to any one of the above schemes having a structure represented by formula (IV-1), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000018.jpg39168 formula, - - and are each independently selected from a single bond or a double bond, and two adjacent bonds may not simultaneously be double bonds; Each Q1, m, R 4 , R 5 , each R a , each R b The definitions of Y1, Y2, Y5, Y6, Y7, and each s are the same as in any one of the above-mentioned schemes.

[0030] Scheme 10-2: A compound according to any one of the above schemes having a structure represented by formula (IV-1'), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000019.jpg39168In formula, R 6 is hydrogen, optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 alkoxy groups, -- and are each independently selected from a single bond or a double bond, and two adjacent bonds may not simultaneously be double bonds; Each Q1, m, R 4 , R 5 , each R a , each R bThe definitions of Y1, Y2, Y5, Y6, Y7, and each s are the same as in any one of the above-mentioned schemes.

[0031] Scheme 10-3: In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product, or its stereoisomer, R 6 is hydrogen, deuterated C 1-6 Alkyl group or deuterated C 1-6 The alkoxy group is selected from the group consisting of aryl, ... and aryl groups.

[0032] Scheme 10-4: In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product, or its stereoisomer, R a , R b are each independently hydrogen.

[0033] Scheme 11: A compound according to any one of the above schemes having a structure represented by formula (V), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. In the formula JPEG0007652935000020.jpg33168, the definitions of Q1, Y1, Y2, and s are the same as in any one of the schemes described above.

[0034] Scheme 11-1: A compound according to any one of the above schemes having a structure represented by formula (V-1), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000021.jpg39168In formula, each Q1, R 4 , R 5 , R a , R b The definitions of Y1, Y2, and each s are the same as in any one of the above schemes.

[0035] Scheme 11-2: A compound according to any one of the above schemes having a structure represented by formula (V-1'), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000022.jpg39168In formula, R 6 is hydrogen, optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 alkoxy groups, Each Q1, R 4 , R 5 , R a , R b The definitions of Y1, Y2, and each s are the same as in any one of the above schemes.

[0036] Scheme 11-3: In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product, or its stereoisomer, R 6 is hydrogen, deuterated C 1-6 Alkyl group or deuterated C 1-6 The alkoxy group is selected from the group consisting of aryl, ... and aryl groups.

[0037] Scheme 12: In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product or its stereoisomer, Each Q1 is independently selected from the group consisting of deuterium, halogen, and C, which may be substituted with 1 to 4 substituents Q2. 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylamino group, di(C 1-6 Alkyl)amino group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl group, carboxy C 1-6 Alkyl group, -(L) m -3-6 membered cycloalkyl group or -(L) m-3-6 membered heterocyclyl groups, each Q2 is independently selected from deuterium, halogen, carboxyl group, hydroxyl group, cyano group, nitro group, amino group, C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl and halogenated C 1-6 The alkoxy group is selected from the group consisting of aryl, ... and aryl groups.

[0038] Scheme 12-1: A compound according to any one of the above schemes, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, Each Q1 is independently selected from the group consisting of deuterium, halogen, and C, which may be substituted with 1 to 3 substituents Q2. 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 each Q2 is independently selected from deuterium, halogen, C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl and halogenated C 1-6 The alkoxy group is selected from the group consisting of aryl, ... and aryl groups.

[0039] Scheme 13: A compound according to any one of the above schemes, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, Each Q1 is independently selected from the group consisting of deuterium, halogen, and C, which may be substituted with 1 to 3 substituents Q2. 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Alkylamino group, di(C 1-4 Alkyl)amino group, halogenated C 1-4 Alkyl groups, halogenated C 1-4 Alkoxy group, hydroxy C 1-4 Alkyl group, amino C 1-4 Alkyl group, carboxy C 1-4each Q2 is independently selected from a deuterium atom, a halogen atom, a carboxyl group, a hydroxyl group, a cyano group, a nitro group, an amino group, a C 1-4 Alkyl group, C 1-4 Alkoxy groups, halogenated C 1-4 Alkyl and halogenated C 1-4 The alkoxy group is selected from the group consisting of aryl, ... and aryl groups.

[0040] Scheme 13-1: A compound according to any one of the above schemes, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, Each Q1 is independently selected from the group consisting of deuterium, halogen, and C, which may be substituted with 1 to 3 substituents Q2. 1-4 Alkyl group, C 1-4 Alkoxy groups, halogenated C 1-4 Alkyl groups, halogenated C 1-4 each Q2 is independently selected from deuterium, C 1-4 Alkyl group, C 1-4 Alkoxy groups, halogenated C 1-4 Alkyl and halogenated C 1-4 The alkoxy group is selected from the group consisting of aryl, ... and aryl groups.

[0041] Scheme 14: A compound according to any one of the above schemes, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, Each Q1 independently represents deuterium, fluorine, chlorine, bromine, iodine, a methyl group optionally substituted by 1 to 3 substituents Q2, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a methylamino group, a dimethylamino group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, an aminomethyl group, a carboxymethyl group, a carboxyethyl group, a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group. mosquito and each Q2 is independently selected from deuterium, a halogen, a carboxy group, a hydroxy group, a cyano group, a nitro group, an amino group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group.

[0042] Scheme 14-1: A compound according to any one of the above schemes, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, Each Q1 is independently deuterium, fluorine, chlorine, bromine, iodine, a methyl group optionally substituted by 1 to 3 substituents Q2, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group. mosquitoand each Q2 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0043] Scheme 15: A compound according to any one of the above schemes, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, Each L is independently -CR a R b - and Each R a , each R b are each independently deuterium, hydrogen, or optionally deuterated C 1-4 Alkyl group, C 1-4 Alkoxy groups, halogenated C 1-4 Alkyl groups, halogenated C 1-4 The alkoxy group is selected from the group consisting of aryl, ... and aryl groups. Scheme 15-1: A compound according to any one of the above schemes, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, Each L is independently -CR a R b - and Each R a and each R b are each independently deuterium, hydrogen, or optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 The alkoxy group is selected from the group consisting of aryl, ... and aryl groups.

[0044] Scheme 16: A compound according to any one of the above schemes, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, Each L is independently -CH2-.

[0045] Scheme 17: A compound according to any one of the above schemes having a structure represented by formula (VI), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000023.jpg35168 where Y8 is N, NR c , C, C.R. a R b or CR a is selected from Y9 is N, C or CR a is selected from -- and are each independently selected from a single bond or a double bond, and two adjacent bonds may not simultaneously be double bonds; Each Q1, each L, m, R 4 , R 5 , Y3, Y4, Y5, Y6, Y7, and each s are defined as in any one of the above schemes.

[0046] Scheme 17-1: In the compound described in Scheme 17, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, Y8 is selected from N, NH, C, CH2 or CH; Y9 is selected from N, C or CH; -- and are each independently selected from a single bond or a double bond, and two adjacent bonds may not simultaneously be double bonds; Each Q1, each L, m, R 4 , R 5 , Y3, Y4, Y5, Y6, Y7, and each s are defined as in any one of the above schemes.

[0047] Scheme 18: A compound according to any one of the above schemes having the structure of formula (VII), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. In the formula JPEG0007652935000024.jpg35168, the definitions of Q1, m, Y1, Y2, and each s are the same as in any one of the schemes described above.

[0048] Scheme 18-1: A compound according to any one of the above schemes having a structure represented by formula (VII-1), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000025.jpg35168In formula, each Q1, m, Y1, Y2, each s, R 4 , R 5 The definition of is the same as in any one of the schemes above.

[0049] Scheme 18-2: A compound according to any one of the above schemes having a structure represented by formula (VII-1'), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000026.jpg35168In formula, R 6 is hydrogen, optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 alkoxy groups, Each Q1, m, Y1, Y2, each s, R 4 , R 5 The definition of is the same as in any one of the schemes above.

[0050] Scheme 18-3: In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product, or its stereoisomer, R 6 is hydrogen, deuterated C 1-6 Alkyl group or deuterated C 1-6 The alkoxy group is selected from the group consisting of aryl, ... and aryl groups.

[0051] Scheme 19: A compound according to any one of the above schemes having a structure represented by formula (VIII), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. In the formula JPEG0007652935000027.jpg34168, the definitions of each Q1, m, and each s are the same as in any one of the schemes described above.

[0052] Scheme 19-1: A compound according to any one of the above schemes having a structure represented by formula (VIII-1), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000028.jpg35168In formula, each Q1, m, R 4 , R 5 , the definition of each s is the same as in any one of the schemes described above.

[0053] Scheme 19-2: A compound according to any one of the above schemes having a structure represented by formula (VIII-1'), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000029.jpg31168In formula, R 6 is hydrogen, optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 alkoxy groups, Each Q1, m, R 4 , R 5 , the definition of each s is the same as in any one of the schemes described above.

[0054] Scheme 19- 3 In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product or its stereoisomer, R 6 is hydrogen, deuterated C 1-6 Alkyl group or deuterated C 1-6 The alkoxy group is selected from the group consisting of aryl, ... and aryl groups.

[0055] Scheme 20: A compound according to any one of the above schemes having a structure represented by formula (IX), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000030.jpg34168 formula, - - and are each independently selected from a single bond or a double bond, and two adjacent bonds may not simultaneously be double bonds; The definitions of Q1, Y1, Y2, Y5, Y6, Y7, and s are the same as those in any one of the above schemes.

[0056] Scheme 20-1: A compound according to any one of the above schemes having a structure represented by formula (IX-1), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000031.jpg34167In formula, R 6 is hydrogen, optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 alkoxy groups, -- and are each independently selected from a single bond or a double bond, and two adjacent bonds may not simultaneously be double bonds; The definitions of Q1, Y1, Y2, Y5, Y6, Y7, and s are the same as those in any one of the above schemes.

[0057] Scheme 20-2: In the compound according to any one of the above schemes, its pharma- ceutically acceptable salt, its ester, its deuterated product, or its stereoisomer, R 6 is hydrogen, optionally deuterated C 1-6 Alkyl group or deuterated C 1-6 The alkoxy group is selected from the group consisting of aryl, ... and aryl groups.

[0058] Scheme 21: In any one of the above schemes, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, R 4 , R 5 , each R a , each R b , each R c are each independently hydrogen.

[0059] Scheme 22: A compound according to any one of the above schemes having a structure represented by formula (II-2), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000032.jpg35168 In the formula, Y3, Y4, and Y6 each independently represent N, C, or CR. a is selected from Y5 and Y7 each independently represent N or NR c , C, C.R. a R b or CR a is selected from -- and are each independently selected from a single bond or a double bond, and two adjacent bonds may not simultaneously be double bonds; each s is independently selected from an integer of 0 to 2; Each Q1, each Q2, each L, m, R 1 , R 4 , R 5 , each R a , each R b , each R c The definition of is the same as in any one of the schemes above.

[0060] Scheme 23: A compound according to any one of the above schemes having a structure represented by formula (II-3), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000033.jpg35168In formula, each Q1, each Q2, each s, each L, m, R 1 , R 4 , R 5 , Y5, Y6, Y7, each Ra , each R b , each R c The definition of is the same as in any one of the schemes above.

[0061] Scheme 24: A compound according to any one of the above schemes having a structure represented by formula (II-3), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000034.jpg35168In formula, R 1 is selected from a phenyl group or a 5-6 membered nitrogen-containing heteroaryl group optionally substituted with 1-3 Q1, preferably R 1 may be substituted with 1-3 Q1 Selected from JPEG0007652935000035.jpg17168, R 4 and R 5 are each independently deuterium, hydrogen, or optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl and halogenated C 1-6 alkoxy groups, Each L is independently -CR a R b - and Each R a and each R b are each independently deuterium, hydrogen, or optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 alkoxy groups, Each Q1 is independently selected from the group consisting of deuterium, halogen, and C, which may be substituted with 1 to 3 substituents Q2. 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 each Q2 is independently selected from deuterium, halogen, C 1-6Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl and halogenated C 1-6 alkoxy groups, JPEG0007652935000036.jpg11168 has the following structure: Selected from JPEG0007652935000037.jpg16168, m is an integer of 1 or 2; Each s is independently an integer of 0, 1, or 2.

[0062] Scheme 25: A compound according to any one of the above schemes having a structure represented by formula (II-4), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000038.jpg39168 each Q1, each Q2, each s, m, R 1 , R 4 , R 5 , Y5, Y6, Y7, each R a , each R b , each R c The definition of is the same as in any one of the schemes above.

[0063] Scheme 26: A compound according to any one of the above schemes having a structure represented by formula (II-4), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000039.jpg39168In formula, R 1 is selected from a phenyl group or a 5-6 membered nitrogen-containing heteroaryl group optionally substituted with 1-3 Q1, preferably R 1 may be substituted with 1-3 Q1 Selected from JPEG0007652935000040.jpg17168, R 4 , R 5 are each independently deuterium, hydrogen, or optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C1-6 Alkyl and halogenated C 1-6 alkoxy groups, Each Q1 is independently selected from the group consisting of deuterium, halogen, and C, which may be substituted with 1 to 3 substituents Q2. 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 each Q2 is independently selected from deuterium, halogen, C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl and halogenated C 1-6 alkoxy groups, JPEG0007652935000041.jpg11168 has the following structure: Selected from JPEG0007652935000042.jpg16168, m is an integer of 1 or 2; Each s is independently an integer of 0, 1, or 2.

[0064] Scheme 27: A compound according to any one of the above schemes having a structure represented by formula (II-5), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000043.jpg28168 each Q1, each Q2, s, m, R 1 , Y5, Y6, Y7, each R a , each R b , each R c The definition of is the same as in any one of the schemes above.

[0065] Scheme 28: A compound according to any one of the above schemes having a structure represented by formula (II-5), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000044.jpg28168In formula, R 1is selected from a phenyl group or a 5-6 membered nitrogen-containing heteroaryl group optionally substituted with 1-3 Q1, preferably R 1 may be substituted with 1-3 Q1 Selected from JPEG0007652935000045.jpg30168, Each Q1 is independently selected from the group consisting of deuterium, halogen, and C, which may be substituted with 1 to 3 substituents Q2. 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 each Q2 is independently selected from deuterium, C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl and halogenated C 1-6 alkoxy groups, JPEG0007652935000046.jpg11168 has the following structure: Selected from JPEG0007652935000047.jpg16168, m is an integer of 1 or 2; Each s is independently an integer of 0, 1, or 2.

