Tri-cyclic ubiquitin-specific protease 1 inhibitors and uses thereof

Abstract

The present application relates to the technical field of medicine, and particularly relates to a tri-cyclic ubiquitin-specific protease 1 inhibitor compound, a pharmaceutically acceptable salt, an ester, a deuterium or a stereoisomer thereof, a pharmaceutical composition and preparation containing the compound, the pharmaceutically acceptable salt, the ester, the deuterium or the stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt, the ester, the deuterium or the stereoisomer thereof, and an application of the compound, the pharmaceutically acceptable salt, the ester, the deuterium or the stereoisomer thereof in preparing a medicine for treating and / or preventing a disease mediated by USP1 and related diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a tricyclic ubiquitin specific protease 1 inhibitor compound, a pharmaceutically acceptable salt, an ester, a deuterium or a stereoisomer thereof, a pharmaceutical composition and preparation containing the compound, the pharmaceutically acceptable salt, the ester, the deuterium or the stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt, the ester, the deuterium or the stereoisomer thereof, and the use of the compound, the pharmaceutically acceptable salt, the ester, the deuterium or the stereoisomer thereof in the preparation of a medicament for treating and / or preventing diseases mediated by USP1 and related diseases. BACKGROUND

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

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

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

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

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

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

[0008] Scheme 1: The present application first provides a compound represented by general formula (I), a pharmaceutically acceptable salt, ester, deuterium or stereoisomer thereof:

[0009]

[0010] wherein,

[0011] X1, X2, X3, X4are each independently selected from N or CR a ;

[0012] R 1 , R 2 , R 3 are each independently selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-12 membered heteroaryl optionally substituted with one or more Q1;

[0013] R 4 , R 5 are each independently selected from deuterium, hydrogen, carboxyl, cyano, nitro, amino, halogen, C 2-6 alkyl, C 2-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoc 1-6 alkyl, carboxyC 1-6 alkyl, or haloC 1-6 alkoxy;

[0014] each Q1is independently selected from deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, sulfonamido, C 1-6 alkylamino, di(C 1-6 alkyl)amino, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoc 1-6 alkyl, carboxyC 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylamidyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, C m alkylamino, -(L) 1-6 alkyl, -(L) m alkenyl, -(L) 2-6 alkynyl, -(L) m alkyl, -(L) 2-6 alkenyl, -(L) m alkynyl, -(L) 1-6 alkoxy, -(L) m -6-10 membered aryl, -(L) m-5-12 membered heteroaryl, -(L) m -3-8 membered cycloalkyl or -(L) m -3-8 membered heterocyclyl, each Q2is independently selected from the group consisting of deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, hydroxyC 1-6 alkyl, carboxyC 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, -CO-C 1-6 alkylene-NH2, -CO-C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl and haloC 1-6 alkoxy;

[0015] each L is independently selected from the group consisting of -CO-, -O-, -S-, -SO-, -S(O)2-, -NR c -, -CR a R b -;

[0016] each R a , each R b is independently selected from the group consisting of deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylaminoacyl, C 1-6 alkylamido, C 1-6 alkylsulfonamido, C 1-6 alkylaminosulfonyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl;

[0017] each R c is independently selected from the group consisting of deuterium, hydrogen, C 1-6 alkyl optionally substituted with deuterium, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl;

[0018] each m is independently an integer from 0-3;

[0019] each n is independently an integer from 0-6.

[0020] Scheme 2: The compound of the preceding Scheme 1, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, wherein,

[0021] X1, X2, X3, X4are each independently selected from N or CR a ;

[0022] R 1 , R 2 , R 3 are each independently selected from 5-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl optionally substituted with one or more Q1;

[0023] R 4 , R 5 are each independently selected from deuterium, hydrogen, cyano, halogen, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl, or haloC 1-6 alkoxy;

[0024] each Q1is independently selected from deuterium, halogen, cyano, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl, -(L) m -C 1-6 alkyl, -(L) m -3-6 membered cycloalkyl, or -(L) m -3-6 membered heterocyclyl, each Q2is independently selected from deuterium, halogen, carboxy, hydroxy, cyano, nitro, amino, C 1-6 alkyl, hydroxyC 1-6 alkyl, carboxyC 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6alkoxy, haloC 1-6 alkyl and haloC 1-6 alkoxy;

[0025] each L is independently selected from -CO-, -O-, -NR c -, -CR a R b -;

[0026] each R a , each R b is independently selected from deuterium, hydrogen, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy optionally substituted with deuterium, C 1-6 alkylamino, di(C 1-6 alkyl)amino, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl;

[0027] each R c is independently selected from deuterium, hydrogen, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy;

[0028] each m is independently an integer from 0 to 2;

[0029] each n is independently an integer from 0 to 5.

[0030] Scheme 3: The compound of the preceding Scheme 1 or 2, a pharmaceutically acceptable salt thereof, an ester, a deuterated form, or a stereoisomer thereof, wherein,

[0031] X1, X2, X3, X4are each independently selected from N;

[0032] R 1 , R 2 , R 3 are each independently selected from phenyl optionally substituted with 1-4 Q1or 5-6 membered heteroaryl;

[0033] R 4 , R 5 is independently selected from deuterium, hydrogen, C 1-4 alkyl optionally substituted with deuterium, C 1-4 alkoxy optionally substituted with deuterium, C 1-4 alkylamino, di(C 1-4 alkyl)amino, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, aminoC1-4 alkyl, carboxy C 1-4 alkyl or halo C 1-4 alkoxy;

[0034] each Q1is independently selected from deuterium, halogen, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halo C 1-4 alkyl, halo C 1-4 alkoxy, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, carboxy C 1-4 alkyl, -(L) m -C 1-4 alkyl, -(L) m -3-6 membered cycloalkyl, each Q2is independently selected from deuterium, halogen, carboxy, hydroxy, cyano, nitro, amino, C 1-4 alkyl, hydroxy C 1-4 alkyl, carboxy C 1-4 alkyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkoxy, halo C 1-4 alkyl and halo C 1-4 alkoxy;

[0035] each L is independently selected from -CR a R b - or -O-;

[0036] each R a , each R b is independently selected from deuterium, hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halo C 1-4 alkyl, halo C 1-4 alkoxy, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, carboxy C 1-4 alkyl;

[0037] each R c is independently selected from deuterium, hydrogen, C 1-4 alkyl, halo C 1-4 alkyl, halo C 1-4 alkoxy;

[0038] each m is independently an integer from 0 to 2;

[0039] each n is independently an integer from 0 to 4.

[0040] Scheme 4: The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, wherein,

[0041] X1, X2, X3, X4are each independently selected from N;

[0042] R 1 , R 2 , R 3 are each independently selected from phenyl, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, optionally substituted with 1-3 Q1;

[0043] R 4 , R 5 are each independently selected from deuterium, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, trifluoromethoxy;

[0044] each Q1is independently selected from deuterium, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, -(L) m -C 1-4 alkyl, -(L) m -3-6 membered cycloalkyl, each Q2is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl, carboxyethyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

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

[0046] each R is independently selected from the group consisting of deuterium, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, each optionally substituted with deuterium; a , each R is independently selected from the group consisting of deuterium, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, each optionally substituted with deuterium; b , each R is independently selected from the group consisting of deuterium, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, each optionally substituted with deuterium;

[0047] each m is independently selected from 0, 1, 2;

[0048] each n is independently 0, 1, 2, 3.

[0049] Scheme 5: A compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, wherein,

[0050] R 1 , R 2 , R 3 is independently selected from the group consisting of phenyl or 5-6 membered nitrogen-containing heteroaryl, each optionally substituted with 1-4 Q1.

[0051] Scheme 6: A compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, wherein,

[0052] R 1 , R 2 , R 3 is independently selected from the group consisting of phenyl, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, each optionally substituted with 1-3 Q1.

[0053] Scheme 7: A compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, wherein,

[0054] R 1 , R 2 , R 3 is independently selected from the group consisting of phenyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, each optionally substituted with 1-3 Q1.

[0055] Scheme 7-1: A compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, wherein,

[0056] R 1 , R 2 , R 3 is independently selected from the group consisting of phenyl, pyrimidinyl, pyridyl, pyrazolyl, imidazolyl, pyrrolyl, pyridazinyl, pyrazinyl, each optionally substituted with 1-3 Q1.

[0057] Scheme 7-2: The compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein,

[0058] R 1 , R 3 are each independently selected from the group consisting of phenyl optionally substituted with 1-3 Q1.

[0059] Scheme 7-3: The compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein,

[0060] R 1 is selected from the group consisting of phenyl optionally substituted with 1-3 Q1. Preferably, R 1 is selected from the group consisting of phenyl optionally substituted with 1-3 Q1.

[0061] Scheme 7-4: The compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein,

[0062] R 3 is selected from the group consisting of phenyl optionally substituted with 1-3 Q1. Preferably, R 3 is selected from the group consisting of phenyl optionally substituted with 1-3 Q1. Preferably, R 3 is selected from the group consisting of phenyl optionally substituted with 1-3 Q1.

[0063] Scheme 7-5: The compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein,

[0064] R 2 is selected from the group consisting of phenyl or pyridyl optionally substituted with 1-3 Q1.

[0065] Scheme 8: The compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, having the structure of Formula (II),

[0066]

[0067] wherein each L, each R a , each R b , each R c , R1 , R 2 , R 3 , each Q1, each Q2, m, n are defined in any of the preceding embodiments.

[0068] Scheme 8-1: A compound of any of the preceding embodiments, a pharmaceutically acceptable salt thereof, an ester, a deuterated form, or a stereoisomer thereof, having the structure of Formula (II-1),

[0069]

[0070] wherein each L, each R a , each R b , each R c , R 1 , R 2 , R 3 , R 4 , R 5 , each Q1, each Q2, m, n are defined in any of the preceding embodiments.

[0071] Scheme 9: A compound of any of the preceding embodiments, a pharmaceutically acceptable salt thereof, an ester, a deuterated form, or a stereoisomer thereof, having the structure of Formula (III):

[0072]

[0073] wherein,

[0074] Y1, Y2, Y3, Y4, Y6are each independently selected from N, C, or CR a ;

[0075] Y5, Y7are each independently selected from N, NR c , C, CR a R b , or CR a ;

[0076] are each independently selected from a single bond or a double bond, and no more than two adjacent bonds are double bonds;

[0077] each s is independently selected from an integer from 0 to 2;

[0078] each Q1, m, each L, each R a , each R b , each R c are defined in any of the preceding embodiments.

[0079] Scheme 9-1: A compound of any preceding scheme, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, having the structure of Formula (III-1):

[0080]

[0081] wherein,

[0082] Y1, Y2, Y3, Y4, Y6are each independently selected from N, C, or CR a ;

[0083] Y5, Y7are each independently selected from N, NR c , C, CR a R b or CR a ;

[0084] are each independently selected from a single bond or a double bond, and no more than two adjacent bonds can be double bonds;

[0085] each s is independently an integer selected from 0-3;

[0086] each Q1, m, each L, each R a , each R b , each R c , R 4 , R 5 are as defined in any preceding scheme.

[0087] Scheme 9-2: A compound of any preceding scheme, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, having the structure of Formula (III-1’):

[0088]

[0089] wherein, R 6 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy optionally substituted with deuterium;

[0090] Y1, Y2, Y3, Y4, Y6are each independently selected from N, C, or CR a ;

[0091] Y5, Y7are each independently selected from N, NR c , C, CR a R b or CR a ;

[0092] each independently selected from a single or double bond, and no more than two adjacent bonds can be double bonds;

[0093] each s is independently selected from an integer from 0-3;

[0094] each Q1, m, each L, each R a , each R b , each R c , R 4 , R 5 are as described in any of the preceding Schemes.

[0095] Scheme 9-3: A compound of any of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein R 6 is selected from hydrogen, deuterated C 1-6 alkyl, or deuterated C 1-6 alkoxy.

[0096] Scheme 9-4: A compound of any of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein,

[0097] Y1, Y2, Y3, Y4, Y6are each independently selected from N, C, or CH;

[0098] Y5, Y7are each independently selected from N, NH, C, CH2, or CH.

[0099] Scheme 9-5: A compound of any of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein,

[0100] is selected from the following structures:

[0101] Scheme 9-6: A compound of any of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein,

[0102] is selected from the following structures:

[0103] Scheme 10: A compound of any of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, having the structure of Formula (IV),

[0104]

[0105] wherein,

[0106] each Q1, m are as described in any of the preceding Schemes;

[0107] are each independently selected from a single or double bond, and no two adjacent bonds can be double bonds at the same time;

[0108] Y1, Y2, Y5, Y6, Y7, and the definition of each s are described in any of the preceding aspects.

[0109] Scheme 10-1: A compound of any of the preceding aspects, a pharmaceutically acceptable salt thereof, an ester, a deuterated form, or a stereoisomer thereof, having the structure of Formula (IV-1),

[0110]

[0111] wherein,

[0112] are each independently selected from a single or double bond, and no two adjacent bonds can be double bonds at the same time;

[0113] each Q1, m, R 4 , R 5 , each R a , each R b , Y1, Y2, Y5, Y6, Y7, and the definition of each s are described in any of the preceding aspects.

[0114] Scheme 10-2: A compound of any of the preceding aspects, a pharmaceutically acceptable salt thereof, an ester, a deuterated form, or a stereoisomer thereof, having the structure of Formula (IV-1’),

[0115]

[0116] wherein, R 6 is selected from hydrogen, C 1-6 alkyl optionally deuterated, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy;

[0117] are each independently selected from a single or double bond, and no two adjacent bonds can be double bonds at the same time;

[0118] each Q1, m, R 4 , R 5 , each R a , each R b , Y1, Y2, Y5, Y6, Y7, and the definition of each s are described in any of the preceding aspects.

[0119] Scheme 10-3: A compound of any of the preceding aspects, a pharmaceutically acceptable salt thereof, an ester, a deuterated form, or a stereoisomer thereof, wherein, R 6selected from hydrogen, deuterated C 1-6 alkyl or deuterated C 1-6 alkyl or deuterated C a alkoxy.

