CN117263944A

CN117263944A - Ubiquitin-specific protease 1 inhibitors and uses thereof

Info

Publication number: CN117263944A
Application number: CN202311066807.0A
Authority: CN
Inventors: 刘斌
Original assignee: Xuanzhu Biopharmaceutical Co Ltd
Current assignee: Xuanzhu Biopharmaceutical Co Ltd
Priority date: 2022-08-24
Filing date: 2023-08-23
Publication date: 2023-12-22

Abstract

The invention relates to the technical field of medicines, in particular to a ubiquitin-specific protease 1 inhibitor compound, pharmaceutically acceptable salt, ester, deuteride or stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salt, the ester, the deuteride or the stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt, the ester, the deuteride or the stereoisomer thereof, and application of the compound, the pharmaceutically acceptable salt, the ester, the deuteride or the stereoisomer thereof in preparing medicines for treating and/or preventing diseases mediated by USP1 and related diseases.

Description

Ubiquitin-specific protease 1 inhibitors and uses thereof

Technical Field

Background

There are many relevant targets in the development of tumors, deubiquitinase DUB (Deubiquitylating enzyme), a gene encoding more than 100 humans, into 6 families, with ubiquitin-specific proteases (USP) comprising more than 50 members, the largest family of DUBs. Ubiquitination is a reversible process by which DUBs act on the ubiquitin-proteinase system, cleaving the isopeptidic bond between lysine and the C-terminus of UBQ, affecting cell proliferation, cycle, apoptosis, DNA damage response, tumor suppression, development and metastasis.

USP1 (Ubiquitin specific protease, ubiquitin-specific protease 1) is a member of the USP family, being a cysteine isopeptidase comprising Cys90, his593 and Asp751 triplet structures. The human USP1 gene was cloned in 1998, encoding a 785 amino acid protein. Normal USP1 is relatively inactive and is activated after binding to UAF1 (USP l-associated factor1, USP1 related factor1, a cofactor comprising WD40 repeats binding and modulating USP1 activity) as a heterodimeric complex, acting as a deubiquitinase, stabilizing replication forks, and localizing in the nucleus.

USP1 is highly expressed in cancers such as breast cancer and ovarian cancer, and the expression is increased in other cancers, and USP1 overexpression is related to breast cancer/ovarian cancer BRCA1 deficiency. USP1 deubiquitination is involved in various processes related to cancer, acting on the pathways of Fanconi anemia (Fanconi anemia, FA), trans-injury synthesis (Translesion DNA synthesis, TLS), cell differentiation, and the like. Wherein in FA, USP1 deubiquitinates FANCD2 (Fanconi anaemia group D protein, fanconi anemia histone D2); in TLS, USP1 deubiquitinates PCNA (Proliferating cell nuclear antigen ); in cell differentiation, USP1 affects ubiquitination of ID (family of DNA binding protein inhibitors), regulating cell proliferation and differentiation.

These DNA damage response (DNA damage response, DDR) pathways are critical to repair of DNA damage induced by DNA crosslinkers (e.g., cisplatin, uv radiation, etc.). In the TLS pathway, PCNA affected by USP1 is co-involved in DNA fragment repair with USP1/UAF1, BRCA 1/2. RAD 18-mediated monoubiquitination of PCNA promotes conversion of PCNA binding from replicative polymerase (poldelta/epsilon) to TLS polymerase (e.g., POLK), and USP1 debubiquitinates PCNA after bypassing the lesion by the TLS polymerase, promoting conversion of PCNA binding back to replicative polymerase. Inhibition of USP1 results in replication fork instability and synthetic lethality with BRCA mutations.

Inhibitors of USP1 inhibit repair of DNA breaks that PCNA participates in with USP1/UAF1, BRCA1/2, destabilizing the replication fork. Therefore, the use of small molecule inhibitors to inhibit USP1 has potential for the treatment of cancer and other diseases, and has not been commercialized or clinically developed.

Disclosure of Invention

The invention aims to provide an ubiquitin-specific protease 1 inhibitor and application thereof. The specific technical scheme is as follows:

in certain embodiments, the invention first provides a compound of formula (I), a pharmaceutically acceptable salt, ester, deuterate, or stereoisomer thereof:

Wherein,

X ₁ 、X ₂ independently selected from N, C or CR ^a ；

X ₄ Selected from N or C;

X ₃ 、X ₅ are respectively and independently selected from N, NR ^a 、C、CR ^a Or CR (CR) ^a R ^b ；

R ¹ 、R ² Are each independently selected from deuterium, hydrogen, carboxyl, cyano, nitro, amino, halogen, C _2-6 Alkenyl, C _2-6 Alkynyl, optionally deuterated C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 Alkyl or halo C _1-6 An alkoxy group;

each R ³ Each R ⁵ Each independently selected from deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, sulfonylamino, optionally substituted with 1-4 substituents Q ₁ Substituted C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, halo C _1-6 Alkyl, halogenated C _1-6 Alkoxy, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 Alkyl, C _1-6 Alkylcarbonyl, C _1-6 Alkoxycarbonyl group, C _1-6 Alkylaminoacyl, C _1-6 Alkylamido, C _1-6 Alkylsulfonyl, C _1-6 Alkylsulfonylamino, C _1-6 Alkylaminosulfonyl, - (L) ₁ ) _m -C _1-6 Alkyl, - (L) ₁ ) _m -C _2-6 Alkenyl, - (L) ₁ ) _m -C _2-6 Alkynyl, - (L) ₁ ) _m -C _1-6 Alkoxy, - (L) ₁ ) _m -6-10 membered aryl, - (L) ₁ ) _m -5-12 membered heteroaryl, - (L) ₁ ) _m -3-8 membered cycloalkyl or- (L) ₁ ) _m -3-8 membered heterocyclyl;

each R ⁴ Each independently selected from halogen, cyano, carboxy, hydroxy, amino, nitro, optionally substituted with 1-4 substituents Q ₁ Substituted C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, halo C _1-6 Alkyl, halogenated C _1-6 Alkoxy, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 Alkyl, C _1-6 Alkylcarbonyl, C _1-6 Alkoxycarbonyl group, C _1-6 Alkylaminoacyl, C _1-6 Alkylamido, C _1-6 Alkylsulfonyl, C _1-6 Alkylsulfonylamino, C _1-6 Alkylaminosulfonyl, - (L) ₁ ) _m -C _1-6 Alkyl, - (L) ₁ ) _m -C _1-6 Alkoxy, - (L) ₁ ) _m -6-10 membered aryl, - (L) ₁ ) _m -5-12 membered heteroaryl, - (L) ₁ ) _m -3-8 membered cycloalkyl or- (L) ₁ ) _m -3-8 membered heterocyclyl;

each Q ₁ Each independently selected from deuterium, cyano, carboxyl, hydroxyl, amino, halogen, C optionally substituted with 1 or more substituents q _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, C _1-6 Alkylaminoacyl, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogenated C _1-6 Alkoxy, - (L) ₁ ) _m -6-10 membered aryl, - (L) ₁ ) _m -5-12 membered heteroaryl, - (L) ₁ ) _m -3-12 membered cycloalkyl or- (L) ₁ ) _m -3-12 membered heterocyclyl, each q is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C _1-6 Alkyl, hydroxy C _1-6 Alkyl, carboxyl C _1-6 Alkyl, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, -CO-C _1-6 alkylene-NH ₂ 、-CO-C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl and halogenated C _1-6 An alkoxy group;

each L, each L ₁ Are each independently selected from the group consisting of-C (O) -, -O-, -S-, -S (O) ₂ -、-NR ^c -、-CR ^a R ^b -；

Each R ^a Each R ^b Are each independently selected from deuterium, hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, optionally deuterated C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, C _1-6 Alkylaminoacyl, C _1-6 Alkylamido, C _1-6 Alkylsulfonylamino, C _1-6 Alkylaminosulfonyl, halogenated C _1-6 Alkyl, halogenated C _1-6 Alkoxy, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 An alkyl group;

each R ^c Independently selected from deuterium, hydrogen, optionally deuterated C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogenated C _1-6 Alkoxy, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 An alkyl group;

is a single bond or a double bond, and adjacent +.>Are not double bonds at the same time;

s is an integer of 1 to 4;

each m, m1, n, t is independently an integer from 0 to 4.

In certain embodiments, a compound as set forth in the preceding embodiments, a pharmaceutically acceptable salt thereof, an ester thereof, a deuteride thereof, or a stereoisomer thereof, wherein X ₁ Selected from C or CH.