[0066] Scheme 29: A compound according to any one of the above schemes having a structure represented by formula (IV-1'), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000048.jpg39168 wherein Y1 and Y2 are each independently selected from N, C, or CH; Y5 and Y7 are each independently selected from NH, N, C, CH, or CH2; Y6 is selected from N, CH or C; R 4 , R 5 are each independently deuterium, hydrogen, a cyano group, a halogen, or an optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6Alkylamino group, di(C 1-6 Alkyl)amino group, halogenated C 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl group, carboxy C 1-6 Alkyl or halogenated C 1-6 alkoxy groups, R 6 is hydrogen, deuterated C 1-6 alkoxy groups, Each Q1 is independently selected from the group consisting of deuterium, halogen, and C, which may be substituted with 1 to 4 substituents Q2. 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylamino group, di(C 1-6 Alkyl)amino group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl group, carboxy C 1-6 Alkyl group, -(L) m -3-6 membered cycloalkyl group or -(L) m -3-6 membered heterocyclyl groups, R a , R b are each independently hydrogen; Each Q2 is independently deuterium, halogen, or C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl and halogenated C 1-6 alkoxy groups, -- and are each independently selected from a single bond or a double bond, and two adjacent bonds may not simultaneously be double bonds; Each m and each s is independently 0, 1 or 2.

[0067] Scheme 30: A compound according to any one of the above schemes having a structure represented by formula (VIII-1'), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof. JPEG0007652935000049.jpg31168 Each Q1 is independently a deuterium atom, a halogen atom, or a C group optionally substituted with 1 to 3 substituents Q2. 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Alkylamino group, di(C 1-4 Alkyl)amino group, halogenated C 1-4 Alkyl groups, halogenated C 1-4 Alkoxy group, hydroxy C 1-4 Alkyl group, amino C 1-4 Alkyl group, carboxy C 1-4 alkyl group, 3- to 6-membered cycloalkyl group; Each Q2 is independently deuterium, halogen, or C 1-4 Alkyl group, C 1-4 Alkoxy groups, halogenated C 1-4 Alkyl and halogenated C 1-4 alkoxy groups, R 4 , R 5 are each independently deuterium, hydrogen, a cyano group, a halogen, or an optionally deuterated C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy groups, R 6 is hydrogen, deuterated C 1-4 alkoxy groups, m is 1 or 2; Each s is independently 0, 1 or 2.

[0068] Scheme 31: In the compound according to any one of the above schemes, a pharma- ceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, R 6is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated isobutyl, deuterated sec-butyl, deuterated tert-butyl, deuterated methoxy, deuterated ethoxy, deuterated propoxy, and deuterated isopropoxy, and the number of deuterated atoms is 1, 2, 3, or 4. Scheme 32: In any one of the above schemes, a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof, R 6 is selected from hydrogen, a deuterated methoxy group, a deuterated ethoxy group, a deuterated propoxy group, or a deuterated isopropoxy group, and the number of deuteration is 1, 2, or 3, and is preferably a tritiated methoxy group. Any substituent options in any embodiment of the present invention can be combined with each other, and the combined technical solutions still fall within the protection scope of the present invention. In some embodiments of the present invention, the structure of the compound of general formula (I), its pharma- ceutically acceptable salt, ester, deuterated product, or stereoisomer thereof is shown in Table 1.

[0069] JPEG0007652935000050.jpg238170JPEG0007652935000051.jpg175170

[0070] As used herein, the term "pharmacologically acceptable salts" refers to pharma- ceutically usable acid and base addition salts, such as metal salts, ammonium salts, salts with organic acids, salts with organic bases, salts with inorganic acids, salts with acidic or basic amino acids, and the like.

[0071] The term "ester" as used herein refers to a pharma- ceutically acceptable ester, and in particular to an ester that is hydrolyzed in vivo and readily decomposed in the human body to leave a parent compound (the compound represented by general formula (I)) or a salt thereof. The term "ester" as used herein refers to, for example, (1) a carboxylic acid ester obtained by esterification with a carboxylic acid compound (the non-carbonyl portion of the carboxylic acid compound is, for example, C 1-20 Linear or branched alkyl group, C 1-12 Linear or branched alkyl group, C 1-8 Linear or branched alkyl group, C 1-6 Straight or branched chain alkyl groups (e.g., methyl, ethyl, n-propyl, tert-butyl or n-butyl groups), C 1-6 Alkoxy C 1-6 Alkyl groups (e.g., methoxymethyl groups), C 6-10 Aryl C 1-6 Alkyl groups (e.g., benzyl groups), C 6-10 Aryloxy C 1-6 Alkyl groups (e.g., phenoxymethyl), C 6-10 Aryl groups (e.g., phenyl groups, e.g., halogens, C 1-4 Alkyl group or C 1-4 (2) sulfonic acid esters (e.g., alkylsulfonyl groups or arylalkylsulfonyl groups (e.g., methylsulfonyl groups)); (3) amino acid esters (e.g., L-valyl groups or L-isoleucyl groups); (4) monophosphates, diphosphates, or triphosphates; (5) esters obtained by esterification with alcohol compounds (the non-hydroxyl group portion of the alcohol compound is, for example, C 1-20 Linear or branched alkyl group, C 1-12 Linear or branched alkyl group, C 1-8 Linear or branched alkyl group, C 1-6 Straight or branched chain alkyl groups (e.g., methyl, ethyl, n-propyl, tert-butyl or n-butyl groups), C 1-6 Alkoxy C 1-6 Alkyl groups (e.g., methoxymethyl groups), C 6-10 Aryl C 1-6Alkyl groups (e.g., benzyl groups), C 6-10 Aryloxy C 1-6 Alkyl groups (e.g., phenoxymethyl groups), C 6-10 Aryl groups (e.g., phenyl groups, e.g., halogens, C 1-4 Alkyl group or C 1-4 wherein the aryl group is substituted with an alkoxy group or an amino group.

[0072] The "stereoisomer" of the compound represented by the general formula (I) of the present invention refers to an enantiomer formed when the compound represented by the formula (I) has an asymmetric carbon atom; a cis-trans isomer formed when the compound has a carbon-carbon double bond or a cyclic structure; and a tautomer formed when the compound has a ketone or oxime. In some embodiments of the present invention, the stereoisomer includes, but is not limited to, an enantiomer, a diastereomer, a racemic isomer, a cis-trans isomer, a tautomer, a geometric isomer, an epimer, and a mixture thereof.

[0073] The present invention further provides a pharmaceutical composition comprising a compound of general formula (I), a pharma- ceutically acceptable salt, ester, deuterated product or stereoisomer thereof, and one or more second therapeutically active agents. Optionally, said pharmaceutical composition further comprises one or more pharmaceutical carriers and / or diluents.

[0074] The present invention further provides a pharmaceutical formulation comprising the compound represented by the general formula (I), its pharma- ceutically acceptable salt, ester, deuterated product or stereoisomer thereof, and one or more pharmaceutical carriers and / or diluents, the pharmaceutical formulation being in any clinically or pharma- ceutically acceptable dosage form.

[0075] In some embodiments of the present invention, the drug formulation may be administered to a patient or subject in need of such treatment by oral, parenteral, rectal, or pulmonary administration. For oral administration, the pharmaceutical composition may be formulated into an oral preparation, for example, into a conventional oral solid preparation (e.g., tablet, capsule, pill, granule, etc.), or into an oral liquid preparation (e.g., oral solution, oral suspension, syrup, etc.). When formulated into an oral preparation, appropriate fillers, binders, disintegrants, lubricants, etc. may be added. For parenteral administration, the drug formulation may be formulated into an injection material (including injection solution, sterile powder for injection, and concentrated solution for injection). When formulated into an injection, the injection may be prepared by a conventional method in the pharmaceutical field, and additives may not be added, or appropriate additives may be added according to the characteristics of the drug. For rectal administration, the pharmaceutical composition may be formulated into a suppository, etc. For pulmonary administration, the pharmaceutical composition may be formulated into an inhalant or aerosol, etc.

[0076] The pharmaceutical carriers and / or diluents usable in the pharmaceutical composition or drug formulation of the present invention may be any conventional carriers and / or diluents in the field of drug formulation. The selection of a particular carrier and / or diluent depends on the administration form or the type and condition of the disease to be treated for a particular patient. The preparation method of a pharmaceutical composition suitable for a particular administration mode is within the knowledge of a person skilled in the pharmaceutical field. For example, the pharmaceutical carriers and / or diluents may include conventional solvents, diluents, dispersants, suspending agents, surfactants, isotonicity agents, thickeners, emulsifiers, binders, lubricants, stabilizers, hydrating agents, emulsification promoters, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, antioxidants, etc. in the pharmaceutical field. Flavoring agents, preservatives, sweeteners, etc. may be added to the pharmaceutical composition as necessary.

[0077] The present invention further provides a use of a compound of general formula (I), its pharma- ceutically acceptable salt, ester, deuterated product or stereoisomer thereof, said drug formulation or said pharmaceutical composition in the manufacture of a medicament for treating and / or preventing said USP1-mediated and related diseases, wherein said USP1-mediated and related diseases are selected from cancer or benign tumors.

[0078] The present invention further provides the use of the compound of general formula (I), its pharma- ceutically acceptable salt, ester, deuterated product or stereoisomer thereof, said drug formulation or said pharmaceutical composition in the treatment and / or prevention of USP1-mediated and related diseases, wherein said USP1-mediated and related diseases are selected from cancer or benign tumors.

[0079] The present invention further provides a method for treating a disease, comprising administering to a patient in need thereof a therapeutically effective amount of the compound represented by general formula (I), its pharma- ceutically acceptable salt, ester, deuterated product or stereoisomer, said drug formulation or said pharmaceutical composition, said disease being USP1-mediated disease and related disease, said USP1-mediated disease and related disease being selected from cancer or benign tumor.

[0080] The present invention provides a method for preparing the compound, but is not limited to the following method. The reaction scheme of the preparation method is as follows: JPEG0007652935000052.jpg39166 The compound of formula (II-2)-1 is dissolved in a suitable solvent (e.g., DMF), an alkaline reagent (e.g., NaH, potassium carbonate, cesium carbonate, sodium carbonate) is added, and the compound of formula (II-2)-2 is further added and reacted for 1-15 hours. Quench the reaction by adding water, extract with a suitable organic solvent (e.g., dichloromethane, ethyl acetate), swirl dry, and obtain the compound of general formula (II-2) of the present invention by a suitable method (e.g., silica gel column chromatography).

[0081] The above-mentioned production method, simply put, is a method of reacting a compound represented by formula (II-2)-1 with a compound represented by formula (II-2)-2 to obtain a compound represented by general formula (II-2). where X is a halogen, and each Q1, each Q2, each L, m, R 1 , R 4 , R 5 , Y3, Y4, Y5, Y6, Y7, each R a , each R b , each R c , each s is as defined in any one of the schemes above.

[0082] The present invention further provides an intermediate for producing a compound represented by general formula (IX-1), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof from general formula (II-1), the intermediate having the following structural formula: JPEG0007652935000053.jpg25166In formula, R 1 , R 4 , R 5 , each Q1, each Q2, each L, each R a , each R b , each R c , m are as defined in any one of the schemes above.

[0083] The present invention further provides an intermediate for producing a compound represented by general formula (IX-1), a pharma- ceutically acceptable salt thereof, an ester thereof, a deuterated product thereof, or a stereoisomer thereof from general formula (III), the intermediate having the following structural formula: JPEG0007652935000054.jpg35166In the formula, G is a halogen, a hydroxyl group, an amino group, C 1-6 Alkylthio group or C 1-6 alkylsulfonyl groups. Each Q1, each Q2, each L, m, R 1 , R 4 , R 5 , Y3, Y4, Y5, Y6, Y7, each R a , each R b , each R cis as defined in any one of the schemes above.

[0084] In some embodiments, G is selected from a halogen, a hydroxy group, an amino group, a methylthio group, or a methylsulfonyl group.

[0085] In this specification and claims, all compounds are named based on their chemical structure. In the event of a discrepancy between the name and the chemical structure of the same compound, the chemical structure shall prevail.

[0086] In this specification, unless otherwise stated, scientific and technical terms used herein have the meanings that are generally understood by those skilled in the art. However, in order to better understand the present invention, the definitions of some terms are provided below. If the definitions and explanations of terms provided herein conflict with the meanings that are generally understood by those skilled in the art, the definitions and explanations of terms provided herein shall prevail.

[0087] As used herein, "halogen" refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

[0088] As used herein, "halogenated" means that any hydrogen in a substituent is replaced with one or more of the same or different halogens. "Halogen" is as defined above.

[0089] As described herein, 1-6 "Alkyl group" refers to a straight or branched chain alkyl group containing 1-6 carbon atoms, e.g., "C 1-5 Alkyl group," "C 1-4 Alkyl group," "C 1-3 Alkyl group," "C 1-2 Alkyl group," "C 2-6 Alkyl group," "C 2-5 Alkyl group," "C 2-4 Alkyl group," "C 2-3 Alkyl group," "C 3-6 Alkyl group," "C 3-5 Alkyl group," "C3-4 Alkyl group," "C 4-6 Alkyl group," "C 4-5 Alkyl group," "C 5-6 Specific examples include, but are not limited to, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a 2-methylbutyl group, a neopentyl group, a 1-ethylpropyl group, an n-hexyl group, an isohexyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, a 3,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a 2-ethylbutyl group, a 1,2-dimethylpropyl group, and the like. 1-4 "Alkyl group" means C 1-6 It refers to specific examples of alkyl groups containing 1-4 carbon atoms.

[0090] As described herein, 1-6 The alkylene group is defined as 1-6 It refers to a group in which one hydrogen atom has been removed from an alkyl group. For example, "C 1-5 Alkylene group, C 1-4 Alkylene group, C 1-3 Alkylene group, C 1-2 Alkylene group, C 2-6 Alkylene group, C 2-5 Alkylene group, C 2-4 Alkylene group, C 2-3 Alkylene group, C 3-6 Alkylene group, C 3-5 Alkylene group, C 3-4 Alkylene group, C 4-6 Alkylene group, C 4-5 Alkylene group, C 5-6 Specific examples include, but are not limited to, a methylene group, an ethylene group, a propylene group, a butylene group, a pentylene group, a hexylene group, and the like. 1-4 The alkylene group is 1-6It refers to specific examples of alkylene groups containing 1-4 carbon atoms.

[0091] As described herein, 2-6 The term "alkenyl group" refers to a straight-chain, branched-chain or cyclic alkenyl group having 2 to 6 carbon atoms and containing at least one double bond, and examples of such groups include "C 2-5 alkenyl group," "C 2-4 alkenyl group," "C 2-3 Specific examples include vinyl group, 1-propenyl group, 2-propenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 1-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 2-methyl-1-butenyl group, 3-methyl-1-butenyl group, 2-methyl-3-butenyl group, 1,1-dimethyl-2-propenyl group, 1-ethyl-2-propenyl group, 2-hexenyl group, 3-hexenyl group, 2-methyl-1-pentenyl group, 3-methyl-1- pentenyl, 1-methyl-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-1-butenyl, 2-ethyl-1-butenyl, 2-ethyl-3-butenyl and the like.