[0120] Scheme 10-4: The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, having the structure of Formula (XIV), a b are each independently selected from hydrogen.

[0121] Scheme 11: The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, having the structure of Formula (V),

[0122]

[0123] wherein,

[0124] each Q1, Y1, Y2, and each s are as described in any one of the preceding schemes.

[0125] Scheme 11-1: The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, having the structure of Formula (V-1),

[0126]

[0127] wherein,

[0128] each Q1, R 4 , R 5 , R a , R b , Y1, Y2, and each s are as described in any one of the preceding schemes.

[0129] Scheme 11-2: The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, having the structure of Formula (V-1'),

[0130]

[0131] wherein, R 6 is selected from hydrogen, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy;

[0132] each Q1, R 4 , R 5 , R a , R b , Y1, Y2, and each s are as described in any one of the preceding schemes.

[0133] Scheme 11-3: The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein R 6 is selected from hydrogen, deuterated C 1-6 alkyl, or deuterated C 1-6 alkyl.

[0134] Scheme 12: The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein,

[0135] each Q1is independently selected from deuterium, halogen, C 1-6 alkyl optionally substituted with 1-4 substituents Q2, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl, -(L) m -3-6 membered cycloalkyl, or -(L) m -3-6 membered heterocyclyl, each Q2is independently selected from deuterium, halogen, carboxy, hydroxy, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, and halogenated C 1-6 alkoxy.

[0136] Scheme 12-1: The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein,

[0137] each Q1is independently selected from deuterium, halogen, C 1-6 alkyl optionally substituted with 1-3 substituents Q2, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, 3-6 membered cycloalkyl, each Q2is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, and halogenated C 1-6 alkoxy.

[0138] Scheme 13: The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein,

[0139] each Q1is independently selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, carboxyl C 1-4 alkyl, 3-6 membered cycloalkyl, each Q2is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl and halogenated C 1-4 alkoxy.

[0140] Scheme 13-1: A compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, wherein,

[0141] each Q1is independently selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, 3-6 membered cycloalkyl, each Q2is independently selected from deuterium, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl and halogenated C 1-4 alkoxy.

[0142] Scheme 14: A compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, wherein,

[0143] each Q1is independently selected from deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, each Q2is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy.

[0144] Scheme 14-1: The compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein,

[0145] each Q1is independently selected from deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, each Q2is independently selected from deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy.

[0146] Scheme 15: The compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein,

[0147] each L is independently selected from -CR a R b -;

[0148] each R a , each R b is independently selected from deuterium, hydrogen, C 1-4 alkyl optionally substituted with deuterium, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy.

[0149] Scheme 15-1: The compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein,

[0150] each L is independently selected from -CR a R b -;

[0151] each R a , each R b is independently selected from deuterium, hydrogen, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy.

[0152] Scheme 16: The compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein,

[0153] each L is independently selected from -CH2-.

[0154] Scheme 17: The compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, having the structure of Formula (VI),

[0155]

[0156] Y8is selected from N, NR c , C, CR a R b or CR a ;

[0157] Y9is selected from N, C, or CR a ;

[0158] are each independently selected from a single bond or a double bond, and no two adjacent bonds can be double bonds at the same time;

[0159] each Q1, each L, m, R 4 , R 5 , Y3, Y4, Y5, Y6, Y7, each s are as defined in any one of the preceding Schemes.

[0160] Scheme 17-1: The compound of the preceding Scheme 17, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein,

[0161] Y8is selected from N, NH, C, CH2, or CH;

[0162] Y9is selected from N, C, or CH;

[0163] are each independently selected from a single bond or a double bond, and no two adjacent bonds can be double bonds at the same time;

[0164] each Q1, each L, m, R 4 , R 5 , Y3, Y4, Y5, Y6, Y7, each s are as defined in any one of the preceding Schemes.

[0165] Scheme 18: The compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, having the structure of Formula (VII),

[0166]

[0167] wherein each Q1, m, Y1, Y2, each s are as defined in any one of the preceding Schemes.

[0168] Scheme 18-1: A compound of any preceding scheme, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, having the structure of Formula (VII-1),

[0169]

[0170] wherein each Q1, m, Y1, Y2, each s, R 4 , R 5 are as described in any preceding scheme.

[0171] Scheme 18-2: A compound of any preceding scheme, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, having the structure of Formula (VII-1’),

[0172]

[0173] wherein R 6 is selected from hydrogen, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy;

[0174] each Q1, m, Y1, Y2, each s, R 4 , R 5 are as described in any preceding scheme.

[0175] Scheme 18-3: A compound of any preceding scheme, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, wherein R 6 is selected from hydrogen, deuterated C 1-6 alkyl, or deuterated C 1-6 alkoxy.

[0176] Scheme 19: A compound of any preceding scheme, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, having the structure of Formula (VIII),

[0177]

[0178] wherein each Q1, m, each s are as described in any preceding scheme.

[0179] Scheme 19-1: A compound of any preceding scheme, a pharmaceutically acceptable salt thereof, an ester, deuteride, or stereoisomer thereof, having the structure of Formula (VIII-1),

[0180]

[0181] wherein each Q1, m, R 4 , R 5 , each s is as described in any of the preceding Schemes.

[0182] Scheme 19-2: A compound of any of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, having the structure of Formula (VIII-1’),

[0183]

[0184] wherein R 6 is selected from hydrogen, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy;

[0185] each Q1, m, R 4 , R 5 , each s is as described in any of the preceding Schemes.

[0186] Scheme 19-2: A compound of any of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, having the structure of Formula (VIII-1’), 6 is selected from hydrogen, deuterated C 1-6 alkyl, or deuterated C 1-6 alkoxy.

[0187] Scheme 20: A compound of any of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, having the structure of Formula (IX),

[0188]

[0189] are each independently selected from a single or double bond, and no more than two adjacent bonds can be double bonds;

[0190] each Q1, Y1, Y2, Y5, Y6, Y7, each s is as described in any of the preceding Schemes.

[0191] Scheme 20-1: A compound of any of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, having the structure of Formula (IX-1),

[0192]

[0193] wherein R 6 is selected from hydrogen, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C1-6 alkyl, haloC 1-6 alkoxy;

[0194] each independently selected from a single or double bond, and no more than two adjacent bonds can be double bonds;

[0195] each Q1, Y1, Y2, Y5, Y6, Y7, each s is as described in any of the preceding Schemes.

[0196] Scheme 20-2: A compound of any of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, wherein R 6 is selected from hydrogen, C 1-6 alkyl optionally substituted with deuterium, or deuterated C 1-6 alkyl.

[0197] Scheme 21: A compound of any of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof,

[0198] R 4 , R 5 , each R a , each R b , each R c is independently selected from hydrogen.

[0199] Scheme 22: A compound of any of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, having the structure of Formula (II-2),

[0200]

[0201] wherein Y3, Y4, Y6are each independently selected from N, C, or CR a ;

[0202] Y5, Y7are each independently selected from N, NR c , C, CR a R b , or CR a ;

[0203] each independently selected from a single or double bond, and no more than two adjacent bonds can be double bonds;

[0204] each s is independently selected from an integer between 0-2;

[0205] each Q1, each Q2, each L, m, R 1 , R 4 , R 5 , each R a , each Rb each R c is as described in any of the preceding aspects.

[0206] Scheme 23: A compound of any of the preceding aspects, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, having the structure of Formula (II-3),

[0207]

[0208] each Q1, each Q2, each s, each L, m, R 1 , R 4 , R 5 , Y5, Y6, Y7, each R a , each R b , each R c is as described in any of the preceding aspects.

[0209] Scheme 24: A compound of any of the preceding aspects, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, having the structure of Formula (II-3),

[0210]

[0211] R 1 is selected from phenyl or 5-6 membered nitrogen-containing heteroaryl optionally substituted with 1-3 Q1, preferably R 1 is selected from

[0212] R 4 , R 5 are each independently selected from deuterium, hydrogen, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy, haloC 1-6 alkyl, and haloC 1-6 alkoxy;

[0213] each L is independently selected from -CR a R b -;

[0214] each R a , each R b are each independently selected from deuterium, hydrogen, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy, haloC 1-6 alkyl, and haloC 1-6 alkoxy;

[0215] each Q1is independently selected from deuterium, halogen, C 1-6alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, 3-6 membered cycloalkyl, each Q2is independently selected from the group consisting of deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl and haloC 1-6 alkoxy;

[0216] is selected from the group consisting of:

[0217] m is an integer of 1 or 2;

[0218] each s is independently an integer of 0, 1, 2.

[0219] Scheme 25: A compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, a deuterated form, or a stereoisomer thereof, having the structure of Formula (II-4),

[0220]

[0221] 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 are as described in any one of the preceding Schemes.

[0222] Scheme 26: A compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, a deuterated form, or a stereoisomer thereof, having the structure of Formula (II-4),

[0223]

[0224] wherein R 1 is selected from phenyl or 5-6 membered nitrogen-containing heteroaryl optionally substituted with 1-3 Q1, preferably R 1 is selected from phenyl or 5-6 membered nitrogen-containing heteroaryl optionally substituted with 1-3 Q1, preferably R

[0225] R 4 , R 5 are each independently selected from the group consisting of deuterium, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl and haloC 1-6 alkoxy;

[0226] each Q1is independently selected from deuterium, halogen, C1-6alkyl optionally substituted with 1-3 substituents Q2, 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, 3-6 membered cycloalkyl, each Q2is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy;

[0227] is selected from the following structures:

[0228] m is an integer of 1 or 2;

[0229] each s is independently an integer of 0, 1, 2.

[0230] Scheme 27: A compound of any preceding scheme, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, having the structure of Formula (II-5),

[0231]

[0232] each Q1, each Q2, s, m, R 1 , Y5, Y6, Y7, each R a , each R b , each R c are as described in any preceding scheme.

[0233] Scheme 28: A compound of any preceding scheme, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, having the structure of Formula (II-5),

[0234]

[0235] wherein R 1 is selected from phenyl optionally substituted with 1-3 Q1, or 5-6 membered nitrogen-containing heteroaryl; preferably R 1 is selected from phenyl optionally substituted with 1-3 Q1, or 5-6 membered nitrogen-containing heteroaryl;

[0236] each Q1is independently selected from deuterium, halogen, C1-6alkyl optionally substituted with 1-3 substituents Q2, 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, 3-6 membered cycloalkyl, each Q2is independently selected from deuterium, C1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl and haloC 1-6 alkoxy;

[0237] selected from the group consisting of:

[0238] m is an integer of 1 or 2;

[0239] each s is independently an integer of 0, 1, or 2.

[0240] Scheme 29: The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, having the structure of Formula (IV-1’),

[0241]

[0242] wherein Y1, Y2are each independently selected from N, C, or CH;

[0243] Y5, Y7are each independently selected from NH, N, C, CH, or CH2;

[0244] Y6is selected from N, CH, or C;

[0245] R 4 , R 5 are each independently selected from deuterium, hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkylamino, di(C 1-6 alkyl)amino, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl or haloC 1-6 alkoxy;

[0246] R 6 is selected from hydrogen, deuteratedC 1-6 alkoxy;

[0247] each Q1is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkylamino, di(C 1-6 alkyl)amino, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC1-6 alkyl, -(L) m -3-6 membered cycloalkyl or -(L) m -3-6 membered heterocyclyl;

[0248] R a , R b are each independently selected from hydrogen;

[0249] each Q2is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy;

[0250] are each independently selected from a single or double bond, and no more than two adjacent bonds can be double bonds;

[0251] each m, each s is independently 0, 1, 2.

[0252] Scheme 30: The compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or stereoisomer thereof, having the structure of Formula (VIII-1’),

[0253]

[0254] each Q1is independently selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, carboxy C 1-4 alkyl, 3-6 membered cycloalkyl;

[0255] each Q2is independently selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl and halogenated C 1-4 alkoxy;

[0256] R 4 , R 5 are each independently selected from deuterium, hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, or halogenated C 1-6 alkoxy;

[0257] R 6 selected from hydrogen, deuterated C 1-4 alkoxy;

[0258] m is 1, 2;

[0259] each s is independently 0, 1, 2.

[0260] Scheme 31: The compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, wherein R 6 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, or deuterated isopropoxy, the number of deuterium being 1, 2, 3, or 4.

[0261] Scheme 32: The compound of any one of the preceding Schemes, a pharmaceutically acceptable salt thereof, an ester, deuterated form, or a stereoisomer thereof, wherein,

[0262] R 6 selected from hydrogen, deuterated C

[0263] The selection of any substituent in any embodiment of the present application can be combined with each other, and the combination of the technical scheme still falls within the protection scope of the present application.

[0264] In some embodiments of the present application, the structure of the compound of the preceding general formula (I), a pharmaceutically acceptable salt thereof, an ester, a deuterated form, or a stereoisomer thereof is shown in Table 1:

[0265] Table 1

[0266]

[0267]

[0268] The "pharmaceutically acceptable salt" of the present application refers to the addition salt of pharmaceutically acceptable acid and base, such as metal salt, ammonium salt, salt with organic acid, salt with organic base, salt with inorganic acid, salt with acidic amino acid or basic amino acid, etc.