In certain embodiments, a compound as set forth in the preceding embodiments, a pharmaceutically acceptable salt thereof, an ester thereof, a deuteride thereof, or a stereoisomer thereof, wherein X ₁ Selected from N.

In certain embodiments, a compound as set forth in the preceding embodiments, a pharmaceutically acceptable salt thereof, an ester thereof, a deuteride thereof, or a stereoisomer thereof, wherein X ₂ Selected from C or CH.

In certain embodiments, a compound as set forth in the preceding embodiments, a pharmaceutically acceptable salt thereof, an ester thereof, a deuteride thereof, or a stereoisomer thereof, wherein X ₂ Selected from N.

In certain embodiments, a compound as set forth in the preceding embodiments, a pharmaceutically acceptable salt thereof, an ester thereof, a deuteride thereof, or a stereoisomer thereof, wherein X ₃ Selected from C, CH or CH ₂ 。

In certain embodiments, a compound as set forth in the preceding embodiments, a pharmaceutically acceptable salt thereof, an ester thereof, a deuteride thereof, or a stereoisomer thereof, wherein X ₃ Selected from N or NH.

In certain embodiments, the foregoingA compound as shown in scheme (i), a pharmaceutically acceptable salt thereof, an ester thereof, a deuteride thereof, or a stereoisomer thereof, wherein X ₄ Selected from C.

In certain embodiments, a compound as set forth in the preceding embodiments, a pharmaceutically acceptable salt thereof, an ester thereof, a deuteride thereof, or a stereoisomer thereof, wherein X ₄ Selected from N.

In certain embodiments, a compound as set forth in the preceding embodiments, a pharmaceutically acceptable salt thereof, an ester thereof, a deuteride thereof, or a stereoisomer thereof, wherein X ₅ Selected from N or NH.

In certain embodiments, a compound as set forth in the preceding embodiments, a pharmaceutically acceptable salt thereof, an ester thereof, a deuteride thereof, or a stereoisomer thereof, wherein X ₅ Selected from C, CH or CH ₂ 。

In certain embodiments, the compounds of the foregoing schemes, pharmaceutically acceptable salts, esters, deuterides, or stereoisomers thereof, wherein,

selected from->

Each R ⁵ The definition of each t is as defined in any one of the previous technical schemes.

selected from->

selected from the following structures: />

Each R ³ Each n is defined as in any one of the preceding claims.

R ¹ 、R ² each independently selected from deuterium, hydrogen, halogen, optionally deuterated C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 Alkyl or halo C _1-6 An alkoxy group.

R ¹ 、R ² each independently selected from deuterium, hydrogen, halogen, optionally deuterated C _1-4 Alkyl, C _1-4 Alkoxy, halo C _1-4 Alkyl or halo C _1-4 An alkoxy group.

R ¹ 、R ² are each independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl,Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy.

each R ³ Each R ⁵ Independently selected from deuterium, halogen, optionally substituted with 1-4 substituents Q ₁ Substituted C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, halo C _1-6 Alkyl, halogenated C _1-6 Alkoxy, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 Alkyl, - (L) ₁ ) _m -C _1-6 Alkyl, - (L) ₁ ) _m -C _1-6 Alkoxy, - (L) ₁ ) _m -phenyl, - (L) ₁ ) _m -5-6 membered heteroaryl, - (L) ₁ ) _m -3-6 membered cycloalkyl or- (L) ₁ ) _m -3-6 membered heterocyclyl;

each Q ₁ Are independently selected from deuterium, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, C _1-6 Alkylaminoacyl, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogenated C _1-6 An alkoxy group.

each R ³ Each R ⁵ Independently selected from deuterium, halogen, optionally substituted with 1-3 substituents Q ₁ Substituted C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, halo C _1-6 Alkyl, halogenated C _1-6 Alkoxy, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 Alkyl, C _1-6 Alkyl, C _1-6 Alkoxy radicalA group, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;

each Q ₁ Are independently selected from deuterium, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, C _1-6 Alkylaminoacyl, halo C _1-6 Alkyl, halogenated C _1-6 An alkoxy group.

each R ³ Independently selected from deuterium, halogen, optionally substituted with 1-3 substituents Q ₁ Substituted halogenated C _1-4 Alkyl, halogenated C _1-4 Alkoxy, hydroxy C _1-4 Alkyl, amino C _1-4 Alkyl, carboxyl C _1-4 Alkyl, C _1-4 Alkyl, C _1-4 Alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl.

each R ³ Each independently selected from deuterium, fluorine, chlorine, bromine, iodine, optionally 1-3 substituents Q ₁ Substituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

Each R ³ Each independently selected from Q optionally substituted with 1-3 substituents ₁ Substituted halogenated C _1-4 Alkyl, halogenated C _1-4 Alkoxy, C _1-4 Alkyl, C _1-4 Alkoxy, 3-6 membered cycloalkyl.

each R ³ Independently selected from halogenated C _1-4 Alkyl, halogenated C _1-4 Alkoxy, C _1-4 Alkyl, C _1-4 Alkoxy, deuterated C _1-4 Alkyl, deuterated C _1-4 Alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

each R ³ Each independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated isobutyl, deuterated sec-butyl, deuterated tert-butyl, deuterated methoxy, deuterated ethoxy, deuterated propoxy, deuterated isopropoxy, cyclopropyl, the number of deuterations being 1, 2, 3.

each R ⁵ Independently selected from deuterium, halogen, optionally substituted with 1-3 substituents Q ₁ Substituted halogenated C _1-4 Alkyl, halogenated C _1-4 Alkoxy, hydroxy C _1-4 Alkyl, amino C _1-4 Alkyl, carboxyl C _1-4 Alkyl, C _1-4 Alkyl, C _1-4 An alkoxy group.

each R ⁵ Each independently selected from deuterium, fluorine, chlorine, bromine, iodine, optionally 1-3 substituents Q ₁ Substituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxyRadical, difluoromethoxy, trifluoromethoxy.

each R ⁴ Each independently selected from halogen, optionally substituted with 1-4 substituents Q ₁ Substituted C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, halo C _1-6 Alkyl, halogenated C _1-6 Alkoxy, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 Alkyl, - (L) ₁ ) _m -C _1-6 Alkyl, - (L) ₁ ) _m -C _1-6 Alkoxy, - (L) ₁ ) _m -phenyl, - (L) ₁ ) _m -5-6 membered heteroaryl, - (L) ₁ ) _m -3-6 membered cycloalkyl or- (L) ₁ ) _m -3-6 membered heterocyclyl;

each R ⁴ Each independently selected from halogen, optionally substituted with 1-4 substituents Q ₁ Substituted halogenated C _1-4 Alkyl, halogenated C _1-4 Alkoxy, hydroxy C _1-4 Alkyl, amino C _1-4 Alkyl, carboxyl C _1-4 Alkyl, C _1-4 Alkyl, C _1-4 An alkoxy group;

each Q ₁ Are independently selected from deuterium, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, halogenated C _1-6 An alkoxy group.

each R ⁴ Each independently selected from fluorine, chlorine, bromine, iodine, optionally 1-3 substituents Q ₁ Substituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy.

each R ⁴ Each independently selected from fluorine, chlorine, bromine, iodine.

each Q ₁ Are independently selected from deuterium, C _1-4 Alkyl, C _1-4 Alkoxy, halo C _1-4 Alkyl, halogenated C _1-4 An alkoxy group.

each Q ₁ Each independently selected from deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy.

each L, each L ₁ Are each independently selected from-O-, -NR ^c -、-CR ^a R ^b -。

each L, each L ₁ Are each independently selected from-CR ^a R ^b -。

each R ^a Each R ^b Each independently selected from deuterium, hydrogen, halogen, optionally deuterated C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, halo C _1-6 Alkyl, halogenated C _1-6 Alkoxy, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 An alkyl group;

each R ^c Independently selected from deuterium, hydrogen, optionally deuterated C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogenated C _1-6 An alkoxy group.

each R ^a Each R ^b Each independently selected from deuterium, hydrogen, halogen, optionally deuterated C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Alkylamino, di (C) _1-4 Alkyl) amino, halo C _1-4 Alkyl, halogenated C _1-4 Alkoxy, hydroxy C _1-4 Alkyl, amino C _1-4 Alkyl, carboxyl C _1-4 An alkyl group;

each R ^c Independently selected from deuterium, hydrogen, optionally deuterated C _1-4 Alkyl, halogenated C _1-4 Alkyl, halogenated C _1-4 An alkoxy group.

each R ^a Each R ^b Each independently selected from deuterium, hydrogen, methyl, ethyl optionally deuteratedPropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, aminomethyl, carboxymethyl;

each R ^c Each independently selected from deuterium, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy optionally deuterated.

each R ^a Each R ^b Each R ^c Each independently hydrogen.

s is an integer of 1 to 3;

each m, m1, n, t is independently an integer from 0 to 3.

s is 1 and 2;

each m, m1, n, t is independently 0, 1, 2.