[0092] As described herein, 2-6 An "alkynyl group" is a group having 2- 6 For example, "C 2-5 Alkynyl group, C 2-4 Alkynyl group, C 2-3alkynyl groups, and the like, specific examples include, but are not limited to, an ethynyl group, a 1-propynyl group, a 2-butynyl group, a 1-methyl-2-propynyl group, a 2-pentynyl group, a 3-pentynyl group, a 1-methyl-2-butynyl group, a 2-methyl-3-butynyl group, a 1,1-dimethyl-2-propynyl group, a 1-ethyl-2-propynyl group, a 2-hexynyl group, a 3-hexynyl group, a 1-methyl-2-pentynyl group, a 1-methyl-3-pentynyl group, a 2-methyl-3-pentynyl group, a 1,1-dimethyl-3-butynyl group, and a 2-ethyl-3-butynyl group.

[0093] As described herein, 1-6 Alkoxy group, C 1-6 Alkylamino group, di(C 1-6 alkyl)amino group, C 1-6 Alkylaminoacyl group, C 1-6 Alkylamide group, C 1-6 Alkylsulfonyl group, C 1-6 Alkylsulfonylamino group, C 1-6 Alkylaminosulfonyl group, C 1-6 Alkylcarbonyl group, C 1-6 Alkoxycarbonyl group, C 1-6 "Alkylthio group" means C 1-6 Alkyl-O-, C 1-6 Alkyl-NH-, (C 1-6 Alkyl group) 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 1-6 Alkyl-OC(O)-, C 1-6 It refers to a group formed in the form of alkyl-S-. 1-6 The definition of "alkyl group" is as above.

[0094] As described herein, 1-4 Alkoxy group, C 1-4Alkylamino group, di(C 1-4 alkyl)amino group, C 1-4 Alkylaminoacyl group, C 1-4 Alkylamide group, C 1-4 Alkylsulfonyl group, C 1-4 Alkylsulfonylamino group, C 1-4 Alkylaminosulfonyl group, C 1-4 Alkylcarbonyl group, C 1-4 Alkoxycarbonyl group, C 1-4 "Alkylthio group" means C 1-4 Alkyl-O-, C 1-4 Alkyl-NH-, (C 1-4 Alkyl group) 2-N-, C 1-4 Alkyl-NH-C(O)-, C 1-4 Alkyl-C(O)-NH-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkyl-S(O)2-NH-, C 1-4 Alkyl-NH-S(O)2-, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-OC(O)-, C 1-4 It refers to a group formed in the form of alkyl-S-. 1-4 The definition of "alkyl group" is as above.

[0095] The "halogenated C" described herein 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl group, carboxy C 1-6 Alkyl groups, halogenated C 1-6 Alkylene group, halogenated C 1-6 An "alkoxy group" is a group that contains one to multiple (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxyl groups, amino groups, or carboxyl groups, and is C 1-6 Alkyl group, C 1-6 Alkylene group, C 1-6 It refers to a group obtained by replacing each hydrogen atom in an alkoxy group.

[0096] The "halogenated C" described herein 1-4 Alkyl group, hydroxy C1-4 Alkyl group, amino C 1-4 Alkyl group, carboxy C 1-4 Alkyl groups, halogenated C 1-4 Alkylene group, halogenated C 1-4 "Alkoxy group" means a group having one or more (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxyl groups, amino groups, and C 1-4 Alkyl group, C 1-4 Alkylene group, C 1-4 It refers to a group obtained by replacing each hydrogen atom in an alkoxy group.

[0097] As used herein, the term "3-12 membered cycloalkyl group" refers to a saturated or partially saturated, non-aromatic cyclic alkyl group containing 3-12 carbon atoms, and includes "monocycloalkyl groups" and "fused cycloalkyl groups."

[0098] The term "monocycloalkyl group" as used herein refers to a monocyclic cyclic alkyl group that is saturated or partially saturated and has no aromaticity, and includes a "3- to 8-membered saturated cycloalkyl group" and a "3- to 8-membered partially saturated cycloalkyl group", and is preferably a "3- to 4-membered cycloalkyl group", a "3- to 5-membered cycloalkyl group", a "3- to 6-membered cycloalkyl group", a "3- to 7-membered cycloalkyl group", a "4- to 5-membered cycloalkyl group", a "4- to 6-membered cycloalkyl group", a "4- to 7-membered cycloalkyl group", a "4- to 8-membered cycloalkyl group", a "5- to 6-membered cycloalkyl group", a "5- to 7-membered cycloalkyl group", a "5- to 8-membered cycloalkyl group", "6-7 membered cycloalkyl group", "6-8 membered cycloalkyl group", "7-8 membered cycloalkyl group", "3-6 membered saturated cycloalkyl group", "4-7 membered saturated cycloalkyl group", "4-8 membered saturated cycloalkyl group", "5-8 membered saturated cycloalkyl group", "5-7 membered saturated cycloalkyl group", "5-6 membered saturated cycloalkyl group", "3-6 membered partially saturated cycloalkyl group", "4-7 membered partially saturated cycloalkyl group", "4-8 membered partially saturated cycloalkyl group", "5-8 membered partially saturated cycloalkyl group", "5-7 membered partially saturated cycloalkyl group", "5-6 membered partially saturated cycloalkyl group", etc. Specific examples of the "3-8 membered saturated cycloalkyl group" include, but are not limited to, cyclopropane group (cyclopropyl group), cyclobutane group (cyclobutyl group), cyclopentane group (cyclopentyl group), cyclohexane group (cyclohexyl group), cycloheptane group (cycloheptyl group), cyclooctane group (cyclooctyl group), etc. Specific examples of the "3 to 8-membered partially saturated cycloalkyl group" include, but are not limited to, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclopentadienyl group, a cyclohexenyl group, a cyclohexa-1,3-dienyl group, a cyclohexa-1,4-dienyl group, a cycloheptenyl group, a cyclohept-1,3-dienyl group, a cyclohept-1,4-dienyl group, a cyclohept-1,3,5-trienyl group, a cyclooctenyl group, a cycloocto-1,3-dienyl group, a cycloocto-1,4-dienyl group, a cycloocto-1,5-dienyl group, a cycloocto-1,3,5-trienyl group, and a cyclooctatetraenyl group.

[0099] The term "fused cycloalkyl group" as used herein refers to a saturated or partially saturated non-aromatic cyclic group in which two or more ring structures are formed by sharing two adjacent carbon atoms. One ring in the fused ring may be an aromatic ring, but the entire fused ring does not have aromaticity. The fused form is a 5-6 membered cycloalkyl group-5-6 membered cycloalkyl group, a benzo 5-6 membered cycloalkyl group, a benzo 5-6 membered saturated cycloalkyl group, etc. Examples include 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, octahydropentadienyl, octahydro-1H-indenyl, decalinyl, tetradecahydrophenantyl, 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, and bicyclo[4.2.0]octyl. Examples of aryl groups include, but are not limited to, 1,2,3,3a-octahydro-3-enyl, 1,2,3,3a-tetrahydropentadienyl, 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-decahydrophenantyl, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl, and the like.

[0100] The term "3-12 membered heterocyclyl group" as used herein refers to a saturated or partially saturated, non-aromatic monocyclic or fused ring group containing at least one heteroatom (e.g., 1, 2, 3, 4 or 5) and having 3-12 ring atoms. The heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the ring structure may be replaced with oxygen. The term "3-12 membered heterocyclyl group" as used herein includes "3-12 membered saturated heterocyclyl group" and "3-12 membered partially saturated heterocyclyl group". Preferably, the term "3-12 membered heterocyclyl group" as used herein contains 1-3 heteroatoms. Preferably, the term "3-12 membered heterocyclyl group" as used herein contains 1-2 heteroatoms and the heteroatoms are selected from nitrogen and / or oxygen atoms. Preferably, the "3-12 membered heterocyclyl group" described herein contains 1-2 nitrogen atoms. The "3-12 membered heterocyclyl group" is preferably a "3-10 membered heterocyclyl group", a "3-8 membered heterocyclyl group", a "4-8 membered heterocyclyl group", a "3-6 membered heterocyclyl group", a "3-6 membered saturated heterocyclyl group", a "3-6 membered nitrogen-containing heterocyclyl", a "3-6 membered saturated nitrogen-containing heterocyclyl", a "5-6 membered heterocyclyl group", a "5-6 membered saturated heterocyclyl", a "5-6 membered nitrogen-containing heterocyclyl", etc. Specific examples of the "3- to 12-membered heterocyclyl group" include an aziridinyl group, a 2H-aziridinyl group, a diaziridinyl group, a 3H-diaziridinyl group, an azetidinyl group, a 1,4-dioxanyl group, a 1,3-dioxanyl group, a 1,3-dioxolyl group, a 1,4-dioxadienyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a dihydropyrrolyl group, a pyrrolidinyl group, an imidazolidinyl group, a 4,5-dihydroimidazolyl group, a pyrazolinyl ... zolidinyl group, 4,5-dihydropyrazolyl group, 2,5-dihydrothienyl group, tetrahydrothienyl group, 4,5-dihydrothiazolyl group, piperidinyl group, piperazinyl group, morpholinyl group, 4,5-dihydroisoxazolyl group, 4,5-dihydroisoxazolyl group, 2,3-dihydroisoxazolyl group, 2H-1,2-oxazinyl group, 6H-1,3-oxazinyl group, 4H-1,3-thiazinyl group, 6H-1,3-thiazinyl group, 2H-pyranyl group, 2H-pyran-2-one group, 3,4-dihydro-2H-pyranyl group, pyrrolidinocyclopropyl group, cyclopentaziridyl group, pyrrolidinocyclobutyl group, pyrrolidinopyrrolidinyl group, pyrrolidinopiperidyl group, pyrrolidinopiperazinyl group, pyrrolidinomorpholinyl group, piperidinomorpholinyl group, benzopyrrolidyl group, benzocyclopentyl group, benzocyclohexyl group, benzotetrahydrofuranyl group, benzopyrrolidinyl group, benzimidazolidinyl group, benzoxazolidinyl group, benzothiazolidinyl group , benzisoxazolidinyl group, benzisothiazolidinyl group, benzopiperidinyl group, benzomorpholinyl group, benzopiperazinyl group, benzotetrahydropyranyl group, pyridocyclopentyl group, pyridocyclohexyl group, pyridotetrahydrofuryl group, pyridopyrrolidinyl group, pyridoimidazolidinyl group, pyridoxazolidinyl group, pyridothiazolidinyl group, pyridoisoxazolidinyl group, pyridoisothiazolidinyl group, pyridopiperidyl group, pyridomorpholinyl group, pyridopiperazinyl group, pyridotetrahydropyranyl group, pyrim ... pyrimidocyclohexyl group, pyrimidotetrahydrofuranyl group, pyrimidopyrrolidinyl group, pyrimidoimidazolidinyl group, pyrimidooxazolidinyl group, pyrimidothiazolidinyl group, pyrimidoisoxazolidinyl group, pyrimidoisothiazolidinyl group, pyrimidopiperidyl group, pyrimidomorpholinyl group, pyrimidopiperazinyl group, pyrimidotetrahydropyranyl group, tetrahydroimidazo[4,5-c]pyridyl group, 3,4-dihydroquinazolinyl group, 1,2-dihydroquinoxalinyl group, benzo[d][1,3]dioxolyl group, 2H-chromenyl group, group, 2H-chromen-2-one group, 4H-chromenyl group, 4H-chromen-4-one group, 4H-1,3-benzoxazinyl group, 4,6-dihydro-1H-furo[3,4-d]imidazolyl group, 3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazolyl group, 4,6-dihydro-1H-thieno[3,4-d]imidazolyl group, 4,6-dihydro-1H-pyrrolo[3,4-d]imidazolyl group, octahydro-benzo[d]imidazolyl group, decahydroquinolyl group, hexahydrothienoimidazolyl group, hexahydrofuroimidazolyl group, 4,Examples of the aryl group include, but are not limited to, 5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopenta[c]pyrrolyl, and 4H-1,3-benzoxazinyl.

[0101] As used herein, the term "6- to 10-membered aryl group" refers to a cyclic group containing 6-10 ring carbon atoms and having aromaticity, and includes "6- to 8-membered monocyclic aryl group" and "8- to 10-fused ring aryl group".

[0102] The term "6- to 8-membered monocyclic aryl group" as used herein refers to a monocyclic aryl group containing 6 to 8 ring carbon atoms, examples of which include, but are not limited to, a phenyl group, a cyclooctatetraenyl group, and the like, and preferably a phenyl group.

[0103] The term "8-10 fused ring aryl group" as used herein refers to an unsaturated, aromatic cyclic group containing 8-10 ring carbon atoms in which two or more cyclic structures are formed by sharing two adjacent atoms, and is preferably a "9-10 fused ring aryl group". A specific example is a naphthyl group.

[0104] The term "5-12 membered heteroaryl group" as used herein refers to a cyclic group containing 5-12 ring atoms (at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom) and having aromaticity, and may be, for example, a 5-12 membered nitrogen-containing heteroaryl group, a 5-12 membered oxygen-containing heteroaryl group, a 5-12 membered nitrogen-containing heteroaryl group, etc. It includes a "5-8 membered monoheteroaryl group" and an "8-10 membered fused heteroaryl group".

[0105] As used herein, the term "5-8 membered monoheteroaryl group" refers to a monocyclic ring group containing 5-8 ring atoms (at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom) and having aromaticity. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the ring structure may be replaced with oxygen. The term "5-8 membered monoheteroaryl group" includes, for example, "5-7 membered monoheteroaryl group", "5-6 membered monoheteroaryl group", "5-6 membered nitrogen-containing monoheteroaryl group", "5 membered nitrogen-containing monoheteroaryl group", and the like. Specific examples of the "5- to 8-membered nitrogen-containing monoheteroaryl group" include a furyl group, a thienyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, an imidazolyl group, a pyrazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a 1,2,3-oxadiazolyl group, a 1,2,4-oxadiazolyl group, a 1,2,5-oxadiazolyl group, a 1,2,5-oxadiazolyl group, a 1,2,6-oxadiazolyl group, a 1,2,7-oxadiazolyl group, a 1,2,8-oxadiazolyl group, a 1,2,9-oxadiazolyl group, a 1,2,10-oxadiazolyl group, a 1,2,11-oxadiazolyl group, a 1,2,12-oxadiazolyl group, a 1,2,13-oxadiazolyl group, a 1,2,14-oxadiazolyl group, a 1,2,15-oxadiazolyl group, a 1,2,16-oxadiazolyl group, a 1,2,17-oxadiazolyl group, a 1,2,18-oxadiazolyl group, a 1,2,19-oxadiazolyl group, a 1,2,2-oxadiazolyl group, a 1,2,2-oxadiazolyl group, a 1,2,2-oxadiazolyl group, a 1,2,3-oxadiazolyl group, a 1,2,4- Examples of the heteroaryl group include, but are not limited to, an azolyl group, a 1,3,4-oxadiazolyl group, a pyridyl group, a 2-pyridonyl group, a 4-pyridonyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a 1,2,3-triazinyl group, a 1,3,5-triazinyl group, a 1,2,4,5-tetrazinyl group, an azacycloheptathionyl group, a 1,3-diazacycloheptathionyl group, an azacyclooctatetraenyl group, and the like. The "5- to 6-membered heteroaryl group" is a specific example of a 5- to 8-membered heteroaryl group having 5 to 6 ring atoms.