[0269] The "ester" according to the present application means a pharmaceutically acceptable ester, and particularly an ester which is hydrolyzed in vivo and includes an ester which is readily decomposed in the human body to leave a parent compound (a compound according to the general formula (I)) or a salt thereof. The "ester" according to the present application can be selected, for example, from the following groups: (1) a carboxylic acid ester obtained by esterification with a carboxylic acid compound, wherein the non-carbonyl moiety of the carboxylic acid compound is selected from, for example, C 1-20 straight or branched alkyl, C 1-12 straight or branched alkyl, C 1-8 straight or branched alkyl, C 1-6 straight or branched alkyl (e.g., methyl, ethyl, n-propyl, t-butyl or n-butyl), C 1-6 alkoxy C 1-6 alkyl (e.g., methoxymethyl), C 6-10 aryl C 1-6 alkyl (e.g., benzyl), C 6-10 aryloxy C 1-6 alkyl (e.g., phenoxymethyl), C 6-10 aryl (e.g., phenyl, optionally substituted with, for example, halogen, C 1-4 alkyl or C 1-4 alkoxy or amino); (2) a sulfonate ester, such as an alkylsulfonyl or aralkylsulfonyl (e.g., methylsulfonyl); (3) an amino acid ester (e.g., L-valyl or L-isoleucyl); and (4) a mono-, di- or triphosphate ester, etc.; (5) an ester obtained by esterification with an alcohol compound, wherein the non-hydroxy moiety of the alcohol compound is selected from, for example, C 1-20 straight or branched alkyl, C 1-12 straight or branched alkyl, C 1-8 straight or branched alkyl, C 1-6 straight or branched alkyl (e.g., methyl, ethyl, n-propyl, t-butyl or n-butyl), C 1-6 alkoxy C 1-6 alkyl (e.g., methoxymethyl), C 6-10 aryl C 1-6 alkyl (e.g., benzyl), C 6-10 aryloxy C 1-6 alkyl (e.g., phenoxymethyl), C 6-10 aryl (e.g., phenyl, optionally substituted with, for example, halogen, C 1-4 alkyl or C 1-4 alkoxy or amino).

[0270] The "stereoisomers" of the compound of the general formula (I) of the present application refer to enantiomers when the compound of the general formula (I) has asymmetric carbon atoms, to syn and anti isomers when the compound has carbon-carbon double bonds or cyclic structures, to tautomers when the compound has ketone or oxime, and the like. In some embodiments of the present application, the stereoisomers include, but are not limited to, enantiomers, diastereomers, racemates, syn and anti isomers, tautomers, geometric isomers, epimers, and mixtures thereof.

[0271] The present application also provides a pharmaceutical composition comprising the compound of the general formula (I), pharmaceutically acceptable salt, ester, deuteride, or stereoisomer thereof, and one or more second therapeutically active agents, and optionally, one or more pharmaceutically acceptable carriers and / or diluents.

[0272] The present application also provides a pharmaceutical preparation comprising the compound of the general formula (I), pharmaceutically acceptable salt, ester, deuteride, or stereoisomer thereof, and one or more pharmaceutically acceptable carriers and / or diluents; the pharmaceutical preparation is any dosage form that is clinically or pharmaceutically acceptable.

[0273] In some embodiments of the present application, the above pharmaceutical preparation can be administered to a patient or subject in need of such treatment by oral, parenteral, rectal, or pulmonary administration, and the like. For oral administration, the pharmaceutical composition can be formulated into oral preparations, for example, into conventional oral solid preparations such as tablets, capsules, pills, granules, and the like; or into oral liquid preparations such as oral solutions, oral suspensions, syrups, and the like. When formulated into oral preparations, suitable fillers, binders, disintegrants, lubricants, and the like can be added. For parenteral administration, the above pharmaceutical preparation can also be formulated into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When formulated into injections, conventional methods in the pharmaceutical field can be used for production, and no additional agents can be added or suitable additional agents can be added according to the properties of the drug when the injection is prepared. For rectal administration, the pharmaceutical composition can be formulated into suppositories, and the like. For pulmonary administration, the pharmaceutical composition can be formulated into inhalants or sprays, and the like.

[0274] The pharmaceutical carrier and / or diluent used in the pharmaceutical composition or pharmaceutical preparation of the present application can be any conventional carrier and / or diluent in the field of pharmaceutical preparations, and the selection of the specific carrier and / or diluent will depend on the mode of administration for treating a specific patient or the type and state of the disease. The method for preparing a suitable pharmaceutical composition for a specific mode of administration is well within the knowledge of those skilled in the art of medicine. For example, the pharmaceutical carrier and / or diluent can include solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, binders, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, and antioxidants, etc. that are conventional in the field of pharmacy. If necessary, flavoring agents, preservatives, and sweeteners, etc. can also be added to the pharmaceutical composition.

[0275] The present application also provides the use of the aforementioned compound represented by general formula (I), pharmaceutically acceptable salt, ester, deuteride or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in the preparation of a drug for treating and / or preventing a USP1 mediated disease and related diseases; the USP1 mediated disease and related diseases are selected from cancer or benign tumor.

[0276] The present application also provides the use of the aforementioned compound represented by general formula (I), pharmaceutically acceptable salt, ester, deuteride or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in the treatment and / or prevention of a USP1 mediated disease and related diseases; the USP1 mediated disease and related diseases are selected from cancer or benign tumor.

[0277] The present application also provides a method for treating a disease, which comprises administering to a patient in need thereof a therapeutically effective amount of the aforementioned compound represented by general formula (I), pharmaceutically acceptable salt, ester, deuteride or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition, wherein the disease is a USP1 mediated disease and related diseases; the USP1 mediated disease and related diseases are selected from cancer or benign tumor.

[0278] The present application provides a method for preparing the aforementioned compound, but is not limited to the following method, and the reaction equation of the preparation method is as follows:

[0279]

[0280] The compound of formula (II-2)-1 is dissolved in a suitable solvent (for example, DMF), a basic reagent (for example, NaH, potassium carbonate, cesium carbonate, sodium carbonate) is added, the compound of formula (II-2)-2 is added, and the reaction is carried out for 1-15 hours. Water is added for quenching, a suitable organic solvent (for example, dichloromethane, ethyl acetate) is added for extraction, and the solvent is evaporated to dryness, and the compound of general formula (II-2) of the present application is obtained by a suitable method (for example, silica gel column chromatography).

[0281] The above preparation method can be simply summarized as: 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);

[0282] wherein X is halogen; 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 , and each s are as defined in any of the preceding technical solutions.

[0283] The present application also provides intermediates for preparing the compounds represented by general formula (II-1) to general formula (IX-1), pharmaceutically acceptable salts thereof, esters thereof, deuterium derivatives thereof, or stereoisomers thereof, which have the following structural formula:

[0284]

[0285] wherein R 1 , R 4 , R 5 , each Q1, each Q2, each L, each R a , each R b , each R c , and m are as defined in any of the preceding technical solutions.

[0286] The present application also provides intermediates for preparing the compounds represented by general formula (III) to general formula (IX-1), pharmaceutically acceptable salts thereof, esters thereof, deuterium derivatives thereof, or stereoisomers thereof, which have the following structural formula:

[0287]

[0288] wherein G is selected from halogen, hydroxyl, amino, C 1-6 alkylthio, or C 1-6 alkylsulfonyl;

[0289] 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 as defined in any of the preceding technical solutions.

[0290] In certain embodiments, G is selected from halogen, hydroxyl, amino, methylthio, or methylsulfonyl.

[0291] In the specification and claims of this application, compounds are named according to chemical structure, and if the naming of a compound and the chemical structure of the compound do not agree, the chemical structure controls.

[0292] In this application, unless otherwise indicated, the scientific and technical terms used have the meanings commonly understood by one of ordinary skill in the art, and the following definitions are provided to better define the present application. When the definitions and explanations provided in this application are inconsistent with the meanings commonly understood by one of ordinary skill in the art, the definitions and explanations provided in this application control.

[0293] As used herein, "halogen" means fluorine, chlorine, bromine, and iodine, preferably fluorine and chlorine.

[0294] As used herein, "halo" means any hydrogen in a substituent group can be replaced with one or more of the same or different halogens. "Halogen" is as previously defined.

[0295] As used herein, "C 1-6 "Alkyl" means a straight or branched chain alkyl group containing 1 to 6 carbon atoms, including, for example, "C 1-5 "Alkyl", "C 1-4 "Alkyl", "C 1-3 "Alkyl", "C 1-2 "Alkyl", "C 2-6 "Alkyl", "C 2-5 "Alkyl", "C 2-4 "Alkyl", "C 2-3 "Alkyl", "C 3-6 "Alkyl", "C 3-5 "Alkyl", "C 3-4 "Alkyl", "C 4-6 "Alkyl", "C 4-5 "Alkyl", "C 5-6 "Alkyl", etc. Specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. As used herein, "C 1-4 "Alkyl" means a straight or branched chain alkyl group containing 1 to 4 carbon atoms. 1-6 "Alkyl" means a straight or branched chain alkyl group containing 1 to 4 carbon atoms.

[0296] As used herein, "C 1-6"Alkylene" refers to a divalent radical derived from an alkyl group as described above, including, for example, "C 1-6 "Alkyl" refers to a straight or branched chain monovalent radical of 1-8 carbon atoms, including, for example, "C 1-5 "Alkylene", "C 1-4 "Alkylene", "C 1-3 "Alkylene", "C 1-2 "Alkylene", "C 2-6 "Alkylene", "C 2-5 "Alkylene", "C 2-4 "Alkylene", "C 2-3 "Alkylene", "C 3-6 "Alkylene", "C 3-5 "Alkylene", "C 3-4 "Alkylene", "C 4-6 "Alkylene", "C 4-5 "Alkylene", "C 5-6 "Alkylene", etc. Specific examples include, but are not limited to: methylene, ethylene, propylene, butylene, pentylene, hexylene, etc. "C 1-4 "Alkylene" refers to a divalent radical derived from an alkyl group as described above, including, for example, "C 1-6 Specific examples of alkylene groups containing 1-4 carbon atoms.

[0297] "Alkyl" refers to a straight or branched chain monovalent radical of 1-8 carbon atoms, including, for example, "C 2-6 "Alkenyl" refers to a straight or branched chain or cyclic hydrocarbon group containing at least one double bond and having from 2 to 6 carbon atoms, including, for example, "C 2-5 "Alkenyl", "C 2-4 "Alkenyl", "C 2-3 "Alkenyl", etc. Specific examples include, but are not limited to: ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-l- propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl- 1-butenyl, 3-methyl-l-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2- propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-l-pentenyl, 3- methyl-l-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-l-butenyl, 2-ethyl-l-butenyl, 2-ethyl-3-butenyl, etc.

[0298] "Alkyl" refers to a straight or branched chain monovalent radical of 1-8 carbon atoms, including, for example, "C 2-6 "Akynyl" refers to a straight or branched chain hydrocarbon group containing a triple bond and having from 2 to 8 carbon atoms, including, for example, "C 2-5 "Akynyl", "C2-4 alkynyl", "C 2-3 alkynyl", "C

[0299] alkynyl", "C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylamidino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, C 1-6 alkylaminosulfonyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylthio" means a group of the formula -C 1-6 alkyl-O-, C 1-6 alkyl-NH-, (C 1-6 alkyl)2-N-, C 1-6 alkyl-NH-C(O)-, C 1-6 alkyl-C(O)-NH-, C 1-6 alkyl-S(O)2-, C 1-6 alkyl-S(O)2-NH-, C 1-6 alkyl-NH-S(O)2-, C 1-6 alkyl-C(O)-, C 1-6 alkyl-O-C(O)-, C 1-6 alkyl-S- groups, wherein "C 1-6 alkyl" is as previously described.

[0300] alkynyl", "C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylamidino, C 1-4 alkylcarbonylamino, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, C 1-4 alkylaminosulfonyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-4"Alkylthio" means a group of the formula -C 1-4 alkyl-O-, C 1-4 alkyl-NH-, (C 1-4 alkyl)2-N-, C 1-4 alkyl-NH-C(O)-, C 1-4 alkyl-C(O)-NH-, C 1-4 alkyl-S(O)2-, C 1-4 alkyl-S(O)2-NH-, C 1-4 alkyl-NH-S(O)2-, C 1-4 alkyl-C(O)-, C 1-4 alkyl-O-C(O)-, C 1-4 alkyl-S- groups formed by the removal of a hydrogen atom from a 1-4 alkyl group, as previously described.

[0301] "HaloC 1-6 alkyl," "hydroxyC 1-6 alkyl," "aminoC 1-6 alkyl," "carboxyC 1-6 alkyl," "haloC 1-6 alkylene," "haloC 1-6 alkoxy" means a group of the formula -O-C 1-6 alkyl, C 1-6 alkylene, C 1-6 alkoxy formed by the removal of a hydrogen atom from a

[0302] "HaloC 1-4 alkyl," "hydroxyC 1-4 alkyl," "aminoC 1-4 alkyl," "carboxyC 1-4 alkyl," "haloC 1-4 alkylene," "haloC 1-4 alkoxy" means a group of the formula -O-C 1-4 alkyl, C 1-4 alkylene, C 1-4 alkoxy formed by the removal of a hydrogen atom from a

[0303] "3-12 membered cycloalkyl" as used herein means a cyclic alkyl group containing from 3 to 12 carbon atoms which is saturated or partially saturated and which is not aromatic, and includes "monocyclic cycloalkyl" and "fused cycloalkyl".

[0304] The term "monocycloalkyl" as used in this invention refers to a saturated or partially saturated monocycloalkyl group that is non-aromatic, including "3-8 membered saturated cycloalkyl" and "3-8 membered partially saturated cycloalkyl"; preferably "3-4 membered cycloalkyl", "3-5 membered cycloalkyl", "3-6 membered cycloalkyl", "3-7 membered cycloalkyl", "4-5 membered cycloalkyl", "4-6 membered cycloalkyl", "4-7 membered cycloalkyl", "4-8 membered cycloalkyl", "5-6 membered cycloalkyl", "5-7 membered cycloalkyl", "5-8 membered cycloalkyl", "6-7 membered cycloalkyl", "5-8 ... Cycloalkyl, 6-8 membered cycloalkyl, 7-8 membered cycloalkyl, 3-6 membered saturated cycloalkyl, 4-7 membered saturated cycloalkyl, 4-8 membered saturated cycloalkyl, 5-8 membered saturated cycloalkyl, 5-7 membered saturated cycloalkyl, 5-6 membered saturated cycloalkyl, 3-6 membered partially saturated cycloalkyl, 4-7 membered partially saturated cycloalkyl, 4-8 membered partially saturated cycloalkyl, 5-8 membered partially saturated cycloalkyl, 5-7 membered partially saturated cycloalkyl, 5-6 membered partially saturated cycloalkyl, etc. Specific examples of the "3-8 saturated cycloalkyl group" include, but are not limited to: cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane (cycloheptyl), cyclooctane (cyclooctyl), etc.; specific examples of the "3-8 partially saturated cycloalkyl group" include, but are not limited to: cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1,3-diene, cyclohex-1,4-diene, cycloheptenyl, cycloheptenyl-1,3-diene, cycloheptenyl-1,4-diene, cycloheptenyl-1,3,5-trienyl, cyclooctenyl, cyclooctyl-1,3-diene, cyclooctyl-1,4-diene, cyclooctyl-1,5-diene, cyclooctyl-1,3,5-trienyl, cyclooctatetraenyl, etc.