In certain embodiments, the compounds of the foregoing schemes, pharmaceutically acceptable salts, esters, deuterides, or stereoisomers thereof, having the structure of formula (I-1),

X ₁ 、X ₂ 、X ₃ 、X ₄ 、X ₅ each R ^a Each R ^b Each R ^c 、R ¹ 、R ² Each R ³ Each R ⁴ Each R ⁵ Each Q ₁ The definitions of n, s, t are as described in any of the previous schemes.

In certain embodiments, the compounds of the foregoing schemes, pharmaceutically acceptable salts, esters, deuterides, or stereoisomers thereof, having the structure of formula (I-2),

X ₃ 、X ₄ 、X ₅ Each R ^a Each R ^b Each R ^c 、R ¹ 、R ² Each R ³ Each R ⁴ Each R ⁵ Each Q ₁ The definitions of n, s, t are as described in any of the previous schemes.

In certain embodiments, the compounds of the foregoing schemes, pharmaceutically acceptable salts, esters, deuterides, or stereoisomers thereof, having the structure of formula (I-3),

X ₃ 、X ₄ 、X ₅ each R ³ Each R ⁴ Each R ⁵ Each Q ₁ The definitions of n, s, t are as described in any of the previous schemes.

In certain embodiments, the compounds of the foregoing schemes, pharmaceutically acceptable salts, esters, deuterides, or stereoisomers thereof, having the structure of formula (I-4),

R ¹ 、R ² each R ^a Each R ^b Each R ³ Each R ⁴ Each R ⁵ Each Q ₁ The definitions of n, s, t are as described in any of the previous schemes.

In certain embodiments, the compounds of the foregoing schemes, pharmaceutically acceptable salts, esters, deuterides, or stereoisomers thereof, having the structure of formula (I-5),

each R ³ Each R ⁴ Each R ⁵ Each Q ₁ The definitions of n, s, t are as described in any of the previous schemes.

In certain embodiments, the compounds of the foregoing schemes, pharmaceutically acceptable salts, esters, deuterides, or stereoisomers thereof, having the structure of formula (I-6),

R ³ Each R ⁴ Each R ⁵ Each Q ₁ The definition of s and t is as in any one of the previous schemes.

X ₁ 、X ₂ each independently selected from N, C or CH;

X ₄ selected from N or C;

X ₃ 、X ₅ are respectively and independently selected from N, NH, C, CH or CH ₂ ；

R ¹ 、R ² Each independently selected from deuterium, hydrogen, halogen, optionally deuterated C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl, aminoC _1-6 Alkyl, carboxyl C _1-6 Alkyl or halo C _1-6 An alkoxy group;

each Q ₁ Are independently selected from deuterium, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, C _1-6 Alkylaminoacyl, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogenated C _1-6 An alkoxy group;

each L, each L ₁ Are each independently selected from-O-, -NR ^c -、-CR ^a R ^b -；

Each R ^a Each R ^b Independently selected from deuterium, hydrogen, halogen, optionallyDeuterated C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, halo C _1-6 Alkyl, halogenated C _1-6 Alkoxy, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 An alkyl group;

each R ^c Independently selected from deuterium, hydrogen, optionally deuterated C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogenated C _1-6 An alkoxy group;

s is an integer of 1 to 3;

each m, m1, n, t is independently an integer from 0 to 3.

R ¹ 、R ² each independently selected from deuterium, hydrogen, halogen, optionally deuterated C _1-4 Alkyl, C _1-4 Alkoxy, halo C _1-4 Alkyl or halo C _1-4 An alkoxy group;

each R ³ Independently selected from deuterium, halogen, optionally substituted with 1-3 substituents Q ₁ Substituted halogenated C _1-4 Alkyl, halogenated C _1-4 Alkoxy, hydroxy C _1-4 Alkyl, amino C _1-4 Alkyl, carboxyl C _1-4 Alkyl, C _1-4 Alkyl, C _1-4 Alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;

each R ⁵ Independently selected from deuterium, halogen, optionally substituted with 1-3 substituents Q ₁ Substituted halogenated C _1-4 Alkyl, halogenated C _1-4 Alkoxy, hydroxy C _1-4 Alkyl, amino C _1-4 Alkyl, carboxyl C _1-4 Alkyl, C _1-4 Alkyl, C _1-4 An alkoxy group;

each Q ₁ Are independently selected from deuterium, halogen, C _1-4 Alkyl, C _1-4 Alkoxy, halo C _1-4 Alkyl, halogenated C _1-4 An alkoxy group;

R ¹ 、R ² each independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

each R ³ Each independently selected from deuterium, fluorine, chlorine, bromine, iodine, optionally 1-3 substituents Q ₁ Substituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

each R ⁴ Each independently selected from fluorine, chlorine, bromine, iodine, optionally 1-3 substituents Q ₁ Substituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethyl Oxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

each R ⁵ Each independently selected from deuterium, fluorine, chlorine, bromine, iodine, optionally 1-3 substituents Q ₁ Substituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

each Q ₁ Each independently selected from deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

each R ^a Each R ^b Each independently selected from deuterium, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, aminomethyl, carboxymethyl;

Each R ^c Each independently selected from deuterium, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy optionally deuterated;

s is 1 and 2;

n and t are each independently 0, 1, 2.

R ¹ 、R ² independently selected from hydrogen, C _1-6 Alkyl, C _1-6 An alkoxy group;

each of which isR ³ Each independently selected from Q optionally substituted with 1-3 substituents ₁ Substituted C _1-6 Alkyl, C _1-6 Alkoxy, 3-6 membered cycloalkyl;

each R ⁴ Are independently selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, halogenated C _1-6 An alkoxy group;

each Q ₁ Are independently selected from deuterium, C _1-6 Alkyl, C _1-6 An alkoxy group;

each R ⁵ Are independently selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, halogenated C _1-6 An alkoxy group;

each R ^a Each R ^b Are independently selected from hydrogen, C _1-6 Alkyl, C _1-6 An alkoxy group.

R ¹ 、R ² Each independently hydrogen;

each R ³ Each independently selected from Q optionally substituted with 1-3 substituents ₁ Substituted C _1-4 Alkyl, C _1-4 Alkoxy, cyclopropyl;

each R ⁴ Are independently selected from halogen, C _1-4 Alkyl, C _1-4 Alkoxy, halo C _1-4 Alkyl, halogenated C _1-4 An alkoxy group;

each Q ₁ Are independently selected from deuterium, C _1-4 Alkyl, C _1-4 An alkoxy group;

each R ⁵ Are independently selected from halogen, C _1-4 Alkyl, C _1-4 Alkoxy, halo C _1-4 Alkyl, halogenated C _1-4 An alkoxy group;

each R ^a Each R ^b Each independently hydrogen.

wherein R is ¹ 、R ² Are independently selected from hydrogen, C _1-6 Alkyl, C _1-6 An alkoxy group;

each R ³ Are independently selected from C _1-6 Alkyl, C _1-6 Alkoxy, deuterated C _1-6 Alkyl, deuterated C _1-6 Alkoxy, 3-6 membered cycloalkyl;

R ^a 、R ^b are independently selected from hydrogen, C _1-6 Alkyl, C _1-6 An alkoxy group;

n, s, t are each independently 1, 2, 3.

wherein R is ³ Selected from C _1-4 Alkyl, C _1-4 Alkoxy, deuterated C _1-4 Alkyl, deuterated C _1-4 An alkoxy group;

each of which isR ⁵ Are independently selected from halogen, C _1-4 Alkyl, C _1-4 Alkoxy, halo C _1-4 Alkyl, halogenated C _1-4 An alkoxy group;

s and t are respectively 1 and 2 independently.

wherein R is ³ Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated isobutyl, deuterated sec-butyl, deuterated tert-butyl, deuterated methoxy, deuterated ethoxy, deuterated propoxy, deuterated isopropoxy;

Each R ⁴ Each independently selected from fluorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

each R ⁵ Each independently selected from fluorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

s and t are respectively 1 and 2 independently.

Any substituent groups in any embodiment of the invention can be mutually combined, and the combined technical scheme is still included in the protection scope of the invention.

