WO2022233263A1 - 三并环类泛素特异性蛋白酶1抑制剂及其用途 - Google Patents

三并环类泛素特异性蛋白酶1抑制剂及其用途 Download PDF

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WO2022233263A1
WO2022233263A1 PCT/CN2022/089956 CN2022089956W WO2022233263A1 WO 2022233263 A1 WO2022233263 A1 WO 2022233263A1 CN 2022089956 W CN2022089956 W CN 2022089956W WO 2022233263 A1 WO2022233263 A1 WO 2022233263A1
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alkyl
deuterated
compound
independently selected
alkoxy
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PCT/CN2022/089956
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English (en)
French (fr)
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刘斌
陈博
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山东轩竹医药科技有限公司
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Priority to EP22798604.9A priority Critical patent/EP4335852A1/en
Priority to CA3217763A priority patent/CA3217763A1/en
Priority to JP2023567219A priority patent/JP2024516447A/ja
Priority to KR1020237040720A priority patent/KR20240004634A/ko
Priority to CN202280032573.5A priority patent/CN117337290A/zh
Publication of WO2022233263A1 publication Critical patent/WO2022233263A1/zh
Priority to US18/499,843 priority patent/US20240101566A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to the technical field of medicine, in particular to tricyclic ubiquitin-like specific protease 1 inhibitor compounds, pharmaceutically acceptable salts thereof, esters, deuterated compounds or stereoisomers thereof, containing the compounds, their pharmacy Pharmaceutical compositions and preparations of acceptable salts, esters, deuterated compounds or stereoisomers thereof above, and methods of preparing said compounds, pharmaceutically acceptable salts thereof, esters, deuterated compounds or stereoisomers thereof , and the use of the compounds, their pharmaceutically acceptable salts, their esters, deuterated compounds or their stereoisomers in the preparation of a medicament for the treatment and/or prevention of diseases mediated by USP1 and related diseases.
  • DUB Deubiquitylating enzyme
  • Ubiquitination is a reversible process
  • DUB acts on the ubiquitin-protease system, cleaves the isopeptide bond between lysine and the C-terminus of UBQ, affects cell proliferation, cycle, apoptosis, DNA damage response, tumor suppression, occurrence and transfer.
  • USP1 (Ubiquitin specific protease 1, ubiquitin specific protease 1) is a member of the USP family and is a cysteine isopeptidase containing a triplet structure of Cys90, His593 and Asp751.
  • the human USP1 gene was cloned in 1998 and encodes a protein of 785 amino acids. In normal state, USP1 is relatively inactive, and is activated after binding to UAF1 (USP1-associated factor 1, USP1-associated factor 1, a cofactor containing WD40 repeats that binds to and regulates USP1 activity) into a heterodimeric complex.
  • Ubiquitinase acts to stabilize replication forks and localize in the nucleus.
  • 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/ovarian cancer BRCA1 deficiency. USP1 deubiquitination is involved in various processes related to cancer, and acts on Fanconian anemia (FA), Translesion DNA synthesis (TLS), cell differentiation and other pathways.
  • FA Fanconian anemia
  • TLS Translesion DNA synthesis
  • USP1 deubiquitinates FANCD2 (Fanconi anaemia group D2 protein, Fanconi anemia histone D2); in TLS, USP1 deubiquitinates PCNA (Proliferating cell nuclear antigen, proliferating cell nuclear antigen); In differentiation, USP1 affects the ubiquitination of ID (a family of inhibitors of DNA-binding proteins), regulating cell proliferation and differentiation.
  • FANCD2 Feconi anaemia group D2 protein, Fanconi anemia histone D2
  • PCNA Proliferating cell nuclear antigen
  • ID a family of inhibitors of DNA-binding proteins
  • DDR DNA damage response pathway
  • PCNA affected by USP1 participates in DNA break repair together with USP1/UAF1 and BRCA1/2.
  • RAD18-mediated PCNA monoubiquitination promotes the switch of PCNA binding from replicative polymerases (pol ⁇ / ⁇ ) to TLS polymerases (such as POLK), and after bypassing the foci by TLS polymerase, USP1 re-uses PCNA Deubiquitination promotes the conversion of PCNA binding back to a replicative polymerase. Inhibition of USP1 results in replication fork instability and is synthetically lethal with BRCA mutations.
  • USP1 inhibitors inhibit the DNA break repair that PCNA participates in together with USP1/UAF1 and BRCA1/2, and destabilize the replication fork. Therefore, the use of small molecule inhibitors to inhibit USP1 has potential for the treatment of cancer and other diseases, which has not been commercialized or has not yet been clinically developed.
  • the purpose of the present invention is to provide a tricyclic ubiquitin-specific protease 1 inhibitor and its application.
  • the specific technical solutions are as follows:
  • Scheme 1 The present invention first provides the compound represented by the general formula (I), its pharmaceutically acceptable salt, ester, deuterated product or its stereoisomer:
  • X 1 , X 2 , X 3 , X 4 are each independently selected from N or CR a ;
  • 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 optionally substituted by one or more Q 1 s Yuan Heteroaryl;
  • R 4 and R 5 are 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, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1 -6 alkyl, carboxy C 1-6 alkyl or halogenated C 1-6 alkoxy;
  • Each Q1 is independently selected from deuterium, halogen, cyano, carboxyl, hydroxyl, amino, nitro, sulfonamido, C1-6 alkylamino optionally substituted with 1-4 substituents Q2 , 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, C 1-6 alkyl carbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkyl aminoacyl, C 1-6 alkyl amido, C 1-6 alkyl sulfonyl, C 1 -6 alkylsulfonylamino, C 1-6 alkylaminosulfonyl, -(L) m -C 1-6 alkyl, -(L) m -C 2-6 alkenyl, -(L) m - C 2-6 alkyn
  • each L is independently selected from -CO-, -O-, -S-, -SO-, -S(O) 2 -, -NR c -, -CR a R b -;
  • Each R a , each R b is independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, 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 alkyl amido, C 1-6 alkylsulfonamido, 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 alkyl;
  • Each R c is independently selected from deuterium, hydrogen, optionally deuterated C 1-6 alkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 alkyl, carboxyl C 1-6 alkyl;
  • Each m is independently an integer from 0 to 3;
  • n is independently an integer from 0 to 6.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from N or CR a ;
  • 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 by one or more Q 1 s ;
  • R 4 and R 5 are independently selected from deuterium, hydrogen, cyano, halogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, bis( C 1-6 alkyl) amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl or halogenated C 1-6 alkoxy base;
  • Each Q 1 is independently selected from deuterium, halogen, cyano, C 1-6 alkoxy optionally substituted with 1-4 substituents Q 2 , 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 -C 1-6 alkyl, -(L) m -3-6 membered cycloalkyl or -(L) m -3-6 membered heterocyclyl, each Q 2 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, C 1-6 alkoxy, halogenated C
  • each L is independently selected from -CO-, -O-, -NR c -, -CR a R b -;
  • Each R a , each R b is independently selected from deuterium, hydrogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl) amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl ;
  • Each R c is independently selected from deuterium, hydrogen, optionally deuterated C 1-6 alkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy;
  • Each m is independently an integer from 0 to 2;
  • n is independently an integer from 0 to 5.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from N;
  • R 1 , R 2 , R 3 are each independently selected from phenyl or 5-6 membered heteroaryl optionally substituted by 1-4 Q 1 ;
  • R 4 and R 5 are each independently selected from deuterium, hydrogen, optionally deuterated C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, bis(C 1-4 alkane) group) amino, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, carboxy C 1-4 alkyl or halogenated C 1-4 alkoxy;
  • Each Q 1 is independently selected from deuterium, halogen, C 1-4 alkoxy, C 1-4 alkylamino, bis(C 1-4 alkyl optionally substituted by 1-3 substituents Q 2 ) 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, -(L) m -C 1-4 alkyl, -(L) m -3-6 membered cycloalkyl, each Q 2 is independently selected from deuterium, halogen, carboxyl, hydroxyl, 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, halogenated C 1-4 alkyl and halogenated C 1-4 alkoxy;
  • each L is independently selected from -CR a R b - or -O-;
  • Each R a , each R b is independently selected from deuterium, hydrogen, optionally deuterated C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl) amino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, carboxy C 1-4 alkyl ;
  • Each R c is independently selected from deuterium, hydrogen, optionally deuterated C 1-4 alkyl, halo C 1-4 alkyl, halo C 1-4 alkoxy;
  • Each m is independently an integer from 0 to 2;
  • n is independently an integer from 0 to 4.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from N;
  • R 1 , R 2 , R 3 are each independently selected from phenyl, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazole optionally substituted by 1-3 Q 1 s base, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, 2-pyridone, 4- Pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl;
  • R 4 , R 5 are each independently selected from deuterium, hydrogen, optionally deuterated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy group, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethyl, Hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, trifluoromethoxy;
  • Each Q 1 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, isopropoxy, methyl optionally substituted by 1-3 substituents Q 2 amino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl group, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, -(L) m -C 1-4 alkyl, -(L) m -3-6 membered cycloalkyl, each Q 2 respectively independently selected from deuterium, halogen, carboxyl, hydroxy, cyano, nitro, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, meth
  • each L is independently selected from -CR a R b -;
  • Each R a , each R b is independently selected from deuterium, hydrogen, optionally deuterated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl base, methoxy, ethoxy, propoxy, isopropoxy;
  • each m is independently selected from 0, 1, 2;
  • n is independently 0, 1, 2, 3, respectively.
  • R 1 , R 2 , R 3 are each independently selected from phenyl or 5-6 membered nitrogen-containing heteroaryl optionally substituted with 1-4 Q 1 .
  • R 1 , R 2 , R 3 are each independently selected from phenyl, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazole optionally substituted by 1-3 Q 1 base, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl.
  • R 1 , R 2 , R 3 are each independently selected from phenyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridine optionally substituted with 1-3 Q 1 s azolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl.
  • Scheme 7-1 The compound shown in any one of the preceding schemes, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein,
  • R 1 , R 2 , R 3 are each independently selected from phenyl, pyrimidinyl, pyridyl, pyrazolyl, imidazolyl, pyrrolyl, pyridazinyl, pyrazinyl optionally substituted with 1-3 Q 1 s .
  • R 1 , R 3 are each independently selected from optionally substituted by 1-3 Q 1 s
  • R 1 is selected from optionally substituted by 1-3 Q 1
  • R 1 is selected from optionally substituted by 1-3 Q 1
  • R 3 is selected from optionally substituted by 1-3 Q 1
  • R 3 is selected from optionally substituted by 1-3 Q 1
  • R 3 is selected from optionally substituted by 1-3 Q 1
  • R 2 is selected from phenyl or pyridyl optionally substituted with 1-3 Q 1 .
  • each L, each R a , each R b , each R c , R 1 , R 2 , R 3 , each Q 1 , each Q 2 , m, n is defined as any one of the aforementioned schemes item described.
  • Scheme 8-1 The compound according to any one of the preceding schemes, its pharmaceutically acceptable salt, its ester, deuterated compound or its stereoisomer, which has the structure shown in formula (II-1),
  • each L, each R a , each R b , each R c , R 1 , R 2 , R 3 , R 4 , R 5 , each Q 1 , each Q 2 , m, n Definitions are as described in any of the preceding schemes.
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 6 are each independently selected from N, C or CR a ;
  • Y 5 and Y 7 are independently selected from N, NR c , C, CR a R b or CR a ;
  • each s is independently selected from an integer from 0 to 2;
  • Each Q 1 , m, each L, each R a , each R b , each R c is defined as described in any one of the preceding schemes.
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 6 are each independently selected from N, C or CR a ;
  • Y 5 and Y 7 are independently selected from N, NR c , C, CR a R b or CR a ;
  • each s is independently selected from an integer from 0 to 3;
  • Each Q 1 , m, each L, each R a , each R b , each R c , R 4 , R 5 is as defined in any of the preceding schemes.
  • R 6 is selected from hydrogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy;
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 6 are each independently selected from N, C or CR a ;
  • Y 5 and Y 7 are independently selected from N, NR c , C, CR a R b or CR a ;
  • each s is independently selected from an integer from 0 to 3;
  • Each Q 1 , m, each L, each R a , each R b , each R c , R 4 , R 5 is as defined in any of the preceding schemes.
  • Scheme 9-3 The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester thereof, a deuterated compound or a stereoisomer thereof, wherein R 6 is selected from hydrogen, deuterated C 1-6 alkane or deuterated C 1-6 alkoxy.
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 6 are each independently selected from N, C or CH;
  • Y 5 and Y 7 are each independently selected from N, NH, C, CH 2 or CH.
  • each Q 1 and m is as described in any one of the preceding schemes.
  • Y 1 , Y 2 , Y 5 , Y 6 , Y 7 and each s are as described in any one of the preceding schemes.
  • Scheme 10-1 The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester, a deuterated compound or a stereoisomer thereof, which has the structure shown in formula (IV-1),
  • Each Q 1 , m, R 4 , R 5 , each R a , each R b , Y 1 , Y 2 , Y 5 , Y 6 , Y 7 , each s is defined as in any of the preceding schemes described.
  • Scheme 10-2 The compound described in any one of the preceding schemes, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, which has the structure shown in formula (IV-1'),
  • R 6 is selected from hydrogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy;
  • Each Q 1 , m, R 4 , R 5 , each R a , each R b , Y 1 , Y 2 , Y 5 , Y 6 , Y 7 , each s is defined as in any of the preceding schemes described.
  • Scheme 10-3 The compound shown in any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester thereof, a deuterated compound or a stereoisomer thereof, wherein R 6 is selected from hydrogen, deuterated C 1-6 alkane or deuterated C 1-6 alkoxy.
  • Scheme 10-4 The compound shown in any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester, a deuterated compound or a stereoisomer thereof, wherein R a and R b are each independently selected from hydrogen.
  • each Q 1 , Y 1 , Y 2 , and each s are as described in any one of the preceding schemes.
  • Each Q 1 , R 4 , R 5 , Ra , R b , Y 1 , Y 2 , each s is defined as described in any one of the preceding schemes.
  • Scheme 11-2 The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester, a deuterated compound or a stereoisomer thereof, which has a structure represented by formula (V-1'),
  • R 6 is selected from hydrogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy;
  • Each Q 1 , R 4 , R 5 , Ra , R b , Y 1 , Y 2 , each s is defined as described in any one of the preceding schemes.
  • Scheme 11-3 The compound shown in any one of the preceding schemes, its pharmaceutically acceptable salt, its ester, deuterated compound or its stereoisomer, wherein R 6 is selected from hydrogen, deuterated C 1-6 alkane or deuterated C 1-6 alkoxy.
  • Each Q 1 is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl optionally substituted by 1-4 substituents Q 2 (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 Q is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano , nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy.
  • Scheme 12-1 The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester thereof, a deuterated compound or a stereoisomer thereof, wherein,
  • Each Q 1 is independently selected from deuterium, halogen, C 1-6 alkyl optionally substituted with 1-3 substituents Q 2 , C 1-6 alkoxy, halogenated C 1-6 alkyl, Halogenated C 1-6 alkoxy, 3-6 membered cycloalkyl, each Q 2 is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1 -6 alkyl and halogenated C 1-6 alkoxy.
  • Each Q 1 is independently selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkyl optionally substituted by 1-3 substituents Q 2 (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, each Q 2 is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-4 alkyl, C 1-4 alkoxy , halogenated C 1-4 alkyl and halogenated C 1-4 alkoxy.
  • Each Q 1 is independently selected from deuterium, halogen, C 1-4 alkyl optionally substituted with 1-3 substituents Q 2 , C 1-4 alkoxy, halogenated C 1-4 alkyl, Halogenated C 1-4 alkoxy, 3-6 membered cycloalkyl, each Q 2 is independently selected from deuterium, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 Alkyl and halogenated C 1-4 alkoxy.
  • Each Q 1 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl optionally substituted by 1-3 substituents Q 2 base, sec-butyl, tert-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 Q is independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, methyl, ethyl
  • Scheme 14-1 The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester thereof, a deuterated compound or a stereoisomer thereof, wherein,
  • Each Q 1 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl optionally substituted by 1-3 substituents Q 2 , sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoro Methoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl , each Q is independently selected from deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy,
  • each L is independently selected from -CR a R b -;
  • Each R a , each R b is independently selected from deuterium, hydrogen, optionally deuterated C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, halo C 1-4 alkoxy.
  • Scheme 15-1 The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester thereof, a deuterated compound or a stereoisomer thereof, wherein,
  • each L is independently selected from -CR a R b -;
  • Each R a , each R b is independently selected from deuterium, hydrogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, halo C 1-6 alkoxy.
  • Each L is independently selected from -CH2- .
  • Y 8 is selected from N, NR c , C, CR a R b or CR a ;
  • Y 9 is selected from N, C or CR a ;
  • each s is defined as described in any one of the preceding schemes.
  • Scheme 17-1 The compound of the preceding Scheme 17, a pharmaceutically acceptable salt thereof, an ester, a deuterated compound or a stereoisomer thereof, wherein,
  • Y 8 is selected from N, NH, C, CH 2 or CH;
  • Y 9 is selected from N, C or CH;
  • each s is defined as described in any one of the preceding schemes.
  • each Q 1 , m, Y 1 , Y 2 , and each s are defined as described in any one of the preceding solutions.
  • each Q 1 , m, Y 1 , Y 2 , each s, R 4 , and R 5 are defined as described in any one of the preceding solutions.
  • Scheme 18-2 The compound of any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester, a deuterated compound or a stereoisomer thereof, which has a structure represented by formula (VII-1'),
  • R 6 is selected from hydrogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy;
  • Each Q 1 , m, Y 1 , Y 2 , each s, R 4 , R 5 is defined as described in any of the preceding schemes.
  • Scheme 18-3 The compound shown in any one of the preceding schemes, its pharmaceutically acceptable salt, its ester, deuterated compound or its stereoisomer, wherein R 6 is selected from hydrogen, deuterated C 1-6 alkane or deuterated C 1-6 alkoxy.
  • each Q 1 , m, and each s is as described in any one of the foregoing solutions.
  • each Q 1 , m, R 4 , R 5 , and each s are as described in any one of the foregoing solutions.
  • R 6 is selected from hydrogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy;
  • each Q 1 , m, R 4 , R 5 , and each s are as described in any one of the preceding schemes.
  • Scheme 19-2 The compound shown in any one of the preceding schemes, its pharmaceutically acceptable salt, its ester, deuterated compound or its stereoisomer, wherein R 6 is selected from hydrogen, deuterated C 1-6 alkane or deuterated C 1-6 alkoxy.
  • each Q 1 , Y 1 , Y 2 , Y 5 , Y 6 , Y 7 , and each s is as described in any one of the preceding schemes.
  • Scheme 20-1 The compound according to any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester, a deuterated compound or a stereoisomer thereof, which has a structure represented by formula (IX-1),
  • R 6 is selected from hydrogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy;
  • each Q 1 , Y 1 , Y 2 , Y 5 , Y 6 , Y 7 , and each s is as described in any one of the preceding schemes.
  • Scheme 20-2 The compound shown in any one of the preceding schemes, a pharmaceutically acceptable salt thereof, an ester thereof, a deuterated product or a stereoisomer thereof, wherein R 6 is selected from hydrogen, optionally deuterated C 1-6 alkyl or deuterated C 1-6 alkoxy.
  • R 4 , R 5 , each R a , each R b , each R c are each independently selected from hydrogen.
  • Y 3 , Y 4 , and Y 6 are independently selected from N, C or CR a ;
  • Y 5 and Y 7 are independently selected from N, NR c , C, CR a R b or CR a ;
  • each s is independently selected from an integer from 0 to 2;
  • Each Q 1 , each Q 2 , each L, m, R 1 , R 4 , R 5 , each R a , each R b , each R c is defined as described in any of the preceding schemes.
  • every Q 1 , every Q 2 , every s, every L, m, R 1 , R 4 , R 5 , Y 5 , Y 6 , Y 7 , every Ra , every R b , every Rc is as defined in any of the preceding schemes.
