WO2020207352A1 - 三嗪酮并咪唑类化合物及其医药用途 - Google Patents

三嗪酮并咪唑类化合物及其医药用途 Download PDF

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WO2020207352A1
WO2020207352A1 PCT/CN2020/083270 CN2020083270W WO2020207352A1 WO 2020207352 A1 WO2020207352 A1 WO 2020207352A1 CN 2020083270 W CN2020083270 W CN 2020083270W WO 2020207352 A1 WO2020207352 A1 WO 2020207352A1
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group
membered
alkyl
aryl
heterocyclic group
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PCT/CN2020/083270
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French (fr)
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陈寿军
宋帅
蒋小玲
唐祖建
田强
宋宏梅
薛彤彤
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN202080014151.6A priority Critical patent/CN113423709B/zh
Publication of WO2020207352A1 publication Critical patent/WO2020207352A1/zh

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicine, and specifically relates to triazinone imidazole compounds, and also relates to the medical use of such compounds.
  • UPS ubiquitin-protease system
  • Deubiquitinating enzymes can specifically cut the isopeptide bond formed between the glycine residue at the carbon end of ubiquitin and the target protein, so that ubiquitin can be separated from the target protein, so that the target protein is prevented from degradation, relocation or activation Wait.
  • DUBs Deubiquitin-specific proteases
  • USPs ubiquitin-specific proteases
  • USP7 is located in the nucleus and is a key deubiquitinating enzyme in UPS. It can specifically cut the isopeptide bond formed between the carbon end of ubiquitin and the target protein, so that ubiquitin can be separated from the target protein and the target protein is Free from degradation, relocation or activation (Turnbull and Immunnidis, Nature, 2017, 550, 481-486).
  • USP7 is widely distributed in human tissues and plays an important role in neurodevelopment, cell cycle regulation, epigenetic regulation, DNA damage repair and immune response. Studies have shown that USP7 is overexpressed in cancer cells such as hepatocellular carcinoma, multiple myeloma, colon cancer, lung cancer, prostate cancer, and bladder cancer, and this overexpression is directly related to tumor invasion and poor prognosis ( Pozhidaeva and Bezsonova, DNA Repair, 2019, 76, 30-39).
  • USP7 has a rich variety of substrates, and most of them are proteins related to cell cycle regulation, immune response, apoptosis, and DNA damage repair, such as MDM2, p53, ERCC6, Foxp3, PTEN, and FOXO4 (Chauhan and Tian, Cancer) Cell, 2012, 22, 345-358). In some tumor cells, MDM2 is overexpressed. USP7 can protect MDM2 from ubiquitination. After MDM2 binds to p53 protein, it promotes its ubiquitination and degradation and promotes tumor growth.
  • USP7 can also directly regulate the expression of tumor suppressor proteins (p53, PTEN, FOXO4, p114ARF, p16INK4) and tumor promoting proteins (N-MYC, REST), up-regulate the expression of tumor-related factors (HIF-1), and regulate tumor-related signals Pathways (SHH signaling pathway, Wnt/ ⁇ -catenin signaling pathway, androgen receptor signaling pathway, DNA damage repair signaling pathway), and play a tumor-promoting effect (Zhou and Wang, Medicinal Chemistry, 2018, 14, 3-18).
  • tumor suppressor proteins p53, PTEN, FOXO4, p114ARF, p16INK4
  • N-MYC, REST tumor promoting proteins
  • USP7 also regulates the upstream signal molecules of Treg cells (such as the transcription factor FOXP3 and the epigenetic regulator Tip60) to up-regulate the activity of Treg cells (Wang and Wu, PLoS One, 2017, 12, 1-23), and inhibit Teff cells ( CD8+T cells) activity, thereby playing the role of tumor immune surveillance escape.
  • Treg cells such as the transcription factor FOXP3 and the epigenetic regulator Tip60
  • the present invention provides triazone-imidazole compounds, which have a strong inhibitory effect on the activity of the deubiquitinating enzyme USP7, have good pharmacokinetic properties, and can be used for the prevention or treatment of cancer diseases. On this basis, the present invention also provides the medical use of triazinone imidazole compounds.
  • the first aspect of the present invention relates to compounds of formula I, their pharmaceutically acceptable salts, esters, solvates (e.g. hydrates), stereoisomers, tautomers, prodrugs, arbitrary crystal forms, metabolites or Their mixture:
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl , 5-12 membered aromatic heterocyclic group and Wherein, the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, 5-12 membered alicyclic group, C 6-10 aryl group and 5 The -12-membered aromatic heterocyclic group is each independently optionally substituted by one or more groups within the range of R 4 ;
  • R 6 Groups within the scope of R 6 include hydrogen, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -OR a , -NR b R c , -C(O) q R 8 , -C(O)NR b R c , -S(O) q R 8 , -S(O) q NR b R c , -O-(C 2-6 alkylene-O) t -R a ,- OC 2-6 alkylene-NR b R c , C 1-6 alkylene, -C 1-6 alkylene-OR a, and -C 1-6 alkylene-NR b R c ;
  • Ring A is selected from C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group, wherein the C 3-8 cycloalkyl group, 5 The -12-membered aliphatic heterocyclic group, the C 6-10 aryl group and the 5-12-membered aromatic heterocyclic group are each independently optionally substituted by one or more groups within the range of R;
  • Ring B is selected from C 4-6 cycloalkenyl, C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, 5-12 membered alicyclic group, oxo 5-12 membered alicyclic ring Group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group, wherein the C 3-8 cycloalkyl group, oxo C 3-8 cycloalkyl group, 5-12 membered alicyclic group, The oxo 5-12 membered aliphatic heterocyclic group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group are each independently optionally substituted by one or more groups within the range of R 5 ;
  • Groups in the range of R include hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, halogen, cyano, -OR d and -NR e R f ;
  • Groups in the range of R 5 include hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6- 10 aryl, 5-12 membered aromatic heterocyclic group, -OR d , -NR e R f , halogen, cyano, -C(O) q R 9 , -C(O)NR e R f , -S( O) q R 9 , -S(O) q NR e R f , -O-(C 2-6 alkylene-O) t -R d and -OC 2-6 alkylene-NR e R f , Wherein, the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, 5-12 membered alicyclic group, C 6-10 aryl group and
  • Groups in the K range include hydrogen, halogen, cyano, C 1-6 alkyl, -OR d , -NR e R f , -C (O) q R 10 , -C (O) NR e R f ,- S(O) q R 10 and -S(O) q NR e R f ;
  • R a, R b, R c , R d, R e and R f are each independently selected from hydrogen, -C (O) q R 11 , -S (O) q R 11, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group, wherein C 1-6 alkyl, C 6-10 aryl and 5-12 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: hydrogen, halogen, amino, hydroxy;
  • R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-12 membered aliphatic heterocyclic group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: hydrogen , Halogen, cyano, amino, hydroxy, C 1-6 alkyl;
  • R 2 is selected from hydrogen, cyano, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-8 cycloalkyl and 5-12 membered alicyclic group;
  • R 3 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl group, 5-12 membered aromatic heterocyclic group, -C (O ) q R 12 , -C(O)NR g R h , -S(O) q R 12 and -S(O) q NR g R h , wherein the C 1-6 alkyl group, C 3-8 Cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 6-10 aryl, halogenated C 6-10 aryl, 5-12 membered aromatic heterocyclic group, halogenated 5-12 membered aromatic Heterocyclic group, C 3-8 cycloalky
  • R 12 is selected from hydrogen, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 Aryl, 5-12 membered aromatic heterocyclic group, C 3-8 cycloalkyl and C 6-10 aryl group, C 3-8 cycloalkyl and 5-12 membered aromatic heterocyclic group, 5-12 membered heterocyclic group Cyclic group C 6-10 aryl group, 5-12 membered aromatic heterocyclic group 5-12 membered alicyclic group, wherein the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2- 6 alkynyl, C 3-8 cycloalkyl, 5-12 membered aliphatic heterocyclic group, C 6-10 aryl, 5-12 membered aromatic heterocyclic group, C 3-8 cycloalkyl and C 6-10 aryl Group, C 3-8 cycloalkyl and
  • Groups in the range of R 13 include hydrogen, amino, cyano, halogen, -OR j , -NR k R m , -C(O) q R 14 , -C(O)NR k R m , -S(O) q R 14 , -S(O) q NR k R m , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, -C 1-6 alkylene alkyl - (C 6- 10 aryl), C 6-10 aryl, 5-12 membered aromatic heterocyclyl -C 1-6 alkylene and - (5-12 membered aromatic heterocyclic group), wherein, The amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, -C 1-6 alkylene-(C 6-10 aryl) , C 6-10 aryl,
  • R 14 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl group, 5-12 membered aromatic heterocyclic group and C 2-6 Alkenyl, wherein the C 1-6 alkyl, C 2-6 alkenyl and 5-12 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: halogen, C 1-6 alkyl, C 6-10 aryl, and 5-12 membered aromatic heterocyclic group optionally substituted by C 1-6 alkyl;
  • R g , R h , R j , R k and R m are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aliphatic 5-12 membered heterocyclyl, C 6-10 aryl and 5-12-membered aromatic heterocyclic group, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl group, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: hydrogen , Halogen, amino, hydroxyl, 4-8 membered aliphatic heterocyclic group;
  • n is selected from 1, 2, 3, 4, 5, 6, 7 and 8;
  • n 1 and n 2 are each independently selected from 0, 1 and 2;
  • q is selected from 1 and 2;
  • r is selected from 1, 2 and 3;
  • t is selected from 1, 2, 3, and 4.
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-8 membered alicyclic group, C 6-10 aryl, 5- 8-membered aromatic heterocyclic group and wherein, the C 1-6 alkyl group, C 3-8 cycloalkyl group, 5-8 membered alicyclic group, C 6-10 aryl group and 5-8 membered aromatic heterocyclic group are each independently optionally Substituted by one or more groups within R 4 ;
  • Groups in the range of R 4 include hydrogen, halogen, oxo, -OR a , -NR b R c , -C(O) q R 7 , -C(O)NR b R c , -S(O) q R 7 , -S(O) q NR b R c , -O-(C 2-6 alkylene-O) t -R a , -OC 2-6 alkylene-NR b R c , C 1- 6 alkyl group, C 3-8 cycloalkyl group, 5-8 membered alicyclic group, C 6-10 aryl group and 5-8 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 3-8 cycloalkyl, 5-8 membered alicyclic group, C 6-10 aryl group and 5-8 membered aromatic heterocyclic group are each independently optionally substituted by one or more groups within the range of R 6 ;
  • R 6 Groups within the scope of R 6 include hydrogen, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -OR a , -NR b R c , -C(O) q R 8 , -C(O)NR b R c , -S(O) q R 8 , -S(O) q NR b R c , -O-(C 2-6 alkylene-O) t -R a ,- OC 2-6 alkylene-NR b R c , -C 1-6 alkylene-OR a and -C 1-6 alkylene-NR b R c ;
  • Ring A is selected from C 6-10 aryl groups and 5-8 membered aromatic heterocyclic groups.
  • the C 6-10 aryl groups and 5-8 membered aromatic heterocyclic groups are each independently optionally selected by one or more of R Substituted by a group;
  • Ring B is selected from C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, 5-8 membered alicyclic group, oxo 5-8 membered alicyclic group and 5-8 membered heterocyclic group Cyclic group, wherein the C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, 5-8 membered alicyclic group, oxo 5-8 membered alicyclic group and 5-8 Each membered aromatic heterocyclic group is independently optionally substituted with one or more groups within the scope of R 5 ;
  • Groups in the range of R include hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, halogen, cyano, -OR a and -NR b R c ;
  • Groups in the range of R 5 include hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-8 membered alicyclic group, C 6- 10 aryl, 5-8 membered aromatic heterocyclic group, -OR d , -NR e R f , halogen, cyano, -C(O) q R 9 , -C(O)NR e R f , -S( O) q R 9 , -S(O) q NR e R f , -O-(C 2-6 alkylene-O) t -R d and -OC 2-6 alkylene-NR e R f , Wherein, the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, 5-8 membered alicyclic group, C 6-10 aryl group,
  • Groups in the K range include hydrogen, halogen, cyano, C 1-6 alkyl, -OR d , -NR e R f , -C (O) q R 10 , -C (O) NR e R f ,- S(O) q R 10 and -S(O) q NR e R f ;
  • R a, R b, R c , R d, R e and R f are each independently selected from hydrogen, -C (O) q R 11 , -S (O) q R 11, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-8 membered alicyclic group, C 6-10 aryl group and 5-8 membered aromatic heterocyclic group, wherein the C 1-6 alkyl, C 6-10 aryl and 5-8 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: hydrogen, halogen, amino, hydroxy;
  • R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-8 membered aliphatic heterocyclic group, C 6-10 aryl, and 5-8 membered aromatic heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl group, C 3-8 cycloalkyl, 5-8 membered alicyclic group, C 6-10 aryl group and 5-8 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: halogen , Cyano, amino, hydroxyl, C 1-6 alkyl;
  • q is selected from 1 and 2;
  • t is selected from 1, 2, 3 and 4;
  • r is selected from 1, 2 and 3;
  • n is selected from 1, 2, 3, 4, 5, 6, 7, and 8.
  • R 1 is selected from C 6-10 aryl, 5-8 membered aromatic heterocyclic group and Wherein, the C 6-10 aryl group and the 5-8 membered aromatic heterocyclic group are each independently optionally substituted by one or more groups within the range of R 4 ;
  • Groups in the range of R 4 include hydrogen, halogen, -OR a , -NR b R c , -C (O) q R 7 , -C (O) NR b R c , -S (O) q R 7 ,- S(O) q NR b R c , C 1-6 alkyl, C 3-8 cycloalkyl, 5-8 membered alicyclic group, C 6-10 aryl group and 5-8 membered aromatic heterocyclic group, wherein, the C 1-6 alkyl group, C 3-8 cycloalkyl group, 5-8 membered alicyclic group, C 6-10 aryl group, 5-8 membered aromatic heterocyclic group are each independently optionally Substituted by one or more groups within the range of R 6 ;
  • Groups in the range of R 6 include hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -OR a , -NR b R c , -C(O) q R 8 , -S( O) q R 8 , -C 1-6 alkylene-OR a and -C 1-6 alkylene-NR b R c ;
  • Ring A is a phenyl group, and the phenyl group is optionally substituted by one or more groups within the scope of R;
  • Ring B is selected from C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, 5-8 membered alicyclic group, oxo 5-8 membered alicyclic group and 5-8 membered heterocyclic group Cyclic group, wherein the C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, 5-8 membered alicyclic group, oxo 5-8 membered alicyclic group and 5-8 Each membered aromatic heterocyclic group is independently optionally substituted with one or more groups within the scope of R 5 ;
  • Groups in the range of R include: hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, halogen, cyano;
  • Groups in the range of R 5 include: hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -OR d , -NR e R f and halogen;
  • R a , R b and R c are each independently selected from hydrogen, -C (O) q R 11 , -S (O) q R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2- 6- alkynyl, C 3-8 cycloalkyl, 5-8 membered aliphatic heterocyclic group, C 6-10 aryl and 5-8 membered aromatic heterocyclic group, wherein the C 1-6 alkyl, C 6 --10 aryl, 5-8 membered aromatic heterocyclic group are each independently optionally one or more of the following substituents: hydrogen, halogen, amino, hydroxy;
  • R d , R e and R f are each independently selected from hydrogen and C 1-6 alkyl;
  • R 7 , R 8 and R 11 are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-8 membered aliphatic hetero cycloalkyl group, C 6-10 aryl, and 5-8 membered aromatic heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 8 cycloalkyl Group, 5-8 membered alicyclic group, C 6-10 aryl group, 5-8 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: hydrogen, halogen, cyano, Amino, hydroxyl, C 1-6 alkyl;
  • q is selected from 1 and 2;
  • t is selected from 1, 2, 3 and 4;
  • r is selected from 1, 2 and 3;
  • n is selected from 1 and 2.
  • R 1 is selected from phenyl, p-fluorophenyl, p-chlorophenyl, p-aminophenyl, p-hydroxyphenyl,
  • R 1 is selected from C 6-10 aryl, 5-8 membered aromatic heterocyclic group and Wherein, the C 6-10 aryl group and the 5-8 membered aromatic heterocyclic group are each independently optionally substituted by one or more groups within the range of R 4 ;
  • Groups in the range of R 4 include halogen, -OR a , C 1-6 alkyl, 5-8 membered alicyclic group and 5-8 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, The 5-8 membered aliphatic heterocyclic group and the 5-8 membered aromatic heterocyclic group are each independently optionally substituted by one or more groups within the range of R 6 ;
  • Groups in the range of R 6 include halogen, C 1-6 alkyl, -OR a and -NR b R c ;
  • Ring A is a phenyl group, which is optionally substituted by one or more groups within the scope of R;
  • Ring B is selected from C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, 5-8 membered alicyclic group, oxo 5-8 membered alicyclic group and 5-8 membered heterocyclic group Cyclic group, wherein the C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, 5-8 membered alicyclic group, oxo 5-8 membered alicyclic group and 5-8 Each membered aromatic heterocyclic group is independently optionally substituted with one or more groups within the scope of R 5 ;
  • Groups in the range of R include: hydrogen, C 1-6 alkyl and halogen;
  • Groups in the range of R 5 include: hydrogen, C 1-6 alkyl, -OR d and -NR e R f ;
  • R a , R b and R c are each independently selected from hydrogen and C 1-6 alkyl;
  • R d , R e and R f are each independently selected from hydrogen and C 1-6 alkyl;
  • r 1 and 2;
  • n is selected from 1 and 2.
  • R 1 is selected from phenyl, p-fluorophenyl, p-chlorophenyl, p-hydroxyphenyl,
  • R 1 is selected from C 6-10 aryl and Wherein said C 6- 10 aryl is optionally substituted with one or more radicals R 4 of the range;
  • Groups in the range of R 4 include -OR a and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by one or more -NR b R c groups;
  • Ring A is a phenyl group, which is optionally substituted by one or more groups within the range of R;
  • Ring B is selected from a C 3-8 cycloalkyl group and a 5-8 membered alicyclic heterocyclic group, wherein the C 3-8 cycloalkyl group and a 5-8 membered alicyclic heterocyclic group are each independently optionally ranged by R 5 Is substituted by one or more groups within;
  • Groups in the R range include hydrogen;
  • Groups in the range of R 5 include hydrogen, -NR e R f ;
  • R a , R b and R c are each independently hydrogen
  • R e and R f are each independently selected from hydrogen and C 1-6 alkyl
  • n is selected from 1 and 2.
  • R 1 is selected from p-hydroxyphenyl
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-8 membered alicyclic group, C 6-10 aryl and 5- 8-membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 3-8 cycloalkyl group, 5-8 membered aliphatic heterocyclic group, C 6-10 aryl group and 5-8 membered aromatic heterocyclic group Each of the groups is independently optionally substituted with one or more groups within the scope of R 4 ;
  • Groups in the range of R 4 include hydrogen, halogen, oxo, -OR a , -NR b R c , -C(O) q R 7 , -C(O)NR b R c , -S(O) q R 7 , -S(O) q NR b R c , -O-(C 2-6 alkylene-O) t -R a , -OC 2-6 alkylene-NR b R c , C 1- 6 alkyl group, C 3-8 cycloalkyl group, 5-12 membered alicyclic group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group are each independently optionally substituted by one or more groups within the range of R 6 ;
  • R 6 Groups within the scope of R 6 include hydrogen, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -OR a , -NR b R c , -C(O) q R 8 , -C(O)NR b R c , -S(O) q R 8 , -S(O) q NR b R c , -O-(C 2-6 alkylene-O) t -R a ,- OC 2-6 alkylene-NR b R c , -C 1-6 alkylene-OR a and -C 1-6 alkylene-NR b R c ;
  • R a , R b , and R c are each independently selected from hydrogen, -C (O) q R 11 , -S (O) q R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2- 6- alkynyl group, C 3-8 cycloalkyl group, 5-12 membered alicyclic group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 6 The -10 aryl group and the 5-12 membered heterocyclic group are each independently optionally substituted by one or more of the following substituents: hydrogen, halogen, amino, and hydroxyl;
  • R 7 , R 8 and R 11 are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-12 membered aliphatic hetero Cyclic groups, C 6-10 aryl groups and 5-12 membered aromatic heterocyclic groups, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkane Group, 5-12 membered aliphatic heterocyclic group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: halogen, cyano, amino, Hydroxy, C 1-6 alkyl;
  • q is selected from 1 and 2;
  • t is selected from 1, 2, 3, and 4.
  • R 1 is selected from C 6-10 aryl and a 5-8 membered aromatic heterocyclyl group, the C 6- 10 aryl, 5-8 membered aromatic heterocyclic group each Independently optionally substituted by one or more groups within the range of R 4 ;
  • Groups in the range of R 4 include hydrogen, halogen, -OR a , -NR b R c , -C (O) q R 7 , -C (O) NR b R c , -S (O) q R 7 ,- S(O) q NR b R c , C 1-6 alkyl, C 3-8 cycloalkyl, 5-10 membered alicyclic group, C 6-10 aryl group and 5-8 membered aromatic heterocyclic group, wherein, the C 1-6 alkyl, C 3-8 cycloalkyl, 5-10 membered alicyclic group, C 6-10 aryl group, 5-8 membered aromatic heterocyclic group are each independently optionally Substituted by one or more groups within the range of R 6 ;
  • Groups in the range of R 6 include hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -OR a , -NR b R c , -C(O) q R 8 , -S( O) q R 8 , -C 1-6 alkylene-OR a and -C 1-6 alkylene-NR b R c ;
  • R a , R b , and R c are each independently selected from hydrogen, -C (O) q R 11 , -S (O) q R 11 , C 1-3 alkyl, C 2-6 alkenyl, C 2- 6- alkynyl, C 3-8 cycloalkyl, 5-10 membered aliphatic heterocyclic group, C 6-10 aryl group and 5-8 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 6 The -10 aryl group and the 5-8 membered heterocyclic group are each independently optionally substituted by one or more of the following substituents: hydrogen, halogen, amino, hydroxy;
  • R 7 , R 8 and R 11 are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-10 membered aliphatic hetero Cyclic groups, C 6-10 aryl groups and 5-8 membered aromatic heterocyclic groups, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkane Group, 5-10 membered aliphatic heterocyclic group, C 6-10 aryl group, and 5-8 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: hydrogen, halogen, cyano, Amino, hydroxyl, C 1-6 alkyl;
  • q is selected from 1 and 2;
  • t is selected from 1, 2, 3, and 4.