In some embodiments of the invention, provided compounds, pharmaceutically acceptable salts, esters, deuterated compounds, or stereoisomers thereof, have the structures shown below:

the invention also provides a pharmaceutical composition comprising a compound of the general formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), a pharmaceutically acceptable salt, ester, deuteride or stereoisomer thereof, and one or more second therapeutically active agents, optionally together with one or more pharmaceutically acceptable carriers and/or diluents.

The invention also provides a pharmaceutical preparation which contains the compound shown in the general formula (I), (I-1), (I-2), (I-3), (I-4), (I-5) and (I-6), pharmaceutically acceptable salt, ester, deuteride or stereoisomer thereof and one or more medicinal carriers and/or diluents; the pharmaceutical preparation is any clinically or pharmaceutically acceptable dosage form.

In some embodiments of the invention, the above-described pharmaceutical formulations may be administered orally, parenterally, rectally, or pulmonary, etc., to a patient or subject in need of such treatment. For oral administration, the pharmaceutical composition may be formulated into oral preparations, for example, into conventional oral solid preparations such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparation such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. may be added. For parenteral administration, the pharmaceutical preparations may also be formulated as injections, including injectable solutions, injectable sterile powders, and injectable concentrated solutions. When the injection is prepared, the conventional method in the existing pharmaceutical field can be adopted for production, and when the injection is prepared, no additive can be added, and the proper additive can be added according to the property of the medicine. For rectal administration, the pharmaceutical composition may be formulated as suppositories and the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalant or spray, etc.

The pharmaceutically acceptable carrier and/or diluent useful in the pharmaceutical composition or pharmaceutical formulation of the present invention may be any conventional carrier and/or diluent in the pharmaceutical formulation arts, and the choice of the particular carrier and/or diluent will depend on the mode of administration or type and state of disease for the particular patient being treated. The preparation of suitable pharmaceutical compositions for specific modes of administration is well within the knowledge of those skilled in the pharmaceutical arts. For example, pharmaceutically acceptable carriers and/or diluents may include solvents, diluents, dispersing agents, suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, binders, lubricants, stabilizers, hydration agents, emulsifying accelerators, buffers, absorbents, colorants, ion-exchange agents, mold release agents, coating agents, flavoring agents, antioxidants and the like which are conventional in the pharmaceutical arts. Flavoring agent, antiseptic, sweetener, etc. can be added into the pharmaceutical composition if necessary.

The invention also provides application of the compounds shown in the general formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5) and (I-6), pharmaceutically acceptable salts, esters, deuterated substances or stereoisomers thereof, the medicinal preparation or the medicinal composition in preparation of medicaments for treating and/or preventing USP1 mediated diseases and related diseases; the USP1 mediated disease and related diseases are selected from cancers or benign tumors.

The invention also provides application of the compound shown in the general formula (I), pharmaceutically acceptable salt, ester, deuteride or stereoisomer thereof, the medicinal preparation or the medicinal composition in treating and/or preventing USP1 mediated diseases and related diseases; the USP1 mediated disease and related diseases are selected from cancers or benign tumors.

The present invention also provides a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) above, a pharmaceutically acceptable salt, ester, deuteride or stereoisomer thereof, a pharmaceutical formulation of the foregoing, or a pharmaceutical composition of the foregoing, wherein the disease is USP1 mediated and related; the USP1 mediated disease and related diseases are selected from cancers or benign tumors.

The cancer or benign tumor includes, but is not limited to, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, brain cancer, head and neck cancer, thyroid cancer, lung cancer, bronchial cancer, esophageal cancer, gastric cancer, liver cancer, kidney cancer, pancreatic cancer, gall bladder cancer, colon cancer, bladder cancer, prostate cancer, cap pill cancer, skin cancer, bone cancer, and hematological tumors; the lung cancer includes, but is not limited to, small cell lung cancer and non-small cell lung cancer; such hematological neoplasms include, but are not limited to, leukemia, lymphoma, and myeloma; such brain cancers include, but are not limited to glioma, neuroblastoma, astrocytoma, meningioma.

In the description and claims of the present application, compounds are named according to chemical structural formulas, and if the same compound is represented, the naming and chemical structural formulas of the compounds are not identical, the chemical structural formulas are used as references.

In this application, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art, however, for a better understanding of the invention, the following definitions of some terms are provided. When the definition of a term or an explanation provided herein is inconsistent with the definition of that term or the explanation provided herein, which is commonly understood by those skilled in the art, the definition of the term or the explanation provided herein controls.

"halogen" as used herein refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

"halo" as used herein means that any hydrogen in a substituent may be substituted with one or more of the same or different halogens. "halogen" is as defined above.

"C" as described in the present invention _1-6 Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms and includes, 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 ", and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, etc. "C" as described in the present invention _1-4 Alkyl "means C _1-6 Specific examples of the alkyl group include 1 to 4 carbon atoms.

"C" as described in the present invention _1-6 Alkylene "means C as described above _1-6 Alkyl groups having one hydrogen atom removed to form groups, 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 ", and the like, specific examples include, but are not limited to: methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like. "C" as described in the present invention _1-4 Alkylene "means C _1-6 Specific examples of the alkylene group include those having 1 to 4 carbon atoms.

"C" as described in the present invention _2-6 Alkenyl "refers to straight-chain or branched or cyclic alkenyl groups of 2 to 6 carbon atoms containing at least one double bond and includes, for example," C _2-5 Alkenyl "," C _2-4 Alkenyl "," C _2-3 Alkenyl ", and the like, specific examples include, but are not limited to: vinyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 1-methyl-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1-dimethyl-3-butenyl,1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-2-butenyl, 2-dimethyl-3-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-1-butenyl, 2-ethyl-3-butenyl, and the like.

"C" as described in the present invention _2-6 Alkynyl "refers to straight or branched chain alkynyl groups of 2 to 8 carbon atoms containing triple bonds and includes, for example," C _2-5 Alkynyl "," C _2-4 Alkynyl "," C _2-3 Alkynyl ", and the like, specific examples include, but are not limited to: ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, and the like.

"C" as described herein _1-6 Alkoxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, C _1-6 Alkylaminoacyl, C _1-6 Alkylamido, C _1-6 Alkylsulfonyl, C _1-6 Alkylsulfonylamino, C _1-6 Alkylaminosulfonyl, C _1-6 Alkylcarbonyl, C _1-6 Alkoxycarbonyl "means C _1-6 alkyl-O-, C _1-6 alkyl-NH- (C) _1-6 Alkyl group ₂ -N-、C _1-6 alkyl-NH-C (O) -, C _1-6 alkyl-C (O) -NH-, C _1-6 alkyl-S (O) ₂ -、C _1-6 alkyl-S (O) ₂ -NH-、C _1-6 alkyl-NH-S (O) ₂ -、C _1-6 alkyl-C (O) -, C _1-4 alkyl-O-C (O) -formed radicals, where "C _1-6 The definition of alkyl "is as described above.

"C" as described herein _1-4 Alkoxy, C _1-4 Alkylamino, di (C) _1-4 Alkyl) amino, C _1-4 Alkylaminoacyl, C _1-4 Alkylamido, C _1-4 Alkylsulfonyl, C _1-4 Alkylsulfonylamino, C _1-4 Alkylaminosulfonyl, C _1-4 Alkylcarbonyl, C _1-4 Alkoxycarbonyl "means C _1-4 alkyl-O-, C _1-4 alkyl-NH- (C) _1-4 Alkyl group ₂ -N-、C _1-4 alkyl-NH-C (O) -, C _1-4 alkyl-C (O) -NH-, C _1-4 alkyl-S (O) ₂ -、C _1-4 alkyl-S (O) ₂ -NH-、C _1-4 alkyl-NH-S (O) ₂ -、C _1-4 alkyl-C (O) -, C _1-4 alkyl-O-C (O) -formed radicals, where "C _1-4 The definition of alkyl "is as described above.

"halo C" as described herein _1-6 Alkyl, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 Alkyl, halogenated C _1-6 Alkoxy "means that one to more (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxy, amino, carboxy groups, respectively, are substituted for C _1-6 Alkyl, C _1-6 Alkylene, C _1-6 A group formed by a hydrogen atom in an alkoxy group.

"halo C" as described herein _1-4 Alkyl, hydroxy C _1-4 Alkyl, amino C _1-4 Alkyl, carboxyl C _1-4 Alkyl, halogenated C _1-4 Alkoxy "means that one to more (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxy, amino groups are substituted for C, respectively _1-4 Alkyl, C _1-4 A group formed by a hydrogen atom in an alkoxy group.