  • R 1 is selected from phenyl or 5-6 membered nitrogen-containing heteroaryl optionally substituted by 1-3 Q 1 , preferably, R 1 is selected from optionally substituted by 1-3 Q 1 s
  • R 4 and R 5 are each independently selected from deuterium, hydrogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy;
  • each L is independently selected from -CR a R b -;
  • Each R a , each R b is independently selected from deuterium, hydrogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, halo C 1-6 alkoxy;
  • Each Q 1 is independently selected from deuterium, halogen, C 1-6 alkyl optionally substituted with 1-3 substituents Q 2 , C 1-6 alkoxy, halogenated C 1-6 alkyl, Halogenated C 1-6 alkoxy, 3-6 membered cycloalkyl, each Q 2 is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1 -6 alkyl and halogenated C 1-6 alkoxy;
  • n is an integer of 1 or 2;
  • Each s is independently an integer of 0, 1, 2.
  • Every Q 1 , every Q 2 , every s, m, R 1 , R 4 , R 5 , Y 5 , Y 6 , Y 7 , every Ra , every R b , every R c As described in any of the preceding schemes.
  • R 1 is selected from phenyl or 5-6-membered nitrogen-containing heteroaryl optionally substituted by 1-3 Q 1 , preferably, R 1 is selected from optionally substituted by 1-3 Q 1 s
  • R 4 and R 5 are each independently selected from deuterium, hydrogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy;
  • Each Q 1 is independently selected from deuterium, halogen, C 1-6 alkyl optionally substituted with 1-3 substituents Q 2 , C 1-6 alkoxy, halogenated C 1-6 alkyl, Halogenated C 1-6 alkoxy, 3-6 membered cycloalkyl, each Q 2 is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1 -6 alkyl and halogenated C 1-6 alkoxy;
  • n is an integer of 1 or 2;
  • Each s is independently an integer of 0, 1, 2.
  • Each Q 1 , each Q 2 , s, m, R 1 , Y 5 , Y 6 , Y 7 , each Ra , each R b , each R c is defined as described in any of the preceding schemes .
  • R 1 is selected from phenyl optionally substituted by 1-3 Q 1 or 5-6-membered nitrogen-containing heteroaryl; preferably, R 1 is selected from optionally substituted by 1-3 Q 1
  • Each Q 1 is independently selected from deuterium, halogen, C 1-6 alkyl optionally substituted with 1-3 substituents Q 2 , C 1-6 alkoxy, halogenated C 1-6 alkyl, Halogenated C 1-6 alkoxy, 3-6 membered cycloalkyl, each Q 2 is independently selected from deuterium, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkyl and halogenated C 1-6 alkoxy;
  • n is an integer of 1 or 2;
  • Each s is independently an integer of 0, 1, 2.
  • Y 1 and Y 2 are independently selected from N, C or CH;
  • Y 5 and Y 7 are independently selected from NH, N, C, CH or CH 2 ;
  • Y 6 is selected from N, CH or C
  • R 4 and R 5 are independently selected from deuterium, hydrogen, cyano, halogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, bis( C 1-6 alkyl) amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl or halogenated C 1-6 alkoxy base;
  • R 6 is selected from hydrogen, deuterated C 1-6 alkoxy
  • Each Q 1 is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl optionally substituted by 1-4 substituents Q 2 (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;
  • R a and R b are independently selected from hydrogen
  • Each Q 2 is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy;
  • Each m and each s are independently 0, 1, and 2, respectively.
  • Each Q 1 is independently selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkyl optionally substituted by 1-3 substituents Q 2 (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;
  • Each Q 2 is independently selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl and halogenated C 1-4 alkoxy;
  • R 4 and R 5 are each independently selected from deuterium, hydrogen, cyano, halogen, optionally deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, or halogenated C 1-6 alkoxy;
  • R 6 is selected from hydrogen, deuterated C 1-4 alkoxy
  • n 1, 2;
  • Each s is independently 0, 1, 2.
  • R 6 is selected from hydrogen, deuterated methoxy, deuterated ethoxy, deuterated propoxy or deuterated isopropoxy, and the number of deuterated is 1, 2 or 3, preferably trideuteromethyl Oxygen.
  • compositions and bases such as metal salts, ammonium salts, salts with organic acids, salts with organic bases, and inorganic salts. Salts formed with acids, salts formed with acidic amino acids or basic amino acids, and the like.
  • Ester refers to a pharmaceutically acceptable ester, especially an ester which is hydrolyzed in vivo and includes the parent compound (the compound described in general formula (I)) which is easily decomposed in the human body to leave the parent compound (the compound of general formula (I)) or esters of its salts.
  • the "ester” of the present invention can be selected from, for example, the following groups: (1) Carboxylic acid esters 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 linear or branched alkyl, C 1-12 linear or branched alkyl, C 1-8 linear or branched alkyl, C 1-6 linear or branched alkyl (such as methyl, ethyl, n-propyl, tert-butyl or n-butyl), C 1-6 alkoxy C 1-6 alkyl (eg methoxymethyl), C 6-10 aryl C 1-6 alkyl (eg benzyl), C 6-10 aryloxy C 1-6 alkyl (eg phenoxymethyl), C 6-10 aryl (eg phenyl, optionally by eg halogen, C 1-4 alkane) (2) sulfonic acid esters, such as al
  • stereoisomer of the compound represented by the general formula (I) of the present invention means that when the compound represented by the formula (I) has an asymmetric carbon atom, an enantiomer will be produced; when the compound has a carbon-carbon double When there is a bond or ring structure, cis-trans isomers will be generated; when a compound has ketones or oximes, tautomers will be generated.
  • stereoisomers include but are not limited to: enantiomers Isomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof.
  • the present invention also provides a pharmaceutical composition, which contains the compound represented by the aforementioned general formula (I), a pharmaceutically acceptable salt, ester, deuterated compound or a stereoisomer thereof, and one or more of the first Two therapeutically active agents, optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and/or diluents.
  • a pharmaceutical composition which contains the compound represented by the aforementioned general formula (I), a pharmaceutically acceptable salt, ester, deuterated compound or a stereoisomer thereof, and one or more of the first Two therapeutically active agents, optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and/or diluents.
  • the present invention also provides a pharmaceutical preparation, which contains the compound represented by the aforementioned general formula (I), a pharmaceutically acceptable salt, ester, deuterated compound or a stereoisomer thereof, and one or more pharmaceutically acceptable compounds.
  • carrier and/or diluent; the pharmaceutical preparation is any clinically or pharmaceutically acceptable dosage form.
  • the pharmaceutical formulations described above may be administered orally, parenterally, rectally, or via pulmonary administration to a patient or subject in need of such treatment.
  • the pharmaceutical composition can be made into oral preparations, for example, can be made into conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparations, such as Oral solution, oral suspension, syrup, etc.
  • suitable fillers, binders, disintegrants, lubricants and the like can be added.
  • parenteral administration the above-mentioned pharmaceutical preparations can also be prepared into injections, including injection solutions, sterile powders for injection and concentrated solutions for injection.
  • the pharmaceutical composition When preparing the injection, it can be produced by the conventional methods in the existing pharmaceutical field. When preparing the injection, no additives can be added, or suitable additives can be added according to the properties of the drug.
  • the pharmaceutical composition For rectal administration, the pharmaceutical composition can be formulated into suppositories and the like. When used for pulmonary administration, the pharmaceutical composition can be formulated into an inhaler or a spray or the like.
  • the pharmaceutically acceptable carrier and/or diluent usable in the pharmaceutical composition or pharmaceutical formulation of the present invention may be any conventional carrier and/or diluent in the field of pharmaceutical formulations, and the choice of a particular carrier and/or diluent will depend on the Mode of administration or disease type and state to treat a particular patient.
  • the preparation of suitable pharmaceutical compositions for a particular mode of administration is well within the knowledge of those skilled in the pharmaceutical arts.
  • pharmaceutically acceptable carriers and/or diluents may include solvents, diluents, dispersing agents, suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, binders, lubricants, Stabilizers, hydration agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, mold release agents, coating agents, flavoring agents, and antioxidants, etc.
  • flavoring agents, preservatives, sweeteners, etc. can also be added to the pharmaceutical composition.
  • the present invention also provides the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, ester, deuterated compound or its stereoisomer, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in preparation for treatment and/or use in a medicament for preventing USP1-mediated diseases and related diseases; the USP1-mediated diseases and related diseases are selected from cancer or benign tumors.
  • the present invention also provides the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, ester, deuterated compound or its stereoisomer, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in the treatment/or prevention Use in USP1-mediated diseases and related diseases; the USP1-mediated diseases and related diseases are selected from cancer or benign tumors.
  • the present invention also provides a method for treating a disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of the compound represented by the aforementioned general formula (I), a pharmaceutically acceptable salt, ester, deuterated compound or The 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 diseases and related diseases are selected from cancer or benign tumor.
  • the disease is a USP1-mediated disease and related diseases
  • the USP1-mediated diseases and related diseases are selected from cancer or benign tumor.
  • the present invention provides the preparation method of the above-mentioned compound, but is not limited to the following method, and the reaction equation of the preparation method is as follows:
  • the above preparation method can be simply summarized as: reacting the compound represented by the formula (II-2)-1 with the compound represented by the formula (II-2)-2 to obtain the compound represented by the general formula (II-2);
  • each Q 1 , each Q 2 , each L, m, R 1 , R 4 , R 5 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , each Ra , each R b , each R c , and each s are as defined in any one of the above technical solutions.
  • the present invention also provides intermediates for preparing compounds represented by general formula (II-1) to general formula (IX-1), their pharmaceutically acceptable salts, their esters, deuterated compounds or their stereoisomers, It has the following structural formula:
  • R 1 , R 4 , R 5 , each Q 1 , each Q 2 , each L, each R a , each R b , each R c , and m are defined as any of the above technical solutions defined.
  • the present invention also provides intermediates for the preparation of compounds represented by general formula (III) to general formula (IX-1), their pharmaceutically acceptable salts, their esters, deuterated compounds or their stereoisomers, which have The following structural formula:
  • G is selected from halogen, hydroxyl, amino, C 1-6 alkylthio or C 1-6 alkylsulfonyl;
  • Each R c is as defined in any one of the preceding technical solutions.
  • G is selected from halogen, hydroxy, amino, methylthio, or methylsulfonyl.
  • halogen in the present invention refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
  • halogenated in the present invention means that any hydrogen in the substituent may be replaced by one or more same or different halogens. "Halogen” is as previously defined.
  • C 1-6 alkyl group in the present invention refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms, including, for example, “C 1-5 alkyl group” and “C 1-4 alkyl group” , “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, neopentyl, 1-ethyl
  • the “C 1-6 alkylene group” in the present invention refers to the above-mentioned C 1-6 alkyl group formed by removing one hydrogen atom, including, for example, “C 1-5 alkylene group”, “C 1-4 alkyl group”"Alkylene”,”C 1-3 alkylene", “C 1-2 alkylene”, “C 2-6 alkylene”, “C 2-5 alkylene”, “C 2-4 alkylene”"Alkylene”,”C 2-3 alkylene", “C 3-6 alkylene", “C 3-5 alkylene”, “C 3-4 alkylene”, “C 4-6 alkylene”"Alkylene”,”C 4-5 alkylene", “C 5-6 alkylene”, etc., specific examples include but are not limited to: methylene, ethylene, propylene, butylene, pentylene base, hexyl, etc.
  • the “C 1-4 alkylene group” in the present invention refers to a specific example of the C 1-6 alkylene group containing 1-4 carbon
  • C 2-6 alkenyl in the present invention refers to a straight-chain, branched or cyclic alkenyl with 2-6 carbon atoms containing at least one double bond, including, for example, "C 2-5 alkenyl"","C 2-4 alkenyl", “C 2-3 alkenyl", etc., specific examples include but are not limited to: vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butanyl Alkenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butene base, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexyl Alkenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 1-methyl-2-pentenyl, 3-methyl-1
  • C 2-6 alkynyl in the present invention refers to a straight-chain or branched alkynyl group containing a triple bond and having 2-8 carbon atoms, including, for example, "C 2-5 alkynyl", “C 2-5 alkynyl” 2-4 alkynyl", “C 2-3 alkynyl”, etc., specific examples include but are not limited to: ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1- Ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3- Pentynyl, 1,1-dimethyl-3-but
  • C 1-6 alkoxy refers to one to more (for example, 1-4, 1-3, 1-2) halogen atoms, hydroxyl, amino, and carboxyl groups substituted for C 1-6 alkyl, C 1- A group formed by hydrogen atoms in 6 alkylene groups and C 1-6 alkoxy groups.
  • C 1-4 alkoxy refers to one to more (for example, 1-4, 1-3, 1-2) halogen atoms, hydroxyl, and amino groups substituted for C 1-4 alkyl, C 1-4 alkylene, respectively A group formed by a hydrogen atom in an alkyl group and a C 1-4 alkoxy group.
  • the "3-12-membered cycloalkyl” in the present invention refers to a saturated or partially saturated cyclic alkyl group containing 3-12 carbon atoms without aromaticity, including “monocycloalkyl” and “fused Cycloalkyl”.
  • the "monocyclic alkyl group” in the present invention refers to a saturated or partially saturated monocyclic cyclic alkyl group without aromaticity, including "3-8 membered saturated cycloalkyl group” and “3-8 membered partially saturated cycloalkyl group” Cycloalkyl”; preferably “3-4 membered cycloalkyl", “3-5 membered cycloalkyl", “3-6 membered cycloalkyl”, “3-7 membered cycloalkyl”, “4-5 membered cycloalkyl” membered cycloalkyl", "4-6 membered cycloalkyl”, “4-7 membered cycloalkyl”, “4-8 membered cycloalkyl”, "5-6 membered cycloalkyl", “5-7 membered cycloalkyl” membered cycloalkyl”, “5-8 membered cycloalkyl", “6-7 membered cycloalkyl”, “6-8 membere
  • the "3-8 membered saturated cycloalkyl” include but are not limited to: cyclopropanyl (cyclopropyl), cyclobutanyl (cyclobutyl), cyclopentyl (cyclopentyl), Cyclohexyl (cyclohexyl), cycloheptyl (cycloheptyl), cyclooctyl (cyclooctyl), etc.; specific examples of the "3-8 membered partially saturated cycloalkyl” include but not Limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1,3-diene, cyclohex-1,4-diene, cycloheptenyl , cyclohept-1,3-dienyl, cyclohept-1,4-dienyl, cyclohept-1,3,5-trienyl
  • fused cycloalkyl in the present invention refers to a saturated or partially saturated, non-aromatic cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms.
  • a ring in the fused ring can be an aromatic ring, but the fused ring as a whole does not have aromaticity; its fused mode can be: 5-6-membered cycloalkyl and 5-6-membered cycloalkyl, benzo 5- 6-membered cycloalkyl, benzo 5-6 membered saturated cycloalkyl, etc.
  • Examples include, but are not limited to: bicyclo[3.1.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl , bicyclo[4.2.0]octyl, octahydrocyclopentadienyl, octahydro-1H-indenyl, decalinyl, tetrahydrophenanthryl, bicyclo[3.1.0]hex-2- Alkenyl, Bicyclo[4.1.0]hept-3-enyl, Bicyclo[3.2.0]hept-3-enyl, Bicyclo[4.2.0]oct-3-enyl, 1,2,3,3a- Tetrahydrocyclopentadienyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,
  • the "3-12-membered heterocyclic group” in the present invention refers to at least one heteroatom (for example, containing 1, 2, 3, 4 or 5) and the number of ring atoms is 3-12 A saturated or partially saturated and non-aromatic monocyclic or fused ring cyclic group, the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom in the cyclic structure ( For example carbon atoms, nitrogen atoms or sulfur atoms) can be oxo.
  • the "3-12-membered heterocyclic group” in the present invention includes "3-12-membered saturated heterocyclic group” and "3-12-membered partially saturated heterocyclic group”.
  • the "3-12-membered heterocyclyl" of the present invention contains 1-3 heteroatoms; preferably, the "3-12-membered heterocyclyl” of the present invention contains 1-2 heteroatoms, And the heteroatom is selected from nitrogen atom and/or oxygen atom; preferably, the "3-12 membered heterocyclic group" of the present invention 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 heterocyclic group”, “3-6 membered nitrogen-containing heterocyclic group”, “3-6 membered saturated nitrogen-containing heterocyclic group”, “5-6 membered heterocyclic group”, “5-6 membered heterocyclic group” -6-membered saturated heterocyclic group”, “5-6 membered nitrogen-containing heterocyclic group”, etc.
  • 3-12 membered heterocyclyl include, but are not limited to: aziridine, 2H-aziridinyl, diaziridinyl, 3H-diazacyclopropenyl, aziridine Butyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxanedi Alkenyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2 ,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, 4,5-dihydrooxazoly
  • the "6-10-membered aryl group” in the present invention refers to an aromatic cyclic group containing 6-10 ring carbon atoms, including "6-8-membered monocyclic aryl” and "8-10-membered aryl group” fused ring aryl".
  • the "6-8-membered monocyclic aryl group" in the present invention refers to a monocyclic aryl group containing 6-8 ring carbon atoms, examples of which include but are not limited to: phenyl, cyclooctatetraenyl, etc.; preferably benzene base.
  • the "8-10-membered fused-ring aryl group” mentioned in the present invention refers to a group formed by two or more cyclic structures sharing two adjacent atoms with each other, containing 8-10 ring carbon atoms, not
  • the saturated and aromatic cyclic group is preferably a "9-10-membered fused-ring aryl group", and specific examples are naphthyl and the like.
  • the "5-12-membered heteroaryl group” in the present invention refers to an aromatic ring containing 5-12 ring atoms (at least one of which is a heteroatom, such as nitrogen atom, oxygen atom or sulfur atom).
  • the group for example, can be a 5-12-membered nitrogen-containing heteroaryl group, a 5-12-membered oxygen-containing heteroaryl group, a 5-12-membered sulfur-containing heteroaryl group, and the like. Including "5-8 membered monoheteroaryl" and "8-10 membered fused heteroaryl".
  • the "5-8-membered heteroaryl group” in the present invention refers to an aromatic mono-heteroaryl group containing 5-8 ring atoms (at least one of which is a heteroatom, such as nitrogen atom, oxygen atom or sulfur atom). Cyclic ring group. Optionally, ring atoms (eg, carbon, nitrogen, or sulfur atoms) in the ring structure may be oxo.
  • "5-8 membered monoheteroaryl” includes, for example, "5-7 membered monoheteroaryl", “5-6 membered monoheteroaryl”, “5-6 membered nitrogen-containing monoheteroaryl", “5-membered monoheteroaryl” Nitrogen-containing monoheteroaryl” etc.
  • 5-8 membered monocyclic heteroaryl include, but are not limited to, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadi azolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole base, 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, Azacyclotrienyl, 1,3-Diazepinyl Alkenyl,
  • the "8-10-membered fused heteroaryl group” in the present invention refers to a group formed by two or more cyclic structures sharing two adjacent atoms with each other, containing 8-10 ring atoms (at least one of which is Ring atoms are heteroatoms, such as nitrogen atoms, oxygen atoms or sulfur atoms), unsaturated aromatic ring structures.
  • Ring atoms are heteroatoms, such as nitrogen atoms, oxygen atoms or sulfur atoms
  • unsaturated aromatic ring structures such as nitrogen atoms, oxygen atoms or sulfur atoms
  • ring atoms eg, carbon, nitrogen, or sulfur atoms
  • ring atoms eg, carbon, nitrogen, or sulfur atoms
  • Including "9-10-membered condensed heteroaryl", “8-9-membered condensed heteroaryl”, etc., and the condensing method can be benzo-5-6-membered heteroaryl, 5-6-membered heteroaryl and 5- 6-membered heteroaryl, etc.; specific examples include, but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furanothiophene, pyrazolooxazole, benzofuranyl, benziso furanyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinone, 4 -quinolinone, 1-isoquinolinone, isoquinolinyl, acridine, phenanthridine, benzopyri
  • the present invention Selected from single or double bonds.
  • Any atom of a compound in this application may represent any stable isotope of that atom.
  • H ie, hydrogen (H-1)
  • H-1 hydrogen
  • D i.e. deuterium (H-2)
  • H-2 deuterium
  • Deuterium isotope when one or more positions in the structure of the compound of the present application is defined as D, namely deuterium (H-2), the content of the compound shown in the structure can 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 the compounds of the present application refers to the ratio of the isotope content of label synthesis to the amount of naturally occurring isotopes.
  • the deuteration rate of each designated deuterium atom of the compounds of the present application may be at least 3500 times (52.5%), at least 4000 times (60%), at least 4500 times (67.5%), at least 5000 times (75%), at least 5000 times (75%), At least 5500 times (82.5%), at least 6000 times (90%), at least 6333.3 times (95%), at least 6466.7 times (97%), at least 6566.7 times (98.5%), at least 6600 times ( 99%), at least 6633.3 times (99.5%).