  • R 1 is selected from the group consisting of phenyl, pyridyl, pyrimidinyl and pyrazinyl, and each of said phenyl, pyridyl, pyrimidinyl and pyrazinyl is independently optionally selected by R 4 substituted by one or more groups within the scope;
  • Groups in the range of R 4 include hydrogen, halogen, -OR a , -NR b R c , C 1-6 alkyl, 5-8 membered aliphatic heterocyclic group, C 6-10 aryl group and 5-6 membered aromatic hetero Cyclic group, wherein the C 1-6 alkyl group, 5-8 membered alicyclic group, C 6-10 aryl group, 5-6 membered aromatic heterocyclic group are each independently optionally selected by one of R 6 Or multiple groups;
  • Groups in the range of R 6 include hydrogen, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl, -OR a and -NR b R c ;
  • R a , R b , and R c are each independently selected from hydrogen, -C (O) q R 11 , -S (O) q R 11 , C 1-3 alkyl, C 2-6 alkenyl, C 2- 6- alkynyl group, C 3-8 cycloalkyl group, 5-8 membered alicyclic group, C 6-10 aryl group and 5-6 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 6 --10 aryl, and 5-6 membered aromatic heterocyclic group are each independently optionally one or more of the following substituents: hydrogen, halogen, amino, hydroxy;
  • R 11 is selected from hydrogen, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-8 membered alicyclic group, C 6-10 aryl And 5-6 membered aromatic heterocyclic group, wherein the C 1-3 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, 5-8 membered alicyclic heterocyclic group Group, C 6-10 aryl group, 5-6 membered heterocyclic group are each independently optionally substituted by one or more of the following groups: hydrogen, halogen, cyano, amino, hydroxy, C 1-6 alkyl ;
  • q is selected from 1 or 2.
  • R 1 is selected from phenyl, pyridyl, pyrazinyl and pyrimidinyl, wherein said phenyl, pyridyl, pyrazinyl and pyrimidinyl are each independently optionally is substituted with one or more radicals R 4 of the range; the range of R 4 groups include hydrogen, halogen (e.g. F, Cl), - OH, -OCH 3, -NH 2, -NHCH 3, -N ( CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 ,
  • halogen e.g. F, Cl
  • R 1 is selected from phenyl, pyridyl and pyrimidinyl, wherein said phenyl, pyridyl and pyrimidinyl are each independently optionally within a range of the R 4 or Multiple groups are substituted; groups in the range of R 4 include hydrogen, halogen (for example, F, Cl), -OH, -OCH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 ,
  • groups in the range of R 4 include hydrogen, halogen (for example, F, Cl), -OH, -OCH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 ,
  • R 1 is selected from phenyl, pyridyl, pyrazinyl and pyrimidinyl, wherein said phenyl, pyridyl, pyrazinyl and pyrimidinyl are each independently optionally is substituted with one or more radicals R 4 of the range; the range of R 4 groups include halogen (e.g. F, Cl), - OH, -OCH 3, -NH 2, -CH 2 NH 2, -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 ,
  • halogen e.g. F, Cl
  • R 1 is selected from phenyl, pyridyl and pyrimidinyl, wherein said phenyl, pyridyl and pyrimidinyl are each independently optionally within a range of the R 4 or Multiple groups are substituted; groups in the range of R 4 include halogen (for example, F, Cl), -OH, -OCH 3 , -NH 2 , -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N( CH 3 ) 2 ,
  • R 1 is selected from phenyl, p-fluorophenyl, p-chlorophenyl, p-aminophenyl, p-hydroxyphenyl,
  • R 1 is among them
  • Ring A is selected from C 6-10 aryl groups and 5-12 membered aromatic heterocyclic groups.
  • the C 6-10 aryl groups and 5-12 membered aromatic heterocyclic groups are each independently optionally selected by one or more of R Substituted by a group;
  • Groups in the range of R include hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, halogen, cyano, -OR a and -NR b R c ;
  • R a , R b , and R c are each independently selected from hydrogen, -C (O) q R 11 , -S (O) q R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2- 6- alkynyl group, C 3-8 cycloalkyl group, 5-12 membered alicyclic group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 6 The -10 aryl group and the 5-12 membered heterocyclic group are each independently optionally substituted by one or more of the following substituents: hydrogen, halogen, amino, hydroxy;
  • R 11 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-12 membered aliphatic heterocyclic group, C 6-10 aryl And 5-12 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, 5-12 membered alicyclic heterocyclic group Group, C 6-10 aryl group, 5-12 membered heterocyclic aromatic group are each independently optionally substituted by one or more of the following substituents: hydrogen, halogen, cyano, amino, hydroxyl, C 1-6 alkane base;
  • q is selected from 1 and 2;
  • r is selected from 1, 2 and 3.
  • ring A is a C 6-10 aryl group, and the C 6-10 aryl group is optionally substituted by one or more groups within the range of R;
  • Groups in the range of R include hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, halogen, cyano, -OR a , -NR b R c ;
  • R a , R b , R c are independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl and 5-12 membered aromatic A heterocyclic group, wherein the C 1-6 alkyl group, C 3-8 cycloalkyl group, 5-12 membered alicyclic group, C 6-10 aryl group, and 5-12 membered aromatic heterocyclic group are each independently Optionally substituted by one or more of the following groups: hydrogen, halogen, amino, hydroxyl;
  • r is selected from 1, 2 and 3.
  • the A ring is a phenyl group, and the phenyl group is optionally substituted by one or more groups within the range of R; groups within the range of R include hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl, halogen, cyano; r is selected from 1, 2 and 3.
  • the A ring is selected from phenyl and chlorophenyl.
  • the A ring is phenyl.
  • R 1 is among them
  • Ring B is selected from the group consisting of C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, 5-12 membered alicyclic group and oxo 5-12 membered alicyclic group, wherein the C 3 -8 cycloalkyl, oxo C 3-8 cycloalkyl, 5-12 membered alicyclic group, oxo 5-12 membered alicyclic group are each independently optionally selected by one of R 5 or Replaced by multiple groups;
  • Groups in the range of R 5 include hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6- 10 aryl, 5-12 membered aromatic heterocyclic group, -OR d , -NR e R f , halogen, cyano, -C(O) q R 9 , -C(O)NR e R f , -S( O) q R 9 , -S(O) q NR e R f , -O-(C 2-6 alkylene-O) t -R d and -OC 2-6 alkylene-NR e R f , Wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl, 5 The -12-
  • Groups in the K range include hydrogen, halogen, cyano, C 1-6 alkyl, -OR d , -NR e R f , -C (O) q R 10 , -C (O) NR e R f ,- S(O) q R 10 and -S(O) q NR e R f ;
  • R d , R e and R f are each independently selected from hydrogen, -C (O) q R 11 , -S (O) q R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2- 6- alkynyl group, C 3-8 cycloalkyl group, 5-12 membered alicyclic group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 6 The -10 aryl group and the 5-12 membered heterocyclic group are each independently optionally substituted by one or more of the following substituents: hydrogen, halogen, amino, hydroxy;
  • R 9 , R 10 , R 11 are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-12 membered aliphatic hetero Cyclic groups, C 6-10 aryl groups and 5-12 membered aromatic heterocyclic groups, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkane Group, 5-12 membered alicyclic group, C 6-10 aryl group, 5-12 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: hydrogen, halogen, cyano, Amino, hydroxyl, C 1-6 alkyl;
  • n is selected from 1, 2, 3, 4, 5, 6, 7 and 8;
  • q is selected from 1 and 2;
  • t is selected from 1, 2, 3, and 4.
  • ring B is selected from the group consisting of C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, 5-12 membered alicyclic and oxo 5-12 membered Aliphatic heterocyclic group, wherein the C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, 5-12 membered alicyclic group, and oxo 5-12 membered alicyclic group are independently Is optionally substituted with one or more groups within the range of R 5 ;
  • Groups in the range of R 5 include hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, -OR d , -NR e R f , halogen, cyano, -C (O) q R 9 , -C(O)NR e R f , -S(O) q R 9 , -S(O) q NR e R f , -O-(C 2-6 alkylene-O ) t -R d and -OC 2-6 alkylene-NR e R f , wherein the C 1-6 alkyl group, C 3-8 cycloalkyl group and 5-12 membered alicyclic group are each independently Optionally substituted by one or more of the following groups: hydrogen, halogen and C 1-6 alkyl;
  • R d, R e, R f and R 9 are each independently selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 3-8 halogenated Cycloalkyl
  • n is selected from 1, 2 and 3;
  • q is selected from 1 and 2;
  • t is selected from 1, 2, 3, and 4.
  • ring B is selected from the group consisting of C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, 5-12 membered alicyclic and oxo 5-12 membered Aliphatic heterocyclic group, wherein the C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, 5-12 membered alicyclic group, and oxo 5-12 membered alicyclic group are independently Is optionally substituted with one or more groups within the range of R 5 ;
  • Groups within the scope of R 5 include hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -OR d , -NR e R f , halogen, -C(O) q R 9 , -C (O)NR e R f , -S(O) q R 9 and -S(O) q NR e R f ;
  • R d, R e, R f and R 9 are each independently selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl and C 3-8 cycloalkyl;
  • n 1 and 2;
  • q is selected from 1 and 2.
  • ring B is selected from C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, oxo 5-10 membered alicyclic group and 5-10 membered Aliphatic heterocyclic group, wherein the C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, oxo 5-10 membered alicyclic group and 5-10 membered aliphatic heterocyclic group are each independently Is optionally substituted by one or more groups within the range of R 5 ; preferably, ring B is selected from C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl and 5-10 membered aliphatic hetero Cyclic group, wherein the C 3-8 cycloalkyl group, the oxo C 3-8 cycloalkyl group and the 5-10 membered alicyclic group are each independently optionally selected by one or more groups within the range of R 5 Group
  • Groups in the range of R 5 include hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -OR d , -NR e R f , halogen, -C(O) q R 9 , -C( O)NR e R f , -S(O) q R 9 and -S(O) q NR e R f ;
  • R d, R e, R f and R 9 are each independently selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl and C 3-8 cycloalkyl; m is selected from 1 and 2; q is selected from 1 and 2.
  • ring B is selected from the group consisting of C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, oxo 5-8 membered alicyclic and 5-8 membered Aliphatic heterocyclic group, wherein the C 3-8 cycloalkyl, oxo C 3-8 cycloalkyl, 5-8 membered alicyclic group, and oxo 5-8 membered alicyclic group are each independently are optionally substituted with one or more radicals R 5 within the range; range R 5 groups include hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, -OR d, -NR e R f, and halo, wherein, R d, R e, R f are each independently selected from hydrogen and C 1-6 alkyl; m is selected from 1 and 2;
  • B ring is selected from C 3-8 cycloalkyl, C 3-8 oxo-cycloalkyl and 5-8 membered aliphatic heterocyclyl, wherein said C 3- 8 cycloalkyl, oxo C 3-8 cycloalkyl, and 5-8 membered aliphatic heterocyclic group are each independently optionally substituted with one or more radicals R 5 within the range; range R 5 groups include hydrogen, C 1-6 alkyl Group, halogenated C 1-6 alkyl, -OR d , -NR e R f and halogen, wherein R d , R e , R f are each independently selected from hydrogen and C 1-6 alkyl; m is selected Since 1 and 2.
  • ring B is selected from C 5-6 cycloalkyl, oxo C 5-6 cycloalkyl, oxo 5-6 membered alicyclic and 5-6 membered Aliphatic heterocyclic group, wherein the C 5-6 cycloalkyl, oxo C 5-6 cycloalkyl, oxo 5-6 membered alicyclic group and 5-6 membered aliphatic heterocyclic group are each independently are optionally substituted with one or more radicals R 5 within the range; range R 5 groups include hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl, -OR d, -NR e R f and halo; R d, R e and R f are each independently selected from hydrogen and C 1-3 alkyl; m is selected from 1 and 2.
  • ring B is selected from the group consisting of cyclopentyl, oxocyclopentyl, oxolanyl, oxoazolyl, azolyl And pyrazolyl, wherein the cyclopentyl, oxocyclopentyl, oxolanyl, oxoazolyl and azolyl groups are each independently optionally One or more groups within the range of R 5 are substituted; groups within the range of R 5 include hydrogen, C 1-3 alkyl, -OR d and -NR e R f ; R d , R e and R f are each independent Ground is selected from hydrogen and C 1-3 alkyl; m is selected from 1 and 2.
  • ring B is selected from cyclopentanyl, oxocyclopentanyl, oxolanyl and azepanyl, wherein the cyclopentanyl, oxocyclopentane group, oxolanyl group and azacyclopentane each independently optionally substituted with R 5 within a range of one or more groups;
  • R 5 groups include a range of hydrogen, C 1-3 alkyl, -OR d, and -NR e R f;
  • R d, R e and R f are each independently selected from hydrogen and C 1-3 alkyl;
  • m is selected from 1 and 2.
  • ring B is selected from the group consisting of cyclopentyl, oxocyclopentyl, oxolanyl, 2-pyrrolidone, azepanyl and pyrazolyl, wherein, the cyclopentyl group, oxocyclopentyl group, oxolanyl group, 2-pyrrolidone group, and azepanyl group are each independently optionally substituted by one or more groups within the range of R 5 Groups in the range of R 5 include hydrogen, methyl, -OH, amino, -NHCH 3 and -N(CH 3 ) 2 ; m is selected from 1 and 2.
  • ring B is selected from cyclopentanyl, oxocyclopentanyl, oxolanyl and azepanyl, wherein the cyclopentanyl, oxocyclopentane group, oxolane group, azacyclopentane group is independently optionally substituted with one or more R 5 groups within the range; range R 5 groups include hydrogen, methyl Group, -OH, amino, -NHCH 3 and -N(CH 3 ) 2 ; m is selected from 1 and 2.
  • the B ring is selected from cyclopentyl, oxocyclopentyl, 2-pyrrolidonyl, azepanyl and pyrazolyl, wherein the cyclopentane group, oxo group cyclopentane, 2-pyrrolidone-yl, azepin-pyrazolyl group, and cyclopentane are each independently optionally substituted with one or more radicals R 5 within the range; range R 5 group Including methyl, -OH, amino, -NHCH 3 and -N(CH 3 ) 2 ; m is selected from 1 and 2.
  • ring B is selected from the group consisting of cyclopentyl, oxocyclopentyl and azepanyl, wherein the cyclopentyl, oxocyclopentyl and azacyclopentane group is independently optionally substituted with one or more R 5 groups within the range; range R 5 groups include methyl, -OH, amino, -NHCH 3 and -N (CH 3 ) 2 ; m is selected from 1 and 2.
  • R 1 is selected from
  • R 1 is selected from the following structures:
  • R 2 is selected from hydrogen, cyano, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; preferably, R 2 is selected from hydrogen, cyano , Halogen and C 1-3 alkyl; preferably, R 2 is selected from hydrogen, cyano and chlorine; more preferably, R 2 is hydrogen.
  • R 3 is selected from -C(O) q R 12 , -C(O)NR g R h , -S(O) q R 12 and -S(O) q NR g R h ;
  • R 12 is selected from amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 3-8 cycloalkyl group, 5-12 membered alicyclic group, C 6-10 aryl group, 5-12 membered aromatic hetero Cyclic group, C 3-8 cycloalkyl and C 6-10 aryl, C 3-8 cycloalkyl and 5-12 membered aromatic heterocyclic group, 5-12 membered aliphatic heterocyclic group and C 6-10 aryl And 5-12 membered aliphatic heterocyclic group and 5-12 membered aromatic heterocyclic group, wherein the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 3-8 cycloalkyl group, 5-12 membered aliphatic heterocyclic group, 5-12-membered aromatic heterocyclic group, C 6-10 aryl, C 3-8 cycloalkyl and C 6-10 aryl group, C 3- 8 cycloalkyl, aryl and 5-12 membere
  • Groups in the range of R 13 include hydrogen, amino, cyano, halogen, -OR j , -NR k R m , -C(O) q R 14 , -C(O)NR k R m , -S(O) q R 14 , -S(O) q NR k R m , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl , -C 1-6 alkylene-(C 6-10 aryl), 5-12 membered aromatic heterocyclic group and -C 1-6 alkyl-(5-12 membered aromatic heterocyclic group), wherein said amino, C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, -C 1-6 alkylene - (C 6-10 aryl), 5-12 membered aromatic
  • R 14 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl group, 5-12 membered aromatic heterocyclic group and C 2-6 Alkenyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and 5-12 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: halogen, C 1 -6 alkyl, C 6-10 aryl, and 5-12 membered aromatic heterocyclic group optionally substituted by C 1-6 alkyl;
  • R g , R h , R j , R k , R m are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aliphatic 5-12 membered heterocyclyl, C 6-10 aryl and 5-12-membered aromatic heterocyclic group, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl group, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: hydrogen , Halogen, amino, hydroxyl; q is selected from 1 and 2.
  • R 3 is selected from -C(O) q R 12 , -C(O)NR g R h , -S(O) q R 12 and -S(O) q NR g R h ;
  • R 12 is selected from amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 3-8 cycloalkyl group, 5-12 membered alicyclic group, C 6-10 aryl group, 5-12 membered aromatic hetero Cyclic group, C 3-8 cycloalkyl and C 6-10 aryl, C 3-8 cycloalkyl and 5-12 membered aromatic heterocyclic group, 5-12 membered aliphatic heterocyclic group and C 6-10 aryl And 5-12 membered aliphatic heterocyclic group and 5-12 membered aromatic heterocyclic group, wherein the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 3-8 cycloalkyl group, 5-12 membered aliphatic heterocyclic group, 5-12-membered aromatic heterocyclic group, C 6-10 aryl, C 3-8 cycloalkyl and C 6-10 aryl group, C 3- 8 cycloalkyl, aryl and 5-12 membere
  • Groups in the range of R 13 include hydrogen, amino, halogen, -OR j , -NR k R m , -C(O) q R 14 , -C(O)NR k R m , -S(O) q R 14 , -S(O) q NR k R m , C 1-6 alkyl, C 3-8 cycloalkyl, -C 1-6 alkylene-(C 6-10 aryl), -C 1-6 Alkyl-(5-12 membered aromatic heterocyclic group), C 6-10 aryl group and 5-12 membered aromatic heterocyclic group, wherein the amino group, C 1-6 alkyl group, C 3-8 cycloalkyl group , C 6-10 aryl, 5-12 membered aromatic heterocyclic group, -C 1-6 alkylene-(C 6-10 aryl) and -C 1-6 alkyl-(5-12 membered aromatic hetero Cyclic groups) are each independently optionally substituted
  • R 14 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl group, 5-12 membered aromatic heterocyclic group and C 2-6 Alkenyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and 5-12 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: halogen, C 1 -6 alkyl, C 6-10 aryl, 5-12 membered aromatic heterocyclic group optionally substituted by C 1-6 alkyl;
  • R g , R h , R j , R k , R m are each independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aromatic Group and 5-12 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 3-8 cycloalkyl group, 5-12 membered alicyclic group, C 6-10 aryl group and 5-12 membered
  • the aromatic heterocyclic groups are each independently optionally substituted by one or more of the following substituents: hydrogen, halogen, amino, hydroxy; q is selected from 1 and 2.
  • R 3 is selected from -C(O) q R 12 and -S(O) q R 12 ;
  • R 12 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl group, 5-12 membered aromatic heterocyclic group , C 3-8 cycloalkyl and C 6-10 aryl, C 3-8 cycloalkyl and 5-12 membered aromatic heterocyclic group, 5-12 membered aliphatic heterocyclic group and C 6-10 aryl and 5 -12 membered aliphatic heterocyclic group and 5-12 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 3-8 cycloalkyl group, 5-12 membered alicyclic heterocyclic group Group, C 6-10 aryl, 5-12 membered aromatic heterocyclic group, C 3-8 cycloalkyl and C 6-10 aryl, C 3-8 cycloalkyl and 5-12 membered aromatic heterocyclic group, 5-12 membered
  • Groups in the range of R 13 include hydrogen, amino, halogen, -OR j , -NR k R m , -C (O) q R 14 , -S (O) q R 14 , C 1-6 alkyl, C 3 -8 cycloalkyl, -C 1-6 alkylene-(C 6-10 aryl), -C 1-6 alkyl-(5-12 membered aromatic heterocyclyl), C 6-10 aryl and 5-12 membered aromatic heterocyclic group, wherein the amino group, C 1-6 alkyl group, C 3-8 cycloalkyl group, C 6-10 aryl group, 5-12 membered aromatic heterocyclic group, -C 1- 6 alkylene-(C 6-10 aryl), -C 1-6 alkyl-(5-12 membered aromatic heterocyclic group) are each independently optionally substituted by one or more of the following groups: hydrogen , Halogen, C 1-6 alkyl, C 6-10 aryl, C 6-10
  • R 14 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl group, 5-12 membered aromatic heterocyclic group and C 2-6 Alkenyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and 5-12 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: halogen, C 1 -6 alkyl, C 6-10 aryl, 5-12 membered aromatic heterocyclic group optionally substituted by C 1-6 alkyl;
  • R j , R k , R m are each independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl and 5-12 membered Aromatic heterocyclic group; q is selected from 1 and 2.