[0106] The term "8-10 membered fused heteroaryl group" as used herein refers to an unsaturated, aromatic ring structure having 8-10 ring atoms (at least one ring atom is a heteroatom, for example, a nitrogen atom, an oxygen atom, or a sulfur atom) formed by sharing two adjacent atoms of two or more ring structures. Optionally, a ring atom (for example, a carbon atom, a nitrogen atom, or a sulfur atom) in the ring structure may be substituted with oxygen. It includes "9-10 membered fused heteroaryl group", "8-9 membered fused heteroaryl group", etc. The fused form may be a benzo 5-6 membered heteroaryl group, a 5-6 membered heteroaryl-5-6 membered heteroaryl group, etc. Specific examples include, but are not limited to, a pyrrolopyrrole group, a pyrrolofuran group, a pyrazolopyrrole group, a pyrazolothiophene group, a furanothiophene group, a pyrazolooxazole group, a benzofuranyl group, a benzisofuranyl group, a benzothienyl group, an indolyl group, an isoindolyl group, a benzoxazolyl group, a benzimidazolyl group, an indazolyl group, a benzotriazolyl group, a quinolinyl group, a 2-quinolinonyl group, a 4-quinolinonyl group, a 1-isoquinolinonyl group, an isoquinolinyl group, an acridinyl group, a phenanthridinyl group, a benzopyridazinyl group, a phthalazinyl group, a quinazolinyl group, a quinoxalinyl group, a purinyl group, a naphthyridinyl group, and the like.

[0107] As used herein, "optionally substituted" includes two cases: "substituted" and "unsubstituted".

[0108] The "- -" described in this specification and "-" is selected from a single bond or a double bond.

[0109] Any atom of the compound of the present invention can represent any stable isotope of that atom, unless otherwise specified. Unless otherwise specified, when a position in a structure is defined as H, i.e., hydrogen (Hl), this position contains only naturally occurring isotopes. Similarly, unless otherwise specified, when a position in a structure is defined as D, i.e., deuterium (H-2), the amount of isotope contained in this position is at least 3340 times the amount of naturally occurring isotope (0.015%) (i.e., contains at least 50.1% deuterium isotope). When one or more positions in the structure of a compound of the present invention are defined as D, i.e., deuterium (H-2), the content of the compound represented by this structure is 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%, at least 99.5%.

[0110] The deuteration ratio of the compounds of the present application refers to the ratio of the synthetically labeled isotope content to the amount of naturally occurring isotopes. The deuteration ratio of each designated deuterium atom of the compounds of the present invention is 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%), at least 6633.3 times (99.5%).

[0111] In the present invention, isotopologues refer to compounds that differ only in isotopic composition from the standpoint of chemical structure. In the present invention, compounds containing deuterium at a particular position also contain a negligible amount of hydrogen isotopologue at that position. The amount of hydrogen isotopologue at a deuterated position in the deuterated compounds of the present invention depends on many factors, including the deuterium isotope purity of the deuteration reagent (D2O, D2, NaBD4, L1AID4, etc.) and the effectiveness of the synthesis method for introducing deuterium isotopes. However, as described above, the total amount of hydrogen isotopologue at such deuterated positions will be less than 49.9%. The total amount of hydrogen isotopologue at a deuterated position in the deuterated compounds of the present invention will be less than 47.5%, 40%, 32.5%, 25%, 17.5%, 10%, 5%, 3%, 1% or 0.5%.

[0112] In this invention, each atom not designated as deuterium is present in its natural isotopic abundance.

[0113] As used herein, "deuterated" refers to the replacement of one or more hydrogen atoms on a deuterated group with one or more deuterium atoms, and may be partially deuterated or fully deuterated. For example, a deuterated compound may contain only one deuterium. In some embodiments, a deuterated compound may contain only two deuteriums. In some embodiments, a deuterated compound may contain only three deuteriums. In some embodiments, a deuterated compound may contain four deuteriums.

[0114] As used herein, "optionally deuterated" includes cases where the group is deuterated and cases where the group is not deuterated. The term "deuterated" is as defined above.

[0115] As used herein, the term "therapeutically effective amount" refers to an amount of the compound, drug formulation, or pharmaceutical composition that, when administered to a patient, can at least alleviate the symptoms of the patient's condition. The actual amount, including the "therapeutically effective amount," will vary depending on a variety of circumstances, including, but not limited to, the particular condition being treated, the severity of the condition, the physical condition and health status of the patient, and the route of administration. A skilled physician can easily determine the appropriate amount by methods known in the medical field. Effect of the Invention

[0116] (1) The compound of the present invention, its pharma- ceutically acceptable salt, ester, deuterated product, or stereoisomer thereof has excellent USP1 inhibitory activity and can treat and / or prevent diseases mediated by USP1 and related diseases. (2) The compounds of the present invention have good inhibitory effects on tumor cells. (3) The compounds of the present invention, their pharma- ceutically acceptable salts, esters, deuterated products or stereoisomers thereof have good pharmacokinetic properties, longer lasting effects and high bioavailability. (4) The compound of the present invention, its pharma- ceutically acceptable salt, ester, deuterated product or stereoisomer thereof has good safety. (5) The compound of the present invention has a simple manufacturing process, high chemical purity, stable quality, and is suitable for large-scale industrial production.

[0117] The beneficial effects of the compounds provided in the examples of the present invention will be described below through experiments, but it should not be understood that the compounds provided in the examples of the present invention only have the beneficial effects described below.

[0118] Experimental Example 1: In vitro enzyme activity of the compounds of the present invention Test samples: The structural formulas of the compounds synthesized in the examples of the present invention are shown in Table 1. Experimental Reagents JPEG0007652935000055.jpg40167Experimental consumables JPEG0007652935000056.jpg18167

[0119] Experimental method 1 1. Compound dilution 1) The compound of the present invention was prepared at 10 mM using DMSO to prepare a test stock solution. 2) Stock solutions of the compounds of the present invention were serially diluted 4-fold to 10 concentrations, with the highest concentration being 10 mM. 3) Using Echo550, the compounds of the present invention after dilution (1000-fold dilution) were transferred to a 384-well plate, with two duplicate wells for each concentration, and the final concentration of DMSO was 1%. 4) The final concentrations of the test compounds were 10000nM, 2500nM, 625nM, 156nM, 39nM, 9.8nM, 2.4nM, 0.61nM, 0.15nM, and 0.038nM.

[0120] 2. Enzyme reaction test 1) Enzyme solutions were prepared in 1x test buffer. 2) Ubiquitin rhodamine 110 protein, CF (Ub-Rho), was added to 1× assay buffer to prepare a substrate solution. 3) 10 μL of the enzyme solution and 1× reaction buffer were transferred to a 384-well plate. 4) Incubate at room temperature for 15 minutes. 5) 10 μL of substrate solution was added to each well to initiate the reaction, followed by centrifugation for 30 s and shaking for 30 s.

[0121] 3. Result measurement 1) Read on a SpectraMax Paradigm for 30 minutes. Excitation wavelength was 480 nm, emission wavelength was 540 nm. 2)SpectraMax Paradigm data was collected.

[0122] 4. Data analysis The inhibition rate (%inh) is calculated using the following formula. <Number 1> JPEG0007652935000057.jpg9167In the formula, Max indicates the luminescence signal intensity of the positive control well to which no compound was added. Min indicates the luminescence signal intensity of the negative control wells to which no enzyme was added. Signal indicates the luminescence signal intensity of the test sample compound. IC according to the following formula 50 Calculate. <Number 2> JPEG0007652935000058.jpg11167In the formula, Y indicates % inhibition. X indicates the concentration of the compound.

[0123] Experimental Results

[0124] Table 2: Inhibitory activity of compounds of the present invention against USP-1 JPEG0007652935000059.jpg29167

[0125] As can be seen from the above experimental results, the compounds prepared in the present invention can effectively inhibit the activity of USP1, and are effective USP1 inhibitors.

[0126] Experimental method 2 The enzyme reaction experiment was carried out in the same manner as in Experimental Method 1, except that the incubation time at room temperature in step 4) was changed to 60 minutes, and the following measurement results were obtained.

[0127] Table 3: Inhibitory activity of compounds of the present invention against USP-1 JPEG0007652935000060.jpg60167

[0128] As can be seen from the above experimental results, the compounds prepared in the present invention can effectively inhibit the activity of USP1, and are effective USP1 inhibitors.

[0129] Experimental Example 2: In vitro cytological inhibitory activity of the compounds of the present invention Experiment 1 Test sample: Some compounds of the present invention (see the manufacturing examples for chemical names and structures)

[0130] The cell line used in the experiments described below is MDA-MB-436: human breast cancer cells.

[0131] Definitions of the following abbreviations: FBS: Fetal bovine serum ITS-G: Insulin-transferrin-selenium supplement Glutathione:

[0132] Experimental method (CelltiterGlo assay) 1. Cell Preparation 1.1, Cell culture All cells were adherent cells, the medium was DMEM + 10% FBS + 1% ITS-G + 16 μg / ml glutathione, and the cells were tested in the logarithmic growth phase. 1.2 Preparation of cell suspension Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was measured by trypan blue exclusion and confirmed to be 90% or higher. Appropriate concentrations were adjusted and 90 μL of cell suspension was added to a 96-well plate.

[0133] Table 4: Number of cell seeding JPEG0007652935000061.jpg13167

[0134] 2. Preparation of test compounds 2.1. DMSO stock solutions of test compounds were prepared. The stock solution concentration of each test compound was 10 mM.

[0135] 2.2 Preparation of working stock solutions of test compounds 10 mM stock solutions of test compounds were serially diluted 3-fold with DMSO (total of 8 concentrations), and then 2 μL of each DMSO-diluted compound was added to 198 μL of culture medium to obtain test compound working stock solutions (compound concentrations were 10 times the final concentration, with the highest concentration being 100 μM).

[0136] 2.3 Compound processing 10 μL of compound working stock solution (10-fold dilution, DMSO final concentration 0.1%) was added to each well of the 96-well plate in which the cells were seeded. The final concentrations of test compounds were 10000.00 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, 4.57 nM.

[0137] 2.4. Installation of control wells Solvent control: 0.1% DMSO Blank control: only medium was added and no cells were seeded. 2.5 The 96-well plate was placed in a cell culture incubator at 37°C and 5% CO2 for 7 days. 3. Detection The CTG reagent was thawed, and the 96-well plate was equilibrated at room temperature for 30 minutes. 60 μL of the reagent (Celltiter Glo assay kit) was added to each well, and the plates were shaken for 2 minutes on a shaker to mix evenly (protected from light), and incubated at room temperature for 20 minutes (protected from light). The optical signal was read using a multi-function microplate reader.

[0138] 4. Data processing 1) Inhibition rate (%) = (DMSO solvent control well reading value - test sample well reading value) / (DMSO solvent control well reading value - blank control well reading value) x 100% 2) Enter the data into GraphPad Prism to create a graph and plot the curve and IC 50 obtained.

[0139] Experimental Results and Conclusions

[0140] Table 5: In vitro cytological activity (IC 50 ,nM) JPEG0007652935000062.jpg35167

[0141] As can be seen from Table 5, the compounds of the present invention can effectively inhibit the proliferation of MDA-MB-436 cells, indicating that the compounds of the present invention have potential clinical application in treating BRCA1 gene mutation cancer diseases.

[0142] Experimental Example 3: In vitro cytological inhibitory activity of the compounds of the present invention Experiment 2 Test sample: Some compounds of the present invention (see the manufacturing examples for chemical names and structures)

[0143] The cell lines used in the experiments described below are: MDA-MB-436: human breast cancer cells; Caov-3: human ovarian cancer cells.

[0144] Experimental method 1 (CelltiterGlo assay) 1. Cell Preparation 1.1, Cell culture All cells were adherent cells; MDA-MB-436 cell culture medium was DMEM + 10% FBS + 1% ITS-G + 16 μg / ml glutathione, and Caov-3 cell culture medium was DMEM + 10% FBS, and cells were tested in logarithmic growth phase. 1.2 Preparation of cell suspension Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was measured by trypan blue exclusion and confirmed to be 90% or higher. Appropriate concentrations were adjusted and 90 μL of cell suspension was added to a 96-well plate.

[0145] Table 6: Number of cell seeding JPEG0007652935000063.jpg18167

[0146] 2. Preparation of test compounds 2.1. DMSO stock solutions of test compounds were prepared. The stock solution concentration of each test compound was 10 mM.

[0147] 2.2 Preparation of working stock solutions of test compounds 10 mM stock solutions of test compounds were serially diluted 3-fold with DMSO (total of 8 concentrations), and then 2 μL of each DMSO-diluted compound was added to 198 μL of culture medium to obtain test compound working stock solutions (compound concentrations were 10 times the final concentration, with the highest concentration being 100 μM).

[0148] 2.3 Compound processing 10 μL of compound working stock solution (10-fold dilution, DMSO final concentration 0.1%) was added to each well of the 96-well plate in which the cells were seeded. The final concentrations of test compounds were 10000.00 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, 4.57 nM.

[0149] 2.4. Installation of control wells Solvent control: 0.1% DMSO Blank control: 96-well plate was detected and read at 0 hours of dosing.

[0150] 2.5 The 96-well plate was placed in a cell culture incubator at 37°C and 5% CO2 for 7 days.

[0151] 3. Detection The CTG reagent was thawed, and the 96-well plate was equilibrated at room temperature for 30 minutes. 60 μL of the reagent (Celltiter Glo assay kit) was added to each well, and the plates were shaken for 2 minutes on a shaker to mix evenly (protected from light), and incubated at room temperature for 20 minutes (protected from light). The optical signal was read using a multi-function microplate reader.

[0152] 4. Data processing 1) Inhibition rate (%) = (DMSO solvent control well reading value - test sample well reading value) / (DMSO solvent control well reading value - blank control well reading value) x 100% 2) Enter the data into GraphPad Prism to create a graph and plot the curve and IC 50 obtained. Experimental Results and Conclusions

[0153] Table 7: In vitro cytological activity (IC 50 ,nM) JPEG0007652935000064.jpg68167

[0154] The compounds 11, 16, 18, 19, 1-1, 11-1, 16-1, and 17-1 of the examples of the present invention had an IC 50 The values ​​are 1 nM-600 nM, and the compounds of the present invention can effectively inhibit the proliferation of MDA-MB-436 and Caov-3 cells, indicating that the compounds of the present invention have potential clinical applications in treating HRD-positive (homologous recombination deficient) cancer diseases.