  • Isotopologues in this application refer to compounds that differ in chemical structure only in their isotopic composition.
  • the deuterium-containing compounds of the present application at a particular position will also contain very little hydrogen isotopologues at that position, and the amount of hydrogen isotopologues at the deuterated positions in the deuterated compounds of the present application depends on many factors, including the deuterated reagent ( Deuterium isotopic purity of D2O , D2, NaBD4 , L1AID4 , etc. ) and the effectiveness of incorporating deuterium isotope synthesis methods.
  • the total amount of hydrogen isotopologues at such deuterated positions will be less than 49.9%.
  • the total amount of hydrogen isotopes at the deuterated positions in the deuterated compounds of the present application will be less than 47.5%, 40%, 32.5%, 25%, 17.5%, 10%, 5%, 3%, 1% or 0.5%.
  • any atom not designated as deuterium is present in its natural isotopic abundance.
  • the "deuterated” in the present invention means that one or more hydrogen atoms on the deuterated group are replaced by one or more deuterium atoms, which may be partial deuteration or full deuteration.
  • a deuterated compound may contain only one deuterium.
  • the deuterated compound contains only two deuteriums.
  • the deuterated compound contains only three deuteriums.
  • the deuterated compound contains four deuteriums.
  • the “optionally deuterated” in the present invention includes both cases in which the group is deuterated and not deuterated, wherein the “deuterated” is as defined above.
  • the "therapeutically effective amount” in the present invention refers to the amount of the aforementioned compounds, pharmaceutical preparations, and pharmaceutical compositions that can at least alleviate the symptoms of the patient's condition when administered to a patient.
  • the actual amount encompassing a "therapeutically effective amount” will vary depending on a variety of circumstances, including but not limited to the particular condition being treated, the severity of the condition, the patient's physical and medical condition, and the route of administration. A skilled medical practitioner can readily determine appropriate amounts using methods known in the medical art.
  • the compounds of the present invention have excellent USP1 inhibitory activity, and can treat and/or prevent USP1-mediated diseases and related diseases;
  • the compound of the present invention has a good inhibitory effect on tumor cells
  • the compound of the present invention has a simple preparation process, high drug purity, stable quality, and is easy to carry out large-scale industrial production.
  • Test sample the compound synthesized in the embodiment of the present invention, its structural formula is shown in Table 1.
  • test compounds are 10000nM, 2500nM, 625nM, 156nM, 39nM, 9.8nM, 2.4nM, 0.61nM, 0.15nM, 0.038nM.
  • Max represents: the luminescence signal intensity of the positive control well without compound
  • Min the luminescence signal intensity of the negative control well without enzyme
  • Y represents: %inhibition
  • X represents: the concentration of the compound.
  • step 4 changed the incubation time at room temperature to 60min, and other conditions were the same as in the experimental method 1, and the following test results were obtained:
  • Test sample some compounds of the present invention, see the preparation examples for their chemical names and structures.
  • MDA-MB-436 Human breast cancer cells.
  • FBS Fetal Bovine Serum
  • ITS-G Insulin-Transferrin-Selenium Supplement
  • glutathione glutathione
  • All cells were adherent cells, the medium was DMEM+10%FBS+1%ITS-G+16 ⁇ g/ml glutathione, and the cells were tested in logarithmic growth phase.
  • Cells in logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was detected by trypan blue exclusion method to ensure cell viability was above 90%. Adjust to the appropriate concentration and add 90 ⁇ L of cell suspension to 96-well plates.
  • Test compound stock solutions of 10 mM were serially serially diluted 3-fold in DMSO for a total of 8 concentrations. Then, 2 ⁇ L of the compound diluted in DMSO gradient was added to 198 ⁇ L of the culture medium, which was the working stock solution of the test compound (the compound concentration was 10 times the final concentration, and the highest concentration was 100 ⁇ M).
  • test compounds were: 10000.00nM, 3333.33nM, 1111.11nM, 370.37nM, 123.46nM, 41.15nM, 13.72nM, 4.57nM.
  • Blank control only add medium without inoculating cells.
  • Test substance some compounds of the present invention, their chemical names and structures are shown in the preparation examples.
  • MDA-MB-436 human breast cancer cells
  • Caov-3 human ovarian cancer cells
  • MDA-MB-436 cell culture medium was DMEM+10%FBS+1%ITS-G+16 ⁇ g/ml glutathione
  • Caov-3 cell culture medium was DMEM+10%FBS
  • cells were cultured in Experiments were carried out during the growth period.
  • Cells in logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was detected by trypan blue exclusion method to ensure cell viability was above 90%. Adjust to the appropriate concentration and add 90 ⁇ L of cell suspension to 96-well plates.
  • Test compound stock solutions of 10 mM were serially serially diluted 3-fold in DMSO for a total of 8 concentrations. Then, 2 ⁇ L of the compound diluted in DMSO gradient was added to 198 ⁇ L of the culture medium, which was the working stock solution of the test compound (the compound concentration was 10 times the final concentration, and the highest concentration was 100 ⁇ M).
  • test compounds were: 10000.00nM, 3333.33nM, 1111.11nM, 370.37nM, 123.46nM, 41.15nM, 13.72nM, 4.57nM.
  • Blank control 96-well plate detection reading at 0h of dosing
  • the IC 50 values of the compounds 11, 16, 18, 19, 1-1, 11-1, 16-1, and 17-1 of the examples of the present invention on Caov-3 cell inhibitory activity are 1 nM to 600 nM, indicating that the compounds of the present invention can
  • the proliferation of MDA-MB-436 and Caov-3 cells was effectively inhibited, indicating that the compounds of the present invention have clinical application potential for treating HRD-positive (homologous recombination deficiency) cancerous diseases.
  • Compound stock solutions were prepared at a concentration of 5 mM.
  • Test compound stock solutions of 5 mM were serially serially diluted 3-fold in DMSO for a total of 9 concentrations.
  • test compounds were: 10000.00nM, 3333.33nM, 1111.11nM, 370.37nM, 123.46nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM.
  • Test sample Compounds of the examples of the present invention, for the preparation thereof, refer to the examples in the specification of this application.
  • Intravenous bolus administration Take 2.54 mg of compound 11, add 0.495 ml of DMSO solution, vortex, ultrasonically dissolve, 0.495 ml of PEG400, vortex and mix, then add 1.484 ml of 28% HP- ⁇ -CD , vortex and mix to obtain a clear solution with a concentration of 1 mg/ml.
  • test product was administered by intravenous bolus injection (iv), the dosage was 5mg/kg, and the administration volume was 5ml/kg;
  • Oral administration (po) was administered at a dose of 10 mg/kg and an administration volume of 10 ml/kg.
  • tail vein blood was collected. About 100 ⁇ l of whole blood was collected at each time point, and centrifuged in a high-speed centrifuge at 8000 rpm for 6 min to separate plasma. Plasma was frozen at -80°C.
  • mice The experimental data show that intravenous injection or oral administration of the compound of the present invention has higher exposure in vivo, suitable half-life and clearance rate, and exhibits good pharmacokinetic properties.
  • the exposure in mice is greater than 6000h*ng/ml, which shows that the compounds of the examples of the present invention have good clinical application prospects.
  • Xphos-Pd-G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1, 1'-biphenyl)]palladium(II);
  • Xphos 2-dicyclohexylphosphonium-2',4',6'-triisopropylbiphenyl;
  • Pd(dppf)Cl 2 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
  • 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 mixture was reacted 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. Concentrated to obtain crude product, which was directly used in the next reaction.
  • Methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate (5.0 g, 17.6 mmol) was dissolved in THF (60 mL), dropwise at 0°C DIBAl-H (1.5 mol/L, 46.9 mL, 70.4 mmol) was added, the addition was completed, and the reaction was carried out at 20° C. for 2 hours.
  • 1,3-Cycloheptanedione (9 g, 71.4 mmol) was dissolved in DMF (200 mL), potassium carbonate (30 g, 214.2 mmol) was added, and the reaction was carried out at 20° C. for 0.5 h. Carbon disulfide (8.1 g, 106.4 mmol) was added, and the mixture was reacted at 20° C. for 1 h. Iodomethane (30.4 g, 214.2 mmol) was added, and the mixture was reacted at 20° C. for 1 h. Concentrated to obtain crude product, which was directly used in the next reaction.
  • 1,3-cyclohexanedione (12.5 g, 0.11 mol) was dissolved in DMF (100 mL), potassium carbonate (45.6 g, 0.33 mol) was added, and the reaction was carried out at 20° C. for 0.5 h.
  • Carbon disulfide (12.9 g, 0.17 mol) was added, and the mixture was reacted at 20° C. for 1 h.
  • Iodomethane 46.8 g, 0.33 mol
  • Example 13 4-(4-Cyclopropyl-6-(methoxy- d3 )pyrimidin-5-yl)-2-(4-(1-isopropyl-4-(trifluoromethyl)- Preparation of 1H-imidazol-2-yl)benzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5-tetraazabenzo[cd]chamomile (compound 17- 1)

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Abstract

本发明涉及医药技术领域，具体涉及三并环类泛素特异性蛋白酶1抑制剂化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，含有所述化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体的药物组合物及制剂，制备所述化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体的方法，以及所述化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体在制备治疗和/或预防由USP1介导的疾病及相关疾病的药物中的用途。

Description

三并环类泛素特异性蛋白酶1抑制剂及其用途 技术领域
本发明涉及医药技术领域，具体涉及三并环类泛素特异性蛋白酶1抑制剂化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，含有所述化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体的药物组合物及制剂，制备所述化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体的方法，以及所述化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体在制备治疗和/或预防由USP1介导的疾病及相关疾病的药物中的用途。
背景技术
在肿瘤的发生发展中有很多相关的靶点，去泛素化酶DUB(Deubiquitylating enzyme)，编码100多个人基因编码，分为6个家族，其中泛素-特异性蛋白酶(USP)包含50多个成员，为DUB最大的家族。泛素化是一个可逆的过程，DUB作用于泛素-蛋白酶体系，裂解赖氨酸和UBQ的C端之间的异肽键，影响细胞增殖、周期、凋亡，DNA损伤反应，肿瘤抑制、发生和转移。
USP1(Ubiquitin specific protease 1，泛素特异性蛋白酶1)是USP家族的成员，为包含Cys90、His593和Asp751三联体结构的半胱氨酸异肽酶。人USP1基因克隆于1998年，编码一个785个氨基酸的蛋白质。正常状态USP1是相对无活性的，与UAF1(USPl-associated factor 1，USP1相关因子1，一个含有WD40重复序列结合并调节USP1活性的辅助因子)结合成异二聚复合物后被活化，发挥去泛素化酶作用，稳定复制叉，定位于细胞核中。
USP1在乳腺癌、卵巢癌等癌症中高表达，其他癌症中也存在表达升高，USP1过表达与乳腺癌/卵巢癌BRCA1缺乏相关。USP1去泛素化参与癌症相关的各个过程，作用于范可尼贫血(Fanconi anemia，FA)、跨损伤合成(Translesion DNA synthesis，TLS)、细胞分化等途径。其中FA中，USP1将FANCD2(Fanconi anaemia group D2 protein，范可尼贫血组蛋白D2)去泛素化；TLS中，USP1将PCNA(Proliferating cell nuclear antigen，增殖细胞核抗原)去泛素化；在细胞分化中，USP1影响ID(DNA结合蛋白抑制剂家族)的泛素化，调控细胞增殖和分化。
这些DNA损伤响应(DNA damage response，DDR)途径对于由DNA交联剂(如顺铂和紫外线辐射等)诱导的DNA损伤的修复至关重要。TLS途径中，USP1影响的PCNA与USP1/UAF1、BRCA1/2共同参与DNA断裂修复。复制叉停滞后，RAD18介导的PCNA单泛素化促进PCNA结合从复制型聚合酶(polδ/ε)转换为TLS聚合酶(如POLK)，通过TLS聚合酶绕过病灶后，USP1再使PCNA去泛素化，促进PCNA结合转换回复制性聚合酶。抑制USP1会导致复制叉不稳定，并与BRCA突变具有合成致死性。
USP1抑制剂抑制PCNA与USP1/UAF1、BRCA1/2共同参与的DNA断裂修复，使复制叉不稳定。因此来看，使用小分子抑制剂来抑制USP1具有潜力用于治疗癌症和其它疾病，尚无商业化或尚未临床开发。
发明内容
本发明的目的在于提供一种三并环类泛素特异性蛋白酶1抑制剂及其应用。具体技术方案如下：
方案1：本发明首先提供了通式(I)所示的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体：
Figure PCTCN2022089956-appb-000001
其中，
X 1、X 2、X 3、X 4分别独立地选自N或CR a；
R 1、R 2、R 3分别独立地选自任选被一个或多个Q 1取代的3-12元环烷基、3-12元杂环基、6-10元芳基或5-12元杂芳基；
R 4、R 5分别独立地选自氘，氢，羧基，氰基，硝基，氨基，卤素，C 2-6烯基，C 2-6炔基，任选被氘代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基或卤代C 1-6烷氧基；
每一Q 1分别独立地选自氘，卤素，氰基，羧基，羟基，氨基，硝基，磺酰氨基，任选被1-4个取代基Q 2取代的C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、C 1-6烷基羰基、C 1-6烷氧基羰基、C 1-6烷基氨酰基、C 1-6烷基酰氨基、C 1-6烷基磺酰基、C 1-6烷基磺酰氨基、C 1-6烷基氨基磺酰基、-(L) m-C 1-6烷基、-(L) m-C 2-6烯基、-(L) m-C 2-6炔基、-(L) m-C 1-6烷氧基、-(L) m-6-10元芳基、-(L) m-5-12元杂芳基、-(L) m-3-8元环烷基或-(L) m-3-8元杂环基，每一Q 2分别独立地选自氘、卤素、羧基、羟基、氰基、硝基、氨基、C 1-6烷基、羟基C 1-6烷基、羧基C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、-CO-C 1-6亚烷基-NH 2、-CO-C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基和卤代C 1-6烷氧基；
每一L分别独立地选自-CO-、-O-、-S-、-SO-、-S(O) 2-、-NR c-、-CR aR b-；
每一R a、每一R b分别独立地选自氘，氢，卤素，氨基，羟基，羧基，氰基，C 1-6烷基，C 2-6烯基，C 2-6炔基，任选被氘代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、C 1-6烷基氨酰基、C 1-6烷基酰氨基、C 1-6烷基磺酰氨基、C 1-6烷基氨基磺酰基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基；
每一R c分别独立地选自氘，氢，任选被氘代的C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基；
每一m分别独立地为0-3的整数；
每一n分别独立地为0-6的整数。
方案2：前述方案1所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体， 其中，
X 1、X 2、X 3、X 4分别独立地选自N或CR a；
R 1、R 2、R 3分别独立地选自任选被一个或多个Q 1取代的5-8元环烷基、3-8元杂环基、苯基或5-6元杂芳基；
R 4、R 5分别独立地选自氘，氢，氰基，卤素，任选被氘代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基或卤代C 1-6烷氧基；
每一Q 1分别独立地选自氘，卤素，氰基，任选被1-4个取代基Q 2取代的C 1-6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、-(L) m-C 1-6烷基、-(L) m-3-6元环烷基或-(L) m-3-6元杂环基，每一Q 2分别独立地选自氘、卤素、羧基、羟基、氰基、硝基、氨基、C 1-6烷基、羟基C 1-6烷基、羧基C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、C 1-6烷氧基、卤代C 1-6烷基和卤代C 1-6烷氧基；
每一L分别独立地选自-CO-、-O-、-NR c-、-CR aR b-；