  • R 3 is -C(O)R 12 ;
  • R 12 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, 5-10 membered alicyclic group, C 6-10 aryl group, 5-10 membered aromatic heterocyclic group , C 3-8 cycloalkyl and C 6-10 aryl, C 3-8 cycloalkyl and 5-10 membered aromatic heterocyclic group, 5-10 membered aliphatic heterocyclic group and C 6-10 aryl and 5 -10 membered aliphatic heterocyclic group and 5-10 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 3-8 cycloalkyl group, 5-10 membered alicyclic heterocyclic group Group, C 6-10 aryl, 5-10 membered aromatic heterocyclic group, C 3-8 cycloalkyl and C 6-10 aryl, C 3-8 cycloalkyl and 5-10 membered aromatic heterocyclic group, 5-10 membered
  • Range of R 13 groups include hydrogen, amino, halogen, -C (O) R 14, -OR j, C 1-6 alkyl, C 3-8 cycloalkyl, -C 1- 6 alkylene - ( C 6-10 aryl), -C 1-6 alkyl-(5-10 membered aromatic heterocyclic group), C 6-10 aryl and 5-10 membered aromatic heterocyclic group, wherein the amino group, C 1-6 alkyl, C 3-8 cycloalkyl, -C 1-6 alkylene-(C 6-10 aryl), C 6-10 aryl, 5-10 membered heterocyclic group and -C 1-6 alkyl-(5-10 membered heterocyclic group) are each independently optionally substituted with one or more of the following groups: hydrogen, halogen, C 1-6 alkyl, C 6-10 aryl , 5-10 membered aromatic heterocyclic group optionally substituted by C 1-6 alkyl or halogen;
  • R 14 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-10 membered alicyclic group, C 6-10 aryl group, 5-10 membered aromatic heterocyclic group and C 2-6 Alkenyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and 5-10 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: halogen, C 1 -6 alkyl, C 6-10 aryl, 5-10 membered aromatic heterocyclic group optionally substituted by C 1-6 alkyl;
  • R j is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-12 membered alicyclic group, C 6-10 aryl And 5-12 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, 5-12 membered alicyclic heterocyclic group Group, C 6-10 aryl group and 5-12 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: hydrogen, halogen, amino, hydroxyl, 4-8 membered aliphatic heterocyclic group .
  • R 3 is -C(O)R 12 ;
  • R 12 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, 5-8 membered alicyclic group, C 6-10 aryl group, 5-8 membered aromatic heterocyclic group , C 3-8 cycloalkyl and C 6-10 aryl, C 3-8 cycloalkyl and 5-8 membered aromatic heterocyclic group, 5-8 membered aliphatic heterocyclic group and C 6-10 aryl and 5 -8 membered aliphatic heterocyclic group and 5-8 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 3-8 cycloalkyl group, and 5-8 membered alicyclic heterocyclic group Group, C 6-10 aryl, 5-8 membered aromatic heterocyclic group, C 3-8 cycloalkyl and C 6-10 aryl, C 3-8 cycloalkyl and 5-8 membered aromatic heterocyclic group, 5-8 membered
  • Groups in the range of R 13 include hydrogen, amino, halogen, -C (O) R 14 , -OR j , C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-6 alkylene-( C 6-10 aryl), -C 1-6 alkyl-(5-8 membered aromatic heterocyclic group), C 6-10 aryl and 5-8 membered aromatic heterocyclic group, wherein the amino group, C 1-6 alkyl, -C 1-6 alkylene-(C 6-10 aryl), C 6-10 aryl, 5-8 membered aromatic heterocyclic group, -C 1-6 alkyl-(5 8-membered aromatic heterocyclic group) are each independently optionally substituted with one or more of the following substituents: hydrogen, halogen, C 1-6 alkyl, C 6- 10 aryl group, optionally substituted C 1-3 Alkyl or halogen substituted 5-8 membered aromatic heterocyclic group;
  • R 14 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-8 membered aliphatic heterocyclic group, C 6-10 aryl, 5-8 membered aromatic heterocyclic group and C 2-6 Alkenyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and 5-8 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: halogen, C 1 -6 alkyl, C 6-10 aryl, and 5-8 membered aromatic heterocyclic group optionally substituted by C 1-6 alkyl;
  • R j is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-8 membered alicyclic group, C 6-10 aryl And 5-8 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, 5-8 membered alicyclic heterocyclic group Group, C 6-10 aryl group and 5-8 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: hydrogen, halogen, amino, hydroxyl, 4-8 membered alicyclic heterocyclic group .
  • R 3 is -C(O)R 12 ;
  • R 12 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, 5-8 membered alicyclic group, 5-8 membered alicyclic group and 5-6 membered aromatic heterocyclic group, C 6-10 Aryl and 5-6 membered aromatic heterocyclic groups, wherein the C 1-6 alkyl group, C 3-8 cycloalkyl group, 5-8 membered alicyclic group, C 6-10 aryl group, 5-6 Each membered aromatic heterocyclic group is independently optionally substituted with one or more groups within the scope of R 13 ;
  • Groups in the range of R 13 include hydrogen, amino, halogen, -C (O) R 14 , -OR j , C 1-3 alkyl, C 3-6 cycloalkyl, benzyl, -C 1-3 alkylene Group-(5-6 membered aromatic heterocyclic group), C 6-10 aryl group and 5-6 membered aromatic heterocyclic group, wherein the amino group, C 1-3 alkyl group, C 6-10 aryl group, 5 -6 membered aromatic heterocyclyl, benzyl, -C 1-3 alkyl-(5-6 membered aromatic heterocyclyl) are each independently optionally substituted by one or more of the following substituents: halogen, C 1 -3 alkyl, C 6-10 aryl, 5-6 membered aromatic heterocyclic group optionally substituted by methyl or F;
  • R 14 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-8 membered aliphatic heterocyclic group, C 6-10 aryl, 5-8 membered aromatic heterocyclic group and C 2-6 Alkenyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and 5-8 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: halogen, C 1 -3 alkyl, C 6-10 aryl, and 5-8 membered aromatic heterocyclic group optionally substituted by C 1-3 alkyl;
  • R j is a 5-8 membered aromatic heterocyclic group, and the 5-8 membered aromatic heterocyclic group is optionally substituted by one or more of the following substituents: halogen, 4-6 membered alicyclic heterocyclic group.
  • R 3 is -C(O)R 12 ; wherein,
  • R 12 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, 5-8 membered alicyclic group, 5-8 membered aromatic heterocyclic group and 5-8 membered alicyclic group and 5-6 membered Aromatic heterocyclic group, wherein the C 1-6 alkyl group, C 3-8 cycloalkyl group, 5-8 membered alicyclic group, 5-8 membered aromatic heterocyclic group and 5-8 membered alicyclic group Each 5-6 membered aromatic heterocyclic group is independently optionally substituted by one or more groups within the scope of R 13 ;
  • Groups in the range of R 13 include amino, halogen, -C (O) R 14 , -OR j , C 1-3 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-(C 6 -8 aryl), -C 1-3 alkylene-(5-6 membered aromatic heterocyclic group), C 6-8 aryl and 5-8 membered aromatic heterocyclic group, wherein the amino group, C 1 -3 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-(C 6-8 aryl), C 6-8 aryl, 5-8 membered aromatic heterocyclic group and -C 1 -3 alkylene-(5-6 membered aromatic heterocyclic group) each independently optionally substituted by one or more of the following groups: halogen, C 1-3 alkyl, C 6-8 aryl, any 5-8 membered aromatic heterocyclic group substituted by C 1-3 alkyl or halogen;
  • R 14 is selected from 5-8 membered aromatic heterocyclyl, 5-8 membered aromatic heterocyclic group optionally substituted with one or more of the following substituents: C 1- 3 alkyl, optionally a C 1-3 alkoxy 5- to 8-membered aromatic heterocyclic group substituted by a group;
  • R j is a 5-8 membered aromatic heterocyclic group, and the 5-8 membered aromatic heterocyclic group is optionally substituted by one or more of the following substituents: hydrogen, halogen, and 4-6 membered alicyclic heterocyclic group.
  • R 3 is
  • R 18 is hydrogen
  • R 19 is selected from Or, R 18 , R 19 and the carbon atom to which they are connected together form Wherein, F' is selected from C 3-6 cycloalkyl, 5-10 membered aromatic heterocyclic group, 5-10 membered alicyclic heterocyclic group, 5-10 membered aliphatic heterocyclic group and 5-10 membered aromatic heterocyclic group;
  • t is selected from 1, 2 and 3;
  • R 17 is independently selected from hydrogen, amino, halogen, -OR j , C 6-10 aryl, C 1-6 alkyl, -C 1-6 alkyl-C 6-10 aryl, 5-12 membered aromatic Heterocyclic group, -C 1-6 alkyl-C 6-10 aryl, -C 1-6 alkyl-(5-12 membered aromatic heterocyclic group), -C(O)R 14 and C 3-6 Cycloalkyl, wherein the amino group, C 6-10 aryl group, C 1-6 alkyl group, 5-12 membered aromatic heterocyclic group, -C 1-6 alkyl-C 6-10 aryl group, -C C1-6 alkyl - (5-12 membered aromatic heterocyclic group) is independently optionally substituted with one or more of the following substituents: halo, C 1- 6 alkyl, C 1-6 alkoxy, C 6-10 aryl, 5-6 membered aromatic heterocyclic group optionally substituted by halogen;
  • R j is a 5-6 membered aromatic heterocyclic group, wherein the 5-6 membered aromatic heterocyclic group is optionally substituted by one or more of the following groups: F,
  • R 14 is a 5-6 membered aromatic heterocyclic group, wherein the 5-6 membered aromatic heterocyclic group is optionally substituted by one or more of the following groups: C 1-3 alkyl, optionally C 1-3 alkyl substituted 5-6 membered aromatic heterocyclic group.
  • R 3 is R 17 is selected from hydrogen, methyl, difluoromethyl, cyclopropyl and trifluoromethyl
  • R 18 is hydrogen
  • R 19 is selected from Or
  • R 18 , R 19 and the carbon atom to which they are connected together form F' is selected from
  • t is selected from 1, 2 and 3;
  • R 17 is independently selected from amino, Phenyl, methyl, benzyl, -OR j and cyclopropyl, wherein the amino group, Each independently is optionally substituted by one or more of the following substituents: methyl, phenyl, pyridyl, fluoropyridyl, picoline, pyrazinyl; preferably, R 17 is independently selected from amino, Phenyl, methyl, benzyl, -OR j and cyclopropyl, wherein the amino group, Each independently is optionally substituted by one or more of the following substituents: methyl, phenyl, pyridyl, fluoropyridyl, picoline, pyrazinyl;
  • R j is selected from pyridyl and pyrazinyl, and the pyridyl is optionally substituted by one or more of the following substituents: F,
  • R 3 is R 19 is selected from phenyl, pyrrolyl and 1-pyrazolyl optionally substituted by one or more halogens (for example, F, Cl);
  • R 17 is C 1-6 alkyl optionally substituted by one or more halogens
  • R 3 is R 19 is selected from phenyl and 1-pyrazolyl substituted with one or more halogens (for example, F, Cl);
  • R 17 is C 1-6 alkyl optionally substituted with one or more halogens.
  • R 3 is R 19 is selected from
  • R 17 is selected from methyl, difluoromethyl and trifluoromethyl.
  • R 3 is F'is selected from C 3-6 cycloalkyl, substituted or unsubstituted 5-6 membered aromatic heterocyclic group, wherein the substitution is substituted by one or more of the following substituents: halogen, C 1-6 Alkyl and C 3-6 cycloalkyl;
  • R 17 is selected from hydrogen, C 3-6 cycloalkyl, substituted or unsubstituted -C 1-3 alkyl-C 6-10 aryl and substituted or unsubstituted C 1-3 alkyl-(5-6 Membered aromatic heterocyclic group), wherein the substitution is optionally substituted by one or more of the following substituents: halogen, C 1-3 alkyl, C 1-3 alkoxy;
  • R 17 is selected from Preferably, R 17 is selected from
  • R 3 is F'is selected from optionally substituted with one or more C 1-3 alkyl (e.g. methyl), C 3-6 cycloalkyl (e.g. cyclopropyl) R 17 is selected from Preferably, R 17 is selected from
  • R 3 is -C(O)R 12 ;
  • R 12 is selected from the following groups:
  • R 3 is selected from -C(O)R 12
  • R 12 is selected from
  • R 3 is -C(O)R 12 ; wherein,
  • R 12 is selected from the group consisting of C 1-6 alkyl, 5-8 membered alicyclic group and 5-8 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, 5-8 membered aliphatic heterocyclic group and 5
  • the -8 membered aromatic heterocyclic group is each independently optionally substituted by one or more groups within the scope of R 13 ;
  • Groups in the range of R 13 include -C(O)R 14 , C 1-3 alkyl, C 3-6 cycloalkyl, C 6-8 aryl, and 5-8 membered aromatic heterocyclic group, wherein the C 1-3 alkyl, C 3-6 cycloalkyl, C 6-8 aryl, and 5-8 membered aromatic heterocyclic group are each independently optionally substituted with one or more of the following groups: halogen and C 6-8 aryl;
  • R 14 is selected from 5-8 membered aromatic heterocyclyl, 5-8 membered aromatic heterocyclic group optionally substituted with one or more of the following substituents: C 1- 3 alkyl, optionally a C 1-3 alkoxy 5- to 8-membered aromatic heterocyclic group substituted with a group.
  • R 3 is selected from -C(O)R 12 ;
  • R 12 is selected from
  • R 3 is selected from -C(O)R 12 ;
  • R 12 is selected from the following groups:
  • R 3 is -C(O)R 12 ; wherein,
  • R 12 is selected from the group consisting of C 1-6 alkyl, 5-8 membered alicyclic group and 5-8 membered aromatic heterocyclic group, wherein the C 1-6 alkyl group, 5-8 membered aliphatic heterocyclic group and 5
  • the -8 membered aromatic heterocyclic group is each independently optionally substituted by one or more groups within the scope of R 13 ;
  • Range of R 13 groups include -C (O) R 14, C 1-3 alkyl, C 6-8 aryl, and 5-8 membered aromatic heterocyclyl, wherein said C 13 alkyl, C The 6-8 aryl group and the 5-8 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following groups: halogen and C 6-8 aryl;
  • R 14 is selected from 5-8 membered aromatic heterocyclyl, 5-8 membered aromatic heterocyclic group optionally substituted with one or more of the following substituents: C 1- 3 alkyl, optionally a C 1-3 alkoxy 5- to 8-membered aromatic heterocyclic group substituted with a group.
  • R 3 is selected from -C(O)R 12 ;
  • R 12 is selected from the following groups:
  • R 3 is selected from -C(O)R 12 ;
  • R 12 is selected from the following groups:
  • n 1 and n 2 are both 1.
  • the second aspect of the present invention relates to compounds represented by formula II, their pharmaceutically acceptable salts, esters, solvates, stereoisomers, tautomers, prodrugs, arbitrary crystal forms, metabolites, or mixtures thereof:
  • Y 1 is selected from CH and N;
  • Y 2 is selected from C and N, and when Y 2 is N, R 16 does not exist;
  • Y 3 is selected from CH and N;
  • Z 1 is selected from CH and N;
  • R 15 is selected from hydrogen, halogen, -C 1-6 alkylene-NR n R q , C 1-6 alkoxy, hydroxyl and 5-12 membered alicyclic group
  • R 16 is selected from hydrogen, C 1- 6 alkoxy, 5-12 membered alicyclic group and 5-10 membered aromatic heterocyclic group, wherein the 5-12 membered aliphatic heterocyclic group and 5-10 membered aromatic heterocyclic group are each independently optionally One or more of the following substituents are substituted: hydroxy, C 1-6 alkyl, halogen; or, R 15 , R 16 and the aryl connected to them form any one of the following groups: C 6-12 aryl and 5-12 membered oxocycloalkyl, C 6-12 aryl and 5-12 membered cycloalkyl, C 6-12 aryl and 5-10 membered alicyclic group, C 6-12 aryl and oxo 5-10 membered alicyclic group, C 6-12
  • R n and R q are each independently selected from H and C 1-6 alkyl
  • R 2 is selected from hydrogen, halogen and -CN;
  • R 18 is hydrogen, Z 2 is CH, R 19 is a C 6-12 aryl group or a 5-10 membered aromatic heterocyclic group, wherein the C 6-12 aryl group and a 5-10 membered aromatic heterocyclic group are each independently Optionally substituted by one or more halogens; or, R 18 , Z 1 , Z 2 and R 19 form any of the following groups: 6-12 membered aliphatic heterocyclic group, 5-10 membered arylene heterocyclic ring Group, 3-12 membered cycloalkylene group, 5-10 membered aromatic heterocyclic group and 6-12 membered aliphatic heterocyclic group, wherein the 6-12 membered aliphatic heterocyclic group, 5-10 membered arylene heterocyclic group
  • the cyclic group and the 3-12 membered cycloalkylene group are each independently optionally substituted by one or more of the following substituents: 5-10 membered aromatic heterocyclyl C 1-6 alkylene, substituted 5-10 member
  • R 17 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-12 aryl, and C 6-12 aryl C 1-6 alkylene, wherein the C 1-6 The alkyl group and the C 6-12 aryl C 1-6 alkylene group are each independently optionally substituted with one or more of the following substituents: halogen, C 1-6 alkyl.
  • the compound in some embodiments of the second aspect of the present invention, includes any of the following (A) to (F):
  • Y 1 is CH
  • Y 2 is C
  • Y 3 is CH
  • Z 1 is N.
  • the third aspect of the present invention relates to compounds represented by formula III, their pharmaceutically acceptable salts, esters, solvates, stereoisomers, tautomers, prodrugs, arbitrary crystal forms, metabolites, or mixtures thereof:
  • R 15 is selected from hydrogen, halogen, -C 1-6 alkylene-NR n R q , C 1-6 alkoxy, hydroxyl and 5-12 membered alicyclic group
  • R 16 is selected from hydrogen, C 1- 6 alkoxy, 5-12 membered alicyclic group and 5-10 membered aromatic heterocyclic group, wherein the 5-12 membered aliphatic heterocyclic group and 5-10 membered aromatic heterocyclic group are each independently optionally One or more of the following substituents are substituted: hydroxyl, C 1-6 alkyl, halogen; or, R 15 , R 16 and the phenyl connected to them form any of the following groups: C 6-12 aryl and 5-12 membered oxocycloalkyl, C 6-12 aryl and 5-12 membered cycloalkyl, C 6-12 aryl and 5-10 membered alicyclic group, C 6-12 aryl and oxo 5-10 membered alicyclic group, C 6
  • R n and R q are each independently selected from H and C 1-6 alkyl
  • R 2 is selected from hydrogen, halogen and -CN;
  • R 18 is hydrogen, Z 2 is CH, R 19 is C 6-12 aryl or 5-10 membered aromatic heterocyclic group, wherein the 5-10 membered aromatic heterocyclic group is optionally substituted by one or more halogens.
  • R 18 , Z 2 , R 19 and the carbon atom connected to R 18 form any of the following groups: 6-12 membered aliphatic heterocyclic group, 5-10 membered arylene heterocyclic group, 3- 12-membered cycloalkylene, 5-10 membered aromatic heterocyclic group and 6-12 membered aliphatic heterocyclic group, wherein the 6-12 membered aliphatic heterocyclic group, 5-10 membered arylene heterocyclic group and 3
  • the -12-membered cycloalkylene groups are each independently optionally substituted by one or more of the following substituents: 5-10 membered aromatic heterocyclic group C 1-6 alkylene, substituted 5-10 membered aromatic heterocyclic group C 1-6 alkylene, substituted 5
  • R 17 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-12 aryl, and C 6-12 aryl C 1-6 alkylene, wherein the C 1-6 The alkyl group and the C 6-12 aryl C 1-6 alkylene group are each independently optionally substituted with one or more of the following substituents: halogen, C 1-6 alkyl.
  • R 15 is selected from hydrogen, halogen, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NH-C 1-6 alkyl,- C 1-6 alkylene-N(C 1-6 alkyl) 2 , C 1-6 alkoxy, hydroxyl and 5-10 membered aliphatic heterocyclic group, wherein the 5-10 membered aliphatic heterocyclic group Optionally substituted by one or more of the following substituents: hydroxy, C 1-6 alkyl; R 16 is selected from hydrogen, C 1-6 alkoxy, 6-12 membered alicyclic and 5-10 Membered aromatic heterocyclic group, wherein the 6-12 membered aliphatic heterocyclic group and the 5-10 membered aromatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: C 1-6 alkyl , Halogen; or, R 15 , R 16 and the phenyl group attached to them form any of the following substituents: C 1-6 alkyl
  • R 15 is selected from hydrogen, halogen, NH 2 -C 1-6 alkylene-, CH 3 -NH-C 1-6 alkylene-, (CH 3 ) 2 NC 1-6 alkylene-, C 1-6 alkoxy, hydroxy and pyrrolidinyl group, wherein the pyrrolidinyl group is optionally substituted by one or more of the following substituents: hydroxy, C 1- 6 alkyl;
  • R 16 is selected from hydrogen, C 1-6 alkoxy, piperazinyl, pyrazolyl and N-morpholinyl, wherein the piperazinyl and pyrazolyl are each independently optionally as follows Is substituted by one or more substituents: C 1-6 alkyl, halogen; or, R 15 , R 16 and the phenyl connected to them form any of the following groups: 1-indanonyl, benzocyclopentan Alkyl, benzopyrrolidinyl, 2-indenone, benzo
  • R 15 is selected from hydrogen, fluorine, chlorine, NH 2 CH 2 -, CH 3 NHCH 2 -, (CH 3 ) 2 NCH 2 -, methoxy, hydroxyl and R 16 is selected from hydrogen, methoxy, Alternatively, R 15 , R 16 and the phenyl group attached to them form any of the following groups:
  • R 15 is selected from -C 1-6 alkylene-NH 2 , hydroxyl, halogen, C 1-6 alkoxy, 5-10 membered aliphatic heterocyclic group, wherein, The 5-10 membered aliphatic heterocyclic group is optionally substituted by one or more of the following substituents: hydroxy, C 1-6 alkyl, R 16 is selected from hydrogen and C 1-6 alkoxy; or, R 15 , R 16 and the phenyl groups attached to them form any of the following groups: indenone group, benzo 5-12 membered cycloalkyl, benzo 5-10 membered alicyclic group, benzooxo 5- 10-membered aliphatic heterocyclic group, benzo 5-10 membered aromatic heterocyclic group, wherein the benzo 5-12 membered cycloalkyl group and the benzo 5-10 membered alicyclic group are each independently optionally as follows One or more substituents are substituted: C
  • R 15 is selected from -C 1-6 alkylene-NH 2 , hydroxyl, halogen, C 1-6 alkoxy, pyrrolidinyl, wherein the pyrrolidinyl group Optionally substituted by one or more of the following substituents: hydroxy, C 1-6 alkyl, R 16 is selected from hydrogen and C 1-6 alkoxy; or, R 15 , R 16 and their connected Phenyl forms any of the following groups: 1-indanonyl, benzocyclopentanyl, benzopyrrolidinyl, 2-indenonyl, benzopyrrolidinone, benzopyrazolyl, wherein the benzene
  • the pentacyclopentyl group is optionally substituted with one or more of the following substituents: C 1-6 primary amino group, C 1-6 secondary amino group, hydroxyl group, amino group.