"3-8 membered cycloalkyl" as used herein refers to a saturated or partially saturated cyclic alkyl group having 3 to 8 carbon atoms and having no aromaticity, and includes "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", "6-8 membered cycloalkyl", "7-8 membered cycloalkyl", "3-6 membered saturated cycloalkyl", "4-7 membered saturated cycloalkyl", "4-8 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", "5-7 membered partially saturated cycloalkyl", "5-6 membered partially saturated cycloalkyl", etc. Specific examples of the "3-8 membered saturated cycloalkyl group" include, but are not limited to: cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane (cycloheptyl), cyclooctyl (cyclooctyl), and the like; specific examples of the "3-8 membered partially saturated cycloalkyl group" include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1, 3-diene, cyclohex-1, 4-diene, cycloheptenyl, cyclohepta-1, 3-dienyl, cyclohepta-1, 4-dienyl, cyclohepta-1, 3, 5-trienyl, cyclooctenyl, cycloocta-1, 3-dienyl, cycloocta-1, 4-dienyl, cycloocta-1, 5-dienyl, cycloocta-1, 3, 5-trienyl, cyclooctatetraenyl, and the like.

"3-8 membered heterocyclic group" as used herein refers to a saturated or partially saturated and non-aromatic monocyclic or fused ring group containing at least one heteroatom (e.g., containing 1,2, 3,4 or 5) and having 3 to 8 ring atoms, which is a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom in the ring structure (e.g., carbon atom, nitrogen atom or sulfur atom) may be oxo. The "3-8 membered heterocyclic group" as used herein includes "3-8 membered saturated heterocyclic group" and "3-8 membered partially saturated heterocyclic group". Preferably, the "3-8 membered heterocyclic group" according to the present invention contains 1 to 3 hetero atoms; preferably, the "3-8 membered heterocyclic group" according to the present invention contains 1 to 2 hetero atoms, and the hetero atoms are selected from nitrogen atoms and/or oxygen atoms; preferably, the "3-8 membered heterocyclic group" according to the present invention contains 1 to 2 nitrogen atoms. The "3-8 membered heterocyclic group" is preferably "4-8 membered heterocyclic group", "3-6 membered saturated heterocyclic group", "3-6 membered nitrogen-containing heterocyclic group", "3-6 membered saturated nitrogen-containing heterocyclic group", "5-6 membered saturated heterocyclic group", or the like. Specific examples of "3-8 membered heterocyclyl" include, but are not limited to: aziridinyl, 2H-aziridinyl, diazinoalkyl, 3H-diazinopropenyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxanyl, 1, 4-dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, 2H-1, 2-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-pyranyl, 2, 3-dihydropyran-2, 4-oxo-2H-2-dihydropyran.

The "6-10 membered aryl" as used herein refers to an aromatic cyclic group containing 6-10 ring carbon atoms, and includes "6-8 membered monocyclic aryl" and "8-10 membered condensed ring aryl".

"6-8 membered monocyclic aryl" as used herein refers to monocyclic aryl groups containing 6-8 ring carbon atoms, examples of which include, but are not limited to: phenyl, cyclooctatetraenyl, and the like; phenyl is preferred.

The term "8-to 10-membered condensed ring aryl" as used herein refers to an unsaturated, aromatic cyclic group containing 8 to 10 ring carbon atoms, preferably "9-to 10-membered condensed ring aryl", which is formed by sharing two or more adjacent atoms with each other by two or more cyclic structures, and specific examples thereof are naphthyl and the like.

The term "5-12 membered heteroaryl" as used herein refers to a cyclic group having an aromatic nature and containing 5 to 12 ring atoms (at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom), and may be, for example, a 5-12 membered nitrogen-containing heteroaryl, a 5-12 membered oxygen-containing heteroaryl, a 5-12 membered sulfur-containing heteroaryl, etc. Including "5-8 membered single heteroaryl" and "8-10 membered fused heteroaryl".

"5-8 membered mono-heteroaryl" as used herein refers to an aromatic monocyclic ring group containing 5-8 ring atoms, at least one of which is a heteroatom, such as nitrogen, oxygen or sulfur. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. "5-8 membered mono-heteroaryl" includes, for example, "5-7 membered mono-heteroaryl", "5-6 membered nitrogen containing mono-heteroaryl", "5-nitrogen containing mono-heteroaryl", and the like. Specific examples of "5-8 membered monocyclic heteroaryl" include, but are not limited to, furyl, 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, azepanyl, 1, 3-diazinoheptenyl, azocyclotetraenyl and the like. The "5-6 membered heteroaryl" refers to a specific example in which 5-8 membered heteroaryl contains 5-6 ring atoms.

The "8-to 10-membered fused heteroaryl group" as used herein refers to an unsaturated aromatic ring structure containing 8 to 10 ring atoms (at least one of which is a heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom) formed by two or more ring structures sharing two adjacent atoms with each other. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. Including "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", and the like, which may be fused in such a manner as to be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, and the like; specific examples include, but are not limited to: pyrrolopyrroles, pyrrolofurans, pyrazolopyrroles, pyrazolothiophenes, furanthiophenes, pyrazolooxazoles, benzofuranyl, benzisofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolonyl, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, and the like.

The term "optionally substituted by …" as used herein includes both "substituted" and "unsubstituted".

According to the inventionSelected from single bond or double bond, and adjacent +.>Not both double bonds.

The "pharmaceutically acceptable salt" as used herein refers to addition salts of pharmaceutically acceptable acids and bases, such as metal salts, ammonium salts, salts with organic acids, salts with organic bases, salts with inorganic acids, salts with acidic amino acids or basic amino acids, and the like.

The "ester" as used herein refers to pharmaceutically acceptable esters, particularly esters which hydrolyze in vivo and include esters which readily decompose in humans to leave the parent compound (the compound of formula (I)) or a salt thereof. The "esters" according to the invention may be selected, for example, from the following groups: (1) Carboxylic esters obtained by esterification with carboxylic compounds, wherein the non-carbonyl moiety of the carboxylic compounds is selected from, for example, C _1-20 Straight-chain or branched alkyl, C _1-12 Straight-chain or branched alkyl, C _1-8 Straight-chain or branched alkyl, C _1-6 Straight-chain 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 by e.g. halogen, C _1-4 Alkyl or C _1-4 Alkoxy or amino substitution); (2) Sulfonate esters, such as alkylsulfonyl or aralkylsulfonyl (e.g., methylsulfonyl); (3) Amino acid esters (e.g., L-valyl or L-isoleucyl); and (4) mono-, di-, or triphosphates, etc.; (4) Esters 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-chain or branched alkyl, C _1-12 Straight-chain or branched alkyl, C _1-8 Straight-chain or branched alkyl, C _1-6 Straight-chain or branched alkyl (e.g. methyl, ethyl, n-propyl, t-butyl or n-butyl), C _1-6 Alkoxy C _1-6 Alkyl (examples)Such as 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 by e.g. halogen, C _1-4 Alkyl or C _1-4 Alkoxy or amino substitution).

"stereoisomers" as used herein refers to compounds of the invention which contain one or more asymmetric centers and are thus useful as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention may have asymmetric centers that each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. The compounds of the present invention, if they contain olefinic double bonds, include cis-isomers and trans-isomers unless specified otherwise. The compounds described herein may exist in tautomeric (one of the functional group isomers) forms having different points of attachment of hydrogen through displacement of one or more double bonds, for example, the keto and enol forms thereof are keto-enol tautomers. Each tautomer and mixtures thereof are included within the scope of the present invention. Enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of all compounds are included within the scope of the present invention.

Any atom of a compound in this application, unless specifically indicated, may represent any stable isotope of that atom. Unless otherwise indicated, when a position in a structure is defined as H, i.e., hydrogen (H-l), that position contains only naturally occurring isotopes. Also, unless otherwise specified, when a position in a structure is defined as D, deuterium (h-2), the position contains an isotope that is at least 3340 times greater than the naturally occurring isotope (0.015%), i.e., contains at least 50.1% deuterium isotopes, and when one or more positions in the structure of a compound of the present application is defined as D, deuterium (h-2), the content of the compound shown in the structure may be at least 52.5%, at least 60%, at least 67.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98.5%, at least 99%, at least 99.5%.

The deuteration rate of a compound of the present application refers to the ratio of the amount of isotope that is synthesized to the amount of isotope that is naturally occurring. The deuteration of each designated deuterium atom of a compound of the present application may 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%).