每一R a、每一R b分别独立地选自氘，氢，任选被氘代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基；
每一R c分别独立地选自氘，氢，任选被氘代的C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基；
每一m分别独立地为0-2的整数；
每一n分别独立地为0-5的整数。
方案3：前述方案1或2所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
X 1、X 2、X 3、X 4分别独立地选自N；
R 1、R 2、R 3分别独立地选自任选被1-4个Q 1取代的苯基或5-6元杂芳基；
R 4、R 5分别独立地选自氘，氢，任选被氘代的C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二(C 1-4烷基)氨基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基、羧基C 1-4烷基或卤代C 1-4烷氧基；
每一Q 1分别独立地选自氘，卤素，任选被1-3个取代基Q 2取代的C 1-4烷氧基、C 1-4烷基氨基、二(C 1-4烷基)氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、氨基C 1-4烷基、羧基C 1-4烷基、-(L) m-C 1-4烷基、-(L) m-3-6元环烷基，每一Q 2分别独立地选自氘、卤素、羧基、羟基、氰基、硝基、氨基、C 1-4烷基、羟基C 1-4烷基、羧基C 1-4烷基、C 1-4烷基氨基、二(C 1-4烷基)氨基、C 1-4烷氧基、卤代C 1-4烷基和卤代C 1-4烷氧基；
每一L分别独立地选自-CR aR b-或-O-；
每一R a、每一R b分别独立地选自氘，氢，任选被氘代的C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二(C 1-4烷基)氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、氨基C 1-4烷基、羧基C 1-4烷基；
每一R c分别独立地选自氘，氢，任选被氘代的C 1-4烷基、卤代C 1-4烷基、卤代C 1-4烷氧基；
每一m分别独立地为0-2的整数；
每一n分别独立地为0-4的整数。
方案4：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体 异构体，其中，
X 1、X 2、X 3、X 4分别独立地选自N；
R 1、R 2、R 3分别独立地选自任选被1-3个Q 1取代的苯基、呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、恶唑基、异恶唑基、恶二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基；
R 4、R 5分别独立地选自氘，氢，任选被氘代的甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、甲基氨基、二甲氨基、一氟甲基、二氟甲基、一氟甲氧基、二氟甲氧基、三氟甲基、羟基甲基、羟基乙基、羟基丙基、羟基丁基、氨基甲基、羧基甲基、羧基乙基、三氟甲氧基；
每一Q 1分别独立地选自氘，氟，氯，溴，碘，任选被1-3个取代基Q 2取代的甲氧基、乙氧基、丙氧基、异丙氧基、甲基氨基、二甲氨基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基、三氟甲氧基、羟基甲基、羟基乙基、羟基丙基、羟基丁基、氨基甲基、羧基甲基、羧基乙基、-(L) m-C 1-4烷基、-(L) m-3-6元环烷基，每一Q 2分别独立地选自氘，卤素，羧基，羟基，氰基，硝基，氨基，甲基，乙基，丙基，异丙基，丁基，异丁基，仲丁基，叔丁基，甲氧基，乙氧基，丙氧基，异丙氧基，羟基甲基，羟基乙基，羟基丙基，羟基丁基，羧基甲基，羧基乙基，甲基氨基，二甲氨基，一氟甲基，二氟甲基，三氟甲基，一氟甲氧基，二氟甲氧基，三氟甲氧基；
每一L分别独立地选自-CR aR b-；
每一R a、每一R b分别独立地选自氘，氢，任选被氘代的甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基；
每一m分别独立地选自0、1、2；
每一n分别独立地为0、1、2、3。
方案5：前述方案任一项所述化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
R 1、R 2、R 3分别独立地选自任选被1-4个Q 1取代的苯基或5-6元含氮杂芳基。
方案6：前述方案任一项所示的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
R 1、R 2、R 3分别独立地选自任选被1-3个Q 1取代的苯基、呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、恶唑基、异恶唑基、咪唑基、吡唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基。
方案7：前述方案任一项所示的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
R 1、R 2、R 3分别独立地选自任选被1-3个Q 1取代的苯基、吡咯基、噻唑基、异噻唑基、恶唑基、异恶唑基、咪唑基、吡唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基。
方案7-1：前述方案任一项所示的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
R 1、R 2、R 3分别独立地选自任选被1-3个Q 1取代的苯基、嘧啶基、吡啶基、吡唑基、咪唑基、吡咯基、哒嗪基、吡嗪基。
方案7-2：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体 异构体，其中，
R 1、R 3分别独立地选自任选被1-3个Q 1取代的
Figure PCTCN2022089956-appb-000002
Figure PCTCN2022089956-appb-000003
方案7-3：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
R 1选自任选被1-3个Q 1取代的
Figure PCTCN2022089956-appb-000004
Figure PCTCN2022089956-appb-000005
优选地，R 1选自任选被1-3个Q 1取代的
Figure PCTCN2022089956-appb-000006
Figure PCTCN2022089956-appb-000007
方案7-4：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
R 3选自任选被1-3个Q 1取代的
Figure PCTCN2022089956-appb-000008
Figure PCTCN2022089956-appb-000009
Figure PCTCN2022089956-appb-000010
优选地，R 3选自任选被1-3个Q 1取代的
Figure PCTCN2022089956-appb-000011
Figure PCTCN2022089956-appb-000012
优选地，R 3选自任选被1-3个Q 1取代的
Figure PCTCN2022089956-appb-000013
方案7-5：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
R 2选自任选被1-3个Q 1取代的苯基或吡啶基。
方案8：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(II)所示的结构，
Figure PCTCN2022089956-appb-000014
其中，每一L、每一R a、每一R b、每一R c、R 1、R 2、R 3、每一Q 1、每一Q 2、m、n的定义如前述方案任一项所述。
方案8-1：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(II-1)所示的结构，
Figure PCTCN2022089956-appb-000015
其中，每一L、每一R a、每一R b、每一R c、R 1、R 2、R 3、R 4、R 5、每一Q 1、每一Q 2、m、n的定义如前述方案任一项所述。
方案9：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有通式(III)所示的结构：
Figure PCTCN2022089956-appb-000016
其中，
Y 1、Y 2、Y 3、Y 4、Y 6分别独立地选自N、C或CR a；
Y 5、Y 7分别独立地选自N、NR c、C、CR aR b或CR a；
Figure PCTCN2022089956-appb-000017
分别独立地选自单键或双键，并且相邻的两个键不能同时为双键；
每一s分别独立地选自0-2的整数；
每一Q 1、m、每一L、每一R a、每一R b、每一R c的定义如前述方案任一项所述。
方案9-1：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有通式(III-1)所示的结构：
Figure PCTCN2022089956-appb-000018
其中，
Y 1、Y 2、Y 3、Y 4、Y 6分别独立地选自N、C或CR a；
Y 5、Y 7分别独立地选自N、NR c、C、CR aR b或CR a；
Figure PCTCN2022089956-appb-000019
分别独立地选自单键或双键，并且相邻的两个键不能同时为双键；
每一s分别独立地选自0-3的整数；
每一Q 1、m、每一L、每一R a、每一R b、每一R c、R 4、R 5的定义如前述方案任一项所述。
方案9-2：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有通式(III-1’)所示的结构：
Figure PCTCN2022089956-appb-000020
其中，R 6选自氢，任选被氘代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基；
Y 1、Y 2、Y 3、Y 4、Y 6分别独立地选自N、C或CR a；
Y 5、Y 7分别独立地选自N、NR c、C、CR aR b或CR a；
Figure PCTCN2022089956-appb-000021
分别独立地选自单键或双键，并且相邻的两个键不能同时为双键；
每一s分别独立地选自0-3的整数；
每一Q 1、m、每一L、每一R a、每一R b、每一R c、R 4、R 5的定义如前述方案任一项所述。
方案9-3：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，R 6选自氢、氘代C 1-6烷基或氘代C 1-6烷氧基。
方案9-4：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
Y 1、Y 2、Y 3、Y 4、Y 6分别独立地选自N、C或CH；
Y 5、Y 7分别独立地选自N、NH、C、CH 2或CH。
方案9-5：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体 异构体，其中，
Figure PCTCN2022089956-appb-000022
选自如下结构：
Figure PCTCN2022089956-appb-000023
方案9-6：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
Figure PCTCN2022089956-appb-000024
选自如下结构：
Figure PCTCN2022089956-appb-000025
方案10：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(IV)所示的结构，
Figure PCTCN2022089956-appb-000026
其中，
每一Q 1、m的定义如前述方案任一项所述；
Figure PCTCN2022089956-appb-000027
分别独立地选自单键或双键，并且相邻的两个键不能同时为双键；
Y 1、Y 2、Y 5、Y 6、Y 7、每一s的定义如前述方案任一项所述。
方案10-1：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(IV-1)所示的结构，
Figure PCTCN2022089956-appb-000028
其中，
Figure PCTCN2022089956-appb-000029
分别独立地选自单键或双键，并且相邻的两个键不能同时为双键；
每一Q 1、m、R 4、R 5、每一R a、每一R b、Y 1、Y 2、Y 5、Y 6、Y 7、每一s的定义如前述方案任一项所述。
方案10-2：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(IV-1’)所示的结构，
Figure PCTCN2022089956-appb-000030
其中，R 6选自氢，任选被氘代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基；
Figure PCTCN2022089956-appb-000031
分别独立地选自单键或双键，并且相邻的两个键不能同时为双键；
每一Q 1、m、R 4、R 5、每一R a、每一R b、Y 1、Y 2、Y 5、Y 6、Y 7、每一s的定义如前述方案任一项所述。
方案10-3：前述方案任一项所示的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，R 6选自氢、氘代C 1-6烷基或氘代C 1-6烷氧基。
方案10-4：前述方案任一项所示的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，R a、R b分别独立地选自氢。
方案11：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(V)所示的结构，
Figure PCTCN2022089956-appb-000032
其中，
每一Q 1、Y 1、Y 2、每一s的定义如前述方案任一项所述。
方案11-1：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(V-1)所示的结构，
Figure PCTCN2022089956-appb-000033
其中，
每一Q 1、R 4、R 5、R a、R b、Y 1、Y 2、每一s的定义如前述方案任一项所述。
方案11-2：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(V-1’)所示的结构，
Figure PCTCN2022089956-appb-000034
其中，R 6选自氢，任选被氘代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基；
每一Q 1、R 4、R 5、R a、R b、Y 1、Y 2、每一s的定义如前述方案任一项所述。
方案11-3：前述方案任一项所示的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，R 6选自氢、氘代C 1-6烷基或氘代C 1-6烷氧基。
方案12：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
每一Q 1分别独立地选自氘，卤素，任选被1-4个取代基Q 2取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、-(L) m-3-6元环烷基或-(L) m-3-6元杂环基，每一Q 2分别独立地选自氘、卤素、羧基、羟基、氰基、硝基、氨基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基和卤代C 1-6烷氧基。
方案12-1：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
每一Q 1分别独立地选自氘，卤素，任选被1-3个取代基Q 2取代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、3-6元环烷基，每一Q 2分别独立地选自氘、卤素、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基和卤代C 1-6烷氧基。
方案13：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
每一Q 1分别独立地选自氘，卤素，任选被1-3个取代基Q 2取代的C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二(C 1-4烷基)氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、氨基C 1-4烷基、羧基C 1-4烷基、3-6元环烷基，每一Q 2分别独立地选自氘、卤素、羧基、羟基、氰基、硝基、氨基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基和卤代C 1-4烷氧基。
方案13-1：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
每一Q 1分别独立地选自氘，卤素，任选被1-3个取代基Q 2取代的C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、3-6元环烷基，每一Q 2分别独立地选自氘、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基和卤代C 1-4烷氧基。
方案14：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
每一Q 1分别独立地选自氘，氟，氯，溴，碘，任选被1-3个取代基Q 2取代的甲基、乙 基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、甲基氨基、二甲氨基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基、三氟甲氧基、羟基甲基、羟基乙基、羟基丙基、羟基丁基、氨基甲基、羧基甲基、羧基乙基、环丙基、环丁基、环戊基、环丁基，每一Q 2分别独立地选自氘，卤素，羧基，羟基，氰基，硝基，氨基，甲基，乙基，丙基，异丙基，丁基，异丁基，仲丁基，叔丁基，甲氧基，乙氧基，丙氧基，异丙氧基，一氟甲基，二氟甲基，三氟甲基，一氟甲氧基，二氟甲氧基，三氟甲氧基。
方案14-1：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
每一Q 1分别独立地选自氘，氟，氯，溴，碘，任选被1-3个取代基Q 2取代的甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基、三氟甲氧基、环丙基、环丁基、环戊基、环丁基，每一Q 2分别独立地选自氘，氟，氯，溴，碘，甲基，乙基，丙基，异丙基，丁基，异丁基，仲丁基，叔丁基，甲氧基，乙氧基，丙氧基，异丙氧基，一氟甲基，二氟甲基，三氟甲基，一氟甲氧基，二氟甲氧基，三氟甲氧基。
方案15：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
每一L分别独立地选自-CR aR b-；
每一R a、每一R b分别独立地选自氘，氢，任选被氘代的C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基。
方案15-1：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
每一L分别独立地选自-CR aR b-；
每一R a、每一R b分别独立地选自氘，氢，任选被氘代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基。
方案16：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
每一L分别独立地选自-CH 2-。
方案17：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(VI)所示的结构，
Figure PCTCN2022089956-appb-000035
Y 8选自N、NR c、C、CR aR b或CR a；
Y 9选自N、C或CR a；
Figure PCTCN2022089956-appb-000036
分别独立地选自单键或双键，并且相邻的两个键不能同时为双键；
每一Q 1、每一L、m、R 4、R 5、Y 3、Y 4、Y 5、Y 6、Y 7、每一s的定义如前述方案任一项所述。
方案17-1：前述方案17所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
Y 8选自N、NH、C、CH 2或CH；
Y 9选自N、C或CH；
Figure PCTCN2022089956-appb-000037
分别独立地选自单键或双键，并且相邻的两个键不能同时为双键；
每一Q 1、每一L、m、R 4、R 5、Y 3、Y 4、Y 5、Y 6、Y 7、每一s的定义如前述方案任一项所述。
方案18：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(VII)所示的结构，
Figure PCTCN2022089956-appb-000038
其中，每一Q 1、m、Y 1、Y 2、每一s的定义如前述方案任一项所述。
方案18-1：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(VII-1)所示的结构，
Figure PCTCN2022089956-appb-000039
其中，每一Q 1、m、Y 1、Y 2、每一s、R 4、R 5的定义如前述方案任一项所述。
方案18-2：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(VII-1’)所示的结构，
Figure PCTCN2022089956-appb-000040
其中，R 6选自氢，任选被氘代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基；
每一Q 1、m、Y 1、Y 2、每一s、R 4、R 5的定义如前述方案任一项所述。
方案18-3：前述方案任一项所示的化合物、其药学上可接受的盐、其酯、氘代物或其立 体异构体，其中，R 6选自氢、氘代C 1-6烷基或氘代C 1-6烷氧基。
方案19：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(VIII)所示的结构，
Figure PCTCN2022089956-appb-000041
其中，每一Q 1、m、每一s的定义如前述方案任一项所述。
方案19-1：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(VIII-1)所示的结构，
Figure PCTCN2022089956-appb-000042
其中，每一Q 1、m、R 4、R 5、每一s的定义如前述方案任一项所述。
方案19-2：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(VIII-1’)所示的结构，
Figure PCTCN2022089956-appb-000043
其中，R 6选自氢，任选被氘代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基；
每一Q 1、m、R 4、R 5、每一s的定义如前述方案任一项所述。
方案19-2：前述方案任一项所示的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，R 6选自氢、氘代C 1-6烷基或氘代C 1-6烷氧基。
方案20：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(IX)所示的结构，
Figure PCTCN2022089956-appb-000044
Figure PCTCN2022089956-appb-000045
分别独立地选自单键或双键，并且相邻的两个键不能同时为双键；
每一Q 1、Y 1、Y 2、Y 5、Y 6、Y 7、每一s的定义如前述方案任一项所述。
方案20-1：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(IX-1)所示的结构，
Figure PCTCN2022089956-appb-000046
其中，R 6选自氢，任选被氘代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基；
Figure PCTCN2022089956-appb-000047
分别独立地选自单键或双键，并且相邻的两个键不能同时为双键；
每一Q 1、Y 1、Y 2、Y 5、Y 6、Y 7、每一s的定义如前述方案任一项所述。
方案20-2：前述方案任一项所示的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，R 6选自氢、任选被氘代的C 1-6烷基或氘代C 1-6烷氧基。
方案21：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，
R 4、R 5、每一R a、每一R b、每一R c分别独立地选自氢。
方案22：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(II-2)所示的结构，
Figure PCTCN2022089956-appb-000048
其中，Y 3、Y 4、Y 6分别独立地选自N、C或CR a；
Y 5、Y 7分别独立地选自N、NR c、C、CR aR b或CR a；
Figure PCTCN2022089956-appb-000049
分别独立地选自单键或双键，并且相邻的两个键不能同时为双键；
每一s分别独立地选自0-2的整数；
每一Q 1、每一Q 2、每一L、m、R 1、R 4、R 5、每一R a、每一R b、每一R c的定义如前述方案任一项所述。
方案23：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(II-3)所示的结构，
Figure PCTCN2022089956-appb-000050
每一Q 1、每一Q 2、每一s、每一L、m、R 1、R 4、R 5、Y 5、Y 6、Y 7、每一R a、每一R b、每一R c的定义如前述方案任一项所述。
方案24：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(II-3)所示的结构，
Figure PCTCN2022089956-appb-000051
R 1选自任选被1-3个Q 1取代的苯基或5-6元含氮杂芳基，优选地，R 1选自任选被1-3个Q 1取代的
Figure PCTCN2022089956-appb-000052
R 4、R 5分别独立地选自氘，氢，任选被氘代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基和卤代C 1-6烷氧基；
每一L分别独立地选自-CR aR b-；
每一R a、每一R b分别独立地选自氘，氢，任选被氘代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基；
每一Q 1分别独立地选自氘，卤素，任选被1-3个取代基Q 2取代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、3-6元环烷基，每一Q 2分别独立地选自氘、卤素、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基和卤代C 1-6烷氧基；
Figure PCTCN2022089956-appb-000053
选自如下结构：
Figure PCTCN2022089956-appb-000054
m为1或2的整数；
每一s分别独立地为0、1、2的整数。
方案25：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(II-4)所示的结构，
Figure PCTCN2022089956-appb-000055
每一Q 1、每一Q 2、每一s、m、R 1、R 4、R 5、Y 5、Y 6、Y 7、每一R a、每一R b、每一R c的定义如前述方案任一项所述。
方案26：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(II-4)所示的结构，
Figure PCTCN2022089956-appb-000056
其中，R 1选自任选被1-3个Q 1取代的苯基或5-6元含氮杂芳基，优选地，R 1选自任选被1-3个Q 1取代的
Figure PCTCN2022089956-appb-000057
R 4、R 5分别独立地选自氘，氢，任选被氘代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基和卤代C 1-6烷氧基；
每一Q 1分别独立地选自氘，卤素，任选被1-3个取代基Q 2取代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、3-6元环烷基，每一Q 2分别独立地选自氘、卤素、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基和卤代C 1-6烷氧基；
Figure PCTCN2022089956-appb-000058
选自如下结构：
Figure PCTCN2022089956-appb-000059
m为1或2的整数；
每一s分别独立地为0、1、2的整数。
方案27：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(II-5)所示的结构，