  • R 15 is selected from NH 2 CH 2 -, CH 3 NHCH 2 -, (CH 3 ) 2 NCH 2 -, hydroxyl, fluorine and R 16 is hydrogen; or, R 15 , R 16 and the phenyl group attached to them form any of the following groups:
  • R 15 is selected from NH 2 CH 2 -, hydroxyl, fluorine, methoxy and R 16 is selected from hydrogen and methoxy; or, R 15 , R 16 and the phenyl group attached to them form any of the following groups:
  • R 15 is -C 1-6 alkylene-NH 2 or hydroxyl
  • R 16 is selected from hydrogen
  • R 15 , R 16 and the phenyl group connected to them form any of the following One group: benzo 5-12 membered cycloalkyl group, benzo 5-10 membered alicyclic heterocyclic group, wherein the benzo 5-12 membered cycloalkyl group and benzo 5-10 membered alicyclic heterocyclic group are each It is independently optionally substituted by one or more of the following substituents: C 1-6 primary amino, amino.
  • R 15 is -C 1-6 alkylene-NH 2 or hydroxyl
  • R 16 is hydrogen
  • R 15 , R 16 and the phenyl group connected to them form any of the following Group: benzocyclopentanyl, benzopyrrolidinyl, wherein the benzocyclopentanyl is optionally substituted by one or more of the following substituents: C 1-6 primary amino, amino .
  • R 15 is NH 2 CH 2 -or hydroxyl
  • R 16 is hydrogen
  • R 15 , R 16 and the phenyl group connected to them form any of the following groups:
  • R 15 is NH 2 CH 2 -
  • R 16 is hydrogen; or, R 15 , R 16 and the phenyl group connected to them form any of the following groups:
  • R 2 is selected from hydrogen, cyano, halo, C 1-6 alkyl and halogenated C 1- 6 alkyl; preferably, R 2 is selected from hydrogen, cyano , Halogen and C 1-3 alkyl; more preferably, R 2 is selected from hydrogen, chlorine and -CN.
  • R 2 is hydrogen
  • R 18 is hydrogen, Z 2 is CH, R 19 is a C 6-12 aryl group or a 5-10 membered aromatic heterocyclic group, wherein the C 6-12 aryl group And 5-10 membered aromatic heterocyclic groups are each independently optionally substituted with one or more halogens; or, R 18 , Z 2 , R 19 and the carbon atom connected to R 18 form any of the following groups: 6 12 membered aliphatic heterocyclic group, 5-10 membered arylene heterocyclic group, 3-12 membered cycloalkylene group, 5-10 membered aromatic heterocyclic group and 6-12 membered aliphatic heterocyclic group, wherein the 6 The -12-membered aliphatic heterocyclic group, 5-10-membered arylene heterocyclic group and 3-12-membered cycloalkylene group are each independently optionally substituted by one or more of the following substituents: 5-10 membered heteroaryl Cyclic
  • R 18 is hydrogen, Z 2 is CH, R 19 is a C 6-12 aryl group or a 5-10 membered aromatic heterocyclic group, wherein the C 6-12 aryl group And 5-10 membered aromatic heterocyclic groups are each independently optionally substituted with one or more halogens; or, R 18 , Z 2 , R 19 and the carbon atom connected to R 18 form any of the following groups: 6 12 membered aliphatic heterocyclic group, 5-10 membered arylene heterocyclic group, 3-12 membered cycloalkylene group, 5-10 membered aromatic heterocyclic group and 6-12 membered aliphatic heterocyclic group, wherein the 6 The -12-membered aliphatic heterocyclyl, 5-10-membered arylene heterocyclyl and 3-12-membered cycloalkylene are each independently optionally substituted by one or more of the following substituents: pyrazinyl C 1- 6 alkylene
  • R 18 is hydrogen, Z 2 is CH, and R 19 is phenyl or pyrazolyl, wherein the phenyl and pyrazolyl are each independently optionally substituted by one or more Or, R 18 , Z 2 , R 19 and the carbon atom connected to R 18 form any of the following groups: piperidinylene, pyrazolylidene, pyrrolylene, isoxazolylidene, Cyclohexylene, isothiazolylidene, cyclopropanylene, oxazolylidene, pyrazolopiperidinylene, wherein the piperidinylene, pyrazolylene, isoxazolylidene, and Cyclohexyl, isothiazolylidene, cyclopropanylene and oxazolylidene are each independently optionally substituted by one or more of the following substituents: pyrazinyl C 1-6 alkylene, C 1-6 alkyl,
  • R 18 is hydrogen, Z 2 is CH, and R 19 is selected from phenyl, Wherein, the phenyl group is optionally substituted with a halogen; or, R 18 , Z 2 , R 19 and the carbon atom connected to R 18 form any of the following groups:
  • R 18 is hydrogen, Z 2 is CH, and R 19 is a C 6-12 aryl group or a 5-10 membered aromatic heterocyclic group substituted by one or more halogens; or, R 18 , Z 2 , R 19 and the carbon atom connected to R 18 form any of the following groups: 6-12 membered aliphatic heterocyclic group, 5-10 membered arylene heterocyclic group, wherein the 6-12 membered aliphatic heterocyclic group, and a 5-10 membered heterocyclic arylene group independently is optionally substituted with one or more of the following substituents: thiazolyl substituted with a carbonyl group, C 1- 6 alkyl, and wherein Substituted to be substituted by one or more of the following substituents: C 1-6 alkyl,
  • R 18 is hydrogen, Z 2 is CH, and R 19 is a C 6-12 aryl group or a 5-10 membered aromatic heterocyclic group substituted by one or more halogens; or, R 18 , Z 2 , R 19 and the carbon atom connected to R 18 form any of the following groups: 6-12 membered aliphatic heterocyclic group, 5-10 membered arylene heterocyclic group, wherein the 6-12 The membered aliphatic heterocyclic group and the 5-10 membered arylene heterocyclic group are each independently optionally substituted by one or more of the following substituents: C 1-6 alkyl.
  • R 18 is hydrogen, Z 2 is CH, R 19 is phenyl or pyrazolyl substituted with one or more halogens; or, R 18 , Z 2 , R 19 and
  • the carbon atom connected to R 18 forms any of the following groups: piperidinylene, pyrazolylidene, and isoxazolylidene, wherein the piperidinylene, pyrazolylidene, and isoxazole are each independently Is optionally substituted by one or more of the following substituents: C 1-6 alkyl.
  • R 18 is hydrogen, Z 2 is CH, and R 19 is selected from phenyl, Alternatively, R 18 , Z 2 , R 19 and the carbon atom connected to R 18 form any of the following groups:
  • R 18 is hydrogen, Z 2 is CH, R 19 is phenyl or Alternatively, R 18 , Z 2 , R 19 and the carbon atom connected to R 18 form any of the following groups:
  • R 18 is hydrogen, Z 2 is CH, R 19 is phenyl or
  • R 17 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-12 aryl, and C 6-12 aryl C 1-6 alkylene.
  • R 17 is selected from hydrogen, C 1-6 alkyl, C 6-12 aryl and C 6-12 aryl C 1-6 alkylene, wherein the C 1-6 alkyl and C 6
  • the -12 aryl C 1-6 alkylene group is each independently optionally substituted with one or more of the following substituents: halogen, C 1-6 alkyl.
  • R 17 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl and phenyl C 1-6 alkylene, wherein said C 1-6 alkyl, C 3-6 cycloalkyl and phenyl C 1-6 alkylene are each independently optionally substituted by one or more of the following substituents: halogen, C 1-6 alkyl; preferably Preferably, R 17 is selected from hydrogen, C 1-6 alkyl, phenyl and phenyl C 1-6 alkylene, wherein the C 1-6 alkyl and phenyl C 1-6 alkylene are each independently Optionally substituted by one or more of the following substituents: halogen, C 1-6 alkyl.
  • R 17 is selected from hydrogen, methyl, difluoromethyl, cyclopropyl, phenyl, benzyl, And trifluoromethyl; preferably, 17 is selected from hydrogen, methyl, difluoromethyl, phenyl, benzyl, And trifluoromethyl.
  • R 17 is selected from the group consisting of C 1-6 alkyl, C 6-12 aryl, and C 6-12 aryl C 1-6 alkylene, wherein the C 1- The 6 alkyl group is optionally substituted with one or more halogens.
  • R 17 is selected from the group consisting of C 1-6 alkyl, phenyl and phenyl C 1-6 alkylene, wherein the C 1-6 alkyl is optionally selected by one or Replaced by multiple halogens.
  • R 17 is selected from methyl, difluoromethyl, phenyl and benzyl.
  • R 17 is selected from methyl and difluoromethyl.
  • the compound is selected from the compounds in the following table and compounds 64-68, 76:
  • the atoms in the compounds of the present invention can be replaced by their isotopes.
  • 12 C can be replaced by its isotope 13 C or 14 C;
  • 1 H can be replaced by 2 H (D, deuterium) or 3 H (T, tritium).
  • Any atom in the compound of the present invention is replaced by its isotope to obtain an isotope-labeled compound.
  • the compound of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry, or variations thereof known to those skilled in the art. Preferred methods include but are not limited to those described below.
  • the present invention also relates to a method for preparing any compound of formula I to formula III, which includes the following two synthetic routes:
  • R 1 , R 2 , R 3 , n 1 , and n 2 are as defined above.
  • X is selected from halogen, -OTf, preferably, X is bromine;
  • PG is selected from C 1-6 linear or branched alkyloxycarbonyl, halogen substituted C 1-6 linear or branched alkyloxycarbonyl, C 2 -6alkenyl -alkoxycarbonyl, Cbz, benzyl and 9-fluorenylmethoxycarbonyl, preferably, PG is selected from Boc and Cbz;
  • R 20 is selected from hydroxyl and halogen, preferably, R 20 is hydroxyl;
  • R 21 is selected From boric acid esters and boric acid.
  • the method includes the following steps:
  • Step 1 Compound a to obtain compound b;
  • the reaction is preferably carried out in a suitable organic solvent, and the organic solvent can be selected from acetic acid, halogenated hydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane, etc.), alcohols (such as methanol, Ethanol), nitriles (such as acetonitrile, etc.), N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, preferably N,N-dimethylformamide.
  • the reaction is preferably carried out in the presence of a suitable reagent, and the reagent can be selected from bromine, halogenated succinimide, preferably bromine, brominated succinimide.
  • the reaction is preferably carried out at a suitable temperature, preferably the reaction temperature is 0-200°C, preferably 25-80°C.
  • Step 2 Compound b is reacted with compound g to obtain compound c;
  • the reaction is preferably carried out in a suitable organic solvent
  • the organic solvent may be selected from DMSO, DMF, DMA, alkalis (such as triethylamine, DIPEA, NMP, pyridine, ammonia, etc.), alcohols (such as methanol, ethanol, etc.) , Isopropanol, tert-butanol), ethers (such as diethyl ether, THF, dioxane, etc.), halogenated hydrocarbons (such as dichloromethane, chloroform, carbon tetrachloride), acetonitrile, water, anisole, DMSO and DMF are preferred.
  • alkalis such as triethylamine, DIPEA, NMP, pyridine, ammonia, etc.
  • alcohols such as methanol, ethanol, etc.
  • ethers such as diethyl ether, THF, dioxane, etc.
  • halogenated hydrocarbons such as
  • the reaction is preferably carried out under suitable acidic or basic conditions, the acid or base is an organic acid/base or an inorganic acid/base, and the organic acid is selected from acetic acid, trifluoroacetic acid, boron trifluoride ether,
  • the inorganic acid is selected from hydrochloric acid and hydrobromic acid
  • the organic base is selected from triethylamine, DIPEA, pyridine, NMM, DMAP, sodium acetate, potassium acetate, ammonium acetate, sodium tert-butoxide
  • the inorganic base is selected from Potassium carbonate, sodium hydroxide, sodium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, preferably, the base is selected from pyridine, cesium carbonate, potassium carbonate.
  • the reaction is preferably carried out at a suitable temperature, preferably the reaction temperature is 0-200°C, preferably 50-150°C.
  • Step 3 Compound c is deprotected to obtain compound d;
  • the reaction is preferably carried out in a suitable organic solvent
  • the organic solvent can be selected from water, DMF, DMA, N-methylpyrrolidone, alcohols (such as methanol, ethanol, isopropanol, etc.), ethers (such as ether , THF, dioxane, etc.), halogenated hydrocarbons (for example, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.), acetonitrile, preferably dichloromethane, methanol, tetrahydrofuran.
  • the reaction is carried out in the presence of hydrogen.
  • the reaction is preferably carried out under suitable acidic or alkaline conditions.
  • the acid or base is an organic acid/base or an inorganic acid/base.
  • the organic acid is selected from acetic acid, trifluoroacetic acid, trifluoride Boron ether, hydrochloric acid, hydrochloric acid/dioxane solution, hydrochloric acid/ethyl acetate solution
  • the inorganic acid is selected from hydrochloric acid, hydrobromic acid
  • the inorganic base is selected from potassium carbonate, sodium bicarbonate, lithium hydroxide, hydrogen Sodium oxide
  • the organic base is selected from diethylamine, piperidine, and ammonia.
  • the reaction is preferably carried out at a suitable temperature, preferably the reaction temperature is 0-200°C, preferably 0-50°C.
  • Step 4 Reaction of compound d with compound h to obtain compound e;
  • the reaction is preferably carried out in a suitable organic solvent, and the organic solvent may be selected from halogenated hydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane, etc.), nitriles (such as acetonitrile, etc.), N-methylpyrrolidone, DMF, DMA, dioxane, DMSO and any combination thereof, preferably dichloromethane, DMF.
  • halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • nitriles such as acetonitrile, etc.
  • N-methylpyrrolidone such as dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • DMF dichloromethane
  • DMA dioxane
  • DMSO dioxane
  • any combination thereof preferably dichloromethane, DMF.
  • the reaction is preferably carried out in the presence of a suitable condensing agent, which can be selected from thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, ethyl chloroformate, chloroformic acid Isopropyl ester, HATU, HBTU, EEDQ, DEPC, DCC, DIC, EDC, BOP, PyAOP or PyBOP, preferably, the condensing agent is HATU, EDC.
  • a suitable condensing agent which can be selected from thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, ethyl chloroformate, chloroformic acid Isopropyl ester, HATU, HBTU, EEDQ, DEPC, DCC, DIC, EDC, BOP
  • the reaction is preferably carried out under suitable alkaline conditions, the organic base is selected from triethylamine, DIPEA, pyridine, NMM or DMAP, and the inorganic base is selected from sodium hydride, sodium hydroxide, sodium carbonate, carbonic acid Potassium, preferably, the base is selected from DIPEA.
  • the reaction is preferably carried out at a suitable temperature, preferably the reaction temperature is 0-100°C, more preferably 15-50°C.
  • Step 5 reacting compound e with compound j to obtain formula I;
  • the reaction is preferably carried out in a suitable organic solvent, and the organic solvent may be selected from halogenated hydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane, etc.), methanol, ethanol, DMF, acetonitrile, Ethers (such as ethylene glycol dimethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (such as toluene, benzene, xylene), water and any combination thereof, preferably dioxane/water, ethylene glycol dimethyl Ether/water.
  • the reaction is preferably carried out under suitable alkaline conditions.
  • the base is an organic base or an inorganic base.
  • the organic base is selected from triethylamine, DIPEA, pyridine, NMM, sodium tert-butoxide, potassium acetate , Sodium acetate, the inorganic base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, potassium dihydrogen phosphate, preferably, the base is selected from potassium carbonate, potassium phosphate, and cesium carbonate.
  • the reaction is preferably carried out under the catalysis of a catalyst selected from the group consisting of palladium tetraphenylphosphine, palladium acetate, Pd 2 (dba) 3 , Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 2 Cl 2 Dichloromethane complex, Pd(dppf)Cl 2 , preferably palladium acetate, Pd(dppf)Cl 2 , and palladium tetrakistriphenylphosphine.
  • a catalyst selected from the group consisting of palladium tetraphenylphosphine, palladium acetate, Pd 2 (dba) 3 , Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 2 Cl 2 Dichloromethane complex, Pd(dppf)Cl 2 , preferably palladium acetate, Pd(dppf)Cl 2 , and palladium t
  • the reaction is carried out in the presence of a ligand selected from BINAP, tris(o-methylphenyl)phosphorus, triphenylphosphine, tricyclohexylphosphine tetrafluoroborate, X-PHOS.
  • a ligand selected from BINAP, tris(o-methylphenyl)phosphorus, triphenylphosphine, tricyclohexylphosphine tetrafluoroborate, X-PHOS.
  • the reaction is preferably carried out at a suitable temperature, preferably the reaction temperature is 0-200°C, preferably 50-150°C.
  • R 1 , R 2 , R 3 , n 1 , n 2 are as defined above;
  • X is selected from halogen and -OTf, preferably, X is bromine;
  • PG is selected from C 1-6 linear or branched alkyl Oxycarbonyl, halogen-substituted C 1-6 linear or branched alkyloxycarbonyl, C 2-6 alkenyl-alkoxycarbonyl, Cbz, benzyl and 9-fluorenylmethoxycarbonyl, preferably, PG is selected from Boc and Cbz;
  • R 20 is selected from hydroxyl and halogen, preferably LG is hydroxyl;
  • R 21 is selected from boric acid ester and boric acid.
  • the method includes the following steps:
  • Step 1 Compound a to obtain compound b; the method is the same as step one of route one.
  • Step 2 Compound b to obtain compound k; the method is the same as step 5 of route 1.
  • Step 3 Compound k is reacted with compound g to obtain compound p; the method is the same as step 2 of route 1.
  • Step 4 Compound p to obtain compound s; the method is the same as step 3 of route 1.
  • Step 5 Compound s and compound h obtain formula I; the method is the same as step 4 of route 1.
  • the fourth aspect of the present invention relates to a pharmaceutical composition, which comprises the compound described in any one of the first to third aspects of the present invention, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, or tautomer , Prodrugs, arbitrary crystal forms, metabolites or their mixtures, and optional pharmaceutical excipients.
  • the pharmaceutical composition is a tablet, pill, capsule, lozenge, hard candy, powder, spray, cream, ointment, suppository, gel, paste Preparations, lotions, ointments, aqueous suspensions, injectable solutions, elixirs or syrups.
  • the pharmaceutical composition can be administered parenterally, locally, intravenously, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular It can be administered internally or as an inhalant, and can also be administered in all use forms well known to those skilled in the medical field.
  • the pharmaceutical excipients are selected from diluents, lubricants, binders, disintegrants, absorbents, colorants, flavoring agents, sweeteners, emulsifiers, dispersants, enhancers Reagents and fillers for compound absorption.
  • Diluents include but are not limited to water, triglycerides such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils such as docosahexaenoic acid or its esters or Triglycerides or mixtures, omega-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, glucose and/or glycine; lubricants include but are not limited to silicon dioxide , Talc, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; binders include but not Limited to magnesium aluminum silicate, starch paste, gelatin, methyl cellulose, sodium carboxymethyl cellulose, magnesium carbonate, natural sugars such as glucose or ⁇ -lactose, corn sweeteners, natural and
  • the pharmaceutical composition further comprises other effective ingredients that inhibit the activity of the deubiquitinating enzyme USP7 or other effective ingredients that prevent or treat cancer.
  • the pharmaceutical composition further comprises other pharmaceutical active ingredients for preventing or treating diseases or disorders related to USP7 regulation, and the diseases or disorders related to USP7 regulation are selected from cancer, neurodegeneration Diseases (e.g. Alzheimer's disease and Parkinson's disease), diabetes, osteoarthropathy, arthritis inflammatory disorders, osteoporosis, immune disorders, cardiovascular diseases, ischemic diseases, viral infections and/or Latent, viral infection or disease and bacterial infection or disease.
  • diseases or disorders related to USP7 regulation are selected from cancer, neurodegeneration Diseases (e.g. Alzheimer's disease and Parkinson's disease), diabetes, osteoarthropathy, arthritis inflammatory disorders, osteoporosis, immune disorders, cardiovascular diseases, ischemic diseases, viral infections and/or Latent, viral infection or disease and bacterial infection or disease.
  • the pharmaceutical composition or suitable dosage form may contain 0.01 mg to 1000 mg of the compound of the present invention.
  • the compound of the present invention When administered orally, the compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, can be prepared into any orally acceptable preparation form, including but not limited to tablets, capsules, aqueous solutions or suspensions.
  • the carriers used in tablets generally include lactose and corn starch, and lubricants such as magnesium stearate can also be added.
  • the diluents used in capsule formulations generally include lactose and dried corn starch.
  • Aqueous suspension formulations usually mix the active ingredients with suitable emulsifiers and suspending agents.
  • some sweeteners, fragrances or coloring agents can be added to the above oral preparation forms.
  • the compound of the present invention or its pharmaceutically acceptable salt or pharmaceutical composition can be made into an appropriate ointment, lotion or cream preparation form, wherein the active ingredient is suspended or dissolved in one or more In the carrier.
  • Carriers that can be used in ointment preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water; carriers that can be used in lotions or creams include, but are not limited to: minerals Oil, sorbitan monostearate Tween 60, cetyl ester wax, hexadecenyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compound of the present invention or its pharmaceutically acceptable salt or pharmaceutical composition can also be administered in the form of a sterile injection preparation, including a sterile injection water or oil suspension or a sterile injection solution.
  • a sterile injection preparation including a sterile injection water or oil suspension or a sterile injection solution.
  • the usable carriers and solvents include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized non-volatile oils can also be used as solvents or suspension media, such as monoglycerides or diglycerides.
  • an effective amount of the composition of the present invention sufficient to achieve a preventive or therapeutic effect is about 0.001 mg/kg body weight/day to about 10,000 mg/kg body weight/day. Where appropriate, the dosage is about 0.01 mg/kg body weight/day to about 1000 mg/kg body weight/day.
  • the dosage can range from about 0.01 to 1000 mg/kg of the subject's body weight per day, every two days, or every three days, and more usually 0.1 to 500 mg/kg of the subject's body weight.
  • An exemplary treatment regimen is once every two days or once a week or once a month.