Isotopologues in this application refer to compounds that differ only in terms of their chemical structure in terms of their isotopic composition. The deuterium containing compounds of the present application at a particular position will also contain very little hydrogen isotopologue at that position, the amount of hydrogen isotopologue at the deuterated position in the deuterated compounds of the present application will depend on a number of factors, including the deuterating agent (D ₂ O、D ₂ 、NaBD ₄ 、L1AID ₄ Etc.) deuterium isotope purity and the effectiveness of the method of synthesizing the introduced deuterium isotopes. However, as previously mentioned, the total number of hydrogen isotopologues at such deuterated positions will be less than 49.9%. The total amount of hydrogen isotopologues at the deuterated positions in the deuterated compounds of the present application will be less than 47.5%, 40%, 32.5%, 25%, 17.5%, 10%, 5%, 3%, 1% or 0.5%.

In this application, any individual atom not designated as deuterium is present in its natural isotopic abundance.

"deuterated" as used herein refers to a group that is deuterated in which one or more hydrogen atoms are replaced with one or more deuterium atoms, either partially deuterated or fully deuterated. For example, a deuterated compound may contain only one deuterium. In some embodiments, the deuterated compound contains only two deuterium. In some embodiments, the deuterated compound contains only three deuterium. In some embodiments, the deuterated compound contains four deuterium.

The term "optionally deuterated" as used herein includes both cases where the group is deuterated and is not deuterated, wherein "deuterated" is as defined above.

The term "therapeutically effective amount" as used herein refers to an amount of a compound, pharmaceutical formulation, pharmaceutical composition, as described above, that is capable of at least alleviating the symptoms of a disorder in a patient when administered to the patient. The actual amount comprising a "therapeutically effective amount" will vary depending on a variety of circumstances including, but not limited to, the particular disorder being treated, the severity of the disorder, the physical and health of the patient, and the route of administration. The skilled medical practitioner can readily determine the appropriate amount using methods known in the medical arts.

Advantageous effects of the invention

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

(2) The compound has good inhibition effect on tumor cells;

(3) The compound, pharmaceutically acceptable salt, ester, deuteride or stereoisomer thereof has good pharmacokinetic property, longer action and high bioavailability;

(4) The compound, pharmaceutically acceptable salts, esters, deuterated compounds or stereoisomers thereof have good safety;

(5) The compound has the advantages of simple preparation process, high purity of the medicine, stable quality and easy mass industrial production.

The advantageous effects of the compounds provided by the examples of the present invention are further illustrated by the experiments below, but this should not be construed as the compounds provided by the examples of the present invention only have the following advantageous effects.

Experimental example 1 in vitro enzymatic Activity of Compounds of the invention

Test article: the chemical names and structures of the compounds synthesized in the examples of the invention are shown in the preparation examples.

Experimental reagent:

experiment consumable:

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

the experimental method comprises the following steps:

1. dilution of the Compounds

1) The compounds of the invention were formulated to 10mM using DMSO as assay stock.

2) The stock solution of the compound of the present invention was diluted 4-fold in gradient to 10 concentrations, the highest concentration being 10mM.

3) The diluted compounds of the invention were transferred separately to 384 well plates using Echo550, diluted 1000-fold, with 2 duplicate wells per concentration set and 1% DMSO final concentration.

4) The final concentrations of the test compounds were 10000nM, 2500nM, 625nM, 156nM, 39nM, 9.8nM, 2.4nM, 0.61nM, 0.15nM, 0.038nM.

2. Enzyme reaction experiment

1) Enzyme solutions were prepared in 1 x test buffer.

2) Ubiquitin Rhodamine 110 protein, CF (Ub-Rho) was added to the 1 Xtest buffer to prepare a substrate solution.

3) Transfer 10. Mu.L of enzyme solution and 1 Xreaction buffer into 384-well plates.

4) Incubate at room temperature for 60 minutes.

5) The reaction was started by adding 10. Mu.L of substrate solution to each well, centrifuging for 30s and shaking for 30s.

3. Result detection

1) The plate was read on SpectraMax Paradigm for 30 minutes with an excitation wavelength of 480nm and an emission wavelength of 540nm.

2) Data on SpectraMax Paradigm is collected.

4. Data analysis

Inhibition (% inh) was calculated using the following formula:

wherein, max represents: luminescence signal intensity of positive control wells without compound;

min represents: luminescence signal intensity of negative control wells without enzyme;

signal represents: indicating the luminescence signal intensity of the test compound;

IC is calculated using the following formula ₅₀ ：

Wherein Y represents: % inhibition;

x represents: concentration of the compound.

Experimental results:

TABLE 1 inhibitory Activity of the Compounds of the invention against USP-1

From the above experimental results, it can be seen that the compounds prepared by the present invention can effectively inhibit the activity of USP1, and are effective USP1 inhibitors.

Experimental example 2 in vitro cytological Activity of the Compounds of the invention

Test article: some of the compounds of the invention have the chemical names and structures shown in the preparation examples.

The cell lines used in the following experiments were as follows:

MDA-MB-436: BRCA1 mutates human breast cancer cells; caov-3: homologous recombination repair defective (hrd+) human ovarian cancer cells

Experimental method (CelltiterGlo assay)

1. Preparation of cells

1.1 cell culture:

all cells were adherent cells, the MDA-MB-436 cell culture medium was DMEM+10% FBS+1% ITS-G+16 μg/ml glutethione, the Caov-3 cell culture medium was DMEM+10% FBS, and the cells were tested in the logarithmic growth phase.

1.2 preparation of cell suspension:

cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion, ensuring that cell viability was above 90%. To the appropriate concentration, 90. Mu.L of the cell suspension was added to each 96-well plate.

TABLE 2 cell seed number

2. Formulation of test compounds

2.1 preparing test compound DMSO stock solutions, the stock solution concentration of each test compound was 10mM.

2.2 preparation of test Compound working stock solution

The test compound stock 10mM was serially diluted 3-fold in DMSO at 8 concentrations. Then 2. Mu.L of DMSO gradient diluted compound was added to 198. Mu.L of culture medium, respectively, to give working stock solutions of test compounds (compound concentration 10 times final concentration, maximum concentration 100. Mu.M).

2.3 Compound treatment

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

The final concentrations of the test compounds were: 10000.00nM,3333.33nM,1111.11nM,370.37nM,123.46nM,41.15nM,13.72nM,4.57nM.

2.4 control well settings

Solvent control: 0.1% DMSO.

Blank control: at 0h dosing, the reading was measured in 96-well plates.

2.5 96 well plates were placed at 37℃with 5% CO ₂ The cells were cultured in a cell incubator for 7 days.

3. Detection of

The CTG reagent was thawed and the 96-well plate was equilibrated to room temperature for 30 minutes, 60 μl of reagent (Celltiter Glo assay kit) was added to each well, shaken with a shaker for 2 minutes and mixed well (protected from light), and incubated at room temperature for 20 minutes (protected from light). The multifunctional enzyme label instrument reads the optical signal value.

4. Data processing

1) Inhibition (%) = (DMSO solvent control well reading-test substance well reading)/(DMSO solvent control well reading-blank control well reading) ×100%;

2) Inputting GraphPad Prism for plotting to obtain curve and IC ₅₀ 。

Experimental results and conclusions

TABLE 3 in vitro cytologic Activity (IC) of the inventive compounds ₅₀ ,nM)

As shown in Table 3, the compounds of the invention can effectively inhibit the proliferation of MDA-MB-436 and Caov-3 cells, and show that the compounds of the invention have clinical application potential in treating HRD positive (homologous recombination defect) cancerous diseases.

Experimental example 3 pharmacokinetic experiments of the Compounds of the invention

Test articles the preparation of the compounds of the invention is described in the examples in the specification of the present application.

Sample solution preparation

1. Preparation of solutions of the Compounds

(1) Intravenous bolus administration (iv): taking a compound, adding a proper amount of DMSO, and performing vortex ultrasonic treatment to dissolve the compound; then adding a proper amount of PEG 400, and uniformly mixing by vortex; finally, 28 percent HP-beta-CD solution is added, and vortex mixing is carried out to prepare the medicine liquid with the final concentration of 1 mg/ml.

(2) Oral administration (po): placing a proper amount of the compound into a tissue grinder, adding 2% HPC+0.1% Tween solvent for full grinding, and transferring the grinding liquid into a glass bottle; shaking and mixing uniformly to prepare the liquid medicine with the final concentration of 1 mg/ml.

Experimental method

1. Administration of drugs

Intravenous injection administration (iv) of the test sample, wherein the administration dosage is 5mg/kg, and the administration volume is 5ml/kg;

the administration dosage of oral administration (po) was 10mg/kg, and the administration volume was 10ml/kg.

2. Blood collection

After administration, 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours, tail vein blood collection was performed, about 100. Mu.l of whole blood was collected at each time point, and plasma was separated by centrifugation in a high-speed centrifuge at 8000rpm for 6 minutes and frozen at-80 ℃.