Figure PCTCN2022089956-appb-000060
每一Q 1、每一Q 2、s、m、R 1、Y 5、Y 6、Y 7、每一R a、每一R b、每一R c的定义如前述方案任一项所述。
方案28：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(II-5)所示的结构，
Figure PCTCN2022089956-appb-000061
其中，R 1选自任选被1-3个Q 1取代的苯基或5-6元含氮杂芳基；优选地，R 1选自任选被1-3个Q 1取代的
Figure PCTCN2022089956-appb-000062
Figure PCTCN2022089956-appb-000063
每一Q 1分别独立地选自氘，卤素，任选被1-3个取代基Q 2取代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、3-6元环烷基，每一Q 2分别独立地选自氘、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基和卤代C 1-6烷氧基；
Figure PCTCN2022089956-appb-000064
选自如下结构：
Figure PCTCN2022089956-appb-000065
m为1或2的整数；
每一s分别独立地为0、1、2的整数。
方案29：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(IV-1’)所示的结构，
Figure PCTCN2022089956-appb-000066
其中，Y 1、Y 2分别独立地选自N、C或CH；
Y 5、Y 7分别独立地选自NH、N、C、CH或CH 2；
Y 6选自N、CH或C；
R 4、R 5分别独立地选自氘，氢，氰基，卤素，任选被氘代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基 或卤代C 1-6烷氧基；
R 6选自氢、氘代C 1-6烷氧基；
每一Q 1分别独立地选自氘，卤素，任选被1-4个取代基Q 2取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、-(L) m-3-6元环烷基或-(L) m-3-6元杂环基；
R a、R b分别独立地选自氢；
每一Q 2分别独立地选自氘、卤素、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基和卤代C 1-6烷氧基；
Figure PCTCN2022089956-appb-000067
分别独立地选自单键或双键，并且相邻的两个键不能同时为双键；
每一m、每一s分别独立地为0、1、2。
方案30：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其具有式(VIII-1’)所示的结构，
Figure PCTCN2022089956-appb-000068
每一Q 1分别独立地选自氘，卤素，任选被1-3个取代基Q 2取代的C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二(C 1-4烷基)氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、氨基C 1-4烷基、羧基C 1-4烷基、3-6元环烷基；
每一Q 2分别独立地选自氘、卤素、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基和卤代C 1-4烷氧基；
R 4、R 5分别独立地选自氘，氢，氰基，卤素，任选被氘代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、或卤代C 1-6烷氧基；
R 6选自氢、氘代C 1-4烷氧基；
m为1、2；
每一s分别独立地为0、1、2。
方案31：前述方案任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，R 6选自氢、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基、三氟甲氧基、氘代甲基、氘代乙基、氘代丙基、氘代异丙基、氘代丁基、氘代异丁基、氘代仲丁基、氘代叔丁基、氘代甲氧基、氘代乙氧基、氘代丙氧基或氘代异丙氧基，氘代的数目为1个、2个、3个或4个。
方案32：前述方案任一项所述的化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体，其中，
R 6选自氢、氘代甲氧基、氘代乙氧基、氘代丙氧基或氘代异丙氧基，氘代的数目为1个、2个或3个，优选三氘代甲氧基。
本发明所述的任一实施方式中的任一取代基的选择可以相互组合，其组合后的技术方案仍包含在本发明的保护范围之内。
本发明的一些实施方式中，前述通式(I)所述的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体的结构见表1：
表1
Figure PCTCN2022089956-appb-000069
Figure PCTCN2022089956-appb-000070
本发明所述的“药学上可接受的盐”是指可药用的酸和碱的加成盐，例如金属盐、铵盐、与有机酸形成的盐、与有机碱形成的盐、与无机酸形成的盐、与酸性氨基酸或碱性氨基酸形成的盐等。
本发明所述的“酯”是指药学上可接受的酯，尤其指如下酯，其在活体内水解且包括容易在人体内分解留下母体化合物(通式(I)所述的化合物)或其盐的酯。本发明所述的“酯”例如可以选自下列各组：(1)通过与羧酸类化合物的酯化作用所获得的羧酸酯，其中羧酸类化合物的非羰基部分选自例如C 1-20直链或支链烷基、C 1-12直链或支链烷基、C 1-8直链或支链烷基、C 1-6直链或支链烷基(例如甲基、乙基、正丙基、叔丁基或正丁基)、C 1-6烷氧基C 1-6烷基(例如甲氧基甲基)、C 6-10芳基C 1-6烷基(例如苄基)、C 6-10芳氧基C 1-6烷基(例如苯氧基甲基)、C 6-10芳基(例如苯基，任选被例如卤素、C 1-4烷基或C 1-4烷氧基或氨基取代)；(2)磺酸酯，例如烷基磺酰基或芳烷基磺酰基(例如甲基磺酰基)；(3)氨基酸酯(例如L-缬氨酰基或L-异亮氨酰基)；和(4)单-、二-或三磷酸酯等；(5)通过与醇类化合物的酯化作用所获得的酯，其中醇类化合物的非羟基部分选自例如C 1-20直链或支链烷基、C 1-12直链或支链烷基、C 1-8直链或支链烷基、C 1-6直链或支链烷基(例如甲基、乙基、正丙基、叔丁基或正丁基)、C 1-6烷氧基C 1-6烷基(例如甲氧基甲基)、C 6-10芳基C 1-6烷基(例如苄基)、C 6-10芳氧基C 1-6烷基(例如苯氧基甲基)、C 6-10芳基(例如苯基，任选被例如卤素、C 1-4烷基或C 1-4烷氧基或氨基取代)。
本发明通式(I)所示的化合物的“立体异构体”是指当式(I)所示的化合物存在不对称碳原子时，会产生对映异构体；当化合物存在碳碳双键或环状结构时，会产生顺反异构体；当化合物存在酮或肟时，会产生互变异构体，本发明的一些实施方式中，立体异构体包括但不限于：对映异构体、非对映异构体、消旋异构体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物。
本发明还提供了一种药物组合物，其含有前述通式(I)所示的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体，及一种或多种第二治疗活性剂，任选地，所述药物组合物还包含一种或多种药用载体和/或稀释剂。
本发明还提供了一种药物制剂，其含有前述通式(I)所示的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体，及一种或多种药用载体和/或稀释剂；所述药物制剂为临床上或药学上可接受的任一剂型。
在本发明的一些实施方式中，上述药物制剂可以以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时，所述药物组合物可制成口服制剂，例如可以制成常规的口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，上述药物制剂也可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配置注射剂时，可以不加入附加剂，也可以根据药物的性质加入适宜的附加剂。用于直肠给药时，所述药物组合物可制成栓剂等。用于经肺给药时，所述药物组合物可制成吸入剂或喷雾剂等。
本发明的药物组合物或药物制剂中可用的药用载体和/或稀释剂可以是药物制剂领域中任何常规的载体和/或稀释剂，特定载体和/或稀释剂的选择将取决于用于治疗特定患者的给药方式或疾病类型和状态。用于特定给药模式的合适药物组合物的制备方法完全在药物领域技术人员的知识范围内。例如，药用载体和/或稀释剂可以包括药学领域常规的溶剂、稀释剂、分散剂、助悬剂、表面活性剂、等渗剂、增稠剂、乳化剂、粘合剂、润滑剂、稳定剂、水合剂、乳化加速剂、缓冲剂、吸收剂、着色剂、离子交换剂、脱模剂、涂布剂、矫味剂、和抗 氧化剂等。必要时，还可以在药物组合物中加入香味剂、防腐剂和甜味剂等。
本发明还提供了前述通式(I)所示的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体、前述的药物制剂或前述的药物组合物在制备用于治疗和/或预防USP1介导的疾病及相关疾病的药物中的用途；所述USP1介导的疾病及相关疾病选自癌症或良性肿瘤。
本发明还提供了前述通式(I)所示的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体、前述的药物制剂或前述的药物组合物在治疗/或预防USP1介导的疾病及相关疾病中的应用；所述USP1介导的疾病及相关疾病选自癌症或良性肿瘤。
本发明还提供了一种治疗疾病的方法，该方法包括向有需要的患者给药治疗有效量的前述通式(I)所示的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体、前述的药物制剂或前述的药物组合物，其中，所述疾病为USP1介导的疾病及相关疾病；所述USP1介导的疾病及相关疾病选自癌症或良性肿瘤。
本发明提供了上述化合物的制备方法，但不仅限于以下方法，制备方法的反应方程式如下：
Figure PCTCN2022089956-appb-000071
将式(II-2)-1化合物溶于适当溶剂(例如DMF)，加入碱性试剂(例如NaH、碳酸钾、碳酸铯、碳酸钠)，加入式(II-2)-2化合物，反应1-15小时。加入水淬灭，适当有机溶剂(例如二氯甲烷、乙酸乙酯)萃取，旋干，经适当方法(例如硅胶柱层析)得本发明通式(II-2)化合物。
上述制备方法可以简单概括为：将式(II-2)-1所示的化合物与式(II-2)-2所示的化合物反应，得到通式(II-2)所示的化合物；
其中，X为卤素；每一Q 1、每一Q 2、每一L、m、R 1、R 4、R 5、Y 3、Y 4、Y 5、Y 6、Y 7、每一R a、每一R b、每一R c、每一s如上述技术方案任一项所定义。
本发明还提供了用于制备通式(II-1)至通式(IX-1)所示化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体的中间体，其具有以下结构式：
Figure PCTCN2022089956-appb-000072
其中，R 1、R 4、R 5、每一Q 1、每一Q 2、每一L、每一R a、每一R b、每一R c、m的定义如上述技术方案任一项所定义。
本发明还提供了用于制备通式(III)至通式(IX-1)所示化合物、其药学上可接受的盐、其酯、氘代物或其立体异构体的中间体，其具有以下结构式：
Figure PCTCN2022089956-appb-000073
其中，G选自卤素、羟基、氨基、C 1-6烷基硫基或C 1-6烷基磺酰基；
每一Q 1、每一Q 2、每一L、m、R 1、R 4、R 5、Y 3、Y 4、Y 5、Y 6、Y 7、每一R a、每一R b、每一R c如前述技术方案任一项所定义。
在某些实施方案中，G选自卤素、羟基、氨基、甲硫基或甲基磺酰基。
在本申请的说明书和权利要求书中，化合物都是依据化学结构式而命名，如果表示同一化合物时化合物的命名和化学结构式不符，以化学结构式为准。
在本申请中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员通常理解的含义，然而为了更好地理解本发明，下面提供了部分术语的定义。当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不符的时候，以本申请所提供的术语的定义和解释为准。
本发明所述的“卤素”是指氟、氯、溴和碘，优选氟和氯。
本发明所述的“卤代”是指取代基中的任一氢可被一个或多个相同或不同的卤素取代。“卤素”如前文所定义。
本发明所述的“C 1-6烷基”表示直链或支链的含有1-6个碳原子的烷基，包括例如“C 1-5烷基”、“C 1-4烷基”、“C 1-3烷基”、“C 1-2烷基”、“C 2-6烷基”、“C 2-5烷基”、“C 2-4烷基”、“C 2-3烷基”、“C 3-6烷基”、“C 3-5烷基”、“C 3-4烷基”、“C 4-6烷基”、“C 4-5烷基”、“C 5-6烷基”等，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。本发明所述的“C 1-4烷基”指C 1-6烷基中的含有1-4个碳原子的具体实例。
本发明所述的“C 1-6亚烷基”指上述所述C 1-6烷基去除一个氢原子形成的基团，包括例如“C 1-5亚烷基”、“C 1-4亚烷基”、“C 1-3亚烷基”、“C 1-2亚烷基”、“C 2-6亚烷基”、“C 2-5亚烷基”、“C 2-4亚烷基”、“C 2-3亚烷基”、“C 3-6亚烷基”、“C 3-5亚烷基”、“C 3-4亚烷基”、“C 4-6亚烷基”、“C 4-5亚烷基”、“C 5-6亚烷基”等，具体实例包括但不限于：亚甲基、亚乙基、亚丙基、亚丁基、亚戊基、亚己基等。本发明所述的“C 1-4亚烷基”指C 1-6亚烷基中的含有1-4个碳原子的具体实例。
本发明所述的“C 2-6烯基”是指含有至少一个双键的碳原子数为2-6的直链或支链或环状的烯基，包括例如“C 2-5烯基”、“C 2-4烯基”、“C 2-3烯基”等，具体实例包括但不限于：乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、1-甲基-2-丙烯基、1-戊烯基、2-戊烯基、3-戊烯基、2-甲基-1-丁烯基、3-甲基-1-丁烯基、2-甲基-3-丁烯基、1,1-二甲基-2-丙烯基、1-乙基-2-丙烯基、2-己烯基、3-己烯基、2-甲基-1-戊烯基、3-甲基-1-戊烯基、1-甲基 -2-戊烯基、3-甲基-2-戊烯基、2-甲基-3-戊烯基、1-甲基-4-戊烯基、3-甲基-4-戊烯基、1,1-二甲基-3-丁烯基、1,2-二甲基-3-丁烯基、1,3-二甲基-2-丁烯基、2,2-二甲基-3-丁烯基、2,3-二甲基-2-丁烯基、2,3-二甲基-1-丁烯基、2-乙基-1-丁烯基、2-乙基-3-丁烯基等。
本发明所述的“C 2-6炔基”是指含有三键的碳原子数为2-8的直链或支链的炔基，其中包括例如“C 2-5炔基”、“C 2-4炔基”、“C 2-3炔基”等，具体实例包括但不限于：乙炔基、1-丙炔基、2-丁炔基、1-甲基-2-丙炔基、2-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-甲基-3-丁炔基、1,1-二甲基-2-丙炔基、1-乙基-2-丙炔基、2-己炔基、3-己炔基、1-甲基-2-戊炔基、1-甲基-3-戊炔基、2-甲基-3-戊炔基、1,1-二甲基-3-丁炔基、2-乙基-3-丁炔基等。
本文所述的“C 1-6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、C 1-6烷基氨酰基、C 1-6烷基酰氨基、C 1-6烷基磺酰基、C 1-6烷基磺酰氨基、C 1-6烷基氨基磺酰基、C 1-6烷基羰基、C 1-6烷氧基羰基、C 1-6烷基硫基”是指以C 1-6烷基-O-、C 1-6烷基-NH-、(C 1-6烷基) 2-N-、C 1-6烷基-NH-C(O)-、C 1-6烷基-C(O)-NH-、C 1-6烷基-S(O) 2-、C 1-6烷基-S(O) 2-NH-、C 1-6烷基-NH-S(O) 2-、C 1-6烷基-C(O)-、C 1-6烷基-O-C(O)-、C 1-6烷基-S-方式形成的基团，其中“C 1-6烷基”的定义如前文所述。
本文所述的“C 1-4烷氧基、C 1-4烷基氨基、二(C 1-4烷基)氨基、C 1-4烷基氨酰基、C 1-4烷基酰氨基、C 1-4烷基磺酰基、C 1-4烷基磺酰氨基、C 1-4烷基氨基磺酰基、C 1-4烷基羰基、C 1-4烷氧基羰基、C 1-4烷基硫基”是指以C 1-4烷基-O-、C 1-4烷基-NH-、(C 1-4烷基) 2-N-、C 1-4烷基-NH-C(O)-、C 1-4烷基-C(O)-NH-、C 1-4烷基-S(O) 2-、C 1-4烷基-S(O) 2-NH-、C 1-4烷基-NH-S(O) 2-、C 1-4烷基-C(O)-、C 1-4烷基-O-C(O)-、C 1-4烷基-S-方式形成的基团，其中“C 1-4烷基”的定义如前文所述。
本文所述的“卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、卤代C 1-6亚烷基、卤代C 1-6烷氧基”是指一至多个(例如1-4个、1-3个、1-2个)卤素原子、羟基、氨基、羧基分别取代C 1-6烷基、C 1-6亚烷基、C 1-6烷氧基中的氢原子所形成的基团。
本文所述的“卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基、羧基C 1-4烷基、卤代C 1-4亚烷基、卤代C 1-4烷氧基”是指一至多个(例如1-4个、1-3个、1-2个)卤素原子、羟基、氨基分别取代C 1-4烷基、C 1-4亚烷基、C 1-4烷氧基中的氢原子所形成的基团。
本发明所述的“3-12元环烷基”是指含有3-12个碳原子的饱和或部分饱和的且不具有芳香性的环状烷基，包括“单环烷基”和“稠环烷基”。
本发明所述的“单环烷基”是指饱和或部分饱和的且不具有芳香性的单环环状烷基，包括“3-8元饱和环烷基”和“3-8元部分饱和环烷基”；优选“3-4元环烷基”、“3-5元环烷基”、“3-6元环烷基”、“3-7元环烷基”、“4-5元环烷基”、“4-6元环烷基”、“4-7元环烷基”、“4-8元环烷基”、“5-6元环烷基”、“5-7元环烷基”、“5-8元环烷基”、“6-7元环烷基”、“6-8元环烷基”、“7-8元环烷基”、“3-6元饱和环烷基”、“4-7元饱和环烷基”、“4-8元饱和环烷基”、“5-8元饱和环烷基”、“5-7元饱和环烷基”、“5-6元饱和环烷基”、“3-6元部分饱和环烷基”、“4-7元部分饱和环烷基”、“4-8元部分饱和环烷基”、“5-8元部分饱和环烷基”、“5-7元部分饱和环烷基”、“5-6元部分饱和环烷基”等。所述的“3-8元饱和环烷基”的具体实例包括但不限于：环丙烷基(环丙基)、环丁烷基(环丁基)、环戊烷基(环戊基)、环己烷基(环己基)、环庚烷基(环庚基)、环辛烷基(环辛基)等；所述的“3-8元部分饱和环烷基”的具体实例包括但不限于环丙烯基、环丁烯基、环戊烯基、环戊二烯基、环己烯基、环己-1,3-二烯、环己-1,4-二烯、环庚烯基、环庚-1,3-二烯基、环庚-1,4-二烯基、环庚-1,3,5-三烯基，环辛烯基、环辛-1,3-二烯基、环辛-1,4-二烯基、环辛-1,5-二烯基、环辛-1,3,5-三烯基、环辛四烯基等。
本发明所述的“稠环烷基”是指由两个或两个以上环状结构彼此共用两个相邻的碳原子所形成的饱和或部分饱和的、非芳香性环状基团，所述的稠环中的一个环可以为芳香性环，但稠环整体不具备芳香性；其稠和方式可以为：5-6元环烷基并5-6元环烷基、苯并5-6元环烷基、苯并5-6元饱和环烷基等。其实例包括但不限于：二环[3.1.0]己烷基、二环[4.1.0]庚烷基、二环[2.2.0]己烷基、二环[3.2.0]庚烷基、二环[4.2.0]辛烷基、八氢并环戊二烯基、八氢-1H-茚基、十氢化萘基、十四氢菲基、双环[3.1.0]己-2-烯基、双环[4.1.0]庚-3-烯基、双环[3.2.0]庚-3-烯基、双环[4.2.0]辛-3-烯基、1,2,3,3a-四氢并环戊二烯基、2,3,3a,4,7,7a-六氢-1H-茚基、1,2,3,4,4a,5,6,8a-八氢化萘基、1,2,4a,5,6,8a-六氢化萘基、1,2,3,4,5,6,7,8,9,10-十氢菲基、苯并环戊基、苯并环己基、苯并环己烯基、苯并环戊烯基等。
本发明所述的“3-12元杂环基”是指至少含有一个杂原子(例如，含有1个、2个、3个、4个或5个)的且环原子数为3-12个的饱和或部分饱和的且不具有芳香性的单环或稠环环状基团，所述杂原子为氮原子、氧原子和/或硫原子，任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。本发明所述的“3-12元杂环基”包括“3-12元饱和杂环基”和“3-12元部分饱和杂环基”。优选地，本发明所述的“3-12元杂环基”含有1-3个杂原子；优选地，本发明所述的“3-12元杂环基”含有1-2个杂原子，且所述的杂原子选自氮原子和/或氧原子；优选地，本发明所述的“3-12元杂环基”含有1-2个氮原子。所述“3-12元杂环基”优选“3-10元杂环基”、“3-8元杂环基”、“4-8元杂环基”、“3-6元杂环基”、“3-6元饱和杂环基”、“3-6元含氮杂环基”、“3-6元饱和含氮杂环基”、“5-6元杂环基”、“5-6元饱和杂环基”、“5-6元含氮杂环基”等。“3-12元杂环基”的具体实例包括但不仅限于：氮杂环丙烷基、2H-氮杂环丙烷基、二氮杂环丙烷基、3H-二氮杂环丙烯基、氮杂环丁烷基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,4-二氧杂环己二烯基、四氢呋喃基、四氢吡喃基、二氢吡咯基、吡咯烷基、咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、哌啶基、哌嗪基、吗啉基、4,5-二氢噁唑基、4,5-二氢异噁唑基、2,3-二氢异噁唑基、2H-1,2-噁嗪基、6H-1,3-噁嗪基、4H-1,3-噻嗪基、6H-1,3-噻嗪基、2H-吡喃基、2H-吡喃-2-酮基、3,4-二氢-2H-吡喃基、吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、吡咯烷基并吗啉基、哌啶基并吗啉基、苯并吡咯烷基、苯并环戊基、苯并环己基、苯并四氢呋喃基、苯并吡咯烷基、苯并咪唑烷基、苯并噁唑烷基、苯并噻唑烷基、苯并异噁唑烷基、苯并异噻唑烷基、苯并哌啶基、苯并吗啉基、苯并哌嗪基、苯并四氢吡喃基、吡啶并环戊基、吡啶并环己基、吡啶并四氢呋喃基、吡啶并吡咯烷基、吡啶并咪唑烷基、吡啶并噁唑烷基、吡啶并噻唑烷基、吡啶并异噁唑烷基、吡啶并异噻唑烷基、吡啶并哌啶基、吡啶并吗啉基、吡啶并哌嗪基、吡啶并四氢吡喃基、嘧啶并环戊基、嘧啶并环己基、嘧啶并四氢呋喃基、嘧啶并吡咯烷基、嘧啶并咪唑烷基、嘧啶并噁唑烷基、嘧啶并噻唑烷基、嘧啶并异噁唑烷基、嘧啶并异噻唑烷基、嘧啶并哌啶基、嘧啶并吗啉基、嘧啶并哌嗪基、嘧啶并四氢吡喃基；四氢咪唑并[4,5-c]吡啶基、3,4-二氢喹唑啉基、1,2-二氢喹喔啉基、苯并[d][1,3]二氧杂环戊烯基、2H-色原烯基、2H-色原烯-2-酮基、4H-色烯基、4H-色烯-4-酮基、4H-1,3-苯并噁嗪基、4,6-二氢-1H-呋喃并[3,4-d]咪唑基、3a,4,6,6a-四氢-1H-呋喃并[3,4-d]咪唑基、4,6-二氢-1H-噻吩并[3,4-d]咪唑基、4,6-二氢-1H-吡咯并[3,4-d]咪唑基、八氢-苯并[d]咪唑基、十氢喹啉基、六氢噻吩并咪唑基、六氢呋喃并咪唑基、4,5,6,7-四氢-1H-苯并[d]咪唑基、八氢环戊 烯并[c]吡咯基、4H-1,3-苯并噁嗪基等。
本发明所述的“6-10元芳基”是指含有6-10个环碳原子的具有芳香性的环状基团，包括“6-8元单环芳基”和“8-10元稠环芳基”。
本发明所述的“6-8元单环芳基”是指含有6-8个环碳原子的单环芳基，其实例包括但不限于：苯基、环辛四烯基等；优选苯基。
本发明所述的“8-10元稠环芳基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的、含有8-10个环碳原子的、不饱和的、具有芳香性的环状基团，优选“9-10元稠环芳基”，具体实例如萘基等。
本发明所述的“5-12元杂芳基”是指含有5-12个环原子(其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子)的具有芳香性的环状基团，例如可以是5-12元含氮杂芳基、5-12元含氧杂芳基、5-12元含硫杂芳基等。包括“5-8元单杂芳基”和“8-10元稠杂芳基”。
本发明所述的“5-8元单杂芳基”是指含有5-8个环原子(其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子)的具有芳香性的单环环状基团。任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。“5-8元单杂芳基”包括例如“5-7元单杂芳基”、“5-6元单杂芳基”、“5-6元含氮单杂芳基”、“5元含氮单杂芳基”等。“5-8元单环杂芳基”的具体实例包括但不仅限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基、氮杂环辛四烯基等。所述“5-6元杂芳基”是指5-8元杂芳基中含有5-6个环原子的具体实例。
本发明所述的“8-10元稠杂芳基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的、含有8-10个环原子(其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子)的、不饱和的具有芳香性的环状结构。任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。包括“9-10元稠杂芳基”，“8-9元稠杂芳基”等，其稠和方式可以为苯并5-6元杂芳基、5-6元杂芳基并5-6元杂芳基等；具体实例包括但不限于：吡咯并吡咯、吡咯并呋喃、吡唑并吡咯、吡唑并噻吩、呋喃并噻吩、吡唑并噁唑、苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、异吲哚基、苯并噁唑基、苯并咪唑基、吲唑基、苯并三唑基、喹啉基、2-喹啉酮基、4-喹啉酮基、1-异喹啉酮基、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、嘌呤基、萘啶基等。
本发明所述的“任选被…取代”包括“被取代”和“未被取代”两种情形。
本发明所述的
Figure PCTCN2022089956-appb-000074
选自单键或双键。
本申请中的化合物的任何原子若没有特别指定，可代表该原子的任何一种稳定的同位素。除非特别说明，当结构中某一位置被定义为H即氢(H-l)时，该位置仅含天然存在的同位素。同样，除非特别说明，当结构中某一位置被定义为D即氘(Η-2)时，该位置含同位素量至少比天然存在的同位素量(0.015％)大3340倍(即至少含50.1％氘同位素)，当本申请化合物的结构中某一个或多个位置被定义为D即氘(Η-2)时，该结构所示的化合物的含量可至少为52.5％、至少为60％、至少为67.5％、至少为75％、至少为82.5％、至少为90％、至少 为95％、至少为97％、至少为98.5％、至少为99％、至少为99.5％。
本申请化合物的氘代率是指标记合成的同位素含量与天然存在的同位素量的比值。本申请化合物的每个指定氘原子的氘代率可至少为3500倍(52.5％)、至少为4000倍(60％)、至少为4500倍(67.5％)、至少为5000倍(75％)、至少为5500倍(82.5％)、至少为6000倍(90％)、至少为6333.3倍(95％)、至少为6466.7倍(97％)、至少为6566.7倍(98.5％)、至少为6600倍(99％)、至少为6633.3倍(99.5％)。
本申请中的同位素体(isotopologues)是指在化学结构方面仅有同位素组成上不同的化合物。本申请中的在特定位置含氘化合物也会含非常少的该位置的氢同位素体，本申请氘代化合物中的氘代位置的氢同位素体的量取决于许多因素，其中包括氘代试剂(D 2O、D 2、NaBD 4、L1AID 4等)的氘同位素纯度以及引入氘同位素合成方法的有效性。然而，如前所述，这种氘代位置的氢同位素体的量总数将少于49.9％。本申请氘代化合物中的氘代位置的氢同位素体的量总数将少于47.5％、40％、32.5％、25％、17.5％、10％、5％、3％、1％或0.5％。
本申请中，任何未指定为氘的各原子以其天然同位素丰度存在。
本发明所述的“氘代”是指被氘代的基团上的一个或多个氢原子被一个或多个氘原子取代，可以是部分氘代，也可以是全部氘代。例如，氘代化合物可以仅含有一个氘。在一些实施方案中，氘代化合物仅含有两个氘。在一些实施方案中，氘代化合物仅含有三个氘。在一些实施方案中，氘代化合物含有四个氘。
本发明所述的“任选被氘代”包括基团被氘代和未被氘代两种情况，其中所述“氘代”如前文所定义。
本发明所述的“治疗有效量”是指当给药到患者时至少能够减轻患者病症的症状的前述化合物、药物制剂、药物组合物的量。包含“治疗有效量”的实际量会根据多种情况而变化，多种情况包括但不限于所治疗的特定病症、病症的严重程度、患者的体格和健康状况以及给药途径。熟练的医疗从业者可容易地使用医疗领域中已知的方法确定合适的量。
发明的有益效果
(1)本发明化合物、其药学上可接受的盐、酯、氘代物或其立体异构体具有优异的USP1抑制活性，能够治疗和/或预防USP1介导的疾病及相关疾病；
(2)本发明化合物对肿瘤细胞具有良好的抑制作用；
(3)本发明化合物、其药学上可接受的盐、酯、氘代物或其立体异构体具有良好的药代动力学性质，作用更持久，生物利用度高；
(4)本发明化合物、其药学上可接受的盐、酯、氘代物或其立体异构体具有良好的安全性；
(5)本发明化合物制备工艺简单，药品纯度高，质量稳定，易于进行大规模工业生产。
以下通过实验进一步阐述本发明实施例提供的化合物的有益效果，但不应将此理解为本发明实施例提供的化合物仅具有下列有益效果。
实验例1本发明化合物的体外酶学活性
供试品：本发明实施例合成的化合物，其结构式见表1。
实验试剂：
Figure PCTCN2022089956-appb-000075
Figure PCTCN2022089956-appb-000076
实验耗材：
Consumables Vendor Cat No.