[0155] Experimental method 2 Compound stock solutions were made to a concentration of 5 mM. Test compound stock solutions of 5 mM were serially diluted 3-fold in DMSO (total of 9 concentrations). The final concentrations of test compounds were 10000.00 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, 4.57 nM, 1.52 nM. Other conditions were the same as in Experimental Method 1. Compound 20 had an IC 50 The IC value of compound 20 was 55.7 nM, indicating that compound 20 had an inhibitory activity against Caov-3 cells. 50 The values ​​ranged from 1 nM to 100 nM.

[0156] Experimental Example 4: Pharmacokinetic experiments of the compounds of the present invention 1. Test sample: the compound of the embodiment of the present invention (for its preparation, see the Examples herein).

[0157] JPEG0007652935000065.jpg18167

[0158] 2. Preparation of test sample solution (1) Intravenous bolus administration (iv): 2.54 mg of compound 11 was taken, 0.495 ml of DMSO solution was added, vortexed, and dissolved by ultrasonication. 0.495 ml of PEG400 was added, and the mixture was vortexed to mix uniformly. Then, 1.484 ml of 28% HP-β-CD was added, and the mixture was vortexed to mix uniformly to obtain a clear solution (concentration 1 mg / ml). (2) Oral administration (po): 3.33 mg of compound 11 was taken, and 3.243 ml of a solvent (2% HPC + 0.1% Tween 80) was added thereto. The mixture was then pulverized and mixed uniformly to obtain a uniform suspension (concentration 1 mg / ml).

[0159] 3. Experimental method (1) Administration Intravenous bolus administration of test sample (iv): dose 5mg / kg, dose volume 5ml / kg Oral administration (po): Dose 10 mg / kg, volume 10 ml / kg (2) Blood collection Blood was collected from the tail vein at 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after administration, and approximately 100 μl of whole blood was collected at each time point. The blood was centrifuged for 6 minutes at 8,000 rpm in a high-speed centrifuge to separate plasma, which was then frozen and stored in a -80°C refrigerator. (3) Plasma sample analysis Protein precipitation: 20 μl of plasma was taken and added to a 96-well deep well plate, 200 μl of internal standard (tolbutamide-200 ng / ml) was added, vortexed for 10 min, then centrifuged at 4000 rpm / min for 20 min, 100 μl of supernatant was taken, 100 μL of water was added, vortexed for 3 min, and stored for LC-MS / MS analysis.

[0160] 4. Experimental results and conclusions As can be seen from the experimental data, the compounds of the present invention have high in vivo exposure after intravenous injection or oral administration, suitable half-life and clearance rate, and good pharmacokinetic properties.For example, compound 11 has an exposure of more than 6000h*ng / ml in mice after intravenous bolus administration, which shows that the compounds of the embodiments of the present invention have very good prospects for clinical application. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0161] The technical solutions of the present invention are described below through specific examples. The following examples are only a part of the embodiments of the present invention, but are not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative efforts are all within the scope of protection of the present invention.

[0162] The abbreviations used in the following experiments have the following meanings: Xphos-Pd-G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Pd(dppf)Cl2: Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium DMF: N,N-dimethylformamide EA: Ethyl acetate PE: Petroleum ether DCM: dichloromethane NMP: N-methylpyrrolidone DIBAl-H: Diisobutylaluminum hydride

[0163] Example 1: Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (Compound 1) (1) Preparation of 2-(bis(methylthio)methylene)cyclohexane-1,3-dione JPEG0007652935000066.jpg221681,3-Cyclohexanedione (20g, 178.4mmol) was dissolved in DMF (200mL), potassium carbonate (74g, 535.2mmol) was added, and the mixture was reacted at 20°C for 0.5h. Carbon disulfide (20g, 267.6mmol) was added, and the mixture was reacted at 20°C for 1h. Methyl iodide (76g, 535.2mmol) was added, and the mixture was reacted at 20°C for 1h. The mixture was concentrated to obtain a crude product, which was used as it was in the next reaction.

[0164] (2) Preparation of 2-amino-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one JPEG0007652935000067.jpg211682-(Bis(methylthio)methylene)cyclohexane-1,3-dione (crude product of the previous step) was dissolved in DMF (200 mL), guanidine hydrochloride (17 g, 178.4 mmol) and potassium carbonate (49.3 g, 356.8 mmol) were added, and the mixture was reacted at 100 °C for 16 h, cooled to 25 °C, water (300 mL) was added, and the mixture was filtered to obtain the filter cake, which was then dried in vacuum to obtain 16.3 g of the target compound (yield 44%).

[0165] (3) Preparation of 2-chloro-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one JPEG0007652935000068.jpg171682-Amino-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (16.3 g, 78 mmol) was dissolved in dichloromethane (150 mL), titanium tetrachloride (14.8 g, 78 mmol) and tert-butyl nitrite (48 g, 468 mmol) were added, and the mixture was reacted at 25 ° C for 3 h. Water was added to quench the reaction, and the filtrate was obtained by filtration, concentrated, and subjected to column chromatography (ethyl acetate / petroleum ether = 0-40%) to obtain 6.1 g of the target compound (yield 34%).

[0166] (4) Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one JPEG0007652935000069.jpg301682-Chloro-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (1.2g, 5.15mmol) was dissolved in 1,4-dioxane (30mL), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (1g, 5.15mmol), Xphos-Pd-G2 (408mg, 0.52mmol), Xphos (496mg, 1.04mmol), K3PO4 (1.2g, 5.7mmol), water (10mL) were added, and the mixture was reacted at 90°C for 3h under N2 protection. After the reaction was completed, the solvent was dried by rotary evaporation, and 830mg of the target compound was obtained by normal phase fractionation (ethyl acetate / petroleum ether = 0-50%) (yield 47%).

[0167] (5) Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-hydrazino-7,8-dihydroquinazolin-5(6H)-one JPEG0007652935000070.jpg261682-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (830 mg, 2.4 mmol) was dissolved in ethanol (20 mL), hydrazine hydrate (184 mg, 3.6 mmol) was added, and the mixture was reacted at 70° C. for 3 hours. After the reaction was completed, the mixture was concentrated to obtain 700 mg of the target compound (89%).

[0168] (6) Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline JPEG0007652935000071.jpg261682-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-hydrazino-7,8-dihydroquinazolin-5(6H)-one (300 mg, 0.92 mmol) was dissolved in N-methylpyrrolidone (5 mL) and ethanol (60 mL), and reacted for 1 h at 160° C. under microwave irradiation. The product was separated by column chromatography (methanol / water = 0-60%) to obtain 150 mg of the target compound (yield 53%).

[0169] (7) Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline JPEG0007652935000072.jpg291684-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (130 mg, 0.43 mmol) was dissolved in N,N-dimethylformamide (4 mL), sodium hydride (60%, 34 mg, 0.85 mmol) was added, and the mixture was reacted at 20 ° C for 10 min, and 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (139 mg, 0.51 mmol) was added, and the mixture was reacted at 20 ° C for 3 h. After the reaction, the mixture was separated by column chromatography (methanol / water = 0-40%) to obtain 18.5 mg of the target compound (yield 8%). Molecular formula:C 28 H 25 F3N8O, molecular weight: 546.6, LC-MS (M / e): 547.2 (M+H + ) 1 H-NMR (400 MHz, CDCl3) δ: 8.65(s, 1H), 7.60-7.45 (m, 4H), 7.29(s, 1H), 5.67(s, 2H), 3.91(s,3H), 3.72(s,3H), 3.15-3.02 (m, 4H), 2.45-2.32 (m, 2H), 1.69-1.55 (m, 1H), 1.25-1.19 (m, 2H), 0.92-0.75 (m, 2H).

[0170] Example 2: Preparation of 4-(3-fluoro-2-isopropylphenyl)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (Compound 2) (1) Preparation of 3-fluoro-2-(prop-1-en-2-yl)phenol JPEG0007652935000073.jpg221682-Bromo-3-fluorophenol (11g, 57.6mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborane (13.2g, 78.6mmol), K2CO3 (15.9g, 115.2mmol) and Pd(dppf)Cl2 (4.2g, 5.7mmol) were dissolved in dioxane (120mL) and water (24mL), and reacted at 80°C for 16h under nitrogen protection. After confirming the completion of the reaction by LCMS, the reaction solution was poured into water (200mL) and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, rotary dried, and separated by silica gel column chromatography (EA:PE=1:5) to obtain 5.6g of the product (yield 63.9%).

[0171] (2) Preparation of 3-fluoro-2-isopropylphenol JPEG0007652935000074.jpg181683-Fluoro-2-(prop-1-en-2-yl)phenol (5.6 g, 36.8 mmol) was dissolved in methanol (60 mL), Pd / C (1.2 g) was added, and the reaction was carried out at 25°C for 4 hours. After the completion of the reaction was confirmed by LCMS, the reaction was filtered under suction, and the filtrate was rotary dried to obtain 5 g of product (yield 88.2%).

[0172] (3) Preparation of phenyl 3-fluoro-2-isopropyltrifluoromethanesulfonate JPEG0007652935000075.jpg181683-Fluoro-2-isopropylphenol (1g, 6.49mmol) was dissolved in dichloromethane (20mL), and pyridine (1.0g, 12.6mmol) and Tf2O (2.7g, 9.6mmol) were added dropwise at -10℃. The reaction was continued for 1h. After the completion of the reaction was confirmed by LCMS, the reaction solution was quenched by adding water (50mL), extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate, rotary dried, and separated by silica gel column chromatography (EA:PE=1:5) to obtain 1.6g of the product (yield 86.1%).

[0173] (4) Preparation of 2-(3-fluoro-2-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane JPEG0007652935000076.jpg221683-Fluoro-2-isopropyltrifluoromethanesulfonate phenyl (1.6 g, 5.59 mmol), bis(pinacolato)diboron (2.8 g, 11.18 mmol), Pd(dppf)Cl2 (409 mg, 0.56 mmol) and potassium acetate (1.7 g, 17.32 mmol) were dissolved in dioxane (40 mL), and reacted at 80 ° C for 8 h under nitrogen protection. After confirming the completion of the reaction by LCMS, the reaction solution was dried by rotation, extracted with EA, the organic phase was dried by rotation, and separated by silica gel column chromatography (EA:PE = 1:5) to obtain 1 g of product (yield 67.8%).

[0174] (5) Preparation of 2-(3-fluoro-2-isopropylphenyl)-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one JPEG0007652935000077.jpg311682-(3-fluoro-2-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (1.0 g, 3.79 mmol), 2-chloro-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (870 mg, 3.79 mmol), XPhosPdG2 (299 mg, 0.38 mmol), XPhos (362 mg, 0.76 mmol) and potassium phosphate (892 mg, 4.2 mmol) were dissolved in dioxane (26 mL) and water (7 mL), and reacted at 90 ° C for 2 h under nitrogen protection. After confirming that the reaction was completed by LCMS, the reaction solution was rotary dried and separated by silica gel column chromatography (EA:PE = 1:2) to obtain 350 mg of the product (yield 28.0%).

[0175] (6) Preparation of 2-(3-fluoro-2-isopropylphenyl)-4-hydrazino-7,8-dihydroquinazolin-5(6H)-one JPEG0007652935000078.jpg221682-(3-Fluoro-2-isopropylphenyl)-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (350 mg, 1.06 mmol) was dissolved in ethanol (10 mL), hydrazine hydrate (64 mg, 1.27 mmol) was added, and the reaction was carried out at 70°C for 8 hours. After the reaction was confirmed to be complete by LCMS, the reaction liquid was rotary dried and used as is in the next reaction.

[0176] (7) Preparation of 4-(3-fluoro-2-isopropylphenyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline JPEG0007652935000079.jpg241682-(3-Fluoro-2-isopropylphenyl)-4-hydrazino-7,8-dihydroquinazolin-5(6H)-one (crude product) was dissolved in NMP (2 mL) and reacted at 160°C under microwave irradiation for 1 h. After confirming that the reaction was complete by LCMS, the product was purified by reverse phase chromatography (MeOH:H2O = 0-50%) to obtain 100 mg of the product (two-step yield 31.8%).

[0177] (8) Preparation of 4-(3-fluoro-2-isopropylphenyl)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline JPEG0007652935000080.jpg311684-(3-fluoro-2-isopropylphenyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (70 mg, 0.24 mmol) was dissolved in DMF (3 mL), and NaH (60%, 19 mg, 0.48 mmol) was added in batches at 25 ° C., and 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (77 mg, 0.28 mmol) was added after 10 min, and the reaction was continued for 4 h. After confirming that the reaction was completed by LCMS, the reaction solution was quenched by adding water (20 mL), extracted with dichloromethane, the organic phase was rotary dried, and the crude product was purified by silica gel column chromatography (EA:PE=1:1) to obtain 16 mg of the product (yield 12.5%). Molecular formula:C 29 H 26 F4N6;Molecular weight:534.6;LC-MS(M / e):535.0(M+H + ) 1 H-NMR(400MHz,DMSO)δ: 7.90 (s, 1H), 7.60-7.70 (m, 2H), 7.40-7.50 (m,2H), 7.18- 7.35 (m, 3H), 5.63 (s, 2H), 3.73 (s, 3H), 3.15 - 3.22 (m, 1H), 2.95- 3.05 (m,4H), 2.20-2.30 (m, 2H), 1.25 (d, J = 6.8 Hz, 6H).

[0178] Example 3: Preparation of 4-(3-fluoro-2-isopropylphenyl)-2-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (compound 3) (1) Preparation of methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate JPEG0007652935000081.jpg241684-Methyl hydrazinobenzoate hydrochloride (9.0 g, 44.4 mmol) and 1,1,1-trifluoropropane-2,4-dione (6.8 g, 44.1 mmol) were dissolved in hexafluoroisopropanol (70 mL), triethylamine (8.9 g, 87.9 mmol) was added dropwise at 0 ° C, and then reacted at 20 ° C for 2 h. The reaction system was rotary dried, and the residue was purified by silica gel column chromatography (PE: EA = 10: 1) to obtain the product (9.0 g, yield 71.3%).

[0179] (2) Preparation of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol JPEG0007652935000082.jpg201684-(5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl benzoate (5.0 g, 17.6 mmol) was dissolved in THF (60 mL), and DIBAl-H (1.5 mol / L, 46.9 mL, 70.4 mmol) was added dropwise at 0 ° C., and the mixture was reacted at 20 ° C. for 2 hours. Water was slowly added to quench the reaction, and a saturated aqueous ammonium chloride solution (50 mL) and EA (150 mL) were added to extract and separate the liquids. The organic phase was dried in a rotary swirl, and the residue was purified by silica gel column chromatography (PE:EA = 3:1) to obtain the product (4.0 g, yield 88.7%).