3. Plasma sample analysis

The protein precipitation method is adopted: taking 20 μl of plasma into a 96-well deep well plate, adding 200 μl of internal standard solution, swirling for 10min, centrifuging for 20min at 4000 rpm, taking 100 μl of supernatant, adding 100 μl of water, and swirling for 3min; LC-MS/MS was analyzed.

Experimental results and conclusions

Experimental results show that the compound of the invention has higher exposure in organisms, proper half-life and clearance rate, good pharmacokinetic property and good clinical application prospect.

Detailed Description

The technical solution of the present invention will be described below with reference to specific embodiments, and the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

Abbreviations used in the following experiments represent the following meanings:

Xphos-Pd-G2: chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II); xphos: 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl; LAH: lithium aluminum hydride; DMF: dimethylformamide; DIBAL-H: diisobutyl aluminum hydride

Preparation of 1 4- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -2,6,7, 8-tetrahydropyrazolo [3,4,5-de ] quinazoline

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

1, 3-cyclohexanedione (20 g,178.4 mmol) was dissolved in DMF (200 mL) and potassium carbonate (74 g,535.2 mmol) was added and reacted at 20℃for 0.5h. Carbon disulphide (20 g,267.6 mmol) was added and reacted for 1h at 20 ℃. Methyl iodide (76 g,535.2 mmol) was added thereto and the mixture was reacted at 20℃for 1 hour. Concentrating to obtain crude product, and directly using for the next reaction.

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

2- (bis (methylthio) methylene) cyclohexane-1, 3-dione (crude product of the above step) was dissolved in DMF (200 mL), guanidine hydrochloride (17 g,178.4 mmol), potassium carbonate (49.3 g,356.8 mmol) was added, reacted at 100℃for 16h, cooled to 25℃and water (300 mL) was added, and the filter cake was obtained by filtration, and 16.3g of the objective compound was obtained by vacuum drying in 44% yield.

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

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) was added, and tert-butyl nitrite (48 g, 268 mmol) was reacted at 25℃for 3H. Water was added to quench the reaction, the filtrate was filtered, concentrated, and column chromatography (ethyl acetate/petroleum ether=0 to 40%) was performed to obtain 6.1g of the target compound in 34% yield.

(4) Preparation of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (methylthio) -7, 8-dihydroquinazolin-5 (6H) -one

2-chloro-4- (methylthio) -7, 8-dihydroquinazolin-5 (6H) -one (1.2G, 5.15 mmol) was dissolved in 1, 4-dioxane (30 mL), and (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (1G, 5.15 mmol), xphos-Pd-G2 (408 mg,0.52 mmol), xphos (496 mg,1.04 mmol), K was added ₃ PO ₄ (1.2 g,5.7 mmol), water (10 mL), N ₂ Under the protection, the reaction is carried out for 3 hours at 90 ℃, after the reaction is finished, the solvent is dried by spin, and 830mg of the target compound is obtained through normal phase preparation and separation (ethyl acetate/petroleum ether=0-50%), and the yield is 47%.

(5) Preparation of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4-hydrazino-7, 8-dihydroquinazolin-5 (6H) -one

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (methylthio) -7, 8-dihydroquinazolin-5 (6H) -one (830 mg,2.4 mmol) was dissolved in ethanol (20 mL), hydrazine hydrate (184 mg,3.6 mmol) was added and reacted at 70℃for 3H. After the completion of the reaction, the reaction mixture was concentrated to give 700mg of the objective compound (89%).

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

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4-hydrazino-7, 8-dihydroquinazolin-5 (6H) -one (300 mg,0.92 mmol) was dissolved in N-methylpyrrolidone (5 mL), ethanol (60 mL) and reacted for 1H at 160℃with microwaves. Column chromatography (methanol/water=0-60%) gave 150mg of the title compound in 53% yield.

Example 14 preparation of- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -2- (2-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2,6,7, 8-tetrahydropyrazolo [3,4,5-de ] quinazoline (Compound 1)

(1) Preparation of methyl 2-fluoro-4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate

3, 3-dibromo-1, 1-trifluoropropan-2-one (6.7 g,25.0 mmol) was dissolved in water (20 mL), sodium acetate (3.9 g,48.0 mmol) was added, and reacted at 100℃for 1 hour, cooled to 0℃and a solution of methyl 2-fluoro-4-formylbenzoate (3.6 g,20.0 mmol) in methanol (60 mL) and aqueous ammonia (20 mL) was added, and the temperature was raised to 100℃and reacted for 16 hours. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phase was collected and purified by silica gel column chromatography (PE: ea=0 to 30%) to give the product (1.5 g, yield 26.3%).

(2) Preparation of methyl 2-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate

Methyl 2-fluoro-4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate (1.3 g,4.5 mmol), K at 30 ℃ ₂ CO ₃ (1.2 g,9.0 mmol) was dissolved in DMF (10 mL), and after stirring for 30min, meI (7.7 g,5.4 mmol) was added and the reaction was stirred for 14h after the addition was complete. And (5) detecting the end of the reaction. Diluting with water, extracting with ethyl acetate, drying and concentrating the organic phase, and purifying the residue by a silica gel column (ethyl acetate: petroleum ether=10:3) to obtain the title compound 1.1g, yield: 80.7%.

(3) Preparation of (2-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol

Methyl 2-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate (600 mg,2.0 mmol) was dissolved in THF (30 mL), LAH (228 mg,6.0 mol) was added and reacted at 0℃for 30min. LCMS detects the end of the reaction. Suction filtration of celite afforded the title compound 520mg, yield: 95.5%.

(4) Preparation of 2- (4- (chloromethyl) -3-fluorophenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole

(2-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol (520 mg,1.9 mmol) was dissolved in DCE (4 mL) and SOCl ₂ (2 mL), at 50℃for 30min. LCMS detects the end of the reaction. Organic phase dryness concentrated silica gel column purification (ethyl acetate: petroleum ether=10:3) gave the title compound 500mg, yield: 90.3%.

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

At 30℃2- (4- (chloromethyl) -3-fluorophenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole (200 mg,0.68 mmol), 4- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -2,6,7, 8-tetrahydropyrazolo [3,4,5-de ]]Quinazoline (232 mg,0.75 mmol) was dissolved in DMF (20 mL) and K was added ₂ CO ₃ (188 mg,1.4 mmol) was stirred for 10 hours. LCMS detects the end of the reaction. Washing with water, extraction with ethyl acetate, and purification on a silica gel column (petroleum ether: ethyl acetate=1:4) gave 40mg of the title compound, yield: 10.4%.

Molecular formula C ₂₈ H ₂₄ F ₄ N ₈ Molecular weight of O564.55 LC-MS (M/e): 565.2 (M+H) ⁺ )

¹ H-NMR(400MHz,CDCl ₃ )δ:8.67(s,1H),7.43-7.36(m,3H),7.31(s,1H),5.36(s,2H),3.94(s,3H),3.78(s,3H),3.15-3.08(m,4H),2.45-2.39(m,2H),1.70-1.67(m,1H),1.32-1.24(m,2H),0.93-0.88(m,2H).

Example 2 4 preparation of- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -2- (3-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2,6,7, 8-tetrahydropyrazolo [3,4,5-de ] quinazoline (Compound 2)

(1) Preparation of methyl 3-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate

3-fluoro-4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzoic acid methyl ester (1.0 g,3.5 mmol), K at 30 ℃ ₂ CO ₃ (966 mg,7.0 mmol) was dissolved in DMF (10 mL), after stirring for 30min, meI (596 mg,4.2 mmol) was added and the reaction was stirred for 3h after the addition was complete. And (5) detecting the end of the reaction. Diluting with water, extracting with ethyl acetate, drying and concentrating the organic phase, and purifying the residue by a silica gel column (ethyl acetate: petroleum ether=1:5) to obtain the title compound 1.0g, yield: 95.4%.

(2) Preparation of (3-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol

Methyl 3-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate (450 mg,1.5 mmol) was dissolved in THF (50 mL), LAH (171 mg,4.5 mol) was added and reacted at 0℃for 30min. LCMS detects the end of the reaction. The reaction solution was suction-filtered through celite to give 360mg of the title compound, yield: 88.2%.

(3) Preparation of 2- (4- (chloromethyl) -2-fluorophenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole

(3-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol (360 mg,1.3 mmol) was dissolved in DCE (5 mL) and SOCl ₂ (1 mL), at 50℃for 30min. LCMS detects the end of the reaction. Organic phase dryness concentrated silica gel column purification (ethyl acetate: petroleum ether=0:100-100:0) gave 333mg of the title compound, yield: 86.8%.