384-Well plate Perkin Elmer 6007279
实验方法一：
1、化合物稀释
1)使用DMSO配制本发明化合物至10mM，作为试验储备液。
2)将本发明化合物储备液4倍梯度稀释至10个浓度，最高浓度为10mM。
3)使用Echo550分别转移稀释后的本发明化合物至384孔板(稀释了1000倍)，每个浓度设定2个复孔，DMSO终浓度为1％。
4)测试化合物终浓度为10000nM、2500nM、625nM、156nM、39nM、9.8nM、2.4nM、0.61nM、0.15nM、0.038nM。
2、酶反应实验
1)在1×的测试缓冲液中配制酶溶液。
2)在1×测定缓冲液中加入Ubiquitin Rhodamine 110 Protein,CF(Ub-Rho)，制成底物溶液。
3)转移10μL的酶溶液以及1×的反应缓冲液到384孔板中。
4)室温孵育15分钟。
5)每孔加入10μL底物溶液开始反应，离心30s，震荡30s。
3、结果检测
1)在SpectraMax Paradigm上读板30分钟，激发波长为480nm，发射波长为540nm。
2)收集SpectraMax Paradigm上的数据。
4、数据分析
使用如下公式计算抑制率inhibition(％inh)：
Figure PCTCN2022089956-appb-000077
其中，Max表示：不加化合物的阳性对照孔的发光信号强度；
Min表示：不加酶的阴性对照孔的发光信号强度；
Signal表示：表示供试品化合物的发光信号强度；
采用如下公式计算IC 50：
Figure PCTCN2022089956-appb-000078
其中，Y表示：％inhibition；
X表示：化合物的浓度。
实验结果：
表2本发明化合物对USP-1抑制活性
Figure PCTCN2022089956-appb-000079
从上述实验结果可以看出，本发明制备的化合物，其能够有效抑制USP1的活性，是有效的USP1抑制剂。
实验方法二：
在酶反应实验中，第4)步更改室温孵育时间为60min，其他条件与实验方法一中的相同，得到以下测试结果：
表3本发明化合物对USP-1抑制活性
Figure PCTCN2022089956-appb-000080
从上述实验结果可以看出，本发明制备的化合物，其能够有效抑制USP1的活性，是有效的USP1抑制剂。
实验例2本发明化合物的体外细胞学抑制活性实验一
供试品：本发明部分化合物，其化学名称和结构见制备实施例。
下述实验中所用细胞株如下：MDA-MB-436：人乳腺癌细胞。
下述缩写所代表的定义如下：
FBS：胎牛血清
ITS-G：胰岛素-转铁蛋白-硒添加剂
glutathione：谷胱甘肽
实验方法(CelltiterGlo assay)
1准备细胞
1.1细胞培养：
所有细胞均为贴壁细胞，培养基为DMEM+10％FBS+1％ITS-G+16μg/ml glutathione，细胞在对数生长期进行试验。
1.2细胞悬液制备：
收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。调整到合适浓度，分别添加90μL细胞悬液至96孔板中。
表4细胞接种数目
Figure PCTCN2022089956-appb-000081
2配制测试化合物
2.1配制测试化合物DMSO储备液，各测试化合物的储备液浓度分别为10mM。
2.2配制测试化合物工作储备液
测试化合物储备液10mM用DMSO 3倍连续梯度稀释，共8个浓度。然后分别取2μL的DMSO梯度稀释的化合物加到198μL的培养液中，为测试化合物工作储备液(化合物浓度为终浓度的10倍，最高浓度为100μM)。
2.3化合物处理
在接种有细胞的96孔板中每孔加入10μL化合物工作储备液(10倍稀释，DMSO终浓度为0.1％)。
测试化合物的终浓度为：10000.00nM，3333.33nM，1111.11nM，370.37nM，123.46nM，41.15nM，13.72nM，4.57nM。
2.4对照孔设置
溶剂对照：0.1％DMSO。
空白对照：只加培养基，不接种细胞。
2.5将96孔板置于37℃、5％CO 2细胞培养箱中培养7天。
3检测
融化CTG试剂并平衡96孔板至室温30分钟，每孔加入60μL试剂(Celltiter Glo assay kit)，振荡器震摇2min混匀(避光)，室温孵育20分钟(避光)。多功能酶标仪读取光信号值。
4数据处理
1)抑制率(％)＝(DMSO溶剂对照孔读数–测试物孔读数)/(DMSO溶剂对照孔读数–空白对照孔读数)×100％；
2)输入GraphPad Prism作图，得到曲线及IC 50。
实验结果及结论
表5本发明化合物的体外细胞学活性(IC 50,nM)
Figure PCTCN2022089956-appb-000082
由表5可知，本发明化合物可以有效地抑制MDA-MB-436细胞的增殖，表明本发明化合物具有治疗BRCA1基因突变的癌性疾病的临床应用潜力。
实验例3本发明化合物的体外细胞学抑制活性实验二
测试物：本发明部分化合物，其化学名称和结构见制备实施例。
下述实验中所用细胞株如下：MDA-MB-436：人乳腺癌细胞；Caov-3：人卵巢癌细胞
实验方法一(CelltiterGlo assay)
1.准备细胞
1.1细胞培养：
所有细胞均为贴壁细胞，MDA-MB-436细胞培养基为DMEM+10％FBS+1％ITS-G+16μg/ml glutathione，Caov-3细胞培养基为DMEM+10％FBS，细胞在对数生长期进行试验。
1.2细胞悬液制备：
收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。调整到合适浓度，分别添加90μL细胞悬液至96孔板中。
表6细胞接种数目
Figure PCTCN2022089956-appb-000083
2配制测试化合物
2.1配制测试化合物DMSO储备液，各测试化合物的储备液浓度分别为10mM。
2.2配制测试化合物工作储备液
测试化合物储备液10mM用DMSO 3倍连续梯度稀释，共8个浓度。然后分别取2μL的DMSO梯度稀释的化合物加到198μL的培养液中，为测试化合物工作储备液(化合物浓度为终浓度的10倍，最高浓度为100μM)。
2.3化合物处理
在接种有细胞的96孔板中每孔加入10μL化合物工作储备液(10倍稀释，DMSO终浓度为0.1％)。
测试化合物的终浓度为：10000.00nM，3333.33nM，1111.11nM，370.37nM，123.46nM，41.15nM，13.72nM，4.57nM。
2.4对照孔设置
溶剂对照：0.1％DMSO。
空白对照：加药0h时，96孔板检测读数
2.5将96孔板置于37℃、5％CO 2细胞培养箱中培养7天。
3.检测
融化CTG试剂并平衡96孔板至室温30分钟，每孔加入60μL试剂(Celltiter Glo assay kit)，振荡器震摇2min混匀(避光)，室温孵育20分钟(避光)。多功能酶标仪读取光信号值。
4.数据处理
1)抑制率(％)＝(DMSO溶剂对照孔读数–测试物孔读数)/(DMSO溶剂对照孔读数–空白对照孔读数)×100％；
2)输入GraphPad Prism作图，得到曲线及IC 50。
实验结果及结论
表7本发明化合物的体外细胞学活性(IC 50,nM)
Figure PCTCN2022089956-appb-000084
Figure PCTCN2022089956-appb-000085
本发明实施例化合物11、16、18、19、1-1、11-1、16-1、17-1对Caov-3细胞抑制活性的IC 50值为1nM～600nM，说明了本发明化合物可以有效地抑制MDA-MB-436及Caov-3细胞的增殖，表明本发明化合物具有治疗HRD阳性(同源重组缺陷)的癌性疾病的临床应用潜力。
实验方法二：
配制化合物储备液浓度为5mM。
测试化合物储备液5mM用DMSO 3倍连续梯度稀释，共9个浓度。
测试化合物的终浓度为：10000.00nM，3333.33nM，1111.11nM，370.37nM，123.46nM，41.15nM，13.72nM，4.57nM，1.52nM。
其他条件与实验方法一中的相同，得到化合物20对MDA-MB-436细胞抑制活性的IC 50值55.7nM；化合物20对Caov-3细胞抑制活性的IC 50值为1nM～100nM。
实验例4本发明化合物的药代动力学实验
1、供试品本发明实施例化合物，其制备参见本申请说明书中实施例。
Figure PCTCN2022089956-appb-000086
2、供试品溶液准备
(1)静脉推注给药(iv)：取化合物11 2.54mg，加入DMSO溶液0.495ml，涡旋、超声溶解，PEG400 0.495ml，涡旋混匀，然后加入28％HP-β-CD 1.484ml，涡旋混匀，即得澄清溶液，浓度为1mg/ml。
(2)口服给药(po)：取化合物11 3.33mg加入溶媒(2％HPC+0.1％吐温80)3.243ml，研磨均匀，即得均匀混悬液。浓度为1mg/ml。
3、实验方法
(1)给药
供试品静脉推注给药(iv)，给药剂量为5mg/kg，给药体积5ml/kg；
口服给药(po)，给药剂量为10mg/kg，给药体积10ml/kg。
(2)采血
给药后0.083、0.25、0.5、1、2、3、4、6、8、24h，进行尾静脉采血，每个时间点采取100μl左右全血，在8000rpm的高速离心机中离心6min分离血浆，血浆于-80℃冰箱冻存。
(3)血浆样品分析
采用蛋白沉淀法：取20μl血浆至96孔深孔板中，加入200μl内标溶液(甲苯磺丁脲-200ng/ml)，涡旋10min，然后4000转/分钟离心20min，取100μl上清液，加入100μL水，涡旋3min；LC-MS/MS待分析。
4、实验结果及结论
实验数据表明，静脉注射或口服本发明化合物在生物体内具有较高的暴露量，适宜的半衰期和清除率，展现出良好的药代动力学性质，例如化合物11静脉推注给药，其在小鼠上的暴露量大于6000h*ng/ml，说明了本发明实施例化合物具有很好的临床应用前景。
具体实施方式
下面将结合具体实施例对本发明的技术方案进行描述，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
下述实验中所用缩写代表的含义如下：
Xphos-Pd-G2：氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)；Xphos：2-二环己基磷-2',4',6'-三异丙基联苯；Pd(dppf)Cl 2:二氯[1,1'-二(二苯基膦)二茂铁]钯；DMF：N,N-二甲基甲酰胺EA：乙酸乙酯；PE：石油醚；DCM：二氯甲烷；NMP：N-甲基吡咯烷酮；DIBAl-H：二异丁基氢化铝
实施例1 4-(4-环丙基-6-甲氧基嘧啶-5-基)-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备(化合物1)
(1)2-(双(甲硫基)亚甲基)环己烷-1,3-二酮的制备
Figure PCTCN2022089956-appb-000087
将1,3-环己二酮(20g,178.4mmol)溶于DMF(200mL)，加入碳酸钾(74g,535.2mmol)，20℃反应0.5h。加入二硫化碳(20g,267.6mmol)，20℃反应1h。加入碘甲烷(76g,535.2mmol)，20℃反应1h。浓缩得到粗品，直接用于下步反应。
(2)2-氨基-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮的制备
Figure PCTCN2022089956-appb-000088
将2-(双(甲硫基)亚甲基)环己烷-1,3-二酮(上步粗品)溶于DMF(200mL)，加入盐酸胍(17g,178.4mmol)，碳酸钾(49.3g,356.8mmol)，100℃反应16h，冷却至25℃，加入水(300mL)，过滤得到滤饼，真空干燥得目标化合物16.3g，收率44％。
(3)2-氯-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮的制备
Figure PCTCN2022089956-appb-000089
将2-氨基-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮(16.3g,78mmol)溶于二氯甲烷(150mL)，加入四氯化钛(14.8g,78mmol)，亚硝酸叔丁酯(48g,468mmol)，25℃反应3h。加入水淬灭反应，过滤得滤液，浓缩，柱层析(乙酸乙酯/石油醚＝0-40％)得目标化合物6.1g，收率34％。
(4)2-(4-环丙基-6-甲氧基嘧啶-5-基)-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮的制备
Figure PCTCN2022089956-appb-000090
将2-氯-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮(1.2g,5.15mmol)溶于1,4-二氧六环(30mL)，加入(4-环丙基-6-甲氧基嘧啶-5-基)硼酸(1g,5.15mmol)，Xphos-Pd-G2(408mg,0.52mmol)，Xphos(496mg,1.04mmol)，K 3PO 4(1.2g,5.7mmol)，水(10mL)，N 2保护下，90℃反应3h，反应完毕，旋干溶剂，经正相制备分离(乙酸乙酯/石油醚＝0-50％)得目标化合物830mg，收率47％。
(5)2-(4-环丙基-6-甲氧基嘧啶-5-基)-4-肼基-7,8-二氢喹唑啉-5(6H)-酮的制备
Figure PCTCN2022089956-appb-000091
将2-(4-环丙基-6-甲氧基嘧啶-5-基)-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮(830mg,2.4mmol)溶于乙醇(20mL)，加入水合肼(184mg,3.6mmol)，70℃下反应3h。反应完毕，浓缩得到目标化合物700mg，89％。
(6)4-(4-环丙基-6-甲氧基嘧啶-5-基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备
Figure PCTCN2022089956-appb-000092
将2-(4-环丙基-6-甲氧基嘧啶-5-基)-4-肼基-7,8-二氢喹唑啉-5(6H)-酮(300mg，0.92mmol)溶于N-甲基吡咯烷酮(5mL)，乙醇(60mL)，微波160℃反应1h。柱层析分离(甲醇/水＝0-60％)得目标化合物150mg，收率53％。
(7)4-(4-环丙基-6-甲氧基嘧啶-5-基)-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备
Figure PCTCN2022089956-appb-000093
将4-(4-环丙基-6-甲氧基嘧啶-5-基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉(130mg,0.43mmol)溶于N,N-二甲基甲酰胺(4mL)，加入氢化钠(60％,34mg,0.85mmol)，20℃反应10min，加入2-(4-(氯甲基)苯基)-1-甲基-4-(三氟甲基)-1H-咪唑(139mg,0.51mmol)，20℃反应3h。反应完毕，柱层析分离(甲醇/水＝0-40％)得目标化合物18.5mg，收率8％。
分子式:C 28H 25F 3N 8O 分子量:546.6 LC-MS(M/e):547.2(M+H +)
1H-NMR(400MHz,CDCl 3)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)。
实施例2 4-(3-氟-2-异丙基苯基)-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备(化合物2)
(1)3-氟-2-(丙-1-烯-2-基)苯酚的制备
Figure PCTCN2022089956-appb-000094
将2-溴-3-氟苯酚(11g,57.6mmol)，4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼烷(13.2g,78.6mmol),K 2CO 3(15.9g,115.2mmol)和Pd(dppf)Cl 2(4.2g,5.7mmol)溶于二氧六环(120mL)和水(24mL)中，氮气保护，80℃下反应16h，LCMS检测反应完成，反应液倒入水(200mL)中，EA萃取，有机相用无水硫酸钠干燥，旋干，硅胶柱层析分离(EA:PE＝1：5)得产品5.6g，收率63.9％。
(2)3-氟-2-异丙基苯酚的制备
Figure PCTCN2022089956-appb-000095
将3-氟-2-(丙-1-烯-2-基)苯酚(5.6g,36.8mmol)溶于甲醇(60mL)中，加入Pd/C(1.2g),25℃下反应4h，LCMS检测反应完成，抽滤，滤液旋干，得产品5g，收率88.2％。
(3)3-氟-2-异丙基苯基三氟甲磺酸酯的制备
Figure PCTCN2022089956-appb-000096
将3-氟-2-异丙基苯酚(1g,6.49mmol)溶于二氯甲烷(20mL)中，-10℃滴加吡啶(1.0g,12.6mmol)和Tf 2O(2.7g,9.6mmol),继续反应1h，LCMS检测反应完成，反应液倒入水中(50mL)淬灭，DCM萃取，有机相用无水硫酸钠干燥，旋干，硅胶柱层析分离(EA:PE＝1：5)，得产品1.6g，收率86.1％。
(4)2-(3-氟-2-异丙基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷的制备
Figure PCTCN2022089956-appb-000097
将3-氟-2-异丙基苯基三氟甲磺酸酯(1.6g,5.59mmol),双联硼酸频那醇酯(2.8g,11.18mmol),Pd(dppf)Cl 2(409mg,0.56mmol)和乙酸钾(1.7g,17.32mmol)二氧六环(40mL)中，氮气保护，80℃下反应8h，LCMS检测反应完成，反应液旋干，EA萃取，有机相旋干，硅胶柱层析分离(EA:PE＝1：5)，得产品1g，收率67.8％。
(5)2-(3-氟-2-异丙基苯基)-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮的制备
Figure PCTCN2022089956-appb-000098
将2-(3-氟-2-异丙基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(1.0g,3.79mmol),2-氯-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮(870mg,3.79mmol)，XPhosPdG2(299mg,0.38mmol),XPhos(362mg,0.76mmol)和磷酸钾(892mg,4.2mmol)溶于二氧六环(26mL)和水(7mL)中，氮气保护，90℃下反应2h，LCMS检测反应完成，反应液旋干，硅胶柱层析分离(EA:PE＝1：2)，得产品350mg，收率28.0％。
(6)2-(3-氟-2-异丙基苯基)-4-肼基-7,8-二氢喹唑啉-5(6H)-酮的制备
Figure PCTCN2022089956-appb-000099
将2-(3-氟-2-异丙基苯基)-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮(350mg,1.06mmol)溶于乙醇(10mL)中，加入水合肼(64mg,1.27mmol)，70℃反应8h，LCMS检测反应完成，反应液旋干，直接用于下一步反应。
(7)4-(3-氟-2-异丙基苯基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备
Figure PCTCN2022089956-appb-000100
将2-(3-氟-2-异丙基苯基)-4-肼基-7,8-二氢喹唑啉-5(6H)-酮(粗品)溶于NMP(2mL)中，160℃下微波反应1h，LCMS检测反应完成，反相色谱纯化(MeOH:H 2O＝0-50％)得产品100mg,两步收率31.8％。
(8)4-(3-氟-2-异丙基苯基)-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备
Figure PCTCN2022089956-appb-000101
将4-(3-氟-2-异丙基苯基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉(70mg,0.24mmol)溶于DMF(3mL)中，25℃下分批加入NaH(60％,19mg,0.48mmol)，10min后加入2-(4-(氯甲基)苯基)-1-甲基-4-(三氟甲基)-1H-咪唑(77mg,0.28mmol)，继续反应4h，LCMS检测反应完成。向反应液中加入水(20mL)淬灭，二氯甲烷萃取，有机相旋干，粗品经硅胶柱层析分离(EA:PE＝1:1)纯化，得产品16mg，产率12.5％。
分子式:C 29H 26F 4N 6 分子量:534.6 LC-MS(M/e):535.0(M+H +)
1H-NMR(400MHz,DMSO)δ:7.90(s,1H),7.60-7.70(m,2H),7.40-7.50(m,2H),7.18-7.35(m,3H),5.63(s,2H),3.73(s,3H),3.15–3.22(m,1H),2.95-3.05(m,4H),2.20-2.30(m,2H),1.25(d,J＝6.8Hz,6H).