[0305] The "fused ring alkyl" of the present application refers to a saturated or partially saturated, non-aromatic cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other, one of the rings in the fused ring can be an aromatic ring, but the whole fused ring is not aromatic; the fused manner can be: 5-6 membered ring alkyl and 5-6 membered ring alkyl, benzene 5-6 membered ring alkyl, benzene 5-6 membered saturated ring alkyl and the like. Examples thereof include, but are not limited to: bicyclo[3.1.0]hexane, bicyclo[4.1.0]heptane, bicyclo[2.2.0]hexane, bicyclo[3.2.0]heptane, bicyclo[4.2.0]octane, octahydrocyclopenta-diene, octahydro-1H-indene, decahydro-naphthalene, tetradeca-hydrophenanthrene, bicyclo[3.1.0]hex-2-ene, bicyclo[4.1.0]hept-3-ene, bicyclo[3.2.0]hept-3-ene, bicyclo[4.2.0]oct-3-ene, 1,2,3,3a-tetrahydrocyclopenta-diene, 2,3,3a,4,7,7a-hexahydro-1H-indene, 1,2,3,4,4a,5,6,8a-octahydro-naphthalene, 1,2,4a,5,6,8a-hexahydro-naphthalene, 1,2,3,4,5,6,7,8,9,10-decahydrophenanthrene, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl and the like.

[0306] The "3-12 membered heterocyclyl" of the present application refers to a saturated or partially saturated and non-aromatic monocyclic or fused ring cyclic group having at least one heteroatom (e.g., having 1, 2, 3, 4, or 5) which is a nitrogen atom, an oxygen atom, and / or a sulfur atom, and having 3-12 ring atoms. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure can be oxo. The "3-12 membered heterocyclyl" of the present application includes "3-12 membered saturated heterocyclyl" and "3-12 membered partially saturated heterocyclyl". Preferably, the "3-12 membered heterocyclyl" of the present application contains 1-3 heteroatoms; preferably, the "3-12 membered heterocyclyl" of the present application contains 1-2 heteroatoms, and the heteroatoms are selected from a nitrogen atom and / or an oxygen atom; preferably, the "3-12 membered heterocyclyl" of the present application contains 1-2 nitrogen atoms. The "3-12 membered heterocyclyl" is preferably "3-10 membered heterocyclyl", "3-8 membered heterocyclyl", "4-8 membered heterocyclyl", "3-6 membered heterocyclyl", "3-6 membered saturated heterocyclyl", "3-6 membered nitrogen-containing heterocyclyl", "3-6 membered saturated nitrogen-containing heterocyclyl", "5-6 membered heterocyclyl", "5-6 membered saturated heterocyclyl", "5-6 membered nitrogen-containing heterocyclyl", and the like.Specific examples of "3- to 12-membered heterocyclyl groups" include, but are not limited to, aziridinyl, 2H-aziridinyl, diaziridinyl, 3H-diaziridinyl, azetidinyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, 2H-l,2-oxazinyl, 6H-l,3-oxazinyl, 4H-l,3-thiazinyl, 6H-l,3-thiazinyl, 2H-pyranyl, 2H-pyr- an-2-onyl, 3,4-dihydro-2H-pyranyl, pyrrolidinylcyclopropyl, cyclopentylazetidinyl, pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, pyrrolidinylmorpholinyl, piperidinylmorpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzimidazolidinyl, benzoxazolidinyl, benzothiazolidinyl, benzoisoxazolidinyl, benzoisothiazolidinyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzotetrahydropyranyl, pyridinocyclopentyl, pyridinocyclohexyl, pyridinotetrahydrofuranyl, pyridinopyrrolidinyl, pyridinimidazolidinyl, pyridinooxazolidinyl, pyridinothiazolidinyl, pyridinoisoxazolidinyl, pyridinoisothiazolidinyl, pyridinopiperidinyl, pyridinomorpholinyl, pyridinopiperazinyl, pyridinotetrahydropyranyl, pyrimidinocyclopentyl, pyrimidinocyclohexyl, pyrimidinotetrahydrofuranyl, pyrimidinopyrrolidinyl, pyrimidinimidazolidinyl, pyrimidinooxazolidinyl, pyrimidinothiazolidinyl, pyrimidinoisoxazolidinyl, pyrimidinoisothiazolidinyl, pyrimidinopiperidinyl, pyrimidinomorpholinyl, pyrimidinopiperazinyl, pyrimidinotetrahydropyranyl; tetrahydroimidazo[4,5-c]pyridinyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][l,3]dioxolyl, 2H-chromenyl, 2H-chromen-2-onyl, 4H-chromenyl, 4H-chromen-4-onyl, 4H-l,3-benzoxazinyl, 4,6-dihydro-lH-furo[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-lH-furo[3,4-d]imidazolyl, 4,6-dihydro-lH-thieno[3,4-d]imidazolyl, 4,6-dihydro-lH-pyrrolo[3,4-d]imidazolyl, octahydro-benzo[d]imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuroimidazolyl, 4,5,6,7-tetrahydro-lH-benzo[d]imidazolyl, octahydrocyclopenta[c]pyrrolyl, 4H-l,3-benzoxazinyl, and the like.

[0307] The "6-10 membered aryl" as used herein refers to a cyclic group having aromaticity containing 6-10 ring carbon atoms, including "6-8 membered monocyclic aryl" and "8-10 membered fused aryl".

[0308] The "6-8 membered monocyclic aryl" as used herein refers to a monocyclic aryl group containing 6-8 ring carbon atoms, examples of which include, but are not limited to, phenyl, cyclooctatetraenyl, and the like; preferably phenyl.

[0309] The "8-10 membered fused aryl" as used herein refers to an unsaturated cyclic group having aromaticity containing 8-10 ring carbon atoms formed by two or more cyclic structures sharing two adjacent atoms with each other, preferably "9-10 membered fused aryl", and specific examples thereof include naphthyl and the like.

[0310] The "5-12 membered heteroaryl" as used herein refers to a cyclic group having aromaticity containing 5-12 ring atoms (at least one of which is a heteroatom such as a nitrogen atom, an oxygen atom, or a sulfur atom), for example, 5-12 membered nitrogen-containing heteroaryl, 5-12 membered oxygen-containing heteroaryl, 5-12 membered sulfur-containing heteroaryl, and the like. This includes "5-8 membered monocyclic heteroaryl" and "8-10 membered fused heteroaryl".

[0311] The "5-8 membered monocyclic heteroaryl" as used herein refers to a monocyclic cyclic group having aromaticity containing 5-8 ring atoms (at least one of which is a heteroatom such as a nitrogen atom, an oxygen atom, or a sulfur atom). Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure can be oxidized. The "5-8 membered monocyclic heteroaryl" includes, for example, "5-7 membered monocyclic heteroaryl", "5-6 membered monocyclic heteroaryl", "5-6 membered nitrogen-containing monocyclic heteroaryl", "5 membered nitrogen-containing monocyclic heteroaryl", and the like. Specific examples of the "5-8 membered monocyclic heteroaryl" include, but are not limited to, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azepinyl, 1,3-diazepinyl, azocinyl, and the like. The "5-6 membered heteroaryl" refers to a specific example of the "5-8 membered heteroaryl" containing 5-6 ring atoms.

[0312] The "8-10 membered fused heteroaryl" as used herein refers to a cyclic structure having 8-10 ring atoms (at least one of which is a heteroatom, such as nitrogen, oxygen, or sulfur) that is unsaturated and aromatic, formed by two or more cyclic structures sharing two adjacent atoms with each other. Optionally, a ring atom (such as a carbon atom, nitrogen atom, or sulfur atom) in the cyclic structure can be oxidized. Included are "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", and the like, which can be fused in the manner of benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl, 5-6 membered heteroaryl, and the like; specific examples include, but are not limited to, pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furan thiophene, pyrazolooxazole, benzofuryl, benzisofuryl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinonyl, isoquinolyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthylidinyl, and the like.

[0313] The "optionally substituted" as used herein includes both "substituted" and "unsubstituted".

[0314] The "substituted" as used herein includes "substituted" and "unsubstituted". is selected from a single bond or a double bond.

[0315] Any atom in the compounds of the present application, unless otherwise specified, can represent any stable isotope of that atom. Unless otherwise specified, when a position in a structure is defined as H, it is intended to mean hydrogen (H-l). Likewise, unless otherwise specified, when a position in a structure is defined as D, it is intended to mean deuterium (H-2) in an amount of at least 3340 times greater than the amount of the naturally occurring isotope (0.015%), i.e., at least 50.1% deuterium isotope. When one or more positions in the structure of a compound of the present application is defined as D, it is intended that the compound represented by the structure is present in an amount of 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%.

[0316] The deuterium incorporation of the compounds of the present application is the ratio of the amount of the isotopic content of the synthesis label to the amount of the naturally occurring isotope. The deuterium incorporation of each specified deuterium atom of the compounds of the present application can be at least 3500 fold (52.5%), at least 4000 fold (60%), at least 4500 fold (67.5%), at least 5000 fold (75%), at least 5500 fold (82.5%), at least 6000 fold (90%), at least 6333.3 fold (95%), at least 6466.7 fold (97%), at least 6566.7 fold (98.5%), at least 6600 fold (99%), at least 6633.3 fold (99.5%).

[0317] Isotopologues, as used herein, refer to compounds that differ only in their isotopic composition. Compounds herein that contain deuterium at a particular position will also contain a very small amount of the hydrogen isotopologues at that position. The amount of hydrogen isotopologues at a deuterated position in a deuterated compound of the present application will depend on a number of factors, including the deuterium isotopic purity of the deuterium reagent (D2O, D2, NaBD4, LiAlD4, etc.) and the effectiveness of the method of synthesis used to introduce the deuterium isotopes. However, as noted above, the total amount of hydrogen isotopologues at a deuterated position will be less than 49.9%. The total amount of hydrogen isotopologues at a deuterated position in a deuterated compound of the present application will be less than 47.5%, 40%, 32.5%, 25%, 17.5%, 10%, 5%, 3%, 1%, or 0.5%.

[0318] As used herein, each atom not designated as deuterium is present at its natural isotopic abundance.

[0319] As used herein, "deuterated" means that one or more hydrogen atoms of a group are replaced by one or more deuterium atoms. The deuterated compound can be partially deuterated or fully deuterated. For example, a deuterated compound can contain only one deuterium. In some embodiments, a deuterated compound contains only two deuteriums. In some embodiments, a deuterated compound contains only three deuteriums. In some embodiments, a deuterated compound contains four deuteriums.

[0320] As used herein, "optionally deuterated" includes both deuterated and non-deuterated groups, wherein "deuterated" is as defined above.

[0321] As used herein, "therapeutically effective amount" means that amount of the aforementioned compound, pharmaceutical formulation, pharmaceutical composition which, when administered to a patient, is capable of at least alleviating the symptoms of the patient's condition. The actual amount which constitutes a "therapeutically effective amount" will vary depending on a number of factors, including but not limited to the particular condition being treated, the severity of the condition, the size and health of the patient, and the route of administration. A skilled medical practitioner can readily determine the appropriate amount using methods known in the medical arts.

[0322] Advantages of the Invention

[0323] (1) The compound, pharmaceutically acceptable salt, ester, deuterium or stereoisomer thereof has excellent USP1 inhibitory activity, and can treat and / or prevent USP1 mediated diseases and related diseases;

[0324] (2) The compound has good inhibitory effect on tumor cells;

[0325] (3) The compound, pharmaceutically acceptable salt, ester, deuterium or stereoisomer thereof has good pharmacokinetic properties, longer lasting effect and high bioavailability;

[0326] (4) The compound, pharmaceutically acceptable salt, ester, deuterium or stereoisomer thereof has good safety;

[0327] (5) The compound has simple preparation process, high drug purity, stable quality and is easy to produce on a large scale.

[0328] The advantages of the compound provided by the embodiments of the present application are further illustrated by the following experiments, but this should not be understood as the compound provided by the embodiments of the present application only has the following advantages.

[0329] In vitro enzymatic activity of compounds of the invention

[0330] Test sample: The compound synthesized by the embodiments of the present application, the structural formula is shown in Table 1.

[0331] Experimental reagents:

[0332]

[0333]

[0334] Experimental consumables:

[0335] Consumables Vendor Cat No. 384-Well plate Perkin Elmer 6007279

[0336] Experimental method one:

[0337] 1. Compound dilution

[0338] 1) Use DMSO to prepare the compound of the present application to 10mM as a test stock solution.

[0339] 2) Dilute the compound stock solution of the present application by 4 times gradient to 10 concentrations, the highest concentration is 10mM.

[0340] 3) Using Echo 550 to transfer the diluted compounds of the present application to 384-well plates (diluted 1000 times), 2 replicates for each concentration, final DMSO concentration is 1%.

[0341] 4) The final concentration of the test compounds is 10000 nM, 2500 nM, 625 nM, 156 nM, 39 nM, 9.8 nM, 2.4 nM, 0.61 nM, 0.15 nM, 0.038 nM.

[0342] 2. Enzyme reaction experiment

[0343] 1) Prepare enzyme solution in 1x test buffer.

[0344] 2) Add Ubiquitin Rhodamine 110 Protein, CF (Ub-Rho) in 1x assay buffer to make substrate solution.

[0345] 3) Transfer 10 μL of enzyme solution and 1x reaction buffer to 384-well plates.

[0346] 4) Incubate at room temperature for 15 minutes.

[0347] 5) Add 10 μL of substrate solution to each well to start the reaction, centrifuge for 30 s, and shake for 30 s.