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

At 30℃2- (4- (chloromethyl) -2-fluorophenyl) -4- (trifluoromethyl) -1H-imidazole (100 mg,0.34 mmol), 4- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -2,6,7, 8-tetrahydropyrazolo [3,4,5-de ]]Quinazoline (95 mg,0.31 mmol) was dissolved in DMF (20 mL) and K was added ₂ CO ₃ (85 mg,0.62 mmol) was stirred for 10 hours. LCMS detects the end of the reaction. Washing with water, extraction with ethyl acetate, and purification on a silica gel column (petroleum ether: ethyl acetate=1:4) gave the title compound 95mg, yield: 49.2%. Molecular formula C ₂₈ H ₂₄ F ₄ N ₈ Molecular weight of O564.5 LC-MS (M/e): 565.2 (M+H) ⁺ )

¹ H-NMR(400MHz,CDCl ₃ )δ:8.68(s,1H),7.61-7.57(m,1H),7.36-7.33(m,2H),7.28-7.23(m,1H),5.68(s,2H),3.95(s,3H),3.64(s,3H),3.16-3.10(m,4H),2.47-2.40(m,2H),1.69-1.63(m,1H),1.29-1.25(m,2H),0.94-0.92(m,2H).

Example 34 preparation of- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -2- (3, 5-difluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2,6,7, 8-tetrahydropyrazolo [3,4,5-de ] quinazoline (Compound 3)

(1) Preparation of methyl 3, 5-difluoro-4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate

Methyl 3, 5-difluoro-4-formylbenzoate (2.0 g,10.0 mmol) was dissolved in 25mL of methanol, sodium acetate (1.0 g,12.2 mmol), dibromotrifluoroacetone (3.2 g,11.9 mmol) was added, the system was cooled to 0℃and then 6mL of aqueous ammonia was added, the temperature after the addition was raised to 30℃for 4.0 hours, the reaction was completed, the reaction solution was concentrated, and the residue was subjected to column chromatography to give 2.0g of the objective product in 65.3% yield.

(2) Preparation of methyl 3, 5-difluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate

Methyl 3, 5-difluoro-4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate (1.9 g,6.2 mmol) was dissolved in DMF (30 mL), potassium carbonate (1.9 g,13.7 mmol) and methyl iodide (1.0 g,7.0 mmol) were added, the reaction was completed at 30℃for 2.0H, water quenching was added and the residue was concentrated, and the product was purified by column chromatography (EA: PE=15%) to give the objective product 1.6g, yield 80.5%.

(3) Preparation of (3, 5-difluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol

Methyl 3, 5-difluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate (800 mg,2.5 mmol) was dissolved in 20mL THF, DIBAL-H (2.0 mL,3.0 mmol) was added, the reaction was carried out at 30℃for 1.0H, after the completion, water quenching was added, and the reaction was directly carried out after concentration.

(4) Preparation of 2- (4- (chloromethyl) -2, 6-difluorophenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole

The crude product of the previous step is dissolved in 30mL of 1, 2-dichloroethane, 5mL of thionyl chloride is added and reacted for 1.0h at 50 ℃, the reaction is finished, the reaction liquid is concentrated, the pH is regulated to 7 by saturated sodium bicarbonate solution, the saturated sodium bicarbonate solution is extracted by ethyl acetate, the concentrated solution is subjected to column chromatography (EA: PE=15%) to obtain 500mg of a product with two steps of yield: 64.4%.

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

2- (4- (chloromethyl) -2, 6-difluorophenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole (200 mg,0.64 mmol) was dissolved in 10mL of DMF, potassium carbonate (160 mg,1.2 mmol) and 4- (4-cyclopropyl-6-methoxypyrimidine-5-

Radical) -2,6,7, 8-tetrahydropyrazolo [3,4,5-de ] quinazoline (180 mg,0.58 mmol), the reaction is carried out at 60 ℃ for 5.0h, the reaction is ended, the residue is concentrated and the product 80mg is obtained by column chromatography (EA: pe=90%) in yield: 21.4%.

Molecular formula C ₂₈ H ₂₃ F ₅ N ₈ Molecular weight of O582.5 LC-MS (M/e): 583.2 (M+H) ⁺ )

¹ H-NMR(400MHz,CDCl ₃ )δ:8.67(s,1H),7.39(s,1H),7.09-7.07(m,2H),5.64(s,2H),4.11(s,3H),3.98(s,3H),3.19-3.05(m,4H),2.42-2.38(m,2H),1.64-1.62(m,1H),1.29-1.22(m,2H),0.94-0.92(m,2H).

Using the same or similar methods as the above examples, compounds shown in the following tables were prepared:

The USP1 inhibitor and the use thereof provided by the present invention are described in detail above. The principles and embodiments of the present invention have been described herein with reference to specific examples, the description of which is intended only to aid in the understanding of the method of the present invention and its central ideas. It should be noted that it will be apparent to those skilled in the art that various changes and modifications can be made herein without departing from the principles of the invention, which also falls within the scope of the appended claims.

Claims

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt, ester, deuteride or stereoisomer thereof,

wherein,

X ₁ 、X ₂ independently selected from N, C or CR ^a ；

X ₄ Selected from N or C;

each R ⁴ Independently selected from halogen, cyano, carboxyl, hydroxyl, ammoniaRadicals, nitro radicals, optionally substituted by 1 to 4 substituents Q ₁ Substituted C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, halo C _1-6 Alkyl, halogenated C _1-6 Alkoxy, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 Alkyl, C _1-6 Alkylcarbonyl, C _1-6 Alkoxycarbonyl group, C _1-6 Alkylaminoacyl, C _1-6 Alkylamido, C _1-6 Alkylsulfonyl, C _1-6 Alkylsulfonylamino, C _1-6 Alkylaminosulfonyl, - (L) ₁ ) _m -C _1-6 Alkyl, - (L) ₁ ) _m -C _1-6 Alkoxy, - (L) ₁ ) _m -6-10 membered aryl, - (L) ₁ ) _m -5-12 membered heteroaryl, - (L) ₁ ) _m -3-8 membered cycloalkyl or- (L) ₁ ) _m -3-8 membered heterocyclyl;

-is a single bond or a double bond, and adjacent ones are not simultaneously double bonds;

s is an integer of 1 to 4;

each m, m1, n, t is independently an integer from 0 to 4.

2. The compound of claim 1, a pharmaceutically acceptable salt, ester, deuteride, or stereoisomer thereof wherein,

X ₁ 、X ₂ each independently selected from N, C or CH;

X ₄ selected from N or C;

R ¹ 、R ² Each independently selected from deuterium, hydrogen, halogen, optionally deuterated C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl, carboxyl C _1-6 Alkyl or halo C _1-6 An alkoxy group;

s is an integer of 1 to 3;

each m, m1, n, t is independently an integer from 0 to 3.

3. The compound of claim 1 or 2, a pharmaceutically acceptable salt, ester, deuteride, or stereoisomer thereof,

4. The compound of any one of claim 1 to 3, a pharmaceutically acceptable salt, ester, deuteride, or stereoisomer thereof,

selected from the following structures: />

Each R ⁵ A definition of each t as defined in any one of claims 1 to 3.

5. The compound of any one of claims 1-4, a pharmaceutically acceptable salt, ester, deuteride, or stereoisomer thereof having the structure of formula (I-4),

R ¹ 、R ² 、R ^a 、R ^b each R ³ Each R ⁴ Each R ⁵ Each Q ₁ The definitions of n, s, t are as defined in any one of claims 1 to 4.

6. The compound, pharmaceutically acceptable salt, ester, deuteride, or stereoisomer thereof according to any one of claims 1-5,

each R ⁴ Each independently selected from fluorine, chlorine, bromine, iodine, optionally 1-3 substituents Q ₁ Substituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

s is 1 and 2;

n and t are each independently 0, 1, 2.

7. A compound, a pharmaceutically acceptable salt, ester, deuterate, or stereoisomer thereof, having the structure:

8. A pharmaceutical formulation comprising a compound of any one of claims 1-7, a pharmaceutically acceptable salt, ester, deuteride, or stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or diluents; the pharmaceutical preparation is any clinically or pharmaceutically acceptable dosage form.

9. A pharmaceutical composition comprising a compound of any one of claims 1-7, a pharmaceutically acceptable salt, ester, deuteride, 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.

10. Use of a compound according to any one of claims 1-7, a pharmaceutically acceptable salt, ester, deuteride or a stereoisomer thereof, or a pharmaceutical formulation according to claim 8, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment and/or prophylaxis of USP1 mediated diseases and related diseases.