实施例3 4-(3-氟-2-异丙基苯基)-2-(4-(5-甲基-3-(三氟甲基)-1H-吡唑-1-基)苄基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备(化合物3)
(1)4-(5-甲基-3-(三氟甲基)-1H-吡唑-1-基)苯甲酸甲酯的制备
Figure PCTCN2022089956-appb-000102
将4-肼基苯甲酸甲酯盐酸盐(9.0g,44.4mmol)，1,1,1-三氟丙烷-2,4-二酮(6.8g,44.1mmol)溶于六氟异丙醇(70mL)中，0℃下滴加三乙胺(8.9g,87.9mmol)，然后20℃反应2h。体系旋干，剩余物经硅胶柱层析提纯(PE:EA＝10:1)，得产品(9.0g，收率71.3％)。
(2)(4-(5-甲基-3-(三氟甲基)-1H-吡唑-1-基)苯基)甲醇的制备
Figure PCTCN2022089956-appb-000103
将4-(5-甲基-3-(三氟甲基)-1H-吡唑-1-基)苯甲酸甲酯(5.0g,17.6mmol)溶于THF(60mL)中，0℃下滴加DIBAl-H(1.5mol/L,46.9mL,70.4mmol)，加料完毕，20℃反应2小时。慢慢加水淬灭反应，加入饱和氯化铵水溶液(50mL)和EA(150mL)萃取分液，有机相旋干，剩余物经硅胶柱层析提纯(PE:EA＝3:1)，得产品(4.0g，收率88.7％)。
(3)1-(4-(氯甲基)苯基)-5-甲基-3-(三氟甲基)-1H-吡唑的制备
Figure PCTCN2022089956-appb-000104
将(4-(5-甲基-3-(三氟甲基)-1H-吡唑-1-基)苯基)甲醇(3.7g,14.4mmol)溶于二氯乙烷(30mL)中，加入二氯亚枫(3mL)，然后50℃下反应1小时。体系旋干，剩余物经硅
胶柱层析提纯(PE:EA＝5:1)，得产品(3.6g,收率91.0％)。
(4)4-(3-氟-2-异丙基苯基)-2-(4-(5-甲基-3-(三氟甲基)-1H-吡唑-1-基)苄基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备
Figure PCTCN2022089956-appb-000105
将4-(3-氟-2-异丙基苯基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉(100mg,0.34mmol)溶于DMF(5mL)中，25℃下分批加入NaH(60％,27mg,0.68mmol)，30min后加入1-(4-(氯甲基)苯基)-5-甲基-3-(三氟甲基)-1H-吡唑(139mg,0.51mmol)，继续反应2h。向反应液中加入水(20mL)淬灭，再加入EA(30mL)萃取分液，有机相旋干，剩余物经硅胶柱层析分离(PE:EA＝3:1)纯化得粗品20mg，经C18反向提纯(水/甲醇＝2/8)，冻干得产品(6mg,产率3.3％)。
分子式:C 29H 26F 4N 6 分子量:534.6 LC-MS(M/e):535.0(M+H +)
1H-NMR(400MHz,CDCl 3)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＝6.8Hz,6H).
实施例4 2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-4-(4-(三氟甲基)吡啶-3-基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备(化合物10)
(1)(4-(三氟甲基)吡啶-3-基)硼酸的制备
Figure PCTCN2022089956-appb-000106
将3-溴-4-(三氟甲基)吡啶(9.2g,0.041mol)溶于THF(200mL)，加入硼酸三异丙酯(10.8g,0.057mol)，-78℃下加入n-BuLi(2.5M)(22.9mL,0.057mol)反应3h。加入50.0mL水猝灭后，4N盐酸调节pH至4，碳酸氢钠饱和溶液调节pH至8，乙酸乙酯萃取，有机相浓缩得到粗品，直接用于下步反应。
(2)4-(甲硫基)-2-(4-(三氟甲基)吡啶-3-基)-7,8-二氢喹唑啉-5(6H)-酮的制备
Figure PCTCN2022089956-appb-000107
将2-氯-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮(1.5g,6.6mmol)溶于1,4-二氧六环(75mL)，加入(4-(三氟甲基)吡啶-3-基)硼酸(上步粗品)，Xphos-Pd-G2(514.7mg,0.66mmol)，Xphos(625.3mg,1.3mmol)，K 3PO 4(1.5g，7.2mmol)，水(25mL)，N 2保护下，90℃反应3h，反应完毕，旋干溶剂，剩余物经正相制备分离(乙酸乙酯/石油醚＝0-50％) 得535.0mg。
(3)4-肼基-2-(4-(三氟甲基)吡啶-3-基)-7,8-二氢喹唑啉-5(6H)-酮的制备
Figure PCTCN2022089956-appb-000108
将4-(甲硫基)-2-(4-(三氟甲基)吡啶-3-基)-7,8-二氢喹唑啉-5(6H)-酮(0.48g,1.4mmol)溶于乙醇(20.0mL)，加入水合肼(248.0mg,5.0mmol)，80℃下反应3h。反应完毕，旋干溶剂，剩余物经正相制备分离(乙酸乙酯/石油醚＝0-70％)得240.0mg，收率52.2％。
(4)4-(4-(三氟甲基)吡啶-3-基)-2,6,7,8四氢吡唑并[3,4,5-de]喹唑啉制备
Figure PCTCN2022089956-appb-000109
将4-肼基-2-(4-(三氟甲基)吡啶-3-基)-7,8-二氢喹唑啉-5(6H)-酮(200.0mg,0.62mmol)溶于盐酸1,4-二氧六环溶液(4M,18mL)，70℃反应1h，反应完毕，旋干溶剂，加饱和碳酸氢钠溶液，调节pH至中性，乙酸乙酯萃取，有机相经正相制备分离(乙酸乙酯/石油醚＝0-50％)得产物(130.0mg,收率68.8％)。
(5)2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-4-(4-(三氟甲基)吡啶-3-基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备
Figure PCTCN2022089956-appb-000110
将4-(4-(三氟甲基)吡啶-3-基)-2,6,7,8四氢吡唑并[3,4,5-de]喹唑啉(105mg,0.34mmol)溶于DMF(4mL)，加入碳酸钾(143mg,1.03mmol)，加入2-(4-(氯甲基)苯基)-1-甲基-4-(三氟甲基)-1H-咪唑(71mg,0.26mmol)，50℃反应5h。反应完毕，反应液经正向柱层析分离(甲醇/水＝0-10％)得产品8.8mg，收率4.7％。
分子式:C 26H 19F 6N 7 分子量:543.48 LC-MS(M/e):544.2(M+H +)
1H-NMR(400MHz,CDCl 3)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)。
实施例5 4-(4-环丙基-6-甲氧基嘧啶-5-基)-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]芘的制备(化合物11)
(1)2-(双(甲硫基)亚甲基)环庚烷-1,3-二酮的制备
Figure PCTCN2022089956-appb-000111
将1,3-环庚二酮(9g,71.4mmol)溶于DMF(200mL)，加入碳酸钾(30g,214.2mmol)，20℃反应0.5h。加入二硫化碳(8.1g,106.4mmol)，20℃反应1h。加入碘甲烷(30.4g,214.2mmol)，20℃反应1h。浓缩得到粗品，直接用于下步反应。
(2)2-氨基-4-(甲硫基)-6,7,8,9-四氢-5H-环庚并[d]嘧啶-5-酮的制备
Figure PCTCN2022089956-appb-000112
将2-(双(甲硫基)亚甲基)环庚烷-1,3-二酮(上步粗品)溶于DMF(200mL)，加入盐酸胍(6.8g,71.4mmol)，碳酸钾(14.8g,107.1mmol)，100℃反应16h，冷却至25℃，加入水(300mL)，过滤得到滤饼，真空干燥得10.4g，两步收率65.0％。
(3)2-氯-4-(甲硫基)-6,7,8,9-四氢-5H-环庚并[d]嘧啶-5-酮的制备
Figure PCTCN2022089956-appb-000113
将2-氨基-4-(甲硫基)-6,7,8,9-四氢-5H-环庚并[d]嘧啶-5-酮(10.4g,46.6mmol)溶于二氯甲烷(150mL)，加入四氯化钛(8.8g,46.4mmol)，亚硝酸叔丁酯(28.7g,278.6mmol)，25℃反应3h。加入水淬灭反应，过滤得滤液，浓缩，柱层析(乙酸乙酯/石油醚＝0-30％)得产品1.2g，收率10.6％。
(4)2-(4-环丙基-6-甲氧基嘧啶-5-基)-4-(甲硫基)-6,7,8,9-四氢-5H-环庚并[d]嘧啶-5-酮的制备
Figure PCTCN2022089956-appb-000114
将2-氯-4-(甲硫基)-6,7,8,9-四氢-5H-环庚并[d]嘧啶-5-酮(800mg,3.3mmol)溶于1,4-二氧六环(18mL)，加入(4-环丙基-6-甲氧基嘧啶-5-基)硼酸(640mg,3.3mmol)，Xphos-Pd-G2(259mg,0.33mmol)，Xphos(315mg,0.66mmol)，磷酸钾(770mg,3.6mmol)，水(6mL)，氮气保护下，90℃反应3h，反应完毕，旋干溶剂，经正相制备分离(乙酸乙酯/石油醚＝0-50％)得400mg，收率34.0％。
(5)4-(4-环丙基-6-甲氧基嘧啶-5-基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]芘的制备
Figure PCTCN2022089956-appb-000115
将2-(4-环丙基-6-甲氧基嘧啶-5-基)-4-(甲硫基)-6,7,8,9-四氢-5H-环庚并[d]嘧啶-5- 酮(200mg,0.56mmol)溶于乙醇(5mL)，加入水合肼(84mg,1.69mmol)，80℃下反应3h。反应完毕，旋干溶剂，经正相制备分离(乙酸乙酯/石油醚＝0-70％)得150mg，收率82.9％。
(6)4-(4-环丙基-6-甲氧基嘧啶-5-基)-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]芘的制备
Figure PCTCN2022089956-appb-000116
将4-(4-环丙基-6-甲氧基嘧啶-5-基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]芘(70mg,0.22mmol)溶于DMF(4mL)，加入碳酸铯(143mg,0.44mmol)，20℃反应10min，加入2-(4-(氯甲基)苯基)-1-甲基-4-(三氟甲基)-1H-咪唑(71mg,0.26mmol)，20℃反应3h。反应完毕，反向柱层析分离(甲醇/水＝0-70％)得产品25mg，收率20.2％。
分子式:C 29H 27F 3N 8O 分子量:560.6 LC-MS(M/e):561.2(M+H +)
1H-NMR(400MHz,CDCl3)δ:8.70(s,1H),7.97(s,1H),7.92-7.89(m,2H),7.43-7.41(m,2H),5.67(s,2H),3.92(s,3H),3.75(s,3H),3.25-3.08(m,4H),2.07-2.00(m,4H),1.69-1.55(m,1H),1.22-1.18(m,2H),0.95-0.85(m,2H)。
实施例6 4-(4-环丙基-6-甲氧基嘧啶-5-基)-2-(4-(1-异丙基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备(化合物16)
Figure PCTCN2022089956-appb-000117
将4-(4-环丙基-6-甲氧基嘧啶-5-基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉(100mg,0.32mmol)溶于DMF(4mL)，加入碳酸钾(88mg,0.64mmol)，2-(4-(氯甲基)苯基)-1-异丙基-4-(三氟甲基)-1H-咪唑(98mg,0.32mmol)，70℃反应5h。反应完毕，柱层析分离(甲醇/水＝0-40％)得产品21mg，收率11.4％。
分子式:C 30H 29F 3N 8O 分子量:574.6 LC-MS(M/e):575.2(M+H +)
1H-NMR(400MHz,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)。
实施例7 4-(1-异丙基-4-甲基-1H-吡唑-5-基)-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备(化合物18)
(1)2-(1-异丙基-4-甲基-1H-吡唑-5-基)-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮的制备
Figure PCTCN2022089956-appb-000118
将2-氯-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮(1.0g,4.4mmol)和1-异丙基-4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-吡唑(1.3g,5.2mmol)溶于1,4-二氧六环(20mL)和水(4mL)，加入四三苯基膦钯(760mg,0.66mmol)和碳酸钠(950mg,9.0mmol)。N 2保护下，90℃反应3h，反应完毕，浓缩，用硅胶柱层析纯化(乙酸乙酯:正庚烷＝35％)得产品700mg，收率为50.6％。
(2)4-肼基-2-(1-异丙基-4-甲基-1H-吡唑-5-基)-7,8-二氢喹唑啉-5(6H)-酮的制备
Figure PCTCN2022089956-appb-000119
将2-(1-异丙基-4-甲基-1H-吡唑-5-基)-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮(500mg,1.6mmol)溶于无水乙醇(10mL)，加入98％水合肼(180mg,3.5mmol)，70℃反应7h，反应完毕，浓缩，粗品直接用于下一步反应。
(3)4-(1-异丙基-4-甲基-1H-吡唑-5-基)-2,6,7,8-四氢吡唑并[3,4,5]喹唑啉的制备
Figure PCTCN2022089956-appb-000120
将上步粗品溶于NMP(10mL)中，加入对甲苯磺酸(50mg)，体系在微波160℃反应1.5h，结束后经水洗，乙酸乙酯萃取，分液和浓缩，用硅胶柱层析纯化(正庚烷:乙酸乙酯＝1:1)得目标产物399mg，两步收率为89.4％。
(4)4-(1-异丙基-4-甲基-1H-吡唑-5-基)-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备
Figure PCTCN2022089956-appb-000121
依次称取4-(1-异丙基-4-甲基-1H-吡唑-5-基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉(150mg，0.53mmol)，2-(4-(氯甲基)苯基)-1-甲基-4-(三氟甲基)-1H-咪唑(218mg，0.79mmol)，碳酸铯(518mg,1.6mmol)和DMF(10mL)，50℃反应13h，LC-MS显示反应完毕，反应液用水稀释，EA萃取，有机相旋干，残余物先经prep-TLC(SiO 2，PE：EA＝1:2，Rf＝0.5)分离，再经反相柱层析(C18，H 2O：MeOH＝90:10-65:35)分离，得产物150mg，收率54.2％。
分子式:C 27H 27F 3N 8 分子量:520.6 LC-MS(m/z):521.3(M+H +)
1H-NMR(400MHz,CDCl 3)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).
实施例8 2-(4-(1-异丙基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-4-(1-异丙基-4-甲基-1H-吡唑-5-基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备(化合物19)
Figure PCTCN2022089956-appb-000122
将4-(1-异丙基-4-甲基-1H-吡唑-5-基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉(120mg,0.42mmol)溶于DMF(5mL)，加入2-(4-(氯甲基)苯基)-1-异丙基-4-(三氟甲基)-1H-咪唑(120mg,0.40mmol)和碳酸钾(150mg,1.1mmol)。50℃反应2h，反应完毕，过滤，浓缩，用制备硅胶板纯化(乙酸乙酯:正庚烷＝2:1)得目标产品23mg，收率为10.5％。
分子式:C 29H 31F 3N 8 分子量:548.6 LC-MS(M/e):549.4(M+H +)
1H-NMR(400MHz,CDCl 3)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).
实施例9 4-(4-环丙基-6-(二氟甲氧基)嘧啶-5-基)-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑[3,4,5-de]喹唑啉的制备(化合物20)
(1)2-(双(甲硫基)亚甲基)环己烷-1,3-二酮的制备
Figure PCTCN2022089956-appb-000123
将1,3-环己二酮(12.5g,0.11mol)溶于DMF(100mL)，加入碳酸钾(45.6g,0.33mol)，20℃反应0.5h。加入二硫化碳(12.9g,0.17mol)，20℃反应1h。加入碘甲烷(46.8g,0.33mol)，20℃反应1h。浓缩得到粗品，直接用于下步反应。
(2)2,4-二(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮的制备
Figure PCTCN2022089956-appb-000124
将2-(双(甲硫基)亚甲基)环己烷-1,3-二酮(上步粗品)溶于DMF(200mL)，加入甲基异硫脲二硫酸盐(11.5g,40.1mmol)，碳酸钾(18.5g,133.8mmol)，100℃反应16h，冷却至25℃，加入水(300mL)，过滤得到滤饼，真空干燥得2.48g，收率26％。
(3)4-肼基-2-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮的制备
Figure PCTCN2022089956-appb-000125
将2,4-二(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮(2.0g,8.3mmol)溶于乙醇(20mL)，加入水合肼(1.0g,20.0mmol)，70℃下反应3h。反应完毕，浓缩得到粗品。
(4)4-(甲硫基)-2,6,7,8-四氢吡唑[3,4,5-de]喹唑啉的制备
Figure PCTCN2022089956-appb-000126
将4-肼基-2-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮(上步粗品)溶于DMAc(20ml)中，加入对甲苯磺酸(0.25g,1.5mmol)搅拌下升温至160℃反应2h，停止反应，将DMAc旋蒸出去，得粗品，经正相层析柱(石油醚：乙酸乙酯＝10:0～4:6)分离得产物0.45g，收率：26.3％(两步)。
(5)2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-4-(甲硫基)-2,6,7,8-四氢吡唑[3,4,5-de]喹唑啉的制备
Figure PCTCN2022089956-appb-000127
将4-(甲硫基)-2,6,7,8-四氢吡唑[3,4,5-de]喹唑啉(206mg,1.0mmol)，2-(4-(氯甲基)苯基)-1-甲基-4-(三氟甲基)-1H-咪唑(411mg,1.5mmol)，碳酸钾(414mg,3.0mmol)加入到DMF(20ml)中，加热至80℃，4小时反应完毕，停止反应，过滤，滤液旋蒸得粗品，经正相柱分离(石油醚：乙酸乙酯＝10:0～4:6)得产品200mg，收率45％。
(6)2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-4-(甲磺酰基)-2,6,7,8-四氢吡唑[3,4,5-de]喹唑啉的制备
Figure PCTCN2022089956-appb-000128
将2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-4-(甲硫基)-2,6,7,8-四氢吡唑[3,4,5-de]喹唑啉(200mg,0.45mmol)溶于二氯甲烷(10mL)，加入间氯过氧苯甲酸(155mg,0.90mmol)，20℃反应1小时，停止反应，加入二氯甲烷50ml，饱和碳酸钠水溶液50ml搅拌5min，静置分液，收集有机相旋蒸得粗品，直接用于下一步。
(7)2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑[3,4,5-de]喹唑啉-4-醇的制备
Figure PCTCN2022089956-appb-000129
将2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-4-(甲磺酰基)-2,6,7,8-四氢吡唑[3,4,5-de]喹唑啉(上步粗品)溶于四氢呋喃(20mL)，加入10％KOH水溶液10ml，20℃搅拌4h，停止反应，加入1MHCl调节pH值为4～5，将反应液溶剂旋蒸出来，加入二氯甲烷：甲醇＝10:1混合溶剂200ml，将产品洗脱出来，旋蒸得粗品，加入乙酸乙 酯2ml搅拌均匀，过滤得产品200mg(粗品)。
(8)4-氯-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑[3,4,5-de]喹唑啉的制备
Figure PCTCN2022089956-appb-000130
将2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑[3,4,5-de]喹唑啉-4-醇(200mg粗品)溶于三氯氧磷(6mL)，110℃反应4h，LCMS显示反应完毕，反应液旋干，残余物用饱和碳酸氢钠溶液稀释，EA萃取，有机相旋干，残余物经柱层析(SiO 2，PE：EA＝4:1-2:3)分离，得产物100mg。
(9)4-(4-环丙基-6-(二氟甲氧基)嘧啶-5-基)-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑[3,4,5-de]喹唑啉的制备
Figure PCTCN2022089956-appb-000131
称取4-氯-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑[3,4,5-de]喹唑啉(90mg,021mmol)，4-环丙基-6-(二氟甲氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)嘧啶(330mg粗品)，XPhos-Pd-G2(17mg，0.022mmol)，XPhos(10mg，0.021mmol)，磷酸钾(134mg,0.63mmol)，二氧六环(5mL)和水(1mL)，90℃反应2h，LCMS显示反应完毕，反应液旋干，残余物经柱层析(SiO 2，PE：EA＝4:1-2:3)分离，得产物40mg，收率33.0％。
分子式:C 28H 23F 5N 8O 分子量:582.5 LC-MS(m/z):583.1(M+H +)
1H-NMR(400MHz,CDCl 3)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).