  • the formulation is usually administered multiple times, and the interval between single doses can be daily, weekly, monthly or yearly.
  • the preparation may be administered in the form of a sustained-release preparation, in which case less frequency of administration is required.
  • the dosage and frequency vary according to the half-life of the preparation in the subject. It can also be different depending on whether it is a preventive treatment or a therapeutic treatment. In preventive applications, relatively low doses are given over a long period of time at relatively low frequency intervals. In therapeutic applications, it is sometimes necessary to administer relatively high doses at relatively short intervals until the progression of the disease is delayed or stopped, and preferably until the individual shows partial or complete amelioration of disease symptoms, after which the patient can be administered Prevention program.
  • the fifth aspect of the present invention relates to a medicine box product, which includes:
  • a first container which contains as a first therapeutic agent at least one of the compounds of the first to third aspects of the present invention or a pharmaceutically acceptable salt, ester, solvate (such as hydrate), stereoisomers thereof Forms, tautomers, prodrugs, or any of their crystal forms, metabolites, and mixtures thereof, or the pharmaceutical composition of the fourth aspect of the present invention;
  • an optional second container comprising at least one other therapeutic agent as a second therapeutic agent, or a pharmaceutical composition of other therapeutic agents
  • the other therapeutic agent is selected from other drugs other than the compound of the present invention that can be used to prevent or treat diseases or disorders related to USP7 regulation (especially diseases such as cancer).
  • the sixth aspect of the present invention relates to the compounds described in the first to third aspects of the present invention, their pharmaceutically acceptable salts, esters, solvates, stereoisomers, tautomers, prodrugs, arbitrary crystal forms, metabolites or Use of their mixture or the pharmaceutical composition of the fourth aspect of the present invention to inhibit the activity of deubiquitinating enzyme USP7.
  • the seventh aspect of the present invention relates to a method for inhibiting the activity of deubiquitinating enzyme USP7 in vitro or in vivo, which comprises combining the compounds described in the first to third aspects of the present invention, their pharmaceutically acceptable salts, esters, solvates, and stereoisomers. Constructs, tautomers, prodrugs, arbitrary crystal forms, metabolites or their mixtures or the pharmaceutical composition according to the fourth aspect of the present invention act on the subject (demand).
  • the eighth aspect of the present invention relates to the compounds described in the first to third aspects of the present invention, their pharmaceutically acceptable salts, esters, solvates, stereoisomers, tautomers, prodrugs, arbitrary crystal forms, metabolites or Use of their mixture or the pharmaceutical composition of the fourth aspect of the present invention in the preparation of deubiquitinating enzyme USP7 inhibitors or in the preparation of drugs for preventing or treating cancer.
  • the ninth aspect of the present invention relates to a method for preventing or treating cancer, which comprises combining the compounds described in the first to third aspects of the present invention, their pharmaceutically acceptable salts, esters, solvates, stereoisomers, and tautomers. , Prodrugs, any crystal forms, metabolites or their mixtures or the pharmaceutical composition according to the fourth aspect of the present invention is administered to a subject (in need);
  • the cancer is selected from at least one of hepatocellular carcinoma, multiple myeloma, colon cancer, lung cancer, prostate cancer and bladder cancer.
  • the compounds described in the first to third aspects of the present invention their pharmaceutically acceptable salts, esters, solvates, stereoisomers, tautomers, prodrugs, any crystalline forms, metabolites, or their mixtures, or the present invention
  • the pharmaceutical composition according to the fourth aspect is used to inhibit the activity of deubiquitinating enzyme USP7 or to prevent or treat cancer.
  • the cancer is selected from at least one of hepatocellular carcinoma, multiple myeloma, colon cancer, lung cancer, prostate cancer, and bladder cancer.
  • pharmaceutically acceptable salt refers to (1) a salt formed by an acidic functional group (such as -COOH, -OH, -SO 3 H, etc.) present in the compound of the present invention and an appropriate inorganic or organic cation (base), such as The salt formed by the compound of the present invention with an alkali metal or alkaline earth metal, the ammonium salt of the compound of the present invention, and the salt formed by the compound of the present invention with a nitrogen-containing organic base; and (2) the basic functional group (such as -NH) present in the compound of the present invention 2 etc.) Salts formed with appropriate inorganic or organic anions (acids), such as salts of the compounds of the present invention with inorganic acids or organic carboxylic acids.
  • an acidic functional group such as -COOH, -OH, -SO 3 H, etc.
  • base such as The salt formed by the compound of the present invention with an alkali metal or alkaline earth metal, the ammonium salt of the compound of the present invention, and the salt
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • C 1 - 6 alkyl refers to straight or branched chain alkyl group having 1 to 6 carbon atoms, for example C 1-4 alkyl, C 1-2 -alkyl, C 1 alkyl, C 2 alkyl Group, C 3 alkyl, C 4 alkyl, C 5 alkyl. Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
  • C 1 - 6 alkylene refers to a C 1 - removal of one hydrogen atom of a divalent radical remaining 6 alkyl, wherein "C 1 - 6 alkyl” is defined above.
  • alkenyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and one of its hydrogen atoms is replaced by a bond.
  • the alkenyl group can be straight or branched and contains 2 to 15 carbon atoms.
  • C 2-6 alkenyl herein refers to an alkenyl group containing 2 to 6 carbon atoms.
  • Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • the alkenyl group may be unsubstituted or substituted by one or more substituents which are the same or different, each substituent independently selected from halogen, alkenyl, alkynyl, aryl, cycloalkyl, cyano, Hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH 2 , -NH(alkyl), -N(alkyl) 2 , -NH( Cycloalkyl), -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C(O)OH and -C(O)O-alkyl.
  • substituents which are the same or different, each substituent independently selected from halogen, alkenyl, alkynyl, aryl, cycloalkyl, cyano, Hydroxy, -O-alkyl, -O
  • cycloalkenyl refers to an unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring containing at least one carbon-carbon double bond.
  • C 4-6 cycloalkenyl refers to an unsaturated non-aromatic monocyclic or polycyclic (such as a bicyclic ring) having 4 to 6 carbon atoms with at least one carbon-carbon double bond )
  • a hydrocarbon ring which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclobutenyl.
  • alkynyl refers to a hydrocarbon group having one or more C ⁇ C triple bonds.
  • the alkynyl group has, but is not limited to, 2-18 carbon atoms, for example, it has 2-10 carbon atoms, such as 2-6 carbon atoms.
  • “Lower alkynyl” refers to an alkynyl group with a relatively small carbon number, for example, it has 2-8 carbon atoms, such as 2-6 carbon atoms, such as 2-4 carbon atoms.
  • alkynyl groups herein include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like.
  • C 2-6 alkynyl refers to an alkynyl group that can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms Group, the alkynyl group herein also covers the case where the numerical range is not specified.
  • C 1 - 6 alkoxy refers to the group -O- C 1-6 alkyl group is formed, wherein the definition of "C 1-6 alkyl” is as previously described.
  • C 1-4 alkoxy Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy Oxy, hexyloxy, etc.
  • amine refers to the product in which one or more hydrogen atoms in the ammonia molecule is replaced by a hydrocarbon group, which can be divided into primary, secondary, and tertiary amines.
  • amino group refers to the monovalent group remaining after removing a hydrogen atom attached to the nitrogen in the amine molecule, including primary, secondary, and tertiary amino groups. Specific examples include methylamino, dimethylamino, ethylamino, diethylamino and the like.
  • aliphatic heterocyclic group refers to a monovalent group formed by a non-aromatic monocyclic or polycyclic compound containing at least one N, O or S heteroatom, such as 5-20 membered alicyclic group, 5- 10-membered (5-8 member, 5-7 member) aliphatic heterocyclic group, 5-12 member aliphatic heterocyclic group, 5-20 member (5-8 member, 5-7 member, 5-10 member, 5-12 Member) nitrogen-containing aliphatic heterocyclic group, 5-20 member (5-8 member, 5-7 member, 5-10 member, 5-12 member) member oxygen-containing aliphatic heterocyclic group, 6-12 member nitrogen-containing heterocyclic group Ring base.
  • aliphatic heterocyclic groups include but are not limited to 1-pyrrolidinyl, 1-piperazinyl, N-morpholinyl, 1-piperidinyl, aziridinyl, caprolactam and the like.
  • aliphatic heterocyclic group refers to a divalent group remaining after removing a hydrogen atom from an aliphatic heterocyclic group.
  • the definition of "aliphatic heterocyclic group” is as described above. Specific examples include, but are not limited to, piperidinylene, pyrrolidinylene, piperazinylene, morpholinylene and the like.
  • aryl refers to a monovalent group formed by an aromatic monocyclic or polycyclic compound, such as 5-20 membered aryl, 5-12 membered aryl, 6-12 membered (6-8 member, 6 -9-membered) aryl, 6-10-membered aryl, etc.
  • C 6-10 aryl group refers to the above-mentioned aryl group containing 6-10 carbon atoms. Specific examples include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl and the like.
  • arylene refers to a divalent group remaining after removing a hydrogen atom from an aryl group.
  • aryl refers to a divalent group remaining after removing a hydrogen atom from an aryl group.
  • aryl is as described above, for example, C 6-10 arylene, C 6-12 arylene and the like.
  • aromatic heterocyclic group refers to a monovalent group formed by an aromatic monocyclic or polycyclic compound containing at least one N, O or S heteroatom, such as 5-20 membered aromatic heterocyclic group, 5-10 Member (5-8 member, 5-7 member) aromatic heterocyclic group, 5-12 member aromatic heterocyclic group, 6-10 member aromatic heterocyclic group, 5-8 member aromatic heterocyclic group, 5-20 member (5 -8 member, 5-7 member, 5-10 member, 5-12 member) nitrogen-containing aromatic heterocyclic group, 5-20 member (5-8 member, 5-7 member, 5-10 member, 5-12 member ) Oxygen-containing aromatic heterocyclic group, 6-12 member nitrogen-containing aromatic heterocyclic group, 5-20 member (5-8 member, 5-7 member, 5-10 member, 5-12 member) oxygen and nitrogen aromatic Heterocyclic group.
  • nitrogen-containing aromatic heterocyclic groups include, but are not limited to, pyrazolyl, pyrrolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridyl, imidazolyl, quinolinyl, and pteridine.
  • arylene heterocyclic group refers to a divalent group remaining after removing a hydrogen atom from an aromatic heterocyclic group.
  • aromatic heterocyclic group is as described above. Specific examples include, but are not limited to, pyrazolylidene, pyrrolylene, isoxazolylidene, isothiazolylidene, pyridinylene, imidazolylidene, quinolinylene, and pterridinylene.
  • indenone indenone is widely used in the active molecules of natural products, drugs and pesticides. Its basic structure includes 1-indanone, 2-indanone, 1,2-indenone, and 1,3-indenone. Ketone, ninhydrin. "Indanonyl” refers to the monovalent group remaining after removing one hydrogen atom from the indanone molecule, such as 1-indanonyl, 2-indanonyl and the like.
  • cycloalkyl refers to a monocyclic saturated alkyl group.
  • a 3-12 membered cycloalkyl group contains 3-12 ring members, such as 2-10 membered cycloalkyl, 3 membered, 4 membered, 5 membered, 6 membered, 7-membered, 8-membered, 9-membered, 10-membered cycloalkyl.
  • Specific examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • cycloalkylene refers to the divalent group remaining after one hydrogen atom is removed from the cycloalkyl group.
  • the definition of "cycloalkyl” is as described above.
  • Specific examples include, but are not limited to, cyclohexylene and cyclopropanylene.
  • aromatic heterocyclic carbonyl group refers to an aromatic heterocyclic group -C(O)-, wherein the definition of "aromatic heterocyclic group” is as described above. Examples are 5-20 membered aromatic heterocyclic carbonyl group, 5-12 membered aromatic heterocyclic carbonyl group, 5-10 membered aromatic heterocyclic carbonyl group, 5-12 membered aromatic heterocyclic carbonyl group.
  • pyrazolylcarbonyl pyrrolylcarbonyl
  • isoxazolylcarbonyl isothiazolylcarbonyl
  • thiazolylcarbonyl pyridylcarbonyl
  • imidazolylcarbonyl imidazolylcarbonyl
  • quinolinylcarbonyl quinolinylcarbonyl
  • pteridylcarbonyl examples include, but are not limited to, pyrazolylcarbonyl, pyrrolylcarbonyl, isoxazolylcarbonyl, isothiazolylcarbonyl, thiazolylcarbonyl, pyridylcarbonyl, imidazolylcarbonyl, quinolinylcarbonyl, pteridylcarbonyl.
  • aromatic heterocyclylimino refers to an aromatic heterocyclic group -NH-, wherein the definition of "aromatic heterocyclic group” is as described above. Examples are 5-20 membered aromatic heterocyclylimino, 5-12 membered aromatic heterocyclylimino, 5-10 membered aromatic heterocyclylimino, and 5-12 membered aromatic heterocyclylimino.
  • pyrazolyl imino pyrrolyl imino, isoxazolyl imino, isothiazolyl imino, thiazolyl imino, pyridyl imino, imidazolyl imino, quinolinyl imino , Pteridine imino.
  • aromatic heterocyclic alkylene group refers to an aromatic heterocyclic group -(CH 2 ) n -, wherein the definition of "aromatic heterocyclic group” is as described above. Examples are 5-20 membered aromatic heterocyclic group C 1-2 alkylene, 5-12 membered aromatic heterocyclic group C 1-4 alkylene, and 5-10 membered aromatic heterocyclic group C 1-6 alkylene. Specific examples include, but are not limited to, pyrazolylmethylene, pyrrolylethylene, isoxazolyl propylene, and isothiazolylbutylene.
  • aromatic heterocyclic group refers to an aromatic heterocyclic group -O-, wherein the definition of "aromatic heterocyclic group” is as described above.
  • Examples are 5-20 membered aromatic heterocyclyloxy, 5-12 membered aromatic heterocyclyloxy, 5-10 membered aromatic heterocyclyloxy, and 5-12 membered aromatic heterocyclyloxy. Specific examples include, but are not limited to, pyrazolyloxy, pyrrolyloxy, isoxazolyloxy, isothiazolyloxy, thiazolyloxy, pyridyloxy, imidazolyloxy, quinolinyloxy , Pteridinyloxy.
  • arylimino refers to an aryl group -NH-, where "aryl” is as defined above. Examples are C 5-20 membered arylimino, C 5-12 membered arylimino, C 5-10 membered arylimino, and C 6-12 membered arylimino. Specific examples include, but are not limited to, phenylimino.
  • alkyl arylene heterocyclic group refers to an alkyl-arylene heterocyclic group-, wherein the "arylene heterocyclic group” is as defined above. Examples are C 1-2 alkyl 5-20 membered arylene heterocyclic group, C 1-4 alkyl 5-12 membered arylene heterocyclic group, and C 1-6 alkyl 5-10 membered arylene heterocyclic group. Specific examples include, but are not limited to, methylpyrazolylidene, ethylpyrrolylene, propylisoxazolylidene, and butylisothiazolylidene.
  • substituted means that one or more (eg, one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is The normal valence in the current situation and the substitution forms a stable compound. Combinations of substituents and/or variables are only allowed when such combinations form stable compounds.
  • stereoisomer means an isomer due to at least one asymmetric center.
  • compounds with one or more (for example, one, two, three or four) asymmetric centers it can produce racemates, racemic mixtures, single enantiomers, and diastereomers Conformer mixtures and individual diastereomers.
  • Certain individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the present invention may exist in mixtures of two or more structurally different forms (commonly referred to as tautomers) in rapid equilibrium.
  • Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait.
  • the present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which can be a single polymorph or a mixture of more than one polymorph in any ratio.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may also form a solvate, such as alcoholate and the like.
  • the compound of the present invention can also be a prodrug or a form that can release the active ingredient after metabolic changes in the body.
  • the selection and preparation of appropriate prodrug derivatives are well known to those skilled in the art.
  • the compound of the present invention can also be in a form of chemical protection, the protective group can be protected on the active group (such as amino) of the compound, and the protective group can be metabolized in the body to release the active ingredient.
  • the protective group can be protected on the active group (such as amino) of the compound, and the protective group can be metabolized in the body to release the active ingredient.
  • compositions of the present invention may exist in free form for treatment, or, when appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites, or prodrugs, which can be directly or directly administered to patients in need thereof. Indirectly provide the compound of the present invention or its metabolites or residues.
  • the compound of the present invention may exist in the form of a hydrate or a solvate, wherein the compound of the present invention contains a polar solvent as a structural element of the compound's crystal lattice, especially, for example, water, methanol or ethanol.
  • a polar solvent as a structural element of the compound's crystal lattice, especially, for example, water, methanol or ethanol.
  • the amount of polar solvent, especially water can be present in a stoichiometric or non-stoichiometric ratio.
  • metabolites of the compounds of the present invention that is, compounds formed in the body when the drug is administered.
  • composition includes products containing a therapeutically effective amount of the compounds of the present invention, as well as any products produced directly or indirectly from the combination of the compounds of the present invention.
  • an effective amount used in the present invention refers to an amount sufficient to achieve the desired therapeutic effect, for example, an amount that achieves alleviation of symptoms related to the disease to be treated.
  • treatment used in the present invention is to reduce or eliminate the targeted disease state or disorder. If the subject receives a therapeutic amount of the compound, its optical isomer or its pharmaceutically acceptable salt or its pharmaceutical composition according to the method described herein, the subject exhibits one or more signs and symptoms Observable and/or detectable reduction or improvement, then the subject is successfully "treated”. It should also be understood that the treatment of the disease state or condition not only includes complete treatment, but also includes not achieving complete treatment, but achieving some biological or medical related results.
  • Treatment means any administration of a compound of the invention, including:
  • the compound or the pharmaceutical composition of the present invention has a strong inhibitory effect on the activity of the deubiquitinating enzyme USP7, has good pharmacokinetic properties and extremely low brain intake, and can be used to prevent or treat cancer diseases.
  • the instrument for nuclear magnetic resonance ( 1 H NMR) detection is a Bruker 400MHz nuclear magnetic resonance instrument, and the detection solvent is deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ), hexadeuterated dimethyl sulfoxide (DMSO) -d 6 ), deuterated water (D 2 O), the internal standard substance is tetramethylsilane (TMS). All ⁇ values are expressed in ppm values.
  • s single peak (singlet); d: doublet (doublet); t: triplet (triplet); q: quartet; dd: double doublet; qd: four doublet Peak (quartet doublet); ddd: double double doublet; ddt: double double triplet; dddd: double double doublet; m: multiplet ; Br: broad; J: coupling constant; Hz: Hertz; DMSO-d6: deuterated dimethyl sulfoxide.
  • the instrument for mass spectrometry (MS) detection is an Agilent (ESI) mass spectrometer, and the model is Agilent 6120B.
  • the preparative thin layer chromatography used in the following examples adopts the thin layer chromatography silica gel plate produced by Yantai Xinnuo Chemical Co., Ltd. (the thickness is 1mm, the specification is 200x 200mm, the binder is sodium carboxymethyl cellulose), and the detection instrument is ZF -20D dark box ultraviolet analyzer, detection wavelength is 254nm, 365nm.
  • the chromatographic column is Waters XBridge Prep C18 OBD, the specification is 5 ⁇ m, 19 ⁇ 150mm;
  • Mobile phase A is acetonitrile
  • mobile phase B is water (containing 0.05% formic acid);
  • the chromatographic column is Waters SunFire Prep C18 OBD, the specification is 5 ⁇ m, 19 ⁇ 150mm;
  • Mobile phase A is acetonitrile
  • mobile phase B is water (containing 0.05% formic acid);
  • the chromatographic column is Waters XBridge Prep C18 OBD, the specification is 5 ⁇ m, 19 ⁇ 150mm;
  • Mobile phase A is acetonitrile
  • mobile phase B is water (containing 0.05% ammonium bicarbonate);
  • the chromatographic column is Waters SunFire Prep C18 OBD, the specification is 5 ⁇ m, 19 ⁇ 150mm;
  • Mobile phase A is acetonitrile
  • mobile phase B is water (containing 0.05% formic acid);
  • Chromatographic column Waters SunFire Prep C18 OBD, specifications of 5 ⁇ m, 19 ⁇ 150mm;
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid);
  • Chromatographic column Waters SunFire Prep C18 OBD, specifications of 5 ⁇ m, 19 ⁇ 150mm;
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid);
  • Chromatographic column Waters SunFire Prep C18 OBD, specifications of 5 ⁇ m, 19 ⁇ 150mm;
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid);
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.1% formic acid);
  • Chromatographic column Waters SunFire Prep C18 OBD, specifications of 5 ⁇ m, 19 ⁇ 150mm;
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid);
  • Chromatographic column Waters SunFire Prep C18 OBD, specifications of 5 ⁇ m, 19 ⁇ 150mm;
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% trifluoroacetic acid);
  • Chromatographic column Waters XBridge Prep C18 OBD, the specification is 5 ⁇ m, 19 ⁇ 150mm;
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid);
  • Chromatographic column Waters SunFire Prep C18 OBD, specifications of 5 ⁇ m, 19 ⁇ 150mm;
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% ammonium bicarbonate);
  • Step 1 (R)-7-bromo-3-((4-hydroxy-1-(3-phenylbutyryl)piperidin-4-yl)methyl)imidazole[2,1-f][1, Synthesis of 2,4]triazine-4(3H)-one (compound 1-2)
  • compound 1-1 (151.00 mg, 0.70 mmol) and (R)-3-phenyl-1-(1-oxa-6-azaspirocyclo[2.5]oct-6-yl)butan- 1-ketone (reference ACS Med.Chem.Lett.2018,9(3),238-243.) (218.56mg, 0.84mmol) was dissolved in dimethyl sulfoxide (10mL), and pyridine (277.76mg , 3.51mmol), heated to 80°C, and reacted for 20h.
  • Step 2 (R)-(4-(3-((4-hydroxy-1-(3-phenylbutyryl)piperidin-4-yl)methyl)-4-oxo-3,4-di Synthesis of [2,1-f][1,2,4]triazine-7-yl)benzyl) tert-butyl carbamate (Compound 1-3)
  • Step 3 (R)-7-(4-(aminomethyl)phenyl)-3-((4-hydroxy-1-(3-phenylbutyryl)piperidin-4-yl)methyl)imidazole Synthesis of [2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (compound 1 hydrochloride)
  • reaction solution was prepared by a high-efficiency solution Phase chromatographic separation (operating condition B) yielded compound 4, 4.00 mg.