[0348] 3. Result detection

[0349] 1) Read the plate on SpectraMax Paradigm for 30 minutes, excitation wavelength is 480 nm, and emission wavelength is 540 nm.

[0350] 2) Collect the data on SpectraMax Paradigm.

[0351] 4. Data analysis

[0352] The inhibition rate (inhibition (%inh)) is calculated using the following formula:

[0353]

[0354] Where Max represents the luminescence signal intensity of the positive control well without adding compounds;

[0355] Min represents the luminescence signal intensity of the negative control well without adding enzyme;

[0356] Signal represents the luminescence signal intensity of the test compound;

[0357] The IC is calculated using the following formula: 50

[0358] ​

[0359] wherein Y represents: %inhibition;

[0360] X represents: concentration of the compound.

[0361] Experimental results:

[0362] Table 2 Inhibitory activity of the compounds of the present application on USP-1

[0363]

[0364] From the above experimental results, it can be seen that the compounds prepared in the present application can effectively inhibit the activity of USP1, and are effective USP1 inhibitors.

[0365] Experimental method two:

[0366] In the enzyme reaction experiment, the incubation time at room temperature in step 4) was changed to 60 min, and other conditions were the same as in experimental method one, and the following test results were obtained:

[0367] Table 3 Inhibitory activity of the compounds of the present application on USP-1

[0368]

[0369] From the above experimental results, it can be seen that the compounds prepared in the present application can effectively inhibit the activity of USP1, and are effective USP1 inhibitors.

[0370] In vitro cytological inhibition activity experiment one of compounds of the invention

[0371] Test sample: some of the compounds of the present application, whose chemical names and structures are shown in the preparation examples.

[0372] The cell strains used in the following experiments are as follows: MDA-MB-436: human breast cancer cells.

[0373] The definitions represented by the following abbreviations are as follows:

[0374] FBS: fetal bovine serum

[0375] ITS-G: insulin-transferrin-selenium supplement

[0376] glutathione: glutathione

[0377] Experimental method (CelltiterGlo assay)

[0378] 1 Preparation of cells

[0379] 1.1 Cell culture:

[0380] All cells are adherent cells, the culture medium is DMEM + 10% FBS + 1% ITS-G + 16 μg / ml glutathione, and the cells are in the logarithmic growth phase for testing.

[0381] 1.2 Preparation of cell suspension:

[0382] Harvest cells in the logarithmic growth phase and count the cells using a blood cell counter. Detect cell viability by trypan blue exclusion method to ensure that the cell viability is above 90%. Adjust to the appropriate concentration, and add 90 μL of cell suspension to the 96-well plate, respectively.

[0383] Table 4 Cell inoculation number

[0384]

[0385] 2 Preparation of test compounds

[0386] 2.1 Preparation of test compound DMSO stock solution, the concentration of each test compound stock solution is 10 mM.

[0387] 2.2 Preparation of test compound working stock solution

[0388] The test compound stock solution 10 mM is diluted with DMSO 3 times in a continuous gradient, a total of 8 concentrations. Then take 2 μL of DMSO gradient diluted compound into 198 μL of culture solution, which is the test compound working stock solution (the compound concentration is 10 times the final concentration, and the highest concentration is 100 μM).

[0389] 2.3 Compound treatment

[0390] Add 10 μL of compound working stock solution (10 times dilution, DMSO final concentration is 0.1%) to each well of the 96-well plate inoculated with cells.

[0391] The final concentration of the test compound is: 10000.00 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, 4.57 nM.

[0392] 2.4 Control well setting

[0393] Solvent control: 0.1% DMSO.

[0394] Blank control: only add culture medium, do not inoculate cells.

[0395] 2.5 Place the 96-well plate in a 37°C, 5% CO2 cell incubator for 7 days.

[0396] 3 Detection

[0397] Melt the CTG reagent and equilibrate the 96-well plate to room temperature for 30 minutes. Add 60 μL of reagent (Celltiter Gloassay kit) to each well, mix by shaking for 2 minutes, incubate at room temperature for 20 minutes. Read luminescent signal on a multi-function microplate reader.

[0398] 4Data processing

[0399] 1) Inhibition rate (%) = (DMSO solvent control well reading - test well reading) / (DMSO solvent control well reading - blank control well reading) x 100%;

[0400] 2) Input GraphPad Prism for plotting, get curve and IC 50 .

[0401] Experimental results and conclusions

[0402] Table 5 In vitro cytological activity (IC 50 , nM) of compounds of the present application

[0403]

[0404] As can be seen from Table 5, the compounds of the present application can effectively inhibit the proliferation of MDA-MB-436 cells, indicating that the compounds of the present application have clinical application potential for treating cancer diseases caused by BRCA1 gene mutation.

[0405] In vitro cytological inhibition activity experiment two of compounds of the invention

[0406] Test substance: some compounds of the present application, whose chemical names and structures are shown in the preparation examples.

[0407] The cell strains used in the following experiments are as follows: MDA-MB-436: human breast cancer cells; Caov-3: human ovarian cancer cells

[0408] Experimental method one (Celltiter Glo assay)

[0409] 1. Preparation of cells

[0410] 1.1 Cell culture:

[0411] All cells are adherent cells, the culture medium of MDA-MB-436 cells is DMEM + 10% FBS + 1% ITS-G + 16 μg / ml glutathione, and the culture medium of Caov-3 cells is DMEM + 10% FBS, and the cells are in the logarithmic growth phase for testing.

[0412] 1.2 Preparation of cell suspension:

[0413] Cells in logarithmic growth phase were harvested and counted using a hemocytometer. Cell viability was determined by trypan blue exclusion to ensure that cell viability was greater than 90%. The cells were adjusted to the appropriate concentration and 90 μL of cell suspension was added to each well of a 96-well plate.

[0414] Table 6 Cell Seeding Number

[0415]

[0416] 2. Preparation of Test Compounds

[0417] 2.1 Preparation of Test Compound DMSO Stock Solution

[0418] 2.2 Preparation of Test Compound Working Stock Solution

[0419] The test compound stock solution 10 mM was serially diluted with DMSO at 3-fold gradient, a total of 8 concentrations. Then 2 μL of the DMSO gradient diluted compound was added to 198 μL of culture solution to prepare the test compound working stock solution (the compound concentration was 10 times the final concentration, and the highest concentration was 100 μM).

[0420] 2.3 Compound Treatment

[0421] 10 μL of the compound working stock solution (10-fold dilution, DMSO final concentration 0.1%) was added to each well of the 96-well plate seeded with cells.

[0422] The final concentration of the test compound was: 10000.00 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, 4.57 nM.

[0423] 2.4 Control Well Setup

[0424] Solvent Control: 0.1% DMSO.

[0425] Blank Control: 96-well plate detection reading at 0 h after drug addition

[0426] 2.5 The 96-well plate was incubated in a 37°C, 5% CO2 cell incubator for 7 days.

[0427] 3. Detection

[0428] The CTG reagent was thawed and the 96-well plate was equilibrated to room temperature for 30 minutes, 60 μL of reagent (Celltiter Gloassay kit) was added to each well, mixed well on a shaker for 2 minutes (avoid light), and incubated at room temperature for 20 minutes (avoid light). The multifunctional microplate reader read the light signal value.

[0429] 4. Data processing

[0430] 1) Inhibition rate (%) = (DMSO solvent control well reading - test material well reading) / (DMSO solvent control well reading - blank control well reading) x 100%;

[0431] 2) Input GraphPad Prism for plotting, get curve and IC 50 .

[0432] Experimental results and conclusions

[0433] Table 7 In vitro cytological activity (IC 50 , nM) of compounds of the present application

[0434]

[0435]

[0436] The IC 50 values of compounds 11, 16, 18, 19, 1-1, 11-1, 16-1 and 17-1 of the present application for inhibiting Caov-3 cells are 1 nM to 600 nM, which indicates that the compounds of the present application can effectively inhibit the proliferation of MDA-MB-436 and Caov-3 cells, and indicates that the compounds of the present application have clinical application potential for treating cancerous diseases that are HRD positive (homologous recombination deficiency).

[0437] Experimental method two:

[0438] The concentration of the prepared compound stock solution is 5 mM.

[0439] The test compound stock solution 5 mM is diluted with DMSO 3 times in succession to obtain 9 concentrations.

[0440] The final concentration of the test compound is: 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.

[0441] Other conditions are the same as in experimental method one, and the IC 50 value of compound 20 for inhibiting MDA-MB-436 cells is 55.7 nM; and the IC 50 value of compound 20 for inhibiting Caov-3 cells is 1 nM to 100 nM.

[0442] Pharmacokinetic experiment of compounds of the invention

[0443] 1. The test product is a compound of the present application, the preparation of which is described in the examples of the present application.

[0444]

[0445] 2. Preparation of test solution

[0446] (1) Intravenous injection (iv): Take compound 11 2.54 mg, add DMSO solution 0.495 ml, vortex, ultrasonic dissolution, PEG400 0.495 ml, vortex mixing, then add 28% HP-β-CD 1.484 ml, vortex mixing, to obtain a clear solution, the concentration is 1 mg / ml.

[0447] (2) Oral administration (po): Take compound 11 3.33 mg, add solvent (2% HPC + 0.1% Tween 80) 3.243 ml, grind uniformly, to obtain a uniform suspension. The concentration is 1 mg / ml.

[0448] 3. Experimental method

[0449] (1) Drug administration

[0450] The test sample was administered intravenously (iv) at a dose of 5 mg / kg, and the administration volume was 5 ml / kg;

[0451] Oral administration (po) at a dose of 10 mg / kg, and the administration volume was 10 ml / kg.

[0452] (2) Blood sampling

[0453] At 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after administration, tail vein blood was collected, about 100 μl of whole blood was taken at each time point, and the plasma was separated by centrifugation at 8000 rpm for 6 min, and the plasma was stored at -80°C in the refrigerator.

[0454] (3) Analysis of plasma samples

[0455] Protein precipitation method: Take 20 μl of plasma into a 96-well deep well plate, add 200 μl of internal standard solution (tolbutamide-200 ng / ml), vortex for 10 min, then centrifuge at 4000 rpm for 20 min, take 100 μl of supernatant, add 100 μL water, vortex for 3 min; LC-MS / MS analysis.

[0456] 4. Experimental results and conclusions

[0457] The experimental data show that the intravenous injection or oral administration of the compound of the present application has high exposure in vivo, suitable half-life and clearance rate, and exhibits good pharmacokinetic properties. For example, the exposure of compound 11 in mice is greater than 6000 h*ng / ml after intravenous bolus administration, which indicates that the compound of the present application has a good clinical application prospect. DETAILED DESCRIPTION

[0458] The technical solutions of the present application will be described below in combination with specific examples. The described examples are only a part of the examples of the present application, rather than all the examples. Based on the examples in the present application, all other examples obtained by those skilled in the art without creative labor fall within the protection scope of the present application.

[0459] The meanings of the abbreviations used in the following experiments are as follows:

[0460] Xphos-Pd-G2: chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); Xphos: 2-dicyclohexylphospho-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

[0461] Preparation of 4-(4-cyclopropyl-6-methoxy-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)

[0462] (1) Preparation of 2-(bis(methylthio)methylene)cyclohexane-1,3-dione

[0463]

[0464] 1,3-cyclohexanedione (20 g, 178.4 mmol) was dissolved in DMF (200 mL), potassium carbonate (74 g, 535.2 mmol) was added, and the reaction was carried out at 20°C for 0.5 h. Carbon disulfide (20 g, 267.6 mmol) was added, and the reaction was carried out at 20°C for 1 h. Iodomethane (76 g, 535.2 mmol) was added, and the reaction was carried out at 20°C for 1 h. Concentration gave a crude product, which was directly used in the next step.

[0465] (2) Preparation of 2-amino-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one

[0466]

[0467] The 2-(bis(methylthio)methylene)cyclohexane-1,3-dione (crude from previous step) was dissolved in DMF (200 mL), guanidine hydrochloride (17 g, 178.4 mmol), potassium carbonate (49.3 g, 356.8 mmol) were added, and the reaction was stirred at 100 °C for 16 h. The reaction was cooled to 25 °C, water (300 mL) was added, and the resulting precipitate was filtered and dried under vacuum to give the target compound 16.3 g in 44% yield.

[0468] (3) Preparation of 2-chloro-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one

[0469]

[0470] The 2-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), tert-butyl nitrite (48 g, 468 mmol) were added, and the reaction was stirred at 25 °C for 3 h. The reaction was quenched by the addition of water, and the resulting filtrate was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 0-40%) to give the target compound 6.1 g in 34% yield.

[0471] (4) Preparation of 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-(methylthio)-7,8- dihydroquinazolin-5(6H)-one

[0472]

[0473] The 2-chloro-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (1.2 g, 5.15 mmol) was dissolved in 1,4-dioxane (30 mL), (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)- boronic acid (1 g, 5.15 mmol), Xphos-Pd-G2 (408 mg, 0.52 mmol), Xphos (496 mg, 1.04 mmol), K3PO4 (1.2 g, 5.7 mmol), water (10 mL) were added, and the reaction was stirred at 90 °C for 3 h under N2. The reaction was completed, the solvent was evaporated, and the target compound was isolated by normal phase preparative separation (ethyl acetate / petroleum ether = 0-50%) to give 830 mg in 47% yield.

[0474] (5) Preparation of 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-hydrazinyl-7,8- dihydroquinazolin-5(6H)-one

[0475]

[0476] Dissolve 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-(methylthio)-7,8- dihydroquinazolin-5(6H)-one (830 mg, 2.4 mmol) in ethanol (20 mL), add hydrazine hydrate (184 mg, 3.6 mmol), and react at 70°C for 3 h. After completion of the reaction, concentrate to obtain 700 mg of the target compound, 89%.

[0477] (6) Preparation of 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2,6,7,8- tetrahydropyrazolo[3,4,5-de]quinazoline

[0478]

[0479] Dissolve 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-hydrazinyl-7,8- dihydroquinazolin-5(6H)-one (300 mg, 0.92 mmol) in N-methylpyrrolidone (5 mL), ethanol (60 mL), and react at 160°C for 1 h by microwave. Isolate by column chromatography (methanol / water = 0-60%) to obtain 150 mg of the target compound, 53% yield.