实施例10 4-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备(化合物1-1)
(1)2-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮的制备
Figure PCTCN2022089956-appb-000132
将2-氯-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮(1.2g,5.2mmol)溶于1,4-二氧六环(30mL)，加入(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)硼酸(1g,5.1mmol)，Xphos-Pd-G2(408 mg,0.52mmol)，Xphos(496mg,1.04mmol)，K 3PO 4(1.2g,5.7mmol)，水(10mL)，N 2保护下，90℃反应3h，反应完毕，旋干溶剂，经正相制备分离(乙酸乙酯/石油醚＝0-50％)得600mg，收率34.1％。
(2)2-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-4-肼基-7,8-二氢喹唑啉-5(6H)-酮的制备
Figure PCTCN2022089956-appb-000133
将2-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-4-(甲硫基)-7,8-二氢喹唑啉-5(6H)-酮(500mg,1.4mmol)溶于乙醇(10mL)，加入水合肼(87mg,1.7mmol)，70℃下反应3h。反应完毕，浓缩得到400mg，收率86.8％。
(3)4-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备
Figure PCTCN2022089956-appb-000134
将2-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-4-肼基-7,8-二氢喹唑啉-5(6H)-酮(300mg,0.92mmol)溶于NMP(5mL)，乙醇(60mL)，微波160℃反应1h。柱层析分离(甲醇/水＝0-60％)得产品150mg，收率53％。
(4)4-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备
Figure PCTCN2022089956-appb-000135
将4-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉(100mg,0.32mmol)溶于DMF(4mL)，加入碳酸钾(88mg,0.64mmol)，2-(4-(氯甲基)苯基)-1-甲基-4-(三氟甲基)-1H-咪唑(88mg,0.32mmol)，20℃反应3h。反应完毕，柱层析分离(甲醇/水＝0-40％)得产品42mg，收率24％。
分子式:C 28H 22D 3F 3N 8O 分子量:549.58 LC-MS(M/e):550.2(M+H +)
1H-NMR(400MHz,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)。
实施例11 4-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]甘菊蓝的制备(化合物11-1)
(1)2-(二叔丁氧羰基)氨基-4-(甲硫基)-6,7,8,9-四氢-5H-环庚[d]嘧啶-5-酮的制备
Figure PCTCN2022089956-appb-000136
向2-氨基-4-(甲硫基)-6,7,8,9-四氢-5H-环庚[d]嘧啶-5-酮(2.0g,9.0mmol)的DCM(60mL)溶液中依次加入三乙胺(4.6g,45.5mmol)、对二甲氨基吡啶(110mg,0.9mmol)和Boc 2O(7.9g,36.2mmol)，25℃下反应1h，LC-MS显示反应完毕，反应液旋干，残余物经柱层析(SiO 2，PE：EA＝10:1-2:1)分离，得产物3.4g，收率89.6％。
(2)叔丁基(6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]甘菊蓝-4-基)氨基甲酸酯的制备
Figure PCTCN2022089956-appb-000137
向2-(二叔丁氧羰基)氨基-4-(甲硫基)-6,7,8,9-四氢-5H-环庚[d]嘧啶-5-酮(3.2g,7.6mmol)的乙醇(50mL)溶液中，加入水合肼(1.9g,37.9mmol)，80℃下反应13h，LC-MS显示反应完毕，反应液旋干，残余物经柱层析(SiO 2，DCM：MeOH＝50:1-10:1)分离，得产物1.5g，收率68.6％。
(3)叔丁基(2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]甘菊蓝-4-基)氨基甲酸酯的制备
Figure PCTCN2022089956-appb-000138
依次称取叔丁基(6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]甘菊蓝-4-基)氨基甲酸酯(1.4g,4.8mmol)，2-(4-(氯甲基)苯基)-1-甲基-4-(三氟甲基)-1H-咪唑(1.6g,5.8mmol)，碳酸铯(3.1g,9.5mmol)和DMF(30mL)，70℃反应6h，LC-MS显示反应完毕，反应液用水稀释，乙酸乙酯萃取，有机相干燥，旋干，残余物经柱层析(SiO 2，PE：EA＝2:1-1:1)分离，得产物1.9g，收率74.4％。
(4)2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]甘菊蓝-4-胺的制备
Figure PCTCN2022089956-appb-000139
向叔丁基(2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]甘菊蓝-4-基)氨基甲酸酯(1.9g,3.6mmol)的DCM(10mL)溶液中加HCl/EA(20mL,80.0mmol)，25℃反应2h，LC-MS显示反应完毕，反应液旋干，残余物用水稀释，氨水 调节pH至9，DCM萃取，有机相干燥，旋干，残余物经柱层析(SiO 2，DCM：MeOH＝50:1-30:1)分离，得产物1.2g，收率77.9％。
(5)4-氯-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]甘菊蓝的制备
Figure PCTCN2022089956-appb-000140
0℃下，向2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]甘菊蓝-4-胺(500mg,1.2mmol)的乙腈(3mL)溶液中加入氯化亚铜(238mg,2.4mmol)和亚硝酸叔丁酯(247mg,2.4mmol)，60℃反应4h，LC-MS显示反应完毕，反应液过滤，滤液旋干，残余物经柱层析(SiO 2,DCM:MeOH＝50:1-30:1)分离，得产物100mg，收率19.1％。
(6)4-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]甘菊蓝的制备
Figure PCTCN2022089956-appb-000141
依次称取4-氯-2-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]甘菊蓝(100mg,0.22mmol)、4-环丙基-6-(甲氧基-d 3)-5-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)嘧啶(50mg粗品)、XPhos(10mg,0.021mmol)、XPhos-Pd-G2(17mg,0.022mmol)、磷酸钾(140mg,0.66mmol)、二氧六环(5mL)和水(1mL)，氮气置换3次，90℃反应6h，LC-MS显示反应完毕，反应液过滤，滤液旋干，残余物经制备薄层色谱(SiO 2，DCM：MeOH＝30:1，Rf～0.4)分离，得产物16mg，收率12.7％。
分子式:C 29H 24D 3F 3N 8O 分子量:563.6 LC-MS(m/z):564.2(M+H +)
1H-NMR(400MHz,CDCl 3)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).
实施例12 4-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-2-(4-(1-异丙基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉的制备(化合物16-1)
Figure PCTCN2022089956-appb-000142
将4-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-2,6,7,8-四氢吡唑并[3,4,5-de]喹唑啉(93mg,0.3 mmol)溶于DMF(5mL)，加入碳酸钾(83mg,0.6mmol)，2-(4-(氯甲基)苯基)-1-异丙基-4-(三氟甲基)-1H-咪唑(100mg,0.3mmol)，70℃反应2h。反应完毕，柱层析分离(PE/EA＝3:1～1:1)得产品43mg，收率24.2％。
分子式:C 30H 26D 3F 3N 8O 分子量:577.6 LC-MS(M/e):578.3(M+H +)
1H-NMR(400MHz,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)。
实施例13 4-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-2-(4-(1-异丙基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]甘菊蓝的制备(化合物17-1)
(1)2-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-4-(甲硫基)-6,7,8,9-四氢-5H-环庚[d]嘧啶-5-酮的制备
Figure PCTCN2022089956-appb-000143
依次称取2-氯-4-(甲硫基)-6,7,8,9-四氢-5H-环庚[d]嘧啶-5-酮(400mg,1.6mmol)、(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)硼酸(347mg,1.8mmol)、XPhos(76mg,0.16mmol)、XPhos-Pd-G2(126mg,0.16mmol)、磷酸钾(1.0g,4.7mmol)、二氧六环(20mL)和水(4mL)，氮气置换3次，90℃反应4h，LC-MS显示反应完毕，反应液过滤，滤液旋干，残余物经柱层析(SiO 2，PE：EA＝5:1-3:1)分离，得产物260mg，收率43.9％。
(2)4-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]甘菊蓝的制备
Figure PCTCN2022089956-appb-000144
向2-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-4-(甲硫基)-6,7,8,9-四氢-5H-环庚[d]嘧啶-5-酮(240mg,0.67mmol)的乙醇(6mL)溶液中，加入水合肼(168mg,3.4mmol)，80℃下反应3h，LC-MS显示反应完毕，反应液旋干，残余物经柱层析(SiO 2，PE：EA＝3:1-1:1)分离，得产物200mg，收率92.0％。
(3)4-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-2-(4-(1-异丙基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]甘菊蓝的制备
Figure PCTCN2022089956-appb-000145
向4-(4-环丙基-6-(甲氧基-d 3)嘧啶-5-基)-6,7,8,9-四氢-2H-1,2,3,5-四氮杂苯并[cd]甘菊蓝(200mg,0.61mmol)的DMF(5mL)溶液中加入2-(4-(氯甲基)苯基)-1-异丙基-4-(三氟甲基)-1H-咪唑(203mg,0.67mmol)和碳酸铯(596mg,1.8mmol)，50℃反应13h，LC-MS显示反应完毕， 反应液用水稀释，EA萃取，有机相干燥、旋干，残余物经柱层析(SiO 2,PE:EA＝3:1-1:1)分离，得产物167mg，收率45.9％。
分子式:C 31H 28D 3F 3N 8O 分子量:591.7 LC-MS(m/z):592.3(M+H +)
1H-NMR(400MHz,CDCl 3)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).
使用与上述实施例相同或相似的方法制备了以下表格所示的化合物：
Figure PCTCN2022089956-appb-000146
以上对本发明所提供的USP1抑制剂及其应用进行了详细介绍。本文中应用了具体实施例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其中心思想。应当指出，对于本领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护。

Claims (14)

  1. 通式(I)所示的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体，
    Figure PCTCN2022089956-appb-100001
    其中，
    X 1、X 2、X 3、X 4分别独立地选自N或CR a；
    R 1、R 2、R 3分别独立地选自任选被一个或多个Q 1取代的3-12元环烷基、3-12元杂环基、6-10元芳基或5-12元杂芳基；
    R 4、R 5分别独立地选自氘，氢，羧基，氰基，硝基，氨基，卤素，C 2-6烯基，C 2-6炔基，任选被氘代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基或卤代C 1-6烷氧基；
    每一Q 1分别独立地选自氘，卤素，氰基，羧基，羟基，氨基，硝基，磺酰氨基，任选被1-4个取代基Q 2取代的C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、C 1-6烷基羰基、C 1-6烷氧基羰基、C 1-6烷基氨酰基、C 1-6烷基酰氨基、C 1-6烷基磺酰基、C 1-6烷基磺酰氨基、C 1-6烷基氨基磺酰基、-(L) m-C 1-6烷基、-(L) m-C 2-6烯基、-(L) m-C 2-6炔基、-(L) m-C 1-6烷氧基、-(L) m-6-10元芳基、-(L) m-5-12元杂芳基、-(L) m-3-8元环烷基或-(L) m-3-8元杂环基，每一Q 2分别独立地选自氘，卤素、羧基、羟基、氰基、硝基、氨基、C 1-6烷基、羟基C 1-6烷基、羧基C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、-CO-C 1-6亚烷基-NH 2、-CO-C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基和卤代C 1-6烷氧基；
    每一L分别独立地选自-CO-、-O-、-S-、-SO-、-S(O) 2-、-NR c-、-CR aR b-；
    每一R a、每一R b分别独立地选自氘，氢，卤素，氨基，羟基，羧基，氰基，C 2-6烯基，C 2-6炔基，任选被氘代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、C 1-6烷基氨酰基、C 1-6烷基酰氨基、C 1-6烷基磺酰氨基、C 1-6烷基氨基磺酰基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基；
    每一R c分别独立地选自氘，氢，任选被氘代的C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基；
    每一m分别独立地为0-3的整数；
    每一n分别独立地为0-6的整数。
  2. 如权利要求1所述的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体，
    其中，
    X 1、X 2、X 3、X 4分别独立地选自N或CR a；
    R 1、R 2、R 3分别独立地选自任选被一个或多个Q 1取代的5-8元环烷基、3-8元杂环基、苯基或5-6元杂芳基；
    R 4、R 5分别独立地选自氘，氢，氰基，卤素，任选被氘代的C 1-6烷基、C 1-6烷氧基、C 1-6 烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基或卤代C 1-6烷氧基；
    每一Q 1分别独立地选自氘，卤素，氰基，任选被1-4个取代基Q 2取代的C 1-6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、-(L) m-C 1-6烷基、-(L) m-3-6元环烷基或-(L) m-3-6元杂环基，每一Q 2分别独立地选自氘、卤素、羧基、羟基、氰基、硝基、氨基、C 1-6烷基、羟基C 1-6烷基、羧基C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、C 1-6烷氧基、卤代C 1-6烷基和卤代C 1-6烷氧基；
    每一L分别独立地选自-CO-、-O-、-NR c-、-CR aR b-；
    每一R a、每一R b分别独立地选自氘，氢，任选被氘代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基；
    每一R c分别独立地选自氘，氢，任选被氘代的C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基；
    每一m分别独立地为0-2的整数；
    每一n分别独立地为0-5的整数。
  3. 如权利要求1或2所述的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体，
    其中，
    X 1、X 2、X 3、X 4分别独立地选自N；
    R 1、R 2、R 3分别独立地选自任选被1-3个Q 1取代的苯基、呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、恶唑基、异恶唑基、恶二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基；
    R 4、R 5分别独立地选自氘，氢，任选被氘代的甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、甲基氨基、二甲氨基、一氟甲基、二氟甲基、三氟甲基、羟基甲基、羟基乙基、羟基丙基、羟基丁基、氨基甲基、羧基甲基、羧基乙基、一氟甲氧基、二氟甲氧基、三氟甲氧基；
    每一Q 1分别独立地选自氘，氟，氯，溴，碘，任选被1-3个取代基Q 2取代的甲氧基、乙氧基、丙氧基、异丙氧基、甲基氨基、二甲氨基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基、三氟甲氧基、羟基甲基、羟基乙基、羟基丙基、羟基丁基、氨基甲基、羧基甲基、羧基乙基、-(L) m-C 1-4烷基、-(L) m-3-6元环烷基，每一Q 2分别独立地选自氘，卤素，羧基，羟基，氰基，硝基，氨基，甲基，乙基，丙基，异丙基，丁基，异丁基，仲丁基，叔丁基，甲氧基，乙氧基，丙氧基，异丙氧基，羟基甲基，羟基乙基，羟基丙基，羟基丁基，羧基甲基，羧基乙基，甲基氨基，二甲氨基，一氟甲基，二氟甲基，三氟甲基，一氟甲氧基，二氟甲氧基，三氟甲氧基；
    每一L分别独立地选自-CR aR b-；
    每一R a、每一R b分别独立地选自氘，氢，任选被氘代的甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基；
    每一m分别独立地为0、1、2；
    每一n分别独立地为0、1、2、3。
  4. 如权利要求1-3任一项所述的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体，其具有式(II-1)所示的结构，
    Figure PCTCN2022089956-appb-100002
    其中，
    每一L、每一R a、每一R b、每一R c、R 1、R 2、R 3、R 4、R 5、每一Q 1、每一Q 2、m、n的定义如权利要求1-3任一项所述。
  5. 如权利要求1-4任一项所述的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体，其具有通式(II-2)所示的结构：
    Figure PCTCN2022089956-appb-100003
    其中，Y 3、Y 4、Y 6分别独立地选自N、C或CR a；
    Y 5、Y 7分别独立地选自N、NR c、CR aR b或CR a；
    Figure PCTCN2022089956-appb-100004
    分别独立地选自单键或双键，并且相邻的两个键不能同时为双键；
    每一s分别独立地选自0-2的整数；
    每一Q 1、每一Q 2、每一L、m、R 1、R 4、R 5、每一R a、每一R b、每一R c的定义如权利要求1-4所述。
  6. 如权利要求1-5任一项所述的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体，其具有通式(II-5)所示的结构：
    Figure PCTCN2022089956-appb-100005
    其中，
    R 1选自任选被1-3个Q 1取代的苯基或5-6元含氮杂芳基；
    每一Q 1分别独立地选自氘，卤素，任选被1-3个取代基Q 2取代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、3-6元环烷基，每一Q 2分别独立地选自氘、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基和卤代C 1-6烷氧基；
    Figure PCTCN2022089956-appb-100006
    选自如下结构：
    Figure PCTCN2022089956-appb-100007
    m为1或2的整数；
    每一s分别独立地为0、1、2的整数。
  7. 如权利要求1-6任一项所述的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体，其具有通式(IV-1’)所示的结构：
    Figure PCTCN2022089956-appb-100008
    其中，R 6选自氢，任选被氘代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基；
    Y 1、Y 2分别独立地选自N、C或CR a；
    Figure PCTCN2022089956-appb-100009
    分别独立地选自单键或双键，并且相邻的两个键不能同时为双键；
    每一Q 1、m、R 4、R 5、每一R a、每一R b、Y 5、Y 6、Y 7、每一s的定义如权利要求1-6任一项所述。
  8. 如权利要求7所述的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体，其中，R 6选自氘代甲氧基、氘代乙氧基、氘代丙氧基或氘代异丙氧基，氘代的数目为1个、2个或3个。
  9. 如权利要求1所述的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体，具有以下结构：
    Figure PCTCN2022089956-appb-100010
    Figure PCTCN2022089956-appb-100011
    Figure PCTCN2022089956-appb-100012
  10. 一种药物制剂，其含有权利要求1-9中任一项所述的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体，及一种或多种药用载体和/或稀释剂；所述药物制剂为临床上或药学上可接受的任一剂型。
  11. 一种药物组合物，其含有权利要求1-9中任一项所述的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体，及一种或多种第二治疗活性剂；任选地，所述药物组合物还包含一种或多种药用载体和/或稀释剂。
  12. 权利要求1-9任一项所述的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体、或权利要求10所述的药物制剂、或权利要求11所述的药物组合物在制备用于治疗和/或预防USP1介导的疾病及相关疾病的药物中的用途。
  13. 权利要求1-9任一项所示的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体的制备方法，其包括以下步骤：
    Figure PCTCN2022089956-appb-100013
    将式(II-2)-1所示的化合物与式(II-2)-2所示的化合物反应，得到式(II-2)所示的化合物；
    其中，X为卤素；每一Q 1、每一Q 2、每一L、每一m、R 1、R 4、R 5、Y 3、Y 4、Y 5、Y 6、 Y 7、每一R a、每一R b、每一R c、每一s如权利要求1-9任一项所定义。
  14. 制备如权利要求1-9任一项所示的化合物、其药学上可接受的盐、酯、氘代物或其立体异构体的中间体，其具有如下结构：
    Figure PCTCN2022089956-appb-100014
    其中，G选自卤素、羟基、氨基、C 1-6烷基硫基或C 1-6烷基磺酰基；
    R 1、每一R 4、每一R 5、每一Q 1、每一Q 2、每一L、每一m、Y 3、Y 4、Y 5、Y 6、Y 7的定义如权利要求1-9任一项所定义。
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