  • Step 1 (R)-5-(3-((4-hydroxy-1-(3-phenylbutyryl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydro Synthesis of imidazole[2,1-f][1,2,4]triazine-7-yl)indoline-1-carbamic acid tert-butyl ester (Compound 5-1)
  • Step 1 (5-(3-((4-hydroxy-1-((R)-3-phenylbutyrylpiperidin-4-yl)methyl)-4-oxo-3,4-dihydro Synthesis of imidazole [2,1-f][1,2,4]triazine-7-yl)-2,3-dihydro-1H-inden-2-yl) tert-butyl carbamate
  • Step 2 7-(2-amino-2,3-dihydro-1H-inden-5-yl)-3-((4-hydroxy-1-((R)-3-phenylbutyryl)piperidine -4-yl)methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (compound 6 hydrochloride)
  • Step 2 Methyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indene-1 -Yl) synthesis of tert-butyl carbamate (compound 7-3)
  • Step 3 4-((7-Bromo-4-oxoimidazole[2,1-f][1,2,4]triazine-3(4H)-yl)methyl)-4-hydroxypiperidine- Synthesis of benzyl 1-carboxylate (Compound 7-4)
  • Step 4 4-((7-(1-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)-4-oxoimidazole [2 ,1-f][1,2,4]triazine-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylic acid benzyl ester (compound 7-5)
  • Step 6 (5-(3-((1-(4,4-Difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl )Methyl)-4-oxo-3,4-dihydroimidazole[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-indene- Synthesis of tert-butyl 1-yl)(methyl)carbamate (compound 7-7)
  • Step 7 3-((1-(4,4-Difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl)methyl) -7-(1-(methylamino)-2,3-dihydro-1H-inden-5-yl)imidazole[2,1-f][1,2,4]triazine-4(3H)- Synthesis of Ketoformate (Compound 7 formate)
  • Step 1 4-((7-(4-((tert-butoxycarbonyl)amino)methyl)phenyl)-4-oxoimidazole[2,1-f][1,2,4]triazine -3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylic acid benzyl ester (Compound 8-1)
  • Step 2 4-((3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroimidazole [2,1-f][1,2,4 ] Triazine-7-yl)benzyl) tert-butyl carbamate (Compound 8-2)
  • Step 3 4-((3-((1-(4,4-Difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl )Methyl)-4-oxo-3,4-dihydroimidazole[2,1-f][1,2,4]triazin-7-yl)benzyl)tert-butyl carbamate (Compound 8- 3) Synthesis
  • Step 4 7-(4-(aminomethyl)phenyl)-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl) Synthesis of 4-hydroxypiperidin-4-yl)methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (compound 8 hydrochloride)
  • Step 1 4-((7-Bromo-4-oxoimidazole[2,1-f][1,2,4]triazine-3(4H)-yl)methyl)-4-hydroxypiperidine- Synthesis of tert-butyl 1-formate (Compound 9-1)
  • Step 3 7-bromo-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl )Methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one (Compound 9-3) Synthesis
  • Step 4 Synthesis of tert-butyl (5-bromo-2,3-dihydro-1H-inden-2-yl)(methyl)carbamate (compound 9-5)
  • Step 6 5-((3-((1-(4,4-Difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl )Methyl)-4-oxo-3,4-dihydroimidazole[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-indene- Synthesis of tert-butyl 2-yl)(methyl)carbamate (compound 9-7)
  • compound 9-6 39.61mg, 0.11mmol
  • compound 9-3 50.00mg, 0.10mmol
  • potassium carbonate 40.00mg , 0.29mmol
  • tetrakistriphenylphosphine palladium 15.00mg, 0.01mmol
  • nitrogen three times heated to 80°C and reacted for 5h. It was cooled to room temperature and concentrated under reduced pressure.
  • ESI-MS 685.3 [M+H] + .
  • Step 7 3-((1-(4,4-Difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl)methyl) -7-(2-(methylamino)-2,3-dihydro-1H-inden-5-yl)imidazole[2,1-f][1,2,4]triazine-4(3H)- Synthesis of Ketone Hydrochloride (Compound 9 Hydrochloride)
  • Step 1 (R)-5-(3-((4-hydroxy-1-(3-phenylbutyryl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydro Synthesis of imidazole [[2,1-f][1,2,4]]triazine-7-yl)isoindoline-2-carboxylate tert-butyl ester (Compound 10-1)
  • Step 2 (R)-3-((4-hydroxy-1-(3-phenylbutyryl)piperidin-4-yl)methyl)-7-(isoindolin-5-yl)imidazole[ Synthesis of 2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (compound 10 hydrochloride)
  • Step 1 5-(3-((1-(4,4-Difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl) Methyl)-4-oxo-3,4-dihydroimidazole[2,1-f][1,2,4]triazin-7-yl)indoline-1-carboxylic acid tert-butyl ester (Compound 12 -1) Synthesis
  • Step 2 3-((1-(4,4-Difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl)methyl) Synthesis of -7-(indol-5-yl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (compound 12 hydrochloride)
  • the hydrochloride salt of compound 12 is not shown in the reaction formula of this example, but compound 12 is shown.
  • Step 1 Synthesis of tert-butyl 5-bromo-2,3-dihydro-1H-indene-2-methylcarbamate (Compound 9-5)
  • Step 3 5-(3-((4-hydroxy-1-((R)-3-phenylbutyryl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydro Imidazole[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-inden-2-yl)(methyl) tert-butyl carbamate (Compound 13 -4) Synthesis
  • Step 4 3-((4-Hydroxy-1-((R)-3-phenylbutyryl)piperidin-4-yl)methyl)-7-(2-(methylamino)-2,3- Synthesis of dihydro-dihydro-1H-inden-5-yl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (compound 13 hydrochloride)
  • 3-hydroxy-3-methylpyrrole hydrochloride (123.94mg, 0.9mmol) and compound 15-1 (200.00mg, 0.9mmol) were dissolved in N,N-dimethylacetamide (5mL) , Potassium carbonate (311.19mg, 2.25mmol) was added, replaced with nitrogen three times, and heated to 110°C for 18h.
  • Step 2 3-((1-(4,4-Difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl)methyl) -7-(4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one( Compound 15) Synthesis
  • Example 16 7-(2-amino-2,3-dihydro-1H-inden-5-yl)-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyridine) (Azol-1-yl)butyryl Yl)-4-hydroxypiperidin-4-yl)methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (hydrochloride of compound 17 )of synthesis
  • Step 1 4-((7-(2-((tert-butoxycarbonyl)amino)-2,3-dihydro-1H-inden-5-yl)-4-oxoimidazole [2,1-f ][1,2,4]Triazine-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylic acid benzyl ester (Compound 17-1)
  • ESI-MS (m/z): 615.3 [M+H] + .
  • Step 2 5-((3-((4-Hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-oxoimidazole [2,1-f][1,2,4 ] Triazine-7-yl)-2,3-dihydro-1H-inden-2-yl) tert-butyl carbamate (Compound 17-2)
  • Step 3 5-((3-((1-(4,4-Difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl )Methyl)-4-oxo-3,4-dihydroimidazole[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-indene- Synthesis of tert-butyl 2-yl)carbamate (Compound 17-3)
  • Step 4 7-(2-amino-2,3-dihydro-1H-inden-5-yl)-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyridine) (Azol-1-yl)butyryl)-4-hydroxypiperidin-4-yl)methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (Compound 17 hydrochloride) synthesis
  • step 3 of Example 1 using compound 17-3 (60.00 mg, 0.09 mmol) as a raw material, preparative high performance liquid chromatography (operation condition A), adding 0.5 mL of hydrochloric acid, and lyophilizing to obtain compound 17 Hydrochloride, 38.00mg.
  • Step 1 (5-(3-((1-(1-benzyl-1H-pyrazole-5carbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4 -Dihydroimidazole [2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-inden-2-yl) tert-butyl carbamate (Compound 43- 1) Synthesis
  • Step 2 7-(2-Amino-2,3-dihydro-1H-inden-5-yl)-3-((1-(1-benzyl-1H-pyrazole-5carbonyl)-4-hydroxy Synthesis of piperidin-4-yl)methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-ketoformate (formate of compound 43)
  • step 3 of Example 1 using compound 43-1 (60.00 mg, 0.09 mmol) as a raw material, and separating by preparative high performance liquid chromatography (operation condition B), the formate of compound 43 was obtained, 26.00 mg.
  • Step 1 (5-(3-((1-(5-benzyl-1-methyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-4- Oxo-3,4-dihydroimidazole[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-inden-2-yl)tert-carbamic acid Synthesis of Butyl Ester (Compound 58-1)
  • Step 2 7-(2-amino-2,3-dihydro-1H-inden-5-yl)-3-((1-(5-benzyl-1-methyl-1H-pyrazole-4- Synthesis of carbonyl)-4-hydroxypiperidin-4-yl)methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-ketocarboxylate
  • step 3 of Example 1 using compound 58-1 (25.00 mg, 0.037 mmol) as the raw material, and separating by preparative high performance liquid chromatography (operation condition B), the formate salt of compound 58 was obtained, 23.00 mg.
  • Step 1 Synthesis of 1-(4-methyl-2-(6-methylpyridin-3-yl)thiazole-5-carbonyl)-3-phenylpyridine-4-carboxylic acid (Compound 36-2)
  • Step 2 1-(4-Methyl-2-(6-methylpyridin-3-yl)thiazole-5-carbonyl)-3-phenylpyridine-4-carboxylic acid-isomer A (compound 36- 2-isomer A) and 1-(4-methyl-2-(6-methylpyridin-3-yl)thiazole-5-carbonyl)-3-phenylpyridine-4-carboxylic acid-isomer Preparation of B (Compound 36-2-isomer B)
  • Step 3 4-((7-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)-4-oxoimidazole[2,1-f][1,2,4]triazine -3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylic acid benzyl ester (Compound 8-1)
  • Step 4 4-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroimidazole[2,1-f][1,2,4] Synthesis of tert-butyl triazine-7-yl)benzyl carbamate (Compound 8-2)
  • Step 5 4-(3-((4-hydroxy-1-(1-(4-methyl-2-(6-methylpyridin-3-yl)thiazole-5-carbonyl)-3-phenylpiper (Pyridine-4-carbonyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydroimidazole[2,1-f][1,2,4]triazin-7-yl) Synthesis of tert-butyl benzyl carbamate-isomer A (compound 36-3-isomer A)
  • Step 6 7-(4-(Aminomethyl)phenyl)-3-((4-hydroxy-1-(1-(4-methyl-2-(6-methylpyridin-3-yl)thiazole) -5-carbonyl)-3-phenylpiperidine-4-carbonyl)piperidin-4-yl)methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)- Synthesis of ketone-isomer A formate (Compound 36-isomer A formate)
  • step 3 of Example 1 using compound 36-3-isomer A (35.00 mg, 0.041 mmol) as the raw material, preparative high performance liquid chromatography (operation condition B) was used to obtain compound 36-isomer The formate of A, 24.00mg. Retention time: 1.980min.
  • the product was analyzed by LC-MS under the following conditions: Chromatographic column: Waters XBridge C18, specification of 5 ⁇ m, 4.6 ⁇ 50mm; mobile phase A: 5mmol/L ammonium formate aqueous solution; mobile phase B: acetonitrile; flow rate: 2.0mL/min.
  • reaction formula of this example does not show the formate of compound 36-isomer A, but shows compound 36-isomer A, that is, the isomer of compound 36 in the table of the Summary of the Invention.
  • Step 1 4-(3-((4-hydroxy-1-(1-(4-methyl-2-(6-methylpyridin-3-yl)thiazole-5-carbonyl)-3-phenylpiper (Pyridine-4-carbonyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydroimidazole[2,1-f][1,2,4]triazin-7-yl) Synthesis of tert-butyl benzyl carbamate-isomer B (compound 36-3-isomer B)
  • Step 2 7-(4-(aminomethyl)phenyl)-3-((4-hydroxy-1-(1-(4-methyl-2-(6-methylpyridin-3-yl)thiazole) -5-carbonyl)-3-phenylpiperidine-4-carbonyl)piperidin-4-yl)methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)- Synthesis of ketone-isomer B formate (Compound 36-isomer B formate)
  • step 6 of Example 19 using compound 36-3-isomer B (35.00 mg, 0.041 mmol) as the raw material, preparative high performance liquid chromatography (operation condition B) was used to obtain compound 36-isomer The formate of B, 17.00mg. Retention time: 1.967min.
  • the product was analyzed by LC-MS under the following conditions: Column: Waters XBridge C18 5 ⁇ m 4.6x50mm, mobile phase A: 5mmol/L ammonium formate aqueous solution; mobile phase B: acetonitrile, flow rate: 2.0mL/min.
  • reaction formula of this example does not show the formate of compound 36-isomer B, but shows compound 36-isomer B, which is another isomer of compound 36 in the table of the Summary of the Invention.
  • Step 1 3-((1-(4,4-Difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl)methyl) Synthesis of -7-(2-oxo-2,3-dihydro-1H-inden-5-yl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one
  • Step 1 3-((1-(4,4-Difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl)methyl) Synthesis of -7-(2-hydroxy-2,3-dihydro-1H-inden-5-yl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one
  • Step 1 (4-(3-((1-(3-benzyl-1-methyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-4- Synthesis of tert-butyl oxo-3,4-dihydroimidazole [2,1-f][1,2,4]triazine-7-yl)benzyl)carbamate (Compound 59-1)
  • Step 2 7-(4-(aminomethyl)phenyl)-3-((1-(3-benzyl-1-methyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidine- Synthesis of 4-yl)methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (hydrochloride of compound 59)
  • step 3 of Example 1 using compound 59-1 (32.00 mg, 0.05 mmol) as the raw material, preparative HPLC separation (operating condition B), adding 0.5 mL of hydrochloric acid and lyophilizing to obtain the salt of compound 59 Acid salt, 12.00mg.
  • Step 1 4-(3-((1-(4,4-Difluoro-3-phenylbutyryl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4 -Dihydroimidazole [2,1-f][1,2,4]triazin-7-yl)benzylcarbamic acid tert-butyl ester (Compound 60-1)
  • Step 2 7-(4-(aminomethyl)phenyl)-3-((1-(4,4-difluoro-3-phenylbutyryl)-4-hydroxypiperidin-4-yl)methyl -Based) imidazole[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (hydrochloride of compound 60)
  • step 3 of Example 1 using compound 60-1 (41.67mg, 0.06mmol) as a raw material, preparative high performance liquid chromatography (operating condition B), adding 0.5 mL of dilute hydrochloric acid and lyophilizing to obtain compound 60 Hydrochloride, 12.00mg.
  • the hydrochloride of compound 60 is not shown in the reaction formula of this example, but compound 60 is shown.
  • Step 1 7-bromo-3-((4-hydroxy-1-(1-(4-methyl-2-(6-methylpyridin-3-yl)thiazole-5-carbonyl)-3-phenyl Piperidine-4-carbonyl)piperidin-4-yl)methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one-isomer A (compound 38- Synthesis of 1-isomer A)
  • Step 2 3-((4-Hydroxy-1-(1-(4-methyl-2-(6-methylpyridin-3-yl)thiazole-5-carbonyl)-3-phenylpiperidine-4 -Carbonyl)piperidin-4-yl)methyl)-7-(4-hydroxyphenyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one-isomer Synthesis of Form A (Compound 38-Isomer A)
  • step 2 of Example 1 using compound 38-1-isomer A (26.32 mg, 0.03 mmol) and 4-hydroxy-phenylboronic acid (7.44 mg, 0.05 mmol) as raw materials, high performance liquid chromatography was prepared After separation (operating condition E), compound 38-isomer A was obtained, 20.00 mg, retention time: 2.369 min.
  • the product was subjected to LC-MS analysis under the following conditions: Chromatographic column: Waters XBridge C18 5 ⁇ m 4.6x50mm, mobile phase A: 5mmol/L ammonium formate aqueous solution; mobile phase B: acetonitrile, flow rate: 2.0mL/min.
  • Compound 38-Isomer A is the isomer of compound 38 in the table of the Summary of the Invention.
  • Step 1 7-bromo-3-((4-hydroxy-1-(1-(4-methyl-2-(6-methylpyridin-3-yl)thiazole-5-carbonyl)-3-phenyl Piperidine-4-carbonyl)piperidin-4-yl)methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one-isomer B (compound 38- Synthesis of 1-isomer B)
  • Step 2 3-((4-Hydroxy-1-(1-(4-methyl-2-(6-methylpyridin-3-yl)thiazole-5-carbonyl)-3-phenylpiperidine-4 -Carbonyl)piperidin-4-yl)methyl)-7-(4-hydroxyphenyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one-isomer Synthesis of Form B (Compound 38-Isomer B)
  • step two of Example 1 using compound 38-1-isomer B (31.58 mg, 0.04 mmol) and 4-hydroxy-phenylboronic acid (8.93 mg, 0.06 mmol) as raw materials, high performance liquid chromatography was prepared After separation (operating condition E), compound 38-isomer B was obtained, retention time: 2.397 min, 22.00 mg.
  • the product was analyzed by LC-MS under the following conditions: Chromatographic column: Waters XBridge C18, specification of 5 ⁇ m, 4.6 ⁇ 50mm; mobile phase A: 5mmol/L ammonium formate aqueous solution; mobile phase B: acetonitrile; flow rate: 2.0mL/min.
  • Compound 38-isomer B is another isomer of compound 38 in the table of the Summary of the Invention.
  • Step 1 4-(3-((1-(3-benzyl-5-methylisoxazole-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo- Synthesis of tert-butyl 3,4-dihydroimidazole [2,1-f][1,2,4]triazin-7yl)benzylcarbamate (Compound 63-1)
  • Step 2 7-(4-(aminomethyl)phenyl)-3-((1-(3-benzyl-5-methylisoxazole-4-carbonyl)-4-hydroxypiperidine-4- Synthesis of [2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (hydrochloride of compound 63)
  • Step 1 4-((7-Bromo-6-chloro-4-oxoimidazole[2,1-f][1,2,4]triazine-3(4H)-yl)methyl)-4- Synthesis of tert-butyl hydroxypiperidine-1-carboxylate (Compound 53-1)
  • Step 2 4-((6-Chloro-7-(3,4-dimethoxyphenyl)-4-oxoimidazole[2,1-f][1,2,4]triazine-3( Synthesis of 4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (Compound 53-2)
  • Step 3 6-Chloro-7-(3,4-dimethoxyphenyl)-3-((4-hydroxypiperidin-4-yl)methyl)imidazole [2,1-f][1, Synthesis of 2,4]triazine-4(3H)-one hydrochloride (hydrochloride of compound 53-3)
  • Step 4 (R)-6-chloro-7-(3,4-dimethoxyphenyl)-3-((4-hydroxy-1-(3-phenylbutyryl)piperidin-4-yl )Methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one (Compound 53)
  • Step 1 4-((7-(4-fluorophenyl)-4-oxoimidazole[2,1-f][1,2,4]triazine-3(4H)-yl)methyl)- Synthesis of 4-hydroxypiperidine-1-carboxylic acid benzyl ester (Compound 102-1)
  • Step 3 7-(4-fluorobenzene)-3-((4-hydroxy-1-(3-(1-phenylethyl)-1H-pyrazole-4-carbonyl)piperidin-4-yl)methyl Synthesis of Imidazole[2,1-f][1,2,4]triazine-4(3H)-one (Compound 102)
  • Step 2 (R)-3-((4-hydroxy-1-(3-phenylbutyryl)piperidin-4-yl)methyl)-7-(1H-indazol-6-yl)imidazole[ Synthesis of 2,1-f][1,2,4]triazine-4(3H)-one (Compound 90)
  • Step 1 4-((7-(2-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)-4-oxoimidazole [2, Synthesis of 1-f][1,2,4]triazine-3(4H)methyl)4-hydroxypiperidine-1-carboxylic acid benzyl ester (Compound 92-1)
  • Step 2 (5-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroimidazole [2,1-f][1,2,4 ]Triazine-7-yl)-2,3-dihydro-1H-inden-2-yl)(methyl) carbamate (Compound 92-2)
  • Step 3 5-(3-((1-((S)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidine- 4-yl)methyl)-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro- Synthesis of 1H-inden-2-yl) (methyl) tert-butyl carbamate (Compound 92-3)
  • Step 4 3-((1-((S)-4,4-Difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl )Methyl)-7-(2-(methylamino)2,3-dihydro-1H-inden-5-yl)imidazole[2,1-f][1,2,4]triazine-4( Synthesis of 3H)-ketoformate (formate of compound 92)
  • Step 1 (5-(3-((4-hydroxy-1-(4,4,4-trifluoro-3-phenylbutanol)piperidin-4-yl)methyl)-4-oxo- 3,4-Dihydroimidazo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-inden-2-yl)(methyl)amino Synthesis of tert-butyl formate (compound 93-1)
  • Step 2 3-((4-hydroxy-1-(4,4,4-trifluoro-3-phenylbutanol)piperidin-4-yl)methyl)-7-(2-(methylamino) )-2,3-dihydro-1H-inden-5-yl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (hydrochloric acid of compound 93 Salt) synthesis
  • Example 38 7-(7-chloro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)-3-((1-(4,4-difluoro-3- (3-Fluoro-1H-pyrazole- 1-yl)butyryl)-4-hydroxypiperidin-4-yl)methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (compound 94 salt Acid salt) synthesis
  • Step 1 Synthesis of 6-bromo-4-chloro-2,3-dihydro-1H-inden-1-ol (Compound 94-2):
  • compound 94-1 600 mg, 2.44 mmol was placed in methanol (4 mL), sodium borohydride (185 mg, 4.89 mmol) was added, and the mixture was stirred at room temperature for 2 h. After concentration under reduced pressure, it was diluted with water (30mL), adjusted to pH ⁇ 6 with 1.0mol/L dilute hydrochloric acid, extracted with dichloromethane (30mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 94 -2,605mg.
  • compound 94-2 (605mg, 2.44mmol) was dissolved in toluene (5mL), p-toluenesulfonic acid (42mg, 0.24mmol) was added, and the temperature was raised to 120°C for 3 hours. The reaction solution was concentrated under reduced pressure. Petroleum was used for the crude product. Wash with ether, filter, and concentrate the filtrate under reduced pressure to obtain compound 94-3, 560 mg.