[0180] (3) Preparation of 1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole JPEG0007652935000083.jpg20168 (4-(5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (3.7 g, 14.4 mmol) was dissolved in dichloroethane (30 mL), thionyl chloride (3 mL) was added, and the mixture was reacted at 50°C for 1 hour. The reaction system was rotary dried, and the residue was purified by silica gel column chromatography (PE:EA=5:1) to obtain the product (3.6 g, yield 91.0%).

[0181] (4) Preparation of 4-(3-fluoro-2-isopropylphenyl)-2-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline JPEG0007652935000084.jpg251684-(3-Fluoro-2-isopropylphenyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (100 mg, 0.34 mmol) was dissolved in DMF (5 mL), and NaH (60%, 27 mg, 0.68 mmol) was added in batches at 25 °C. After 30 min, 1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole (139 mg, 0.51 mmol) was added, followed by reaction for 2 h. The reaction mixture was quenched by adding water (20 mL), extracted with EA (30 mL), and separated. The organic phase was rotary dried, and the residue was purified by silica gel column chromatography (PE:EA=3:1) to obtain 20 mg of crude product. This was purified by a C18 reversed-phase column (water / methanol=2 / 8) and lyophilized to obtain the product (6 mg, yield 3.3%). Molecular formula:C 29 H 26 F4N6;Molecular weight:534.6;LC-MS(M / e):535.0(M+H + ) 1 H-NMR(400MHz,CDCl3)δ:7.65-7.61(m,2H),7.42-7.38(m,2H),7.36-7.33(m,1H), 7.27-7.23(m,1H),7.13-7.08(m,1H),6.43(s,1H),5.63(m,2H),3.18-3.11(m,1H), 3.12-3.03 (m, 4H), 2.44-2.38(m,2H),2.32(s,3H),1.36 (d, J = 6.8 Hz, 6H).

[0182] Example 4: Preparation of 2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(4-(trifluoromethyl)pyridin-3-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (compound 10) (1) Preparation of (4-(trifluoromethyl)pyridin-3-yl)boronic acid JPEG0007652935000085.jpg311683-Bromo-4-(trifluoromethyl)pyridine (9.2 g, 0.041 mol) was dissolved in THF (200 mL), triisopropyl borate (10.8 g, 0.057 mol) was added, and the mixture was cooled to -78 o At C, n-BuLi (2.5 M) (22.9 mL, 0.057 mol) was added and the reaction was allowed to proceed for 3 h. After quenching with 50.0 mL of water, the pH was adjusted to 4 with 4N hydrochloric acid, and then to 8 with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic phase was concentrated to obtain the crude product, which was used directly in the next reaction.

[0183] (2) Preparation of 4-(methylthio)-2-(4-(trifluoromethyl)pyridin-3-yl)-7,8-dihydroquinazolin-5(6H)-one JPEG0007652935000086.jpg261682-Chloro-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (1.5 g, 6.6 mmol) was dissolved in 1,4-dioxane (75 mL), (4-(trifluoromethyl)pyridin-3-yl)boronic acid (crude product of the previous step), Xphos-Pd-G2 (514.7 mg, 0.66 mmol), Xphos (625.3 mg, 1.3 mmol), K3PO4 (1.5 g, 7.2 mmol), water (25 mL) were added, and the mixture was reacted at 90 ° C for 3 h under N2 protection. After the reaction was completed, the solvent was rotary dried, and the residue was purified by normal phase separation (ethyl acetate / petroleum ether = 0-50%) to obtain 535.0 mg.

[0184] (3) Preparation of 4-hydrazino-2-(4-(trifluoromethyl)pyridin-3-yl)-7,8-dihydroquinazolin-5(6H)-one JPEG0007652935000087.jpg251684-(Methylthio)-2-(4-(trifluoromethyl)pyridin-3-yl)-7,8-dihydroquinazolin-5(6H)-one (0.48 g, 1.4 mmol) was dissolved in ethanol (20.0 mL), hydrazine hydrate (248.0 mg, 5.0 mmol) was added, and the mixture was reacted at 80 ° C for 3 h. After the reaction was completed, the solvent was rotary dried, and the residue was purified by normal phase fractionation (ethyl acetate / petroleum ether = 0-70%) to obtain 240.0 mg (yield 52.2%).

[0185] (4) Preparation of 4-(4-(trifluoromethyl)pyridin-3-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline JPEG0007652935000088.jpg241684-Hydrazino-2-(4-(trifluoromethyl)pyridin-3-yl)-7,8-dihydroquinazolin-5(6H)-one (200.0 mg, 0.62 mmol) was added to a hydrochloric acid 1,4-dioxane solution (4 M, 18 mL) and reacted at 70 ° C for 1 h. After the reaction was completed, the solvent was rotary dried, and the pH was adjusted to neutral by adding saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was purified by normal phase separation (ethyl acetate / petroleum ether = 0-50%) to obtain the product (130.0 mg, yield 68.8%). (5) Preparation of 2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(4-(trifluoromethyl)pyridin-3-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline JPEG0007652935000089.jpg251684-(4-(trifluoromethyl)pyridin-3-yl)-2,6,7,8 tetrahydropyrazolo[3,4,5-de]quinazoline (105 mg, 0.34 mmol) was dissolved in DMF (4 mL), potassium carbonate (143 mg, 1.03 mmol) was added, and 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (71 mg, 0.26 mmol) was added, and the mixture was reacted at 50 ° C for 5 h. After the reaction was completed, the reaction solution was purified by normal phase column chromatography (methanol / water = 0-10%) to obtain 8.8 mg of the product (yield 4.7%). Molecular formula:C 26 H 19 F6N7;Molecular weight:543.48;LC-MS(M / e):544.2(M+H + ) 1 H-NMR (400 MHz, CDCl3) δ:9.13(s, 1H), 7.97(d, 1H), 7.69 (d, 1H), 7.6(d, 2H), 7.5(d, 2H), 7.28(s,1H), 5.63(d,2H), 3.73 (s, 3H), 3.12-3.08 (m, 4H), 2.43-2.37 (m, 2H).

[0186] Example 5: Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]pyrene (compound 11) (1) Preparation of 2-(bis(methylthio)methylene)cycloheptane-1,3-dione JPEG0007652935000090.jpg241681,3-Cycloheptanedione (9g, 71.4mmol) was dissolved in DMF (200mL), potassium carbonate (30g, 214.2mmol) was added, and the mixture was reacted at 20°C for 0.5h. Carbon disulfide (8.1g, 106.4mmol) was added, and the mixture was reacted at 20°C for 1h. Methyl iodide (30.4g, 214.2mmol) was added, and the mixture was reacted at 20°C for 1h. The mixture was concentrated to obtain a crude product, which was used as it was in the next reaction.

[0187] (2) Preparation of 2-amino-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepto[d]pyrimidin-5-one JPEG0007652935000091.jpg231682-(Bis(methylthio)methylene)cycloheptane-1,3-dione (crude product of the previous step) was dissolved in DMF (200 mL), guanidine hydrochloride (6.8 g, 71.4 mmol) and potassium carbonate (14.8 g, 107.1 mmol) were added, and the mixture was reacted at 100 °C for 16 h, cooled to 25 °C, water (300 mL) was added, and the mixture was filtered to obtain a filter cake, which was dried in vacuum to obtain 10.4 g (two-step yield 65.0%).

[0188] (3) Preparation of 2-chloro-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepto[d]pyrimidin-5-one JPEG0007652935000092.jpg221682-Amino-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepto[d]pyrimidin-5-one (10.4 g, 46.6 mmol) was dissolved in dichloromethane (150 mL), titanium tetrachloride (8.8 g, 46.4 mmol) was added, tert-butyl nitrite (28.7 g, 278.6 mmol) was added, and the mixture was reacted at 25 ° C for 3 h. The reaction was quenched by adding water, filtered to obtain the filtrate, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 0-30%) to obtain 1.2 g of the product (yield 10.6%).

[0189] (4) Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohept[d]pyrimidin-5-one JPEG0007652935000093.jpg281682-Chloro-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepto[d]pyrimidin-5-one (800mg, 3.3mmol) was dissolved in 1,4-dioxane (18mL), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (640mg, 3.3mmol), Xphos-Pd-G2 (259mg, 0.33mmol), Xphos (315mg, 0.66mmol), potassium phosphate (770mg, 3.6mmol), water (6mL) were added, and the mixture was reacted at 90°C for 3h under nitrogen protection. After the reaction was completed, the solvent was dried by rotary evaporation and purified by normal phase fractionation (ethyl acetate / petroleum ether = 0-50%) to obtain 400mg of the product (yield 34.0%).

[0190] (5) Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]pyrene JPEG0007652935000094.jpg251682-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepto[d]pyrimidin-5-one (200 mg, 0.56 mmol) was dissolved in ethanol (5 mL), hydrazine hydrate (84 mg, 1.69 mmol) was added, and the mixture was reacted at 80 ° C for 3 h. After the reaction was completed, the solvent was rotary dried and purified by normal phase fractionation (ethyl acetate / petroleum ether = 0-70%) to obtain 150 mg (yield 82.9%).

[0191] (6) Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]pyrene JPEG0007652935000095.jpg281684-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]pyrene (70 mg, 0.22 mmol) was dissolved in DMF (4 mL), cesium carbonate (143 mg, 0.44 mmol) was added, and the mixture was reacted at 20 ° C for 10 min, and 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (71 mg, 0.26 mmol) was added, and the mixture was reacted at 20 ° C for 3 h. After the reaction was completed, the mixture was separated by reverse phase column chromatography (methanol / water = 0-70%) to obtain 25 mg of the product (yield 20.2%). Molecular formula:C 29 H 27 F3N8O;Molecular weight:560.6;LC-MS(M / e):561.2(M+H + ) 1 H-NMR (400 MHz, CDCl3) δ: 8.70(s, 1H), 7.97(s, 1H), 7.92-7.89 (m, 2H), 7.43-7.41(m, 2H), 5.67(s, 2H), 3.92(s,3H), 3.75(s,3H), 3.25-3.08 (m, 4H), 2.07-2.00 (m, 4H), 1.69-1.55 (m, 1H), 1.22-1.18 (m, 2H), 0.95-0.85 (m, 2H).

[0192] Example 6: Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (Compound 16) JPEG0007652935000096.jpg271684-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (100 mg, 0.32 mmol) was dissolved in DMF (4 mL), potassium carbonate (88 mg, 0.64 mmol), 2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (98 mg, 0.32 mmol) were added, and the mixture was reacted at 70 ° C for 5 h. After the reaction was completed, the mixture was separated by column chromatography (methanol / water = 0-40%) to obtain 21 mg of the product (yield 11.4%). Molecular formula:C 30 H 29 F3N8O; Molecular weight: 574.6; LC-MS (M / e): 575.2(M+H + ) 1 H-NMR (400 MHz, DMSO) δ: 8.67(s, 1H), 7.53-7.51 (m, 4H), 7.48 (s, 1H), 5.68(s, 2H), 4.56-4.55(m, 1H), 3.95(s,3H), 3.15-3.00 (m, 4H), 2.45-2.40(m,2H), 1.69-1.55 (m, 1H), 1.53-1.32 (m, 6H), 1.42-1.21 (m, 2H), 0.96-0.87 (m, 2H).

[0193] Example 7: Preparation of 4-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (Compound 18) (1) Preparation of 2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one JPEG0007652935000097.jpg241682-Chloro-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (1.0g, 4.4mmol) and 1-isopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.3g, 5.2mmol) were dissolved in 1,4-dioxane (20mL) and water (4mL), and tetrakistriphenylphosphine palladium (760mg, 0.66mmol) and sodium carbonate (950mg, 9.0mmol) were added. The reaction was carried out at 90°C for 3h under N2 protection, and after the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (ethyl acetate: n-heptane = 35%) to obtain 700mg of the product (yield 50.6%).

[0194] (2) Preparation of 4-hydrazino-2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-7,8-dihydroquinazolin-5(6H)-one JPEG0007652935000098.jpg231682-(1-Isopropyl-4-methyl-1H-pyrazol-5-yl)-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (500 mg, 1.6 mmol) was dissolved in absolute ethanol (10 mL), 98% hydrazine hydrate (180 mg, 3.5 mmol) was added, and the reaction was carried out at 70°C for 7 hours. After the reaction was completed, the mixture was concentrated, and the crude product was used as it was in the next reaction.

[0195] (3) Preparation of 4-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5]quinazoline JPEG0007652935000099.jpg22167The crude product from the previous step was dissolved in NMP (10 mL), p-toluenesulfonic acid (50 mg) was added, and the reaction system was reacted at 160°C for 1.5 h under microwave irradiation. After the reaction was completed, it was washed with water, extracted with ethyl acetate, separated and concentrated, and then purified by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to obtain 399 mg of the desired product (two-step yield 89.4%).

[0196] (4) Preparation of 4-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline JPEG0007652935000100.jpg221674-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (150 mg, 0.53 mmol), 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (218 mg, 0.79 mmol), cesium carbonate (518 mg, 1. The reaction was allowed to proceed at 50°C for 13 hours. After the completion of the reaction was confirmed by LC-MS, the reaction solution was diluted with water, extracted with EA, the organic phase was dried by rotary drying, and the residue was separated by prep-TLC (SiO2, PE:EA=1:2, Rf=0.5), and then separated by reverse phase column chromatography (C18, H2O:MeOH=90:10-65:35) to obtain 150 mg of the product (yield 54.2%). Molecular formula:C 27 H 27 F3N8; Molecular weight: 520.6; LC-MS (m / z): 521.3 (M+H + ) 1 H-NMR(400 MHz, CDCl3) δ: 7.52 (d, J=8.4, 2H), 7.61 (d, J=8.4, 2H), 7.47 (s, 1H), 7.30 (s, 1H), 5.65 (s, 2H), 5.44-5.37 (m, 1H), 3.75 (s, 3H), 3.11- 3.07 (m, 4H), 2.43- 2.36 (m, 2H), 2.32 (s, 3H), 1.56- 1.53 (m, 6H).

[0197] Example 8: Preparation of 2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (Compound 19) JPEG0007652935000101.jpg271674-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (120 mg, 0.42 mmol) was dissolved in DMF (5 mL), and 2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (120 mg, 0.40 mmol) and potassium carbonate (150 mg, 1.1 mmol) were added. The mixture was reacted at 50°C for 2 h, and after completion of the reaction, the mixture was filtered and concentrated, and then purified by a silica gel plate (ethyl acetate: n-heptane = 2:1) to obtain 23 mg of the target product (yield 10.5%). Molecular formula:C 29 H 31 F3N8;Molecular weight:548.6;LC-MS(M / e):549.4(M+H + ) 1 H-NMR (400 MHz, CDCl3) δ:7.92-7.69(m, 4H), 7.47-7.28 (m,2H), 5.89 (s, 2H), 5.41 (s, 1H), 4.54 (s,1H), 3.19-3.01 (m,4H), 2.5 (s,2H), 2.40 (s,3H), 1.72-1.5 (m, 6H), 1.55-1.43 (m, 6H).