[0480] (7) Preparation of 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2-(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5- de]quinazoline

[0481]

[0482] Dissolve 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2,6,7,8- tetrahydropyrazolo[3,4,5-de]quinazoline (130 mg, 0.43 mmol) in N,N- dimethylformamide (4 mL), add sodium hydride (60%, 34 mg, 0.85 mmol), and react at 20°C for 10 min. Add 2-(4-(chloromethyl)phenyl)-1-methyl-4- (trifluoromethyl)-1H-imidazole (139 mg, 0.51 mmol), and react at 20°C for 3 h. After completion of the reaction, isolate by column chromatography (methanol / water = 0-40%) to obtain 18.5 mg of the target compound, 8% yield.

[0483] Molecular formula: C 28 H 25 F3N8O Molecular weight: 546.6 LC-MS (M / e): 547.2 (M+H + )

[0484] 1H-NMR (400 MHz, CDC13) 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).

[0485] Example 2 Preparation of 4-(3-fluoro-2-isopropylphenyl)-2-(4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5- de]quinazoline (Compound 2)

[0486] (1) Preparation of 3-fluoro-2-(prop-l-en-2-yl)phenol

[0487]

[0488] Dissolve 2-bromo-3-fluorophenol (11 g, 57.6 mmol), 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborinane (13.2 g, 78.6 mmol), K2CO3(15.9 g, 115.2 mmol) and Pd(dppf)Cl2(4.2 g, 5.7 mmol) in dioxane (120 mL) and water (24 mL), protect under nitrogen, react at 80 °C for 16 h, detect reaction completion by LCMS, pour reaction liquid into water (200 mL), extract with EA, dry organic phase with anhydrous sodium sulfate, spin dry, separate product by silica gel column chromatography (EA:PE = 1:5) to obtain 5.6 g with a yield of 63.9%.

[0489] (2) Preparation of 3-fluoro-2-isopropylphenol

[0490]

[0491] Dissolve 3-fluoro-2-(prop-l-en-2-yl)phenol (5.6 g, 36.8 mmol) in methanol (60 mL), add Pd / C (1.2 g), react at 25 °C for 4 h, detect reaction completion by LCMS, filter and spin dry the filtrate to obtain 5 g of product with a yield of 88.2%.

[0492] (3) Preparation of 3-fluoro-2-isopropylphenyl trifluoromethanesulfonate

[0493]

[0494] Dissolve 3-fluoro-2-isopropylphenol (1 g, 6.49 mmol) in dichloromethane (20 mL), dropwise add pyridine (1.0 g, 12.6 mmol) and Tf20 (2.7 g, 9.6 mmol) at -10 ℃, continue to react for 1 h, and detect the completion of the reaction by LCMS. Pour the reaction solution into water (50 mL) to quench, extract with DCM, dry the organic phase with anhydrous sodium sulfate, spin dry, and separate by silica gel column chromatography (EA:PE = 1:5) to obtain 1.6 g of the product with a yield of 86.1%.

[0495] (4) Preparation of 2-(3-fluoro-2-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane

[0496]

[0497] Dissolve 3-fluoro-2-isopropylphenyl triflate (1.6 g, 5.59 mmol), pinacol diboron (2.8 g, 11.18 mmol), Pd(dppf)Cl2 (409 mg, 0.56 mmol), and potassium acetate (1.7 g, 17.32 mmol) in dioxane (40 mL), protect with nitrogen, and react at 80 ℃ for 8 h. Detect the completion of the reaction by LCMS, spin dry the reaction solution, extract with EA, spin dry the organic phase, and separate by silica gel column chromatography (EA:PE = 1:5) to obtain 1 g of the product with a yield of 67.8%.

[0498] (5) Preparation of 2-(3-fluoro-2-isopropylphenyl)-4-(methylthio)-7,8-dihydroquinazolin- 5(6H)-one

[0499]

[0500] Dissolve 2-(3-fluoro-2-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 3.79 mmol), 2-chloro-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (870 mg, 3.79 mmol), XPhos PdG2 (299 mg, 0.38 mmol), XPhos (362 mg, 0.76 mmol), and potassium phosphate (892 mg, 4.2 mmol) in dioxane (26 mL) and water (7 mL), protect with nitrogen, and react at 90 ℃ for 2 h. Detect the completion of the reaction by LCMS, spin dry the reaction solution, and separate by silica gel column chromatography (EA:PE = 1:2) to obtain 350 mg of the product with a yield of 28.0%.

[0501] (6) Preparation of 2-(3-fluoro-2-isopropylphenyl)-4-hydrazinyl-7,8-dihydroquinazolin- 5(6H)-one

[0502]

[0503] 2-(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 h. The reaction was detected by LCMS to be complete, and the reaction solution was evaporated to dryness and used directly in the next step.

[0504] (7) Preparation of 4-(3-Fluoro-2-isopropylphenyl)-2,6,7,8-tetrahydro-pyrazolo[3,4,5- de]quinazoline

[0505]

[0506] 2-(3-Fluoro-2-isopropylphenyl)-4-hydrazinyl-7,8-dihydroquinazolin-5(6H)-one (crude) was dissolved in NMP (2 mL), and the reaction was carried out by microwave at 160 °C for 1 h. The reaction was detected by LCMS to be complete, and the product was purified by reverse phase chromatography (MeOH:H2O = 0-50%) to give 100 mg, 31.8% yield over two steps.

[0507] (8) Preparation of 4-(3-Fluoro-2-isopropylphenyl)-2-(4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)-2,6,7,8-tetrahydro-pyrazolo[3,4,5-de]quinazoline

[0508]

[0509] 4-(3-Fluoro-2-isopropylphenyl)-2,6,7,8-tetrahydro-pyrazolo[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 portionwise at 25 °C. After 10 min, 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (77 mg, 0.28 mmol) was added, and the reaction was continued for 4 h. The reaction was detected by LCMS to be complete. Water (20 mL) was added to quench the reaction, and the organic phase was extracted with dichloromethane and evaporated to dryness. The crude product was purified by silica gel column chromatography (EA:PE = 1:1) to give 16 mg, 12.5% yield.

[0510] Molecular Formula: C 29 H 26 F4N6 Molecular Weight: 534.6 LC-MS (M / e): 535.0 (M+H + )

[0511] 1H-NMR (400 MHz, 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).

[0512] 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)

[0513] (1) Preparation of methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate

[0514]

[0515] Methyl 4-hydrazinylbenzoate hydrochloride (9.0 g, 44.4 mmol), 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 the reaction was carried out at 20 °C for 2 h. The system was spin-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%).

[0516] (2) Preparation of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol

[0517]

[0518] Methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate (5.0 g, 17.6 mmol) was dissolved in THF (60 mL), DIBAl-H (1.5 mol / L, 46.9 mL, 70.4 mmol) was added dropwise at 0 °C, after the addition was completed, the reaction was carried out at 20 °C for 2 h. The reaction was quenched by slowly adding water, saturated aqueous ammonium chloride solution (50 mL) and EA (150 mL) were added to extract and separate, the organic phase was spin-dried, and the residue was purified by silica gel column chromatography (PE:EA = 3:1) to obtain the product (4.0 g, yield 88.7%).

[0519] (3) Preparation of 1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole

[0520]

[0521] (4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)phenyl)methanol (3.7 g, 14.4 mmol) was dissolved in dichloroethane (30 mL), dichloroethane (3 mL) was added, and then the reaction was carried out at 50°C for 1 hour. The system was rotary dried, and the residue was separated by silica gel column chromatography (PE:EA = 5:1) to obtain the product (3.6 g, yield 91.0%).

[0522] (PE:EA = 5:1) to obtain the product (3.6 g, yield 91.0%).

[0523] (4) Preparation of 4-(3-fluoro-2-isopropylphenyl)-2-(4-(5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5- de]quinazoline

[0524]

[0525] (4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)phenyl)methanol (3.7 g, 14.4 mmol) was dissolved in dichloroethane (30 mL), dichloroethane (3 mL) was added, and then the reaction was carried out at 50°C for 1 hour. The system was rotary dried, and the residue was separated by silica gel column chromatography (PE:EA = 5:1) to obtain the product (3.6 g, yield 91.0%).

[0526] Molecular formula: C 29 H 26 F4N6 Molecular weight: 534.6 LC-MS (M / e): 535.0 (M+H + )

[0527] 1 H-NMR (400 MHz, CDC13) 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).

[0528] 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)

[0529] (1) Preparation of (4-(trifluoromethyl)pyridin-3-yl)boronic acid

[0530]

[0531] Dissolve 3-bromo-4-(trifluoromethyl)pyridine (9.2 g, 0.041 mol) in THF (200 mL), add triisopropyl borate (10.8 g, 0.057 mol), and n-BuLi (2.5 M) (22.9 mL, 0.057 mol) at -78 °C for 3 h. After adding 50.0 mL of water to quench, adjust the pH to 4 with 4N hydrochloric acid, adjust the pH to 8 with a saturated sodium bicarbonate solution, and extract with ethyl acetate. Concentrate the organic phase to obtain a crude product, which is used directly in the next step.

[0532] (2) Preparation of 4-(methylthio)-2-(4-(trifluoromethyl)pyridin-3-yl)-7,8- dihydroquinazolin-5(6H)-one

[0533]

[0534] Dissolve 2-chloro-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (1.5 g, 6.6 mmol) in 1,4-dioxane (75 mL), add (4-(trifluoromethyl)pyridin-3-yl)boronic acid (crude product from 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), and water (25 mL), and react at 90 °C for 3 h under N2protection. After the reaction is complete, spin dry the solvent, and separate the remaining material by normal phase preparation (ethyl acetate / petroleum ether = 0-50%) to obtain 535.0 mg.

[0535] (3) Preparation of 4-hydrazinyl-2-(4-(trifluoromethyl)pyridin-3-yl)-7,8- dihydroquinazolin-5(6H)-one

[0536]

[0537] Dissolve 4-(methylthio)-2-(4-(trifluoromethyl)pyridin-3-yl)-7,8-dihydroquinazolin-5(6H)-one (0.48 g, 1.4 mmol) in ethanol (20.0 mL), add hydrazine hydrate (248.0 mg, 5.0 mmol), and react at 80°C for 3 h. After completion of the reaction, dry the solvent by evaporation, and separate the residue by normal phase preparative separation (ethyl acetate / petroleum ether = 0-70%) to obtain 240.0 mg (yield 52.2%).

[0538] (4) Preparation of 4-(4-(trifluoromethyl)pyridin-3-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline

[0539]

[0540] Dissolve 4-hydrazinyl-2-(4-(trifluoromethyl)pyridin-3-yl)-7,8-dihydroquinazolin-5(6H)-one (200.0 mg, 0.62 mmol) in a hydrochloric acid 1,4-dioxane solution (4 M, 18 mL), and react at 70°C for 1 h. After completion of the reaction, dry the solvent by evaporation, add a saturated sodium bicarbonate solution, adjust the pH to neutral, extract with ethyl acetate, and separate the organic phase by normal phase preparative separation (ethyl acetate / petroleum ether = 0-50%) to obtain the product (130.0 mg, yield 68.8%).

[0541] (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

[0542]

[0543] Dissolve 4-(4-(trifluoromethyl)pyridin-3-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (105 mg, 0.34 mmol) in DMF (4 mL), add potassium carbonate (143 mg, 1.03 mmol), and add 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (71 mg, 0.26 mmol). React at 50°C for 5 h. After completion of the reaction, separate the reaction solution by normal phase column chromatography (methanol / water = 0-10%) to obtain the product (8.8 mg, yield 4.7%).

[0544] Molecular formula: C 26 H 19 F6N7 Molecular weight: 543.48 LC-MS (M / e): 544.2 (M+H + )

[0545] 1H-NMR (400 MHz, CDC13) 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).

[0546] Example 5 Preparation of 4-(4-cyclopropyl-6-methoxy- pyrimidin-5-yl)-2-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)- 6,7,8,9-tetrahydro-2H-l,2,3,5-triazabenz[cd]pyraine (Compound 11)

[0547] (1) Preparation of 2-(bis(methylthio)methylene)cycloheptane-l,3-dione

[0548]

[0549] Dissolve 1,3-cycloheptanedione (9 g, 71.4 mmol) in DMF (200 mL), add potassium carbonate (30 g, 214.2 mmol), react at 20 °C for 0.5 h. Add carbon disulfide (8.1 g, 106.4 mmol), react at 20 °C for 1 h. Add iodomethane (30.4 g, 214.2 mmol), react at 20 °C for 1 h. Concentrate to get crude product, which is used directly in the next step.

[0550] (2) Preparation of 2-amino-4-(methylthio)-6,7,8,9-tetrahydro-5H- cyclohepta[d]pyrimidin-5-one

[0551]

[0552] Dissolve 2-(bis(methylthio)methylene)cycloheptane-l,3-dione (crude product from previous step) in DMF (200 mL), add guanidine hydrochloride (6.8 g, 71.4 mmol), potassium carbonate (14.8 g, 107.1 mmol), react at 100 °C for 16 h, cool to 25 °C, add water (300 mL), filter to get filter cake, dry under vacuum to get 10.4 g, 65.0% yield over two steps.

[0553] (3) Preparation of 2-chloro-4-(methylthio)-6,7,8,9-tetrahydro-5H- cyclohepta[d]pyrimidin-5-one

[0554]

[0555] Dissolve 2-amino-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin- 5-one (10.4 g, 46.6 mmol) in dichloromethane (150 mL), add titanium tetrachloride (8.8 g, 46.4 mmol), tert-butyl nitrite (28.7 g, 278.6 mmol), and react at 25 °C for 3 h. Quench the reaction with water, filter the resulting solution, and concentrate. Purify the residue by column chromatography (ethyl acetate / petroleum ether = 0-30%) to give the product 1.2 g in 10.6% yield.