  • Step 5 Synthesis of tert-butyl N-(6-bromo-4-chloro-2,3-dihydro-1H-inden-2-yl)-N-methylcarbamate (Compound 94-6):
  • Step 6 (4-chloro-6-(3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidine -4-yl)methyl)-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro Synthesis of tert-butyl -1H-inden-2-yl)(methyl)carbamate (Compound 94-7)
  • Step 7 7-(7-chloro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)-3-((1-(4,4-difluoro-3- (3-Fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl)methyl)imidazole[2,1-f][1,2,4]triazine-4 Synthesis of (3H)-keto hydrochloride (compound 94 hydrochloride)
  • Step 1 (5-(3-((1-(4,4-Difluoro-3-phenylbutyryl)-4-hydroxypiperidin-4-yl)methyl)4-oxo-3,4- Dihydroimidazole[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-inden-2-yl)(methyl)tert-butyl carbamate ( Compound 95-2) Synthesis
  • Step 2 3-((1-(4,4-Difluoro-3-phenylbutyryl)-4-hydroxypiperidin-4-yl)methyl)-7(2-(methylamino)-2 Synthesis of ,3-Dihydro-1H-inden-5-yl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (compound 95 hydrochloride)
  • Step 1 7-bromo-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl )Methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one (Compound 96-2) Synthesis
  • Step 2 (5-(3-((1-(4,4-Difluoro-3-phenylbutyryl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4 -Dihydroimidazole [2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-inden-1-yl)methyl tert-butyl ester (Compound 96- 3) Synthesis
  • Step 3 3-((1-(4,4-Difluoro-3-phenylbutyryl)-4-hydroxypiperidin-4-yl)methyl)-7-(1-(methylamine)-2, Synthesis of 3-dihydro-1H-inden-5-yl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (compound 96 hydrochloride)
  • Step 1 (5-(3-((3-(3-chloro-1H-pyrazol-1-yl)-4,4-difluorobutyryl)-4-hydroxypiperidin-4-yl)methyl )-4-oxo-3,4-dihydroimidazole[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-inden-2-yl ) Synthesis of tert-butyl (methyl)carbamate (Compound 97-2)
  • Step 2 3-((1-(3-(3-chloro-1H-pyrazol-1-yl)-4,4-difluorobutyryl)-4-hydroxypiperidin-4-yl)methyl) -7-(2-(methylamino)-2,3-dihydro-1H-inden-5-yl)imidazole[2,1-f][1,2,4]triazine-4(3H)- Synthesis of Ketone Hydrochloride (Compound 97 Hydrochloride)
  • Step 1 (5-(3-((1-(3-cyclopropyl-3-phenylpropionyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4 -Dihydroimidazole [2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-inden-1-yl)(methyl)tert-butyl carbamate (Compound 98-1) Synthesis
  • Step 2 3-((1-(3-cyclopropyl-3-phenylpropionyl)-4-hydroxypiperidin-4-yl)methyl)-7-(2-(methylamine)-2, Synthesis of 3-dihydro-1H-inden-5-yl)imidazole[2,1-f][1,2,4]triazine-4(3H)-ketoformate (formate of compound 98)
  • Step 1 7-bromo-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butyryl)-4-hydroxypiperidin-4-yl )Methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one (Compound 99-1) Synthesis
  • Step 2 (5-(3-((1-(3-cyclopropyl-3-phenylpropionyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4 -Dihydroimidazo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-inden-1-yl)(methyl)carbamic acid tert-butyl Synthesis of ester (compound 99-2)
  • Step 3 3-((1-(3-cyclopropyl-3-phenylpropionyl)-4-hydroxypiperidin-4-yl)methyl)-7-(1-(methylamine)-2, 3-Dihydro-1H-inden-5-yl)imidazole[2,1-f][1,2,4]triazine-4(3H)-ketoformate (trifluoroacetate of compound 99) Synthesis
  • reaction formula of this example does not show the trifluoroacetate of compound 99, but shows compound 99.
  • Step 1 Synthesis of (5-bromo-4-chloro-2,3-dihydro-1H-inden-1-yl)(methyl) carbamate (Compound 100-2)
  • compound 100-1 (100mg, 0.41mmol) was dissolved in methanol (2mL), methylamine/ethanol solution (2mL, 33%wt) was added, and reacted at room temperature for 16h.
  • the reaction solution was spin-dried, and the concentrate was then methanol (2mL) was dissolved, sodium borohydride (30mg, 0.81mmol) was added, the reaction was carried out at room temperature for 1 hour, and then di-tert-butyl dicarbonate (0.44g, 2.04mmol) was added, and the reaction was continued at room temperature for 1 hour.
  • Step 2 4-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indene- Synthesis of tert-butyl 1-yl)(methyl)carbamate (Compound 100-3)
  • Step 3 4-Chloro-5-(3-((4-hydroxy-1-((R)-3-phenylbutyryl)piperidin-4-yl)methyl)-4-oxo-3, 4-Dihydroimidazole[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-inden-1-yl)(methyl)tert-butyl carbamate Synthesis of ester (compound 100-4)
  • Step 4 7-(4-chloro-1-(methylamino)-2,3-dihydro-1H-inden-5-yl)-3-((4-hydroxy-1-((R)-3 -Phenylbutyryl)piperidin-4-yl)methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-ketoformate (compound 100 formate) Synthesis
  • Step 1 Synthesis of tert-butyl N-(5-bromo-7-chloro-2,3-dihydro-1H-inden-1-yl)-N-methylcarbamate (Compound 101-2)
  • Step 2 N-(7-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro Synthesis of -1-hydro-inden-1-yl)-N-methylcarbamic acid tert-butyl ester (Compound 101-3)
  • Step 3 (7-chloro-5-(3-((1-(3-cyclopropyl-3-phenylpropionyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo -3,4-Dihydroimidazole[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-inden-1-yl)(methyl)amino Synthesis of tert-butyl formate (compound 101-4)
  • ESI-MS m/z: 701.4, 703.3 [M+H] + .
  • Step 4 7-(7-chloro-1-(methylamino)-2,3-dihydro-1H-inden-5-yl)-3-((1-(3-cyclopropyl-3-benzene Propionyl)-4-hydroxypiperidin-4-yl)methyl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (Compound 101 hydrochloride Salt) synthesis
  • Step 1 5-(3-((4-Hydroxy-1-((R)-3-phenylbutyryl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydro Imidazole[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-inden-2-yl)(methyl) tert-butyl carbamate-isomer Form A (compound 13-4-isomer A) and 5-(3-((4-hydroxy-1-((R)-3-phenylbutyryl)piperidin-4-yl)methyl)- 4-oxo-3,4-dihydroimidazole[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydro-1H-inden-2-yl)( Synthesis of tert-butyl methyl) carbamate-isomer B (compound 13-4-isomer B)
  • Step 2 3-((4-Hydroxy-1-((R)-3-phenylbutyryl)piperidin-4-yl)methyl)-7-(2-(methylamino)-2,3- Dihydro-dihydro-1H-inden-5-yl)imidazole[2,1-f][1,2,4]triazine-4(3H)-one-isomer A hydrochloride (compound 13- Synthesis of Isomer A Hydrochloride)
  • reaction formula of this example does not show the hydrochloride salt of compound 13-isomer A, but shows compound 13-isomer A, that is, the isomer of compound 13 in the table of the Summary of the Invention.
  • reaction formula of this example does not show the hydrochloride salt of compound 13-isomer B, but shows compound 13-isomer B, which is another isomer of compound 13 in the table of the Summary of the Invention.
  • Test example 1 USP7 (deubiquitinating enzyme) in vitro enzyme activity inhibition test
  • Kit USP7 Inhibitor Screening Assay Kit, (BPS Catalog: 79256);
  • Substrate Ub-AMC Substrate, (BPS Catalog: 81150);
  • Buffer 5x USP7 Assay Buffer, (BPS Catalog: 79274);
  • Buffer system 1.25x USP7 Assay Buffer; 0.06% BSA; 1mM DTT; ddH2O;
  • Microplate reader parameters BMG PHERAstar Fluorescence, excitation wavelength 350nm, emission wavelength 460nm;
  • Example 25 1.18 ⁇ 0.19
  • Example 26 15.02 ⁇ 2.93
  • Example 28 1.91 ⁇ 1.59
  • Example 42 77.56 ⁇ 10.29
  • Example 46 55.87 ⁇ 6.81
  • Example 47 22.66 ⁇ 2.93
  • Test Example 2 MM.1S cell (myeloma cell) proliferation inhibition test
  • Test system cell name: MM.1S (purchased from Nanjing Kebai Company); kit: Luminescence cell viability analysis kit (Promega);
  • Test parameters cell number: 3000 cells/well; plating medium: MM.1S: RPMI1640+10% FBS; dosing medium: MM.1S: RPMI1640+10% FBS; compound incubation conditions: 37°C, 5% CO 2 ; incubation time: 5d; detection temperature: room temperature; BMG PHERAstar FS detects chemiluminescence.
  • the cells were cultured in a medium containing 10% fetal bovine serum and placed at 37° C. and 5% CO 2 for culture; an appropriate amount of cells were spread in a 96-well plate and cultured overnight in an incubator. The next day, add the complete medium containing the test compound of each concentration (prepared with the solvent DMSO), and incubate at 37°C for 5 days; after that, add the detection reagent CellTiter-GLo to each well, and chemiluminescence detects the relative luminescence unit of each well (RLU).
  • RLU relative luminescence unit of each well
  • Example number MM.1S,IC 50 (nM) Example 1 65.73 ⁇ 3.95 Example 13 26.30 ⁇ 7.93 Example 25 58.88 ⁇ 9.53
  • the compound of the present invention showed a strong cell proliferation inhibitory activity, especially the compound in Example 13 has a strong inhibitory activity on the MM.1S cell proliferation.
  • Test Example 3 Biochemical hERG inhibition test
  • Test system Kit: Predictor TM hERG fluorescence polarization analysis kit, which contains: compound E4031 as a positive control; hERG cell membrane; affinity tracer; and hERG buffer.
  • Test parameters hERG concentration: 1 ⁇ ; tracer concentration: 1nM; incubation time: 2h; microplate reader parameters: BMG PHERAstar FS fluorescent microplate reader.
  • Test group add different concentrations of test compounds to the microtiter plate containing hERG cell membrane, add a tracer with high hERG affinity to each well, incubate the microtiter plate at room temperature for 2 hours, use the multifunction
  • the microplate reader detects the change of fluorescence polarization (excitation wavelength: 540nm; emission wavelength: 590nm) value.
  • Positive control group 30 ⁇ M compound E4031 was used instead of the test compound, and the experimental method was the same as the test group.
  • Blank control group replace the test compound with hERG buffer and no hERG cell membrane.
  • the experimental method is the same as the test group.
  • Percent inhibition rate (%) (1-(fluorescence polarization value of test compound-fluorescence polarization value of positive control group)/(fluorescence polarization value of blank control group-fluorescence polarization value of positive control group)) ⁇ 100%.
  • Example 42 >10
  • Example 46 >10
  • Example 47 >10
  • test results show that the compounds in Examples 8, 9, 10, 13, 15, 19, 20, 23, 24, 25, 26, 27, 28, 31, 36, 39 and 42 have low affinity with hERG, and affinity tracer compete IC 50 greater than 10 ⁇ M.
  • Test Example 4 Biochemical CYP enzyme (cytochrome P450) inhibition test
  • Test system P450-Glo TM CYP1A2 screening system; P450-Glo TM CYP2D6 screening system; P450-Glo TM CYP3A4 screening system;
  • BMG PHERAstar FS detects chemiluminescence.
  • Test group add different concentrations of the test compound to the microtiter plate, and add Luciferin-ME (100 ⁇ M), K 3 PO 4 (100mM) and CYP1A2 (0.01pmol/ ⁇ L), pre-incubate at room temperature for 10 minutes, then add the NADPH regeneration system to react for 30 minutes at room temperature, and finally add an equal volume of detection buffer and incubate at room temperature for 20 minutes for chemiluminescence detection.
  • Negative control group The experiment method is the same as the test group, except that no test compound is added.
  • Blank control group The experimental method is the same as the test group, except that no test compound is added, and CYP1A2 membrane (0.01pmol/ ⁇ L) is used instead of CYP1A2.
  • test group add different concentrations of the test compound to the microplate, add Luciferin-ME EGE (30 ⁇ M), K 3 PO 4 (100mM) and CYP2D6 (5nM) to each well , Pre-incubate at room temperature for 10 minutes, then add NADPH regeneration system to react for 30 minutes at 37°C, and finally add an equal volume of detection buffer to incubate for 20 minutes at room temperature for chemiluminescence detection.
  • Negative control group The experiment method is the same as the test group, except that no test compound is added.
  • Blank control group The experimental method is the same as the test group, except that no test compound is added, and CYP2D6 membrane (5nM) is used instead of CYP2D6.
  • Test group add different concentrations of test compounds to the microtiter plate, add Luciferin-IPA (3 ⁇ M), K 3 PO 4 (100mM) and CYP3A4 (2nM) to each well, Pre-incubate at room temperature for 10 minutes, then add NADPH regeneration system to react for 30 minutes at room temperature, and finally add an equal volume of detection buffer to incubate at room temperature for 20 minutes, then perform chemiluminescence detection.
  • Negative control group The experiment method is the same as the test group, except that no test compound is added.
  • Blank control group The experimental method is the same as the test group, except that no test compound is added, and CYP3A4 membrane (2nM) is used instead of CYP3A4.
  • percentage inhibition rate (%) (1-(chemiluminescence value of the test compound-chemiluminescence value of the blank control group)/(chemiluminescence value of the negative control group-chemiluminescence value of the blank control group) )) ⁇ 100%. According to the inhibitory rate of the compound on the CYP enzyme at different concentrations, the half inhibitory concentration (IC 50 ) or range of the compound is estimated.
  • IC 50 X ⁇ (1-percent inhibition rate (%))/percent inhibition rate (%), where X is the test concentration of the compound.
  • the compound hydrochloride of Example 13 was administered intravenously (IV) to male SD rats to investigate the pharmacokinetic characteristics.
  • the dosage is 1 mg/kg, and the vehicle is 5% DMSO: 5% Solutol (polyethylene glycol-15 hydroxystearate): 90% normal saline.
  • venous blood samples were collected at 0.083, 0.25, 0.5, 1 , 2 , 4, 6, 8 and 24 hours after administration; the blood was anticoagulated with EDTA.K 2 , and the plasma samples were obtained after centrifugation and stored at -80°C . Plasma samples were processed with precipitated protein and analyzed by LC-MS/MS. WinNonlin 6.3 software was used to calculate the pharmacokinetic parameters using a non-compartmental model. The results are shown in Table 18.
  • Test Example 6 Rat brain tissue distribution test
  • the compound of Example 13 hydrochloride was administered intravenously (IV) to male SD rats to investigate the distribution characteristics of the brain tissue.
  • the dosage is 10mg/kg
  • the solvent is 5% DMSO: 5%
  • Solutol polyethylene glycol-15 hydroxystearate: 90% normal saline, before administration, after administration 0.083, 0.25, 1, 4. Collect blood and brain tissue respectively at 8h and 8h; blood was anticoagulated with EDTA.K2 and centrifuged to obtain plasma sample; brain tissue was homogenized with 1:2 normal saline (g:ml); plasma and brain tissue homogenate were stored in -80°C, plasma and brain tissue samples were processed with precipitated protein and then analyzed by LC-MS/MS. Using WinNonlin 6.3 software, the non-compartmental model was used to calculate the pharmacokinetic parameters. The results are shown in Table 19.
  • the brain tissue and plasma concentration (C max ) ratio of the compound into the brain was 0.01
  • the area under the drug-time curve (AUC last ) ratio was 0.026, that is, the amount of the compound into the brain is very small, and the compound has a small risk of central side effects.