[0198] Example 9: Preparation of 4-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazole[3,4,5-de]quinazoline (Compound 20) (1) Preparation of 2-(bis(methylthio)methylene)cyclohexane-1,3-dione JPEG0007652935000102.jpg201671,3-Cyclohexanedione (12.5g, 0.11mol) was dissolved in DMF (100mL), potassium carbonate (45.6g, 0.33mol) was added, and the mixture was reacted at 20°C for 0.5h. Carbon disulfide (12.9g, 0.17mol) was added, and the mixture was reacted at 20°C for 1h. Methyl iodide (46.8g, 0.33mol) was added, and the mixture was reacted at 20°C for 1h. The mixture was concentrated to obtain a crude product, which was used as it was in the next reaction.

[0199] (2) Preparation of 2,4-bis(methylthio)-7,8-dihydroquinazolin-5(6H)-one JPEG0007652935000103.jpg241672-(bis(methylthio)methylene)cyclohexane-1,3-dione (crude product from previous step) was dissolved in DMF (200 mL), methylisothiourea disulfate (11.5 g, 40.1 mmol), potassium carbonate (18.5 g, 133.8 mmol) were added, and the mixture was reacted at 100 °C for 16 h, cooled to 25 °C, water (300 mL) was added, filtered to obtain the filter cake, and vacuum dried to obtain 2.48 g of product (yield 26%).

[0200] (3) Preparation of 4-hydrazino-2-(methylthio)-7,8-dihydroquinazolin-5(6H)-one JPEG0007652935000104.jpg211672,4-Bis(methylthio)-7,8-dihydroquinazolin-5(6H)-one (2.0 g, 8.3 mmol) was dissolved in ethanol (20 mL), and hydrazine hydrate (1.0 g, 20.0 mmol) was added and reacted at 70° C. for 3 hours. After completion of the reaction, the mixture was concentrated to obtain a crude product.

[0201] (4) Preparation of 4-(methylthio)-2,6,7,8-tetrahydropyrazole[3,4,5-de]quinazoline JPEG0007652935000105.jpg211674-Hydrazino-2-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (crude product from previous step) was dissolved in DMAc (20 ml), p-toluenesulfonic acid (0.25 g, 1.5 mmol) was added, and the mixture was heated to 160 °C with stirring for 2 h. The reaction was then stopped, and the DMAc was removed by rotary evaporation to obtain the crude product. The crude product was separated by normal phase chromatography column (petroleum ether: ethyl acetate = 10:0 to 4:6) to obtain 0.45 g of product (yield: 26.3% (2 steps)).

[0202] (5) Preparation of 2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(methylthio)-2,6,7,8-tetrahydropyrazole[3,4,5-de]quinazoline JPEG0007652935000106.jpg311674-(Methylthio)-2,6,7,8-tetrahydropyrazole[3,4,5-de]quinazoline (206 mg, 1.0 mmol), 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (411 mg, 1.5 mmol), potassium carbonate (414 mg, 3.0 mmol) were added to DMF (20 ml), heated to 80 ° C, reacted for 4 hours, then the reaction was stopped, filtered, and the filtrate was rotary evaporated to obtain the crude product, which was separated by a normal phase chromatography column (petroleum ether: ethyl acetate = 10: 0 to 4: 6) to obtain 200 mg of the product (yield 45%).

[0203] (6) Preparation of 2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(methanesulfonyl)-2,6,7,8-tetrahydropyrazole[3,4,5-de]quinazoline JPEG0007652935000107.jpg251672-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(methylthio)-2,6,7,8-tetrahydropyrazole[3,4,5-de]quinazoline (200 mg, 0.45 mmol) was dissolved in dichloromethane (10 mL), m-chloroperoxybenzoic acid (155 mg, 0.90 mmol) was added, and the mixture was reacted at 20 ° C for 1 hour. The reaction was then stopped, and 50 ml of dichloromethane and 50 ml of saturated aqueous sodium carbonate were added and stirred for 5 min. The mixture was allowed to stand and separated. The organic phase was collected and rotary evaporated to obtain the crude product, which was then used as is in the next reaction.

[0204] (7) Preparation of 2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazole[3,4,5-de]quinazolin-4-ol JPEG0007652935000108.jpg261672-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(methanesulfonyl)-2,6,7,8-tetrahydropyrazole[3,4,5-de]quinazoline (crude product of the previous step) was dissolved in tetrahydrofuran (20 mL), 10% KOH aqueous solution 10 ml was added, stirred at 20 ° C for 4 h, the reaction was stopped, 1M HCl was added to adjust the pH value to 4-5, the reaction solution solvent was removed by rotary evaporation, 200 ml of dichloromethane:methanol = 10:1 mixed solvent was added, the product was eluted, and the crude product was obtained by rotary evaporation, 2 ml of ethyl acetate was added, stirred uniformly, and filtered to obtain 200 mg of the product (crude product).

[0205] (8) Preparation of 4-chloro-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazole[3,4,5-de]quinazoline JPEG0007652935000109.jpg251672-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazole[3,4,5-de]quinazolin-4-ol (200 mg crude product) was dissolved in phosphorus oxychloride (6 mL) and reacted at 110 ° C for 4 h. After confirming the completion of the reaction by LCMS, the reaction solution was dried by rotary drying, the residue was diluted with saturated sodium bicarbonate solution, extracted with EA, the organic phase was dried by rotary drying, and the residue was separated by column chromatography (SiO2, PE:EA = 4:1-2:3) to obtain 100 mg of the product.

[0206] (9) Preparation of 4-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazole[3,4,5-de]quinazoline JPEG0007652935000110.jpg361674-Chloro-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazole[3,4,5-de]quinazoline (90 mg, 021 mmol), 4-cyclopropyl-6-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)pyrimidine (330 m g crude product), XPhos-Pd-G2 (17 mg, 0.022 mmol), XPhos (10 mg, 0.021 mmol), potassium phosphate (134 mg, 0.63 mmol), dioxane (5 mL) and water (1 mL) were weighed out and reacted at 90°C for 2 h. After confirming the completion of the reaction by LCMS, the reaction solution was dried by rotation, and the residue was separated by column chromatography (SiO2, PE:EA = 4:1-2:3) to obtain 40 mg of the product (yield 33.0%). Molecular formula:C 28 H 23 F5N8O; molecular weight: 582.5; LC-MS (m / z): 583.1 (M+H + ) 1H-NMR(400 MHz, CDCl3)δ: 8.66 (s, 1H), 7.72-7.20 (m, 6H), 5.64 (s, 2H), 3.72 (s, 3H), 3.15-3.05 (m, 4H), 2.45-2.35 (m, 2H), 1.85-1.75 (m, 1H), 1.30-1.20 (m, 2H), 1.05-0.95 (m, 2H).

[0207] Example 10: Preparation of 4-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (Compound 1-1) (1) Preparation of 2-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one JPEG0007652935000111.jpg251672-Chloro-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (1.2g, 5.2mmol) was dissolved in 1,4-dioxane (30mL), (4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-ylboronic acid (1g, 5.1mmol), Xphos-Pd-G2 (408mg, 0.52mmol), Xphos (496mg, 1.04mmol), K3PO4 (1.2g, 5.7mmol), water (10mL) were added, and the mixture was reacted at 90°C for 3h under N2 protection. After the reaction was completed, the solvent was dried by rotary evaporation and purified by normal phase fractionation (ethyl acetate / petroleum ether = 0-50%) to obtain 600mg of the product (yield 34.1%).

[0208] (2) Preparation of 2-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-4-hydrazino-7,8-dihydroquinazolin-5(6H)-one JPEG0007652935000112.jpg221672-(4-Cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (500 mg, 1.4 mmol) was dissolved in ethanol (10 mL), hydrazine hydrate (87 mg, 1.7 mmol) was added, and the mixture was reacted at 70° C. for 3 hours. After the reaction was completed, the mixture was concentrated to obtain 400 mg of the product (yield 86.8%).

[0209] (3) Preparation of 4-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline JPEG0007652935000113.jpg211672-(4-Cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-4-hydrazino-7,8-dihydroquinazolin-5(6H)-one (300 mg, 0.92 mmol) was dissolved in NMP (5 mL) and ethanol (60 mL) and reacted at 160°C for 1 h under microwave irradiation. The product was separated by column chromatography (methanol / water = 0-60%) to obtain 150 mg of the product (yield 53%).

[0210] (4) Preparation of 4-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline JPEG0007652935000114.jpg261674-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (100 mg, 0.32 mmol) was dissolved in DMF (4 mL), potassium carbonate (88 mg, 0.64 mmol), 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (88 mg, 0.32 mmol) were added, and the mixture was reacted for 3 h at 20 ° C. After the reaction was completed, the mixture was separated by column chromatography (methanol / water = 0-40%) to obtain 42 mg of the product (yield 24%). Molecular formula:C 28 H 22 D3F3N8O;Molecular weight:549.58;LC-MS(M / e):550.2(M+H + ) 1 H-NMR (400 MHz, DMSO) δ: 8.68(s, 1H), 7.92(s, 1H), 7.76-7.68 (m, 2H), 7.44-7.42 (m, 2H), 5.79(s, 2H), 3.59(s,3H), 3.05-3.00 (m, 4H), 2.45-2.32 (m, 2H), 1.69-1.55 (m, 1H), 1.25-1.19 (m, 2H), 0.92-0.75 (m, 2H).

[0211] Example 11: Preparation of 4-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulene (Compound 11-1) (1) Preparation of 2-(di-tert-butoxycarbonyl)amino-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohept[d]pyrimidin-5-one JPEG0007652935000115.jpg231672-Amino-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepto[d]pyrimidin-5-one (2.0 g, 9.0 mmol) in DCM (60 mL) was added with triethylamine (4.6 g, 45.5 mmol), p-dimethylaminopyridine (110 mg, 0.9 mmol) and Boc2O (7.9 g, 36.2 mmol), and reacted at 25 ° C for 1 h. After confirming the completion of the reaction by LC-MS, the reaction solution was dried in a rotary suction, and the residue was separated by column chromatography (SiO2, PE:EA = 10:1-2:1) to obtain 3.4 g of the product (yield 89.6%).

[0212] (2) Preparation of tert-butyl (6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulen-4-yl)carbamate JPEG0007652935000116.jpg251672-(Di-tert-butoxycarbonyl)amino-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepto[d]pyrimidin-5-one (3.2 g, 7.6 mmol) was added to a solution of hydrazine hydrate (1.9 g, 37.9 mmol) in ethanol (50 mL), and the mixture was reacted at 80°C for 13 hours. After confirming the completion of the reaction by LC-MS, the reaction solution was dried by rotation, and the residue was separated by column chromatography (SiO2, DCM:MeOH=50:1-10:1) to obtain 1.5 g of the product (yield 68.6%).

[0213] (3) Preparation of tert-butyl (2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulen-4-yl)carbamate JPEG0007652935000117.jpg26167 tert-Butyl (6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulen-4-yl)carbamate (1.4g, 4.8mmol), 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (1.6g, 5.8mmol), cesium carbonate (3.1g, 9.5mmol) and DMF (30mL) were weighed in order and reacted at 70°C for 6h. After confirming the completion of the reaction by LC-MS, the reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was dried and rotary dried, and the residue was separated by column chromatography (SiO2, PE:EA=2:1-1:1) to obtain 1.9g of the product (yield 74.4%).

[0214] (4) Preparation of 2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulen-4-amine JPEG0007652935000118.jpg25167 tert-Butyl (2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulen-4-yl)carbamate (1.9 g, 3.6 mmol) in DCM (10 mL) was added with HCl / EA (20 mL, 80.0 mmol), and the mixture was reacted at 25 ° C for 2 h. After confirming the completion of the reaction by LC-MS, the reaction solution was dried by rotary drying, the residue was diluted with water, the pH was adjusted to 9 with aqueous ammonia, extracted with DCM, the organic phase was dried by rotary drying, and the residue was separated by column chromatography (SiO2, DCM:MeOH = 50:1-30:1) to obtain 1.2 g of the product (yield 77.9%).

[0215] (5) Preparation of 4-chloro-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulene JPEG0007652935000119.jpg261670℃, 2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulene-4-amine (500mg, 1.2mmol) in acetonitrile (3mL) was added with cuprous chloride (238mg, 2.4mmol) and tert-butyl nitrite (247mg, 2.4mmol), and reacted at 60℃ for 4h. After confirming the completion of the reaction by LC-MS, the reaction solution was filtered, the filtrate was rotary dried, and the residue was separated by column chromatography (SiO2, DCM:MeOH=50:1-30:1) to obtain 100mg of the product (yield 19.1%).

[0216] (6) Preparation of 4-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulene JPEG0007652935000120.jpg311674-Chloro-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulene (100 mg, 0.22 mmol), 4-cyclopropyl-6-(methoxy-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)pyrimidine (50 mg crude product), X Phos (10 mg, 0.021 mmol), XPhos-Pd-G2 (17 mg, 0.022 mmol), potassium phosphate (140 mg, 0.66 mmol), dioxane (5 mL) and water (1 mL) were weighed out in that order, purged with nitrogen three times, and reacted at 90 °C for 6 h. After confirming the completion of the reaction by LC-MS, the reaction solution was filtered, the filtrate was rotary dried, and the residue was separated by preparative thin layer chromatography (SiO2, DCM:MeOH = 30:1, Rf ~ 0.4) to obtain 16 mg of the product (yield 12.7%). Molecular formula:C 29 H 24 D3F3N8O;Molecular weight:563.6;LC-MS(m / z):564.2(M+H + ) 1 H-NMR(400 MHz, CDCl3) δ: 8.68 (s, 1H), 7.59 (d, 2H, J =8.0), 7.53 (d, 2H, J = 8.0), 7.31 (s, 1H), 5.69 (s, 2H), 3.75 (s, 3H), 3.43-3.33 (m, 2H), 3.24-3.14 (m, 2H), 2.33-2.12 (m, 5H), 1.20-0.90 (m, 4H).