[0556] (4) Preparation of 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-(methylthio)- 6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-5-one

[0557]

[0558] Dissolve 2-chloro-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin- 5-one (800 mg, 3.3 mmol) in 1,4-dioxane (18 mL), add (4-cyclopropyl-6- methoxy-pyrimidin-5-yl)boronic acid (640 mg, 3.3 mmol), Xphos-Pd-G2 (259 mg, 0.33 mmol), Xphos (315 mg, 0.66 mmol), potassium phosphate (770 mg, 3.6 mmol), water (6 mL), and protect from nitrogen. React at 90 °C for 3 h. Concentrate the reaction mixture, and purify the residue by normal phase preparative chromatography (ethyl acetate / petroleum ether = 0-50%) to give 400 mg in 34.0% yield.

[0559] (5) Preparation of 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-6,7,8,9- tetrahydro-2H-1,2,3,5-tetrazabenzo[cd]pyrene

[0560]

[0561] Dissolve 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-(methylthio)-6,7,8,9- tetrahydro-5H-cyclohepta[d]pyrimidin-5-one (200 mg, 0.56 mmol) in ethanol (5 mL), add hydrazine hydrate (84 mg, 1.69 mmol), and react at 80 °C for 3 h. Concentrate the reaction mixture, and purify the residue by normal phase preparative chromatography (ethyl acetate / petroleum ether = 0-70%) to give 150 mg in 82.9% yield.

[0562] (6) Preparation of 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2-(4-(1-methyl-4- (trifluoromethyl)-1 H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5- tetraazabenzo[cd]pyrrole

[0563]

[0564] (Compound 16) Preparation of 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2-(4-(1 -isopropyl-4- (trifluoromethyl)-1 H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5- de]quinazoline

[0565] Molecular Formula: C 29 H 27 F3N8O Molecular Weight: 560.6 LC-MS (M / e): 561.2 (M+H + )

[0566] 1 H-NMR (400 MHz, CDC13) δ: 8.70 (s, 1 H), 7.97 (s, 1 H), 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, 1 H), 1.22-1.18 (m, 2H), 0.95-0.85 (m, 2H).

[0567] (Compound 16) Preparation of 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2-(4-(1 -isopropyl-4- (trifluoromethyl)-1 H-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5- de]quinazoline

[0568]

[0569] To a solution of 4-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2,6,7,8- tetrahydropyrazolo[3,4,5-de]quinazolin (100 mg, 0.32 mmol) in DMF (4 mL) was added potassium carbonate (88 mg, 0.64 mmol), 2-(4-(chloromethyl)phenyl)-1- isopropyl-4-(trifluoromethyl)-1H-imidazole (98 mg, 0.32 mmol) and the reaction mixture was heated at 70 °C for 5 h. After completion of the reaction, the product was isolated by column chromatography (methanol / water = 0-40%) to give 21 mg in 11.4% yield.

[0570] Molecular Formula: C 30 H 29 F3N8O Molecular Weight: 574.6 LC-MS (M / e): 575.2 (M+H + )

[0571] 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).

[0572] 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)

[0573] (1) Preparation of 2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-4-(methylthio)-7,8- dihydroquinazolin-5(6H)-one

[0574]

[0575] Dissolve 2-chloro-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (1.0 g, 4.4 mmol) and l-isopropyl-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.3 g, 5.2 mmol) in 1,4-dioxane (20 mL) and water (4 mL), add tetrakis(triphenylphosphine)palladium (760 mg, 0.66 mmol) and sodium carbonate (950 mg, 9.0 mmol). React at 90 °C for 3 h under N2protection. After the reaction is completed, concentrate, and purify by silica gel column chromatography (ethyl acetate: n-heptane = 35%) to obtain 700 mg of the product, with a yield of 50.6%.

[0576] (2) Preparation of 4-hydrazinyl-2-(l-isopropyl-4-methyl-lH-pyrazol-5-yl)-7,8- dihydroquinazolin-5(6H)-one

[0577]

[0578] Dissolve 2-(l-isopropyl-4-methyl-lH-pyrazol-5-yl)-4-(methylthio)-7,8- dihydroquinazolin-5(6H)-one (500 mg, 1.6 mmol) in anhydrous ethanol (10 mL), add 98% hydrazine hydrate (180 mg, 3.5 mmol), and react at 70 °C for 7 h. After the reaction is completed, concentrate, and directly use the crude product for the next reaction.

[0579] (3) Preparation of 4-(l-isopropyl-4-methyl-lH-pyrazol-5-yl)-2,6,7,8- tetrahydropyrazolo[3,4,5-de]quinazoline

[0580]

[0581] Dissolve the crude product from the previous step in NMP (10 mL), add p-toluenesulfonic acid (50 mg), and react the system at 160 °C for 1.5 h under microwave. After the reaction is completed, wash with water, extract with ethyl acetate, separate, and concentrate. Purify by silica gel column chromatography (n-heptane: ethyl acetate = 1: 1) to obtain 399 mg of the target product, with a yield of 89.4% over two steps.

[0582] (4) Preparation of 4-(l-isopropyl-4-methyl-lH-pyrazol-5-yl)-2-(4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5- de]quinazoline

[0583]

[0584] Take 4-(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, 1.6 mmol) and DMF (10 mL), react at 50 °C for 13 h, LC-MS shows the reaction is complete, dilute the reaction mixture with water, extract with EA, dry the organic phase, separate the residue by prep-TLC (SiO2, PE:EA = 1:2, Rf = 0.5) and then by reverse phase column chromatography (C18, H2O:MeOH = 90:10-65:35), to give the product 150 mg, yield 54.2%.

[0585] Molecular Formula: C 27 H 27 F3N8 Molecular Weight: 520.6 LC-MS (m / z): 521.3 (M+H + )

[0586] 1 H-NMR (400 MHz, CDC13) 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).

[0587] 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)

[0588]

[0589] To a solution of 4-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazolin (120 mg, 0.42 mmol) in DMF (5 mL) was added 2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (120 mg, 0.40 mmol) and potassium carbonate (150 mg, 1.1 mmol). The reaction mixture was stirred at 50 °C for 2 h. After completion of the reaction, the mixture was filtered and concentrated. The residue was purified by preparative silica gel plate (ethyl acetate: n-heptane = 2:1) to give the target product 23 mg in 10.5% yield.

[0590] Molecular Formula: C 29 H 31 F3N8 Molecular Weight: 548.6 LC-MS (M / e): 549.4 (M+H + )

[0591] 1 H-NMR (400 MHz, CDC13) 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).

[0592] 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-tetrahydropyrazolo[3,4,5-de]quinazoline (Compound 20)

[0593] (1) Preparation of 2-(bis(methylthio)methylene)cyclohexane-1,3-dione

[0594]

[0595] To a solution of 1,3-cyclohexanedione (12.5 g, 0.11 mol) in DMF (100 mL) was added potassium carbonate (45.6 g, 0.33 mol) and stirred at 20 °C for 0.5 h. Carbon disulfide (12.9 g, 0.17 mol) was added and stirred at 20 °C for 1 h. Iodomethane (46.8 g, 0.33 mol) was added and stirred at 20 °C for 1 h. The mixture was concentrated to give the crude product which was used directly in the next step.

[0596] (2) Preparation of 2,4-bis(methylthio)-7,8-dihydroquinazolin-5(6H)-one

[0597]

[0598] Dissolve 2-(bis(methylthio)methylene)cyclohexane-l,3-dione (crude from previous step) in DMF (200 mL), add methyl isothiourea disulfate (11.5 g, 40.1 mmol), potassium carbonate (18.5 g, 133.8 mmol), react at 100 °C for 16 h, cool to 25 °C, add water (300 mL), filter to obtain filter cake, dry under vacuum to obtain 2.48 g, yield 26%.

[0599] (3) Preparation of 4-hydrazinyl-2-(methylthio)-7,8-dihydroquinazolin-5(6H)-one

[0600]

[0601] Dissolve 2,4-bis(methylthio)-7,8-dihydroquinazolin-5(6H)-one (2.0 g, 8.3 mmol) in ethanol (20 mL), add hydrazine hydrate (1.0 g, 20.0 mmol), react at 70 °C for 3 h. Upon completion of the reaction, concentrate to obtain crude product.

[0602] (4) Preparation of 4-(methylthio)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline

[0603]

[0604] Dissolve 4-hydrazinyl-2-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (crude from previous step) in DMAc (20 ml), add p-toluenesulfonic acid (0.25 g, 1.5 mmol), stir and warm to 160 °C for 2 h, stop the reaction, spin off the DMAc to obtain crude product, separate the product 0.45 g by normal phase chromatography column (petroleum ether: ethyl acetate = 10:0 to 4:6), yield: 26.3% (over two steps).

[0605] (5) Preparation of 2-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)-4- (methylthio)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline

[0606]

[0607] To a solution of 4-(methylthio)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (206 mg, 1.0 mmol), 2-(4-(chloromethyl)phenyl)-l-methyl-4-(trifluoromethyl)-lH-imidazole (411 mg, 1.5 mmol), potassium carbonate (414 mg, 3.0 mmol) in DMF (20 mL) was heated to 80 °C for 4 h. The reaction was stopped, filtered, and the filtrate was concentrated to give a crude product. The product was purified by column chromatography (petroleum ether: ethyl acetate = 10:0 to 4:6) to give 200 mg of the product in 45% yield.

[0608] (6) Preparation of 2-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)-4- (methylsulfonyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline

[0609]

[0610] To a solution of 2-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)-4- (methylthio)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (200 mg, 0.45 mmol) in dichloromethane (10 mL) was added m-chloroperoxybenzoic acid (155 mg, 0.90 mmol) at 20 °C for 1 h. The reaction was stopped, dichloromethane (50 mL) and saturated aqueous sodium carbonate (50 mL) were added, stirred for 5 min, and allowed to stand. The organic phase was collected and concentrated to give a crude product, which was used directly in the next step.

[0611] (7) Preparation of 2-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)-2,6,7,8- tetrahydropyrazolo[3,4,5-de]quinazolin-4-ol

[0612]

[0613] To a solution of 2-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)-4- (methylsulfonyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazoline (crude product from the previous step) in tetrahydrofuran (20 mL) was added 10% aqueous KOH solution (10 mL) at 20 °C for 4 h. The reaction was stopped, 1 M HC1 was added to adjust the pH to 4-5, and the solvent was concentrated. The product was eluted with dichloromethane:methanol = 10: 1 mixture solvent (200 mL), and concentrated to give a crude product. Ethyl acetate (2 mL) was added, stirred, filtered, and the product was collected as 200 mg of a crude product.

[0614] (8) Preparation of 4-chloro-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazolin

[0615]

[0616] To a solution of 4-chloro-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazolin (90 mg, 0.21 mmol) in DCM (5 mL) was added TFA (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. LCMS showed the reaction was completed. The reaction mixture was concentrated to give a residue, which was diluted with water (5 mL) and extracted with EA (10 mL x 3). The combined organic phase was dried over Na2S04and concentrated to give a residue, which was separated by column chromatography (Si02, PE:EA = 4:1-2:3) to give the product 100 mg, yield 100%.

[0617] (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-tetrahydropyrazolo[3,4,5-de]quinazolin

[0618]

[0619] To a solution of 4-chloro-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)-2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazolin (90 mg, 0.21 mmol) in DCM (5 mL) was added TFA (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. LCMS showed the reaction was completed. The reaction mixture was concentrated to give a residue, which was diluted with water (5 mL) and extracted with EA (10 mL x 3). The combined organic phase was dried over Na2S04and concentrated to give a residue, which was separated by column chromatography (Si02, PE:EA = 4:1-2:3) to give the product 100 mg, yield 100%.

[0620] Molecular Formula: C 28 H 23 F5N8O Molecular Weight: 582.5 LC-MS (m / z): 583.1 (M+H + )

[0621] 1H-NMR(400MHz, 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).

[0622] 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)

[0623] (1) Preparation of 2-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one

[0624]

[0625] 2-Chloro-4-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (1.2 g, 5.2 mmol) was dissolved in 1,4-dioxane (30 mL), and (4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)boronic acid (1 g, 5.1 mmol), Xphos-Pd-G2 (408 mg, 0.52 mmol), Xphos (496 mg, 1.04 mmol), K3PO4 (1.2 g, 5.7 mmol), and water (10 mL) were added. The reaction was carried out at 90 °C for 3 h under N2 protection. After the reaction was completed, the solvent was evaporated and the product was separated by normal phase preparation (ethyl acetate / petroleum ether = 0-50%) to give 600 mg, with a yield of 34.1%.

[0626] (2) Preparation of 2-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-4-hydrazyl-7,8-dihydroquinazoline-5(6H)-one

[0627]

[0628] 2-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-4-(methylthio)-7,8-dihydroquinazoline-5(6H)-one (500 mg, 1.4 mmol) was dissolved in ethanol (10 mL), and hydrazine hydrate (87 mg, 1.7 mmol) was added. The reaction was carried out at 70 °C for 3 h. After the reaction was completed, the solution was concentrated to give 400 mg, with a yield of 86.8%.

[0629] (3) Preparation of 4-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)- 2,6,7,8-tetrahydropyrazolo[3,4,5-de]quinazolin

[0630]

[0631] Dissolve 2-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-4-hydrazinyl-7,8- dihydroquinazolin-5(6H)-one (300 mg, 0.92 mmol) in NMP (5 mL), ethanol (60 mL), and react at 160 °C for 1 h in a microwave. Isolate the product by column chromatography (methanol / water = 0-60%) to give 150 mg, 53% yield.

[0632] (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]quinazolin

[0633]

[0634] Dissolve 4-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-2,6,7,8- tetrahydropyrazolo[3,4,5-de]quinazoline (100 mg, 0.32 mmol) in DMF (4 mL), add potassium carbonate (88 mg, 0.64 mmol), 2-(4-(chloromethyl)phenyl)-1- methyl-4-(trifluoromethyl)-1H-imidazole (88 mg, 0.32 mmol), and react at 20 °C for 3 h. Isolate the product by column chromatography (methanol / water = 0-40%) to give 42 mg, 24% yield.

[0635] Molecular Formula: C 28 H 22 D3F3N8O Molecular Weight: 549.58 LC-MS (M / e): 550.2 (M+H + )

[0636] 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).