[0217] Example 12: Preparation of 4-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (compound 16-1) JPEG0007652935000121.jpg321674-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (93 mg, 0.3 mmol) was dissolved in DMF (5 mL), potassium carbonate (83 mg, 0.6 mmol), 2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (100 mg, 0.3 mmol) were added, and the mixture was reacted at 70 ° C for 2 h. After the reaction was completed, the product was separated by column chromatography (PE / EA = 3:1 to 1:1) to obtain 43 mg of the product (yield 24.2%). Molecular formula:C 30 H 26 D3F3N8O;Molecular weight:577.6;LC-MS(M / e):578.3(M+H + ) 1 H-NMR (400 MHz, DMSO) δ: 8.69(s, 1H), 8.16(s, 1H), 7.55-7.49 (d, 2H), 7.44-7.39 (d, 2H), 5.65(s, 2H), 4.45-4.35(m,1H), 3.09-3.00 (m, 4H), 2.30-2.22 (m, 2H), 1.65-1.55 (m, 1H), 1.38-1.32 (m, 6H), 1.09-1.01 (m, 2H), 0.86-0.80 (m, 2H).

[0218] Example 13: Preparation of 4-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulene (Compound 17-1) (1) Preparation of 2-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohept[d]pyrimidin-5-one JPEG0007652935000122.jpg271672-Chloro-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepto[d]pyrimidin-5-one (400 mg, 1.6 mmol), (4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)boronic acid (347 mg, 1.8 mmol), XPhos (76 mg, 0.16 mmol), XPhos-Pd-G2 (126mg, 0.16mmol), potassium phosphate (1.0g, 4.7mmol), dioxane (20mL) and water (4mL) were weighed out in that order, substituted with nitrogen three times, and reacted at 90℃ for 4h. After confirming the completion of the reaction by LC-MS, the reaction solution was filtered, the filtrate was rotary dried, and the residue was separated by column chromatography (SiO2, PE:EA=5:1-3:1) to obtain 260mg of the product (yield 43.9%).

[0219] (2) Preparation of 4-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulene JPEG0007652935000123.jpg251672-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepto[d]pyrimidin-5-one (240 mg, 0.67 mmol) was added to an ethanol (6 mL) solution of hydrazine hydrate (168 mg, 3.4 mmol) and reacted at 80 ° C for 3 h. After confirming the completion of the reaction by LC-MS, the reaction solution was dried by rotary drying, and the residue was separated by column chromatography (SiO2, PE:EA = 3:1-1:1) to obtain 200 mg of the product (yield 92.0%).

[0220] (3) Preparation of 4-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulene JPEG0007652935000124.jpg311674-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulene (200 mg, 0.61 mmol) was added to a DMF (5 mL) solution of 2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (203 mg, 0.67 mmol) and cesium carbonate (596 mg, 1.8 mmol), and the mixture was reacted at 50 ° C for 13 h. After confirming the completion of the reaction by LC-MS, the reaction solution was diluted with water, extracted with EA, the organic phase was dried and rotary dried, and the residue was separated by column chromatography (SiO2, PE:EA = 3:1-1:1) to obtain 167 mg of the product (yield 45.9%). Molecular formula:C 31 H 28 D3F3N8O; molecular weight: 591.7; LC-MS (m / z): 592.3 (M+H + ) 1 H-NMR(400 MHz, CDCl3) δ: 8.67 (s, 1H), 7.52-7.47 (m, 4H), 7.41 (s, 1H), 5.69 (s, 2H), 4.56-4.49 (m, 1H), 3.37-3.34 (m, 2H), 3.19-3.16 (m, 2H), 2.23-2.12 (m, 4H), 1.70-1.62 (m, 1H), 1.45-1.41 (m, 6H), 1.35-1.23 (m, 2H), 0.91-0.86 (m, 2H).

[0221] The compounds shown in the table below were prepared by the same or similar methods as the above examples. JPEG0007652935000125.jpg52170

[0222] The USP1 inhibitors provided by the present invention and their uses have been described in detail above. The principles and embodiments of the present invention have been described herein with specific examples. The above examples are only used to understand the method and concept of the present invention. Those skilled in the art can make some improvements and modifications to the present invention without departing from the principle of the present invention, and these improvements and modifications are also included in the scope of protection of the present invention.

Claims

1. A compound represented by the general formula (I), a pharma- ceutically acceptable salt thereof, a deuterated product thereof or a stereoisomer thereof. (In the formula, X １ , X ２ , X ３ , X ４ are each independently N; R １ , R ２ , R ３ Each independently represents one or more Q １ a 6-10 membered aryl group or a 5-12 membered heteroaryl group, optionally substituted with R ４ , R ５ are each independently deuterium, hydrogen, a carboxy group, a cyano group, a nitro group, an amino group, a halogen, or C ２－６ Alkenyl group, C ２－６ Alkynyl group, optionally deuterated C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylamino group, di(C １－６ alkyl)amino group, halogenated C １－６ Alkyl group, hydroxy C １－６ Alkyl group, amino C １－６ Alkyl group, carboxy C １－６ Alkyl group or halogenated C １－６ alkoxy groups, Each Q １ each independently represents deuterium, a halogen, a cyano group, a carboxy group, a hydroxyl group, an amino group, a nitro group, a sulfonylamino group, or 1 to 4 substituents Q ２ C optionally substituted with １－６ Alkylamino group, di(C １－６ Alkyl)amino group, halogenated C １－６ Alkyl groups, halogenated C １－６ Alkoxy group, hydroxy C １－６ Alkyl group, amino C １－６ Alkyl group, carboxy C １－６ Alkyl group, C １－６ Alkylcarbonyl group, C １－６ Alkoxycarbonyl group, C １－６ Alkylaminoacyl group, C １－６ Alkylamide group, C １－６ Alkylsulfonyl group, C １－６ Alkylsulfonylamino group, C １－６ Alkylaminosulfonyl group, -(L) ｍ -C １－６ Alkyl group, -(L) ｍ -C ２－６ alkenyl group, -(L) ｍ -C ２－６ Alkynyl group, -(L) ｍ -C １－６ Alkoxy group, -(L) ｍ -6-10 membered aryl group, -(L) ｍ -5-12 membered heteroaryl group, -(L) ｍ -3-8 membered cycloalkyl group or -(L) ｍ -3- to 8-membered heterocyclyl groups, each Q ２ are each independently a deuterium atom, a halogen atom, a carboxy group, a hydroxyl group, a cyano group, a nitro group, an amino group, or C １－６ Alkyl group, hydroxy C １－６ Alkyl group, carboxy C １－６ Alkyl group, C １－６ Alkylamino group, di(C １－６ alkyl)amino group, -CO-C １－６ Alkylene-NH ２ group, -CO-C １－６ Alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkyl groups and halogenated C １－６ alkoxy groups, Each L is independently -CR ａ R ｂ - and Each R ａ , each R ｂ are each independently selected from deuterium and hydrogen; each m is independently an integer from 0 to 3; Each n is independently an integer from 0 to 6.

2. X １ , X ２ , X ３ , X ４ are each independently N; R １ , R ２ , R ３ Each independently represents one or more Q １ a phenyl group or a 5-6 membered heteroaryl group, optionally substituted with R ４ , R ５ are each independently deuterium, hydrogen, a cyano group, a halogen, or an optionally deuterated C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylamino group, di(C １－６ Alkyl)amino group, halogenated C １－６ Alkyl group, hydroxy C １－６ Alkyl group, amino C １－６ Alkyl group, carboxy C １－６ Alkyl group or halogenated C １－６ alkoxy groups, Each Q １ each independently represents deuterium, a halogen, a cyano group, or 1 to 4 substituents Q ２ C optionally substituted with １－６ Alkoxy group, C １－６ Alkylamino group, di(C １－６ Alkyl)amino group, halogenated C １－６ Alkyl groups, halogenated C １－６ Alkoxy group, hydroxy C １－６ Alkyl group, amino C １－６ Alkyl group, carboxy C １－６ Alkyl group, -(L) ｍ -C １－６ Alkyl group, -(L) ｍ -3-6 membered cycloalkyl group or -(L) ｍ -3- to 6-membered heterocyclyl groups, each Q ２ are each independently a deuterium atom, a halogen atom, a carboxy group, a hydroxyl group, a cyano group, a nitro group, an amino group, or C １－６ Alkyl group, hydroxy C １－６ Alkyl group, carboxy C １－６ Alkyl group, C １－６ Alkylamino group, di(C １－６ alkyl)amino group, C １－６ Alkoxy group, halogenated C １－６ Alkyl groups and halogenated C １－６ alkoxy groups, Each L is independently -CR ａ R ｂ - and Each R ａ , each R ｂ are each independently selected from deuterium and hydrogen; each m is independently an integer from 0 to 2; Each n is independently an integer from 0 to 5; 2. The compound according to claim 1, a pharma- ceutically acceptable salt thereof, a deuterated product thereof, or a stereoisomer thereof.

3. X １ , X ２ , X ３ , X ４ are each independently N; R １ , R ２ , R ３ Each independently represents 1 to 3 Q １ a phenyl group, a furyl group, a thienyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, an imidazolyl group, a pyrazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a pyridyl group, a 2-pyridonyl group, a 4-pyridonyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a 1,2,3-triazinyl group, a 1,3,5-triazinyl group, or a 1,2,4,5-tetrazinyl group, each of which may be substituted with R ４ , R ５ are each independently selected from deuterium, hydrogen, an optionally deuterated methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a methylamino group, a dimethylamino group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, an aminomethyl group, a carboxymethyl group, a carboxyethyl group, a monofluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group; Each Q １ each independently represents deuterium, fluorine, chlorine, bromine, iodine, or 1-3 substituents Q ２ a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a methylamino group, a dimethylamino group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, an aminomethyl group, a carboxymethyl group, a carboxyethyl group, -(L) ｍ -C １－４ Alkyl group, -(L) ｍ -3- to 6-membered cycloalkyl groups, each Q ２ are each independently selected from deuterium, a halogen, a carboxy group, a hydroxy group, a cyano group, a nitro group, an amino group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, a carboxymethyl group, a carboxyethyl group, a methylamino group, a dimethylamino group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group; Each L is independently -CR ａ R ｂ - and Each R ａ , each R ｂ are each independently selected from deuterium and hydrogen; each m is independently 0, 1, or 2; Each n is independently 0, 1, 2, or 3; 2. The compound according to claim 1, a pharma- ceutically acceptable salt thereof, a deuterated product thereof, or a stereoisomer thereof.

4. The compound according to claim 1, having a structure represented by formula (II-1), a pharma- ceutically acceptable salt thereof, a deuterated product thereof, or a stereoisomer thereof. (In the formula, each L, each R ａ , each R ｂ , each R ｃ , R １ , R ２ , R ３ , R ４ , R ５ , each Q １ , each Q ２ , m, n are defined as in any one of claims 1 to 3.

5. The compound according to claim 1, having a structure represented by general formula (II-2), its pharma- ceutically acceptable salt, deuterated product or stereoisomer thereof. (In the formula, Y ３ , Y ４ , Y ６ are each independently N, C, or CR ａ is selected from Y ５ , Y ７ are each independently N, NR ｃ , C.R. ａ R ｂ Or CR ａ is selected from - and - are each independently selected from a single bond or a double bond, and two adjacent bonds may not simultaneously be double bonds; each s is independently selected from an integer of 0-2; Each Q １ , each Q ２ , each L, m, R １ , R ４ , R ５ , each R ａ , each R ｂ , each R ｃ is defined as in claim 1.

6. The compound according to claim 1, having a structure represented by general formula (II-5), its pharma- ceutically acceptable salt, deuterated product or stereoisomer thereof. (In the formula, R １ 1-3 Qs １ a phenyl group optionally substituted with Each Q １ each independently represents deuterium, halogen, or 1-3 substituents Q ２ C optionally substituted with １－６ Alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkyl groups, halogenated C １－６ each Q is selected from an alkoxy group, a 3- to 6-membered cycloalkyl group, ２ are each independently deuterium, C １－６ Alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkyl groups and halogenated C １－６ alkoxy groups, has the following structure: is selected from m is an integer of 1 or 2; Each s is independently an integer of 0, 1, or 2.

7. The compound according to claim 1, having a structure represented by general formula (IV-1'), its pharma- ceutically acceptable salt, deuterated product or stereoisomer thereof. (In the formula, R ６ is hydrogen, optionally deuterated C １－６ Alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkyl groups, halogenated C １－６ alkoxy groups, Y １ , Y ２ , Y ６ are each independently N, C, or CR ａ is selected from Y ５ , Y ７ are each independently N, NR ｃ , C.R. ａ R ｂ Or CR ａ is selected from - and - are each independently selected from a single bond or a double bond, and two adjacent bonds may not simultaneously be double bonds; each s is independently selected from an integer of 0-3; Each Q １ , m, R ４ , R ５ , each R ａ , each R ｂ is defined as in claim 1.

8. R ６ is selected from a deuterated methoxy group, a deuterated ethoxy group, a deuterated propoxy group, or a deuterated isopropoxy group, and the number of deuteration is 1, 2, or 3. The compound according to claim 7, its pharma- ceutically acceptable salt, deuterated product, or stereoisomer thereof.

9. 2. The compound of claim 1 having the structure shown in the table below, a pharma- ceutically acceptable salt, deuterated product, or stereoisomer thereof.

10. 1. A drug formulation comprising: A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, a pharma- ceutically acceptable salt, deuterated form or stereoisomer thereof, and one or more pharmaceutical carriers and / or diluents, The drug formulation is in any clinically or pharma- ceutically acceptable dosage form.

11. 1. A pharmaceutical composition comprising:

10. A method for treating or preventing atopic dermatitis comprising administering to a subject the composition of claim 1 , a medicament comprising administering to said subject the composition a therapeutically effective amount of said compound ... Optionally, the pharmaceutical composition further comprises one or more pharmaceutical carriers and / or diluents.

12. Use of a compound according to any one of claims 1 to 9, its pharma- ceutically acceptable salt, deuterated product or its stereoisomer in the manufacture of a medicament for treating and / or preventing diseases mediated by USP1 and related diseases.

13. 11. Use of the pharmaceutical formulation according to claim 10 in the manufacture of a medicament for treating and / or preventing USP1 mediated and related diseases.

14. 12. Use of the pharmaceutical composition according to claim 11 in the manufacture of a medicament for the treatment and / or prevention of USP1 mediated and related diseases.

15. A method for producing a compound according to any one of claims 1 to 9, a pharma- ceutically acceptable salt thereof, a deuterated product thereof, or a stereoisomer thereof, comprising the steps of: A method comprising the step of reacting a compound represented by formula (II-2)-1 with a compound represented by formula (II-2)-2 to obtain a compound represented by formula (II-2).

16. 10. An intermediate for producing a compound according to any one of claims 1 to 9, a pharma- ceutically acceptable salt thereof, a deuterated product thereof, or a stereoisomer thereof, comprising: The intermediate has the structure: (Wherein, G is a halogen, a hydroxyl group, an amino group, C １－６ Alkylthio group or C １－６ alkylsulfonyl groups.

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