[0637] 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- tetrazaceno[cd]azulene (Compound 11-1)

[0638] (1) Preparation of 2-(di-tert-butoxycarbonyl)amino-4-(methylthio)-6,7,8,9- tetrahydro-5H-cyclohepta[d]pyrimidin-5-one

[0639]

[0640] To a solution of 2-amino-4-(methylthio)-6,7,8,9-tetrahydro-5H- cyclohepta[d]pyrimidin-5-one (2.0 g, 9.0 mmol) in DCM (60 mL) was added triethylamine (4.6 g, 45.5 mmol), p-dimethylaminopyridine (110 mg, 0.9 mmol) and Boc20 (7.9 g, 36.2 mmol) successively, and the reaction was carried out at 25 °C for 1 h. LC-MS showed that the reaction was completed. The reaction solution was rotary evaporated to dryness, and the residue was separated by column chromatography (SiO2, PE:EA = 10:1-2:1) to give the product 3.4 g in a yield of 89.6%.

[0641] (2) Preparation of tert-butyl (6,7,8,9-tetrahydro-2H-1,2,3,5-tetrazaceno[cd]azulen-4- yl)carbamate

[0642]

[0643] To a solution of 2-(di-tert-butoxycarbonyl)amino-4-(methylthio)-6,7,8,9- tetrahydro-5H-cyclohepta[d]pyrimidin-5-one (3.2 g, 7.6 mmol) in ethanol (50 mL) was added hydrazine hydrate (1.9 g, 37.9 mmol), and the reaction was carried out at 80 °C for 13 h. LC-MS showed that the reaction was completed. The reaction solution was rotary evaporated to dryness, and the residue was separated by column chromatography (SiO2, DCM:MeOH = 50:1-10:1) to give the product 1.5 g in a yield of 68.6%.

[0644] (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-tetrazaceno[cd]azulen-4-yl)carbamate

[0645]

[0646] tert-Butyl (6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulen-4- yl)carbamate (1.4 g, 4.8 mmol), 2-(4-(chloromethyl)phenyl)-1 -methyl-4- (trifluoromethyl)-1 H-imidazole (1.6 g, 5.8 mmol), cesium carbonate (3.1 g, 9.5 mmol) and DMF (30 mL) were charged in sequence and reacted at 70 °C for 6 h. LC-MS showed the reaction was completed. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried, concentrated and the residue was separated by column chromatography (SiO2, PE:EA = 2:1 -1 :1 ) to give the product 1.9 g, 74.4% yield.

[0647] (4) Preparation of 2-(4-(1 -methyl-4-(trifluoromethyl)-1 H-imidazol-2-yl)benzyl)- 6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulen-4-amine

[0648]

[0649] To a solution of tert-butyl (2-(4-(1 -methyl-4-(trifluoromethyl)-1 H-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 HC1 / EA (20 mL, 80.0 mmol) and reacted at 25 °C for 2 h. LC-MS showed the reaction was completed. The reaction solution was concentrated, diluted with water, adjusted to pH 9 with ammonia and extracted with DCM. The organic phase was dried, concentrated and the residue was separated by column chromatography (SiO2, DCM:MeOH = 50:1 -30:1 ) to give the product 1.2 g, 77.9% yield.

[0650] (5) Preparation of 4-chloro-2-(4-(1 -methyl-4-(trifluoromethyl)-1 H-imidazol-2- yl)benzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]azulen

[0651]

[0652] To a solution of 2-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)-6,7,8,9- tetrahydro-2H-l,2,3,5-triazabenzocycloheptene-4-amine (500 mg, 1.2 mmol) in acetonitrile (3 mL) was added cuprous chloride (238 mg, 2.4 mmol) and tert-butyl nitrite (247 mg, 2.4 mmol) at 0 °C, and the reaction mixture was stirred at 60 °C for 4 h. LC-MS showed the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated. The residue was separated by column chromatography (SiO2, DCM:MeOH = 50:1-30:1) to give the product 100 mg in 19.1% yield.

[0653] (6) Preparation of 4-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-2-(4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-2H-l,2,3,5-triazabenzocycloheptene

[0654]

[0655] 4-chloro-2-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)-6,7,8,9- tetrahydro-2H-l,2,3,5-triazabenzocycloheptene (100 mg, 0.22 mmol), 4-cyclopropyl-6- (methoxy-d3)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (50 mg, crude), XPhos (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 successively, and the reaction mixture was stirred at 90 °C for 6 h under nitrogen. LC-MS showed the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated. The residue was separated by preparative thin layer chromatography (SiO2, DCM:MeOH = 30:1, Rf ~ 0.4) to give the product 16 mg in 12.7% yield.

[0656] Molecular Formula: C 29 H 24 D3F3N8O Molecular Weight: 563.6 LC-MS (m / z): 564.2 (M+H + )

[0657] 1H-NMR (400 MHz, CDC13) 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).

[0658] 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)

[0659]

[0660] 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)

[0661] Molecular Formula: C 30 H 26 D3F3N8O Molecular Weight: 577.6 LC-MS (M / e): 578.3 (M+H + )

[0662] 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).

[0663] 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]chamomile blue (compound 17-1)

[0664] (1) Preparation of 2-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-5-one

[0665]

[0666] 2-Chloro-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepta[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 (126 mg, 0.16 mmol), potassium phosphate (1.0 g, 4.7 mmol), dioxane (20 mL), and water (4 mL) were weighed sequentially. The mixture was purged with nitrogen three times and reacted at 90 °C for 4 h. The reaction was completed by LC-MS. The reaction solution was filtered, the filtrate was evaporated to dryness, and the residue was separated by column chromatography (SiO2, PE:EA = 5:1-3:1) to obtain 260 mg of product, with a yield of 43.9%.

[0667] (2) Preparation of 4-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]chamomile blue

[0668]

[0669] To a solution of 2-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-4-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-5-one (240 mg, 0.67 mmol) in ethanol (6 mL), hydrazine hydrate (168 mg, 3.4 mmol) was added. The reaction was carried out at 80 °C for 3 h. LC-MS showed that the reaction was complete. The reaction solution was evaporated to dryness, and the residue was separated by column chromatography (SiO2, PE:EA = 3:1-1:1) to give 200 mg of product, with a yield of 92.0%.

[0670] (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- tetrazabenz[cd]azulene

[0671]

[0672] To a solution of 4-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-6,7,8,9-tetrahydro- 2H-1,2,3,5-tetrazabenz[cd]azulene (200 mg, 0.61 mmol) in DMF (5 mL) was added 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 reaction was stirred at 50 °C for 13 h. LC-MS showed the reaction was complete. The reaction was diluted with water and extracted with EA. The organic phase was dried and concentrated. The residue was separated by column chromatography (SiO2, PE:EA = 3:1-1:1) to give the product 167 mg, 45.9% yield.

[0673] Molecular Formula: C 31 H 28 D3F3N8O Molecular Weight: 591.7 LC-MS (m / z): 592.3 (M+H + )

[0674] 1 H-NMR (400 MHz, CDC13) 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).

[0675] The following compounds were prepared using the same or similar methods as described in the above examples:

[0676]

[0677] The USP1 inhibitor provided by the application and the application thereof are described in detail above. The principles and implementation manners of the application are described by using specific examples in the present text, and the above examples are only used to help understand the method of the application and the central idea thereof. It should be pointed out that, for those skilled in the art, some improvements and modifications can be made to the application without departing from the principles of the application, and these improvements and modifications also fall within the protection of the claims of the application.

Claims

1. A compound of Formula (II-2), a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, wherein, each m is independently an integer from 0 to 3; each s is independently an integer from 0 to 2.

2. The compound of claim 1, a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, wherein, each m is independently an integer from 0 to 2; each s is independently an integer from 0 to 2. R 1 selected from phenyl or 5-6 membered heteroaryl optionally substituted with 1-4 Q1; R 4 , R 5 are each independently selected from deuterium, hydrogen, carboxyl, cyano, nitro, amino, halogen, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy optionally substituted with deuterium, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxyl C 1-6 alkyl, or halogenated C 1-6 alkoxy; each Q1is independently selected from deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, sulfonamido, C 1-6 alkylamino, di(C 1-6 alkyl)amino, haloC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl, -(L) m -C 1-6 alkyl, -(L) m -C 1-6 alkoxy, -(L) m -3-8 membered cycloalkyl or -(L) m -3-8 membered heterocyclyl, each Q2is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, hydroxyC 1-6 alkyl, carboxyC 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, -CO-C 1-6 alkylene-NH2, -CO-C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl and haloC 1-6 alkoxy; each L is independently selected from -CR a R b -; Y3, Y4are each independently selected from C or CR a ; Y6is independently selected from N, C, or CR a ; Y5, Y7are independently selected from N, NR c , CR a R b or CR a ; each R a , each R b is independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, C 1-6 alkyl optionally substituted with deuterium, C 1-6 haloalkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, C each R is independently selected from the group consisting of deuterium, hydrogen, C c are each independently selected from the group consisting of deuterium, hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl; are each independently selected from a single or double bond, and no more than two adjacent bonds can be double bonds; 3. The compound of claim 1, a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, wherein, each m is independently 0, 1, 2; each s is independently 0, 1, 2.

4. The compound of claim 1, a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, having the structure of Formula (II-5): wherein, each s is independently selected from an integer from 0 to 2.

5. The compound of claim 4, a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, wherein, m is an integer from 1 or 2; each s is independently an integer from 0, 1, 2. R 1 selected from phenyl or 5-6 membered nitrogen-containing heteroaryl optionally substituted with 1-4 Q1; R 4 , R 5 are each independently selected from deuterium, hydrogen, cyano, halogen, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halogeno C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl or halogeno C 1-6 alkoxy; each Q1is independently selected from deuterium, halogen, cyano, C 1-6 alkyl, haloC 1-6 alkyl, -(L) 1-6 alkyl, -(L) 1-6 alkyl, -(L) 1-6 alkyl, -(L) 1-6 alkyl, -(L) 1-6 alkyl, -(L) 1-6 alkyl, -(L) m alkyl, -(L) 1-6 alkyl, -(L) m alkyl, -(L) m alkyl, -(L) 1-6 alkyl, -(L) 1-6 alkyl, -(L) 1-6 alkyl, -(L) 1-6 alkyl, -(L) 1-6 alkyl, -(L) 1-6 alkyl, -(L) 1-6 alkyl, -(L) 1-6 alkyl, -(L) each L is independently selected from -CR a R b -; Y3, Y4are each independently selected from C or CR a ; Y6is independently selected from N, C, or CR a ; Y5, Y7are independently selected from N, NR c , CR a R b or CR a ; each R a , each R b is independently selected from deuterium, hydrogen, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy; each R is independently selected from the group consisting of deuterium, hydrogen, C1-6alkyl, c are each independently selected from the group consisting of deuterium, hydrogen, C1-6alkyl, 1-6 alkyl, haloC1-6alkyl, C3-6cycloalkyl, 1-6 alkyl, haloC1-6alkyl, C3-6cycloalkyl, 1-6 alkoxy; 6. The compound of claim 1, a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, having the structure of Formula (IV-1’):

7. The compound of claim 6, a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, wherein, 8. The compound of claim 1, a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, having the structure of:

9. A pharmaceutical preparation comprising a compound of any one of claims 1-8, a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, and one or more pharmaceutically acceptable carriers and / or diluents; the pharmaceutical preparation is in any clinically or pharmaceutically acceptable dosage form. R 1 selected from phenyl, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl; R 4 , R 5 are each independently selected from deuterium, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, optionally deuterated; each Q1is independently selected from deuterium, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, one to three substituents Q2optionally substituted methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, -(L) m -C 1-4 alkyl, -(L) m -3-6 membered cycloalkyl, each Q2is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl, carboxyethyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy; each L is independently selected from -CR a R b -; Y3, Y4are each independently selected from C or CR a ; Y6is independently selected from N, C, or CR a ; Y5, Y7are independently selected from N, NR c , CR a R b or CR a ; each R a , each R b is independently selected from deuterium, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, optionally deuterated; 10. A pharmaceutical composition comprising a compound of any one of claims 1-8, a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, and one or more second therapeutically active agents; optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and / or diluents.

11. Use of a compound of any one of claims 1-8, a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, or a pharmaceutical preparation of claim 9, or a pharmaceutical composition of claim 10, for the manufacture of a medicament for the treatment and / or prevention of a USP1-mediated disease and related diseases selected from breast cancer or ovarian cancer.

12. A method of preparing a compound of any one of claims 1-8, a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, comprising the steps of: reacting a compound of Formula (II-2)-1 with a compound of Formula (II-2)-2 to obtain a compound of Formula (II-2). wherein Y6is independently selected from N, C, or CR a ; Y5, Y7are independently selected from N, NR c , CR a R b or CR a ; are each independently selected from a single or double bond, and no more than two adjacent bonds can be double bonds; 13. An intermediate for preparing a compound of any one of claims 1-8, a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, having the structure of: each Q1, m, R 1 are as defined in claim 1. ​ ​ R 1 selected from the group consisting of each Q1is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, 3-6 membered cycloalkyl, each Q2is independently selected from deuterium, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy; selected from the group consisting of: ​ ​ ​ wherein, R 6 selected from hydrogen, C 1-6 alkyl optionally substituted with deuterium, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy; Y1, Y2are each independently selected from N, C or CR a ; are each independently selected from a single or double bond, and no more than two adjacent bonds can be double bonds; each Q1, m, R 4 , R 5 , each R a , each R b , Y5, Y6, Y7, each s are as defined in claim 1. ​ R 6 selected from deuterated methoxy, deuterated ethoxy, deuterated propoxy, or deuterated isopropoxy, the number of deuterium being 1, 2, or 3. ​ ​ ​ ​ ​ ​ wherein X is halogen; each Q1, each Q2, each L, each 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 claims 1-8. ​ wherein G is selected from halogen, hydroxy, amino, C 1-6 alkylthio or C 1-6 alkylsulfonyl; R 1 , each R 4 , each R 5 , each Q1, each Q2, each L, each m, Y3, Y4, Y5, Y6, Y7 are as defined in any one of claims 1 to 8.

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