Abstract

本发明属于医药领域，具体涉及式I所示的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物。本发明还涉及式I所示的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物的医药用途。本发明化合物对去泛素化酶USP7的活性具有较强抑制作用，具有良好的药代动力学性质，能用于预防或治疗癌症疾病。

Description

三嗪酮并咪唑类化合物及其医药用途 技术领域
本发明属于医药领域，具体涉及三嗪酮并咪唑类化合物，还涉及该类化合物的医药用途。
背景技术
泛素-蛋白酶体系统(ubiquitin-protease system，UPS)是一种细胞中基本的生理调控过程，通过一系列级联反应，蛋白质被泛素化修饰，被蛋白酶降解。UPS异常与肿瘤、神经退行性疾病、病毒感染疾病密切相关，目前，主要针对蛋白酶、E1活化酶、E2结合酶、E3连接酶及去泛素化酶(deubiquitinases,DUBs)五类靶点来开发药物。
去泛素化酶(DUBs)能特异性切断在泛素碳末端的甘氨酸残基与靶蛋白间形成的异肽键，使泛素脱离靶蛋白，使靶蛋白被免于降解、重新定位或者活化等。目前，在人体内发现近100种DUBs，其中泛素特异性蛋白酶(ubiquitin-specific proteases，USPs)是DUBs的最大家族成员，包括约85个成员，属于半胱氨酸蛋白酶家族中的异肽酶(Wu and Kumar,Journal of Medicinal Chemistry,2018,61:422-443)。目前已发现有超过40种USPs与肿瘤的发生、发展相关。其中，USP7定位于细胞核，是UPS中一种关键性去泛素化酶，能特异性切断在泛素碳末端和靶蛋白间形成的异肽键，使泛素脱离靶蛋白，使得靶蛋白被免于降解、重新定位或者活化等(Turnbull and Ioannidis,Nature,2017,550,481-486)。
USP7在人体组织分布广泛，在神经发育、细胞周期调控、表观遗传调控、DNA损伤修复及免疫反应中扮演重要角色。已有研究表明，USP7在肝细胞癌、多发性骨髓瘤、结肠癌、肺癌、前列腺癌、膀胱癌等癌细胞中存在过度表达的情况，且这种过度表达与肿瘤侵袭和不良预后直接相关(Pozhidaeva and Bezsonova,DNA Repair,2019,76,30-39)。
USP7的底物种类丰富，且大多数为与细胞周期调控、免疫应答、细胞凋亡以及DNA损伤修复等相关的蛋白，如MDM2、p53、ERCC6、Foxp3、PTEN和FOXO4等(Chauhan and Tian,Cancer Cell,2012,22,345-358)。在一些肿瘤细胞中MDM2过度表达，USP7能保护MDM2免于泛素化，MDM2与p53蛋白结合之后促进其泛素化并降解，促进肿瘤生长。
USP7亦可通过直接调控肿瘤抑制蛋白(p53、PTEN、FOXO4、p114ARF、p16INK4)和肿瘤促进蛋白(N-MYC、REST)的表达，上调肿瘤相关因子(HIF-1)表达，以及调控肿瘤相关信号通路(SHH信号通路、Wnt/β-catenin信号通路、雄激素受体信号通路、DNA损伤修复信号通路)，而发挥促肿瘤作用(Zhou and Wang,Medicinal Chemistry,2018,14,3-18)。
此外，USP7还通过调控Treg细胞上游信号分子(如转录因子FOXP3和表观遗传调控因子Tip60)，上调Treg细胞活性(Wang and Wu,PLoS One,2017,12,1-23)，抑制Teff细胞(CD8+T细胞)活性，从而发挥肿瘤免疫监视逃逸的作用。
基于以上研究结果，开发USP7抑制剂是肿瘤研究领域的热点之一。目前，针对USP7靶点全球范围内仍无药物上市，在研化合物全部处于临床前研究阶段。因此，本领域仍亟需新的USP7抑制剂，特别是具有高活性及其它优异性能的USP7抑制剂。
发明内容
本发明提供了三嗪酮并咪唑类化合物，其对去泛素化酶USP7的活性具有较强抑制作用，具有良好的药代动力学性质，能用于预防或治疗癌症疾病。在此基础上，本发明还提供了三嗪酮并咪唑类化合物的医药用途。
本发明第一方面涉及式I所示的化合物、其可药用盐、酯、溶剂化物(例如水合物)、 立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物：
Figure PCTCN2020083270-appb-000001
其中：
R 1选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基和
Figure PCTCN2020083270-appb-000002
其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被R 4范围内的一个或多个基团所取代；
R 4范围的基团包括氢、卤素、氧代基(可表示为＝O)、-OR a、-NR bR c、-C(O) qR 7、-C(O)NR bR c、-S(O) qR 7、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a、-O-C 2-6亚烷基-NR bR c、C 1- 6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被R 6范围内的一个或多个基团所取代；
R 6范围的基团包括氢、卤素、氰基、C 1-6烷基、卤代的C 1-6烷基、-OR a、-NR bR c、-C(O) qR 8、-C(O)NR bR c、-S(O) qR 8、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a、-O-C 2-6亚烷基-NR bR c、C 1-6烷基、-C 1-6亚烷基-OR a和-C 1-6亚烷基-NR bR c；
A环选自C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被R范围内的一个或多个基团所取代；
B环选自C 4-6环烯基、C 3-8环烷基、氧代的C 3-8环烷基、5-12元脂杂环基、氧代的5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 3-8环烷基、氧代的C 3-8环烷基、5-12元脂杂环基、氧代的5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；
R范围的基团包括氢、C 1-6烷基、卤代的C 1-6烷基、卤素、氰基、-OR d和-NR eR f；
R 5范围的基团包括氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基、-OR d、-NR eR f、卤素、氰基、-C(O) qR 9、-C(O)NR eR f、-S(O) qR 9、-S(O) qNR eR f、-O-(C 2-6亚烷基-O) t-R d和-O-C 2-6亚烷基-NR eR f，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被K范围内的一个或多个基团所取代；
K范围的基团包括氢、卤素、氰基、C 1-6烷基、-OR d、-NR eR f、-C(O) qR 10、-C(O)NR eR f、-S(O) qR 10和-S(O) qNR eR f；
R a、R b、R c、R d、R e和R f各自独立地选自氢、-C(O) qR 11、-S(O) qR 11、C 1-6烷基、C 2- 6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 6-10芳基和5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基；
R 7、R 8、R 9、R 10和R 11各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被 如下的一个或多个取代基所取代：氢、卤素、氰基、氨基、羟基、C 1-6烷基；
R 2选自氢、氰基、卤素、C 1-6烷基、卤代的C 1-6烷基、C 3-8环烷基和5-12元脂杂环基；
R 3选自氢、C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基、-C(O) qR 12、-C(O)NR gR h、-S(O) qR 12和-S(O) qNR gR h，其中，所述C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、C 1-6烷基、卤代的C 1-6烷基、C 6-10芳基、卤代的C 6-10芳基、5-12元芳杂环基、卤代的5-12元芳杂环基、C 3-8环烷基、卤代的C 3-8环烷基；
R 12选自氢、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基、C 3-8环烷基并C 6-10芳基、C 3-8环烷基并5-12元芳杂环基、5-12元脂杂环基并C 6-10芳基、5-12元芳杂环并5-12元脂杂环基，其中，所述氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基、C 3-8环烷基并C 6-10芳基、C 3-8环烷基并5-12元芳杂环基、5-12元脂杂环基并C 5-10芳基和5-12元芳杂环并5-12元脂杂环基各自独立地任选被R 13范围内的一个或多个基团所取代；
R 13范围的基团包括氢、氨基、氰基、卤素、-OR j、-NR kR m、-C(O) qR 14、-C(O)NR kR m、-S(O) qR 14、-S(O) qNR kR m、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、-C 1-6亚烷基-(C 6- 10芳基)、C 6-10芳基、5-12元芳杂环基和-C 1-6亚烷基-(5-12元芳杂环基)，其中，所述氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、-C 1-6亚烷基-(C 6-10芳基)、C 6-10芳基、5-12元芳杂环基和-C 1-6亚烷基-(5-12元芳杂环基)各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氰基、C 1-6烷基、C 6-10芳基、任选被C 1-6烷基或卤素取代的5-12元芳杂环基；
R 14选自氢、C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基和C 2-6烯基，其中，所述的C 1-6烷基、C 2-6烯基和5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1-6烷基、C 6-10芳基和任选被C 1-6烷基取代的5-12元芳杂环基；
R g、R h、R j、R k和R m各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2- 6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基、4-8元脂杂环基；
m选自1、2、3、4、5、6、7和8；
n 1和n 2各自独立地选自0、1和2；
q选自1和2；
r选自1、2和3；
t选自1、2、3和4。
本发明第一方面的一些实施方式中，R 1选自氢、C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基、5-8元芳杂环基和
Figure PCTCN2020083270-appb-000003
其中，所述的C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基各自独立地任选被R 4范围内的一个或多个基团所取代；
R 4范围的基团包括氢、卤素、氧代基、-OR a、-NR bR c、-C(O) qR 7、-C(O)NR bR c、-S(O) qR 7、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a、-O-C 2-6亚烷基-NR bR c、C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述的C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基各自独立地任选被R 6范围内的一个或多个基团所取代；
R 6范围的基团包括氢、卤素、氰基、C 1-6烷基、卤代的C 1-6烷基、-OR a、-NR bR c、- C(O) qR 8、-C(O)NR bR c、-S(O) qR 8、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a、-O-C 2-6亚烷基-NR bR c、-C 1-6亚烷基-OR a和-C 1-6亚烷基-NR bR c；
A环选自C 6-10芳基和5-8元芳杂环基，所述C 6-10芳基和5-8元芳杂环基各自独立地任选被R范围内的一个或多个基团所取代；
B环选自C 3-8环烷基、氧代的C 3-8环烷基、5-8元脂杂环基、氧代的5-8元脂杂环基和5-8元芳杂环基，其中，所述C 3-8环烷基、氧代的C 3-8环烷基、5-8元脂杂环基、氧代的5-8元脂杂环基和5-8元芳杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；
R范围的基团包括氢、C 1-6烷基、卤代的C 1-6烷基、卤素、氰基、-OR a和-NR bR c；
R 5范围的基团包括氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基、5-8元芳杂环基、-OR d、-NR eR f、卤素、氰基、-C(O) qR 9、-C(O)NR eR f、-S(O) qR 9、-S(O) qNR eR f、-O-(C 2-6亚烷基-O) t-R d和-O-C 2-6亚烷基-NR eR f，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基、5-8元芳杂环基各自独立地任选被K范围内的一个或多个基团所取代；
K范围的基团包括氢、卤素、氰基、C 1-6烷基、-OR d、-NR eR f、-C(O) qR 10、-C(O)NR eR f、-S(O) qR 10和-S(O) qNR eR f；
R a、R b、R c、R d、R e和R f各自独立地选自氢、-C(O) qR 11、-S(O) qR 11、C 1-6烷基、C 2- 6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述C 1-6烷基、C 6-10芳基和5-8元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基；
R 7、R 8、R 9、R 10和R 11各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2- 6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：卤素、氰基、氨基、羟基、C 1-6烷基；
q选自1和2；
t选自1、2、3和4；
r选自1、2和3；
m选自1、2、3、4、5、6、7和8。
本发明第一方面的一些实施方式中，R 1选自C 6-10芳基、5-8元芳杂环基和
Figure PCTCN2020083270-appb-000004
其中，所述的C 6-10芳基和5-8元芳杂环基各自独立地任选被R 4范围内的一个或多个基团所取代；
R 4范围的基团包括氢、卤素、-OR a、-NR bR c、-C(O) qR 7、-C(O)NR bR c、-S(O) qR 7、-S(O) qNR bR c、C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述的C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基、5-8元芳杂环基各自独立地任选被R 6范围内的一个或多个基团所取代；
R 6范围的基团包括氢、卤素、C 1-6烷基、卤代的C 1-6烷基、-OR a、-NR bR c、-C(O) qR 8、-S(O) qR 8、-C 1-6亚烷基-OR a和-C 1-6亚烷基-NR bR c；
A环为苯基，所述苯基任选的被R范围内的一个或多个基团所取代；
B环选自C 3-8环烷基、氧代的C 3-8环烷基、5-8元脂杂环基、氧代的5-8元脂杂环基和5-8元芳杂环基，其中，所述C 3-8环烷基、氧代的C 3-8环烷基、5-8元脂杂环基、氧代的5-8元脂杂环基和5-8元芳杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；
R范围的基团包括：氢、C 1-6烷基、卤代的C 1-6烷基、卤素、氰基；
R 5范围的基团包括：氢、C 1-6烷基、卤代的C 1-6烷基、-OR d、-NR eR f和卤素；
R a、R b和R c各自独立地选自氢、-C(O) qR 11、-S(O) qR 11、C 1-6烷基、C 2-6烯基、C 2-6炔 基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述C 1-6烷基、C 6- 10芳基、5-8元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基；
R d、R e和R f各自独立地选自氢和C 1-6烷基；
R 7、R 8和R 11各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3- 8环烷基、5-8元脂杂环基、C 6-10芳基、5-8元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氰基、氨基、羟基、C 1-6烷基；
q选自1和2；
t选自1、2、3和4；
r选自1、2和3；
m选自1和2。
本发明第一方面的一些实施方式中，R 1选自苯基、对氟苯基、对氯苯基、对氨基苯基、对羟基苯基、
Figure PCTCN2020083270-appb-000005
Figure PCTCN2020083270-appb-000006
Figure PCTCN2020083270-appb-000007
本发明第一方面的一些实施方式中，R 1选自C 6-10芳基、5-8元芳杂环基和
Figure PCTCN2020083270-appb-000008
其中，所述的C 6-10芳基和5-8元芳杂环基各自独立地任选被R 4范围内的一个或多个基团所取代；
R 4范围的基团包括卤素、-OR a、C 1-6烷基、5-8元脂杂环基和5-8元芳杂环基，其中，所述的C 1-6烷基、5-8元脂杂环基和5-8元芳杂环基各自独立地任选被R 6范围内的一个或多个基团所取代；
R 6范围的基团包括卤素、C 1-6烷基、-OR a和-NR bR c；
A环为苯基，所述苯基任选地被R范围内的一个或多个基团所取代；
B环选自C 3-8环烷基、氧代的C 3-8环烷基、5-8元脂杂环基、氧代的5-8元脂杂环基和5-8元芳杂环基，其中，所述C 3-8环烷基、氧代的C 3-8环烷基、5-8元脂杂环基、氧代的5-8元脂杂环基和5-8元芳杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；
R范围的基团包括：氢、C 1-6烷基和卤素；
R 5范围的基团包括：氢、C 1-6烷基、-OR d和-NR eR f；
R a、R b和R c各自独立地选自氢和C 1-6烷基；
R d、R e和R f各自独立地选自氢和C 1-6烷基；
r为1和2；
m选自1和2。
本发明第一方面的一些实施方式中，R 1选自苯基、对氟苯基、对氯苯基、对羟基苯基、
Figure PCTCN2020083270-appb-000009
Figure PCTCN2020083270-appb-000010
本发明第一方面的一些实施方式中，R 1选自C 6-10芳基和
Figure PCTCN2020083270-appb-000011
其中，所述的C 6- 10芳基任选被R 4范围内的一个或多个基团所取代；
R 4范围的基团包括-OR a和C 1-6烷基，其中，所述的C 1-6烷基任选被一个或多个-NR bR c基团所取代；
A环为苯基，所述苯基任选被一个或多个R范围内的基团所取代；
B环选自C 3-8环烷基和5-8元脂杂环基，其中，所述C 3-8环烷基和5-8元脂杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；
R范围的基团包括氢；
R 5范围的基团包括氢、-NR eR f；
R a、R b和R c各自独立地为氢；
R e和R f各自独立地选自氢和C 1-6烷基；
r为1；
m选自1和2。
本发明第一方面的一些实施方式中，R 1选自对羟基苯基、
Figure PCTCN2020083270-appb-000012
Figure PCTCN2020083270-appb-000013
本发明第一方面的一些实施方式中，R 1选自氢、C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述的C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基各自独立地任选被R 4范围内的一个或多个基团所取代；
R 4范围的基团包括氢、卤素、氧代基、-OR a、-NR bR c、-C(O) qR 7、-C(O)NR bR c、-S(O) qR 7、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a、-O-C 2-6亚烷基-NR bR c、C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述的C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被R 6范围内的一个或多个基团所取代；
R 6范围的基团包括氢、卤素、氰基、C 1-6烷基、卤代的C 1-6烷基、-OR a、-NR bR c、-C(O) qR 8、-C(O)NR bR c、-S(O) qR 8、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a、-O-C 2-6亚烷基-NR bR c、-C 1-6亚烷基-OR a和-C 1-6亚烷基-NR bR c；
R a、R b、R c各自独立地选自氢、-C(O) qR 11、-S(O) qR 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 6-10芳基、5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基；
R 7、R 8和R 11各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：卤素、氰基、氨基、羟基、C 1-6烷基；
q选自1和2；
t选自1、2、3和4。
本发明第一方面的一些实施方式中，R 1选自C 6-10芳基和5-8元芳杂环基，所述的C 6- 10芳基、5-8元芳杂环基各自独立地任选被R 4范围内的一个或多个基团所取代；
R 4范围的基团包括氢、卤素、-OR a、-NR bR c、-C(O) qR 7、-C(O)NR bR c、-S(O) qR 7、-S(O) qNR bR c、C 1-6烷基、C 3-8环烷基、5-10元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述的C 1-6烷基、C 3-8环烷基、5-10元脂杂环基、C 6-10芳基、5-8元芳杂环基各自独立地任选被R 6范围内的一个或多个基团所取代；
R 6范围的基团包括氢、卤素、C 1-6烷基、卤代的C 1-6烷基、-OR a、-NR bR c、-C(O) qR 8、-S(O) qR 8、-C 1-6亚烷基-OR a和-C 1-6亚烷基-NR bR c；
R a、R b、R c各自独立地选自氢、-C(O) qR 11、-S(O) qR 11、C 1-3烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-10元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述C 1-6烷基、C 6-10芳基、5-8元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基；
R 7、R 8和R 11各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-10 元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-10元脂杂环基、C 6-10芳基、5-8元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氰基、氨基、羟基、C 1-6烷基；
q选自1和2；
t选自1、2、3和4。
本发明第一方面的一些实施方式中，R 1选自苯基、吡啶基、嘧啶基和吡嗪基，所述的苯基、吡啶基、嘧啶基和吡嗪基各自独立地任选被R 4范围内的一个或多个基团所取代；
R 4范围的基团包括氢、卤素、-OR a、-NR bR c、C 1-6烷基、5-8元脂杂环基、C 6-10芳基和5-6元芳杂环基，其中，所述C 1-6烷基、5-8元脂杂环基、C 6-10芳基、5-6元芳杂环基各自独立地任选被R 6范围内的一个或多个基团所取代；
R 6范围的基团包括氢、卤素、C 1-3烷基、卤代的C 1-3烷基、-OR a和-NR bR c；
R a、R b、R c各自独立地选自氢、-C(O) qR 11、-S(O) qR 11、C 1-3烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-6元芳杂环基，其中，所述C 1-6烷基、C 6- 10芳基和5-6元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基；
R 11选自氢、C 1-3烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-6元芳杂环基，其中，所述C 1-3烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基、5-6元芳杂环基各自独立地任选被如下的一个或多个基团取代：氢、卤素、氰基、氨基、羟基、C 1-6烷基；
q选自1或2。
本发明第一方面的一些实施方式中，R 1选自苯基、吡啶基、吡嗪基和嘧啶基，其中，所述的苯基、吡啶基、吡嗪基和嘧啶基各自独立地任选被R 4范围内的一个或多个基团所取代；R 4范围的基团包括氢、卤素(例如F、Cl)、-OH、-OCH 3、-NH 2、-NHCH 3、-N(CH 3) 2、-CH 2NH 2、-CH 2NHCH 3、-CH 2N(CH 3) 2、
Figure PCTCN2020083270-appb-000014
本发明第一方面的一些实施方式中，R 1选自苯基、吡啶基和嘧啶基，其中，所述的苯基、吡啶基和嘧啶基各自独立地任选被R 4范围内的一个或多个基团所取代；R 4范围的基团包括氢、卤素(例如F、Cl)、-OH、-OCH 3、-NH 2、-NHCH 3、-N(CH 3) 2、-CH 2NH 2、-CH 2NHCH 3、-CH 2N(CH 3) 2、
Figure PCTCN2020083270-appb-000015
本发明第一方面的一些实施方式中，R 1选自苯基、吡啶基、吡嗪基和嘧啶基，其中，所述的苯基、吡啶基、吡嗪基和嘧啶基各自独立地任选被R 4范围内的一个或多个基团所取代；R 4范围的基团包括卤素(例如F、Cl)、-OH、-OCH 3、-NH 2、-CH 2NH 2、-CH 2NHCH 3、-CH 2N(CH 3) 2、
Figure PCTCN2020083270-appb-000016
本发明第一方面的一些实施方式中，R 1选自苯基、吡啶基和嘧啶基，其中，所述的苯基、吡啶基和嘧啶基各自独立地任选被R 4范围内的一个或多个基团所取代；R 4范围的基团包括卤素(例如F、Cl)、-OH、-OCH 3、-NH 2、-CH 2NH 2、-CH 2NHCH 3、-CH 2N(CH 3) 2、
Figure PCTCN2020083270-appb-000017
本发明第一方面的一些实施方式中，R 1选自苯基、对氟苯基、对氯苯基、对氨基苯基、对羟基苯基、
Figure PCTCN2020083270-appb-000018
Figure PCTCN2020083270-appb-000019
本发明第一方面的一些实施方式中，R 1为
Figure PCTCN2020083270-appb-000020
其中，
A环选自C 6-10芳基和5-12元芳杂环基，所述C 6-10芳基、5-12元芳杂环基各自独立地任选被R范围内的一个或多个基团所取代；
R范围的基团包括氢、C 1-6烷基、卤代的C 1-6烷基、卤素、氰基、-OR a和-NR bR c；
R a、R b、R c各自独立地选自氢、-C(O) qR 11、-S(O) qR 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 6-10芳基、5-12元芳杂环基各自独立地任选被一个或多个如下的取代基所取代：氢、卤素、氨基、羟基；
R 11选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基各自独立地任选被一个或多个如下的取代基所取代：氢、卤素、氰基、氨基、羟基、C 1-6烷基；
q选自1和2；
r选自1、2和3。
本发明第一方面的一些实施方式中，A环为C 6-10芳基，所述C 6-10芳基任选地被R范围内的一个或多个基团所取代；
R范围的基团包括氢、C 1-6烷基、卤代的C 1-6烷基、卤素、氰基、-OR a、-NR bR c；
R a、R b、R c独立地选自氢、C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基各自独立地任选被如下的一个或多个基团所取代：氢、卤素、氨基、羟基；
r选自1、2和3。
本发明第一方面的一些实施方式中，A环为苯基，所述苯基任选的被R范围内的一个或多个基团所取代；R范围的基团包括氢、C 1-6烷基、卤代的C 1-6烷基、卤素、氰基；r选自1、2和3。
本发明第一方面的一些实施方式中，A环选自苯基和氯代苯基，优选地，A环为苯基。
本发明第一方面的一些实施方式中，R 1为
Figure PCTCN2020083270-appb-000021
其中，
B环选自C 3-8环烷基、氧代的C 3-8环烷基、5-12元脂杂环基和氧代的5-12元脂杂环基，其中，所述C 3-8环烷基、氧代的C 3-8环烷基、5-12元脂杂环基、氧代的5-12元脂杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；
R 5范围的基团包括氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基、-OR d、-NR eR f、卤素、氰基、-C(O) qR 9、-C(O)NR eR f、-S(O) qR 9、-S(O) qNR eR f、-O-(C 2-6亚烷基-O) t-R d和-O-C 2-6亚烷基-NR eR f，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基各自独立地任选被K范围内的一个或多个基团所取代；
K范围的基团包括氢、卤素、氰基、C 1-6烷基、-OR d、-NR eR f、-C(O) qR 10、-C(O)NR eR f、-S(O) qR 10和-S(O) qNR eR f；
R d、R e和R f各自独立地选自氢、-C(O) qR 11、-S(O) qR 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 6-10芳基、5-12元芳杂环基各自独立地任选被一个或多个如下的取代基所取代：氢、卤素、氨基、羟基；
R 9、R 10、R 11各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基各自独立地任选被一个或多个如下的取代基所取代：氢、卤素、氰基、氨基、羟基、C 1-6烷基；
m选自1、2、3、4、5、6、7和8；
q选自1和2；
t选自1、2、3和4。
本发明第一方面的一些实施方式中，B环选自C 3-8环烷基、氧代的C 3-8环烷基、5-12元脂杂环基和氧代的5-12元脂杂环基，其中，所述C 3-8环烷基、氧代的C 3-8环烷基、5-12元脂杂环基和氧代的5-12元脂杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；
R 5范围的基团包括氢、C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、-OR d、-NR eR f、卤素、氰基、-C(O) qR 9、-C(O)NR eR f、-S(O) qR 9、-S(O) qNR eR f、-O-(C 2-6亚烷基-O) t-R d和-O-C 2-6亚烷基-NR eR f，其中，所述C 1-6烷基、C 3-8环烷基和5-12元脂杂环基各自独立地任选被如下的一个或多个基团所取代：氢、卤素和C 1-6烷基；
R d、R e、R f和R 9各自独立地选自氢、C 1-6烷基、卤代的C 1-6烷基、C 3-8环烷基和卤代的C 3-8环烷基；
m选自1、2和3；
q选自1和2；
t选自1、2、3和4。
本发明第一方面的一些实施方式中，B环选自C 3-8环烷基、氧代的C 3-8环烷基、5-12元脂杂环基和氧代的5-12元脂杂环基，其中，所述C 3-8环烷基、氧代的C 3-8环烷基、5-12元脂杂环基和氧代的5-12元脂杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；
R 5范围内的基团包括氢、C 1-6烷基、卤代的C 1-6烷基、-OR d、-NR eR f、卤素、-C(O) qR 9、-C(O)NR eR f、-S(O) qR 9和-S(O) qNR eR f；
R d、R e、R f和R 9各自独立地选自氢、C 1-6烷基、卤代的C 1-6烷基和C 3-8环烷基；
m选自1和2；
q选自1和2。
本发明第一方面的一些实施方式中，B环选自C 3-8环烷基、氧代的C 3-8环烷基、氧代的5-10元脂杂环基和5-10元脂杂环基，其中，所述C 3-8环烷基、氧代的C 3-8环烷基、氧代的5-10元脂杂环基和5-10元脂杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；优选地，B环选自C 3-8环烷基、氧代的C 3-8环烷基和5-10元脂杂环基，其中，所述C 3-8环烷基、氧代的C 3-8环烷基和5-10元脂杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；
R 5范围的基团包括氢、C 1-6烷基、卤代的C 1-6烷基、-OR d、-NR eR f、卤素、-C(O) qR 9、-C(O)NR eR f、-S(O) qR 9和-S(O) qNR eR f；
R d、R e、R f和R 9各自独立地选自氢、C 1-6烷基、卤代的C 1-6烷基和C 3-8环烷基；m选自1和2；q选自1和2。
本发明第一方面的一些实施方式中，B环选自C 3-8环烷基、氧代的C 3-8环烷基、氧代的5-8元脂杂环基和5-8元脂杂环基，其中，所述C 3-8环烷基、氧代的C 3-8环烷基、5-8元脂杂环基和氧代的5-8元脂杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；R 5范围的基团包括氢、C 1-6烷基、卤代的C 1-6烷基、-OR d、-NR eR f和卤素，其中，R d、R e、R f各自独立地选自氢和C 1-6烷基；m选自1和2；
优选地，B环选自C 3-8环烷基、氧代的C 3-8环烷基和5-8元脂杂环基，其中，所述C 3- 8环烷基、氧代的C 3-8环烷基和5-8元脂杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；R 5范围的基团包括氢、C 1-6烷基、卤代的C 1-6烷基、-OR d、-NR eR f和卤素，其中，R d、R e、R f各自独立地选自氢和C 1-6烷基；m选自1和2。
本发明第一方面的一些实施方式中，B环选自C 5-6环烷基、氧代的C 5-6环烷基、氧代的5-6元脂杂环基和5-6元脂杂环基，其中，所述C 5-6环烷基、氧代的C 5-6环烷基、氧代的5-6元脂杂环基和5-6元脂杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；R 5范围的基团包括氢、C 1-3烷基、卤代的C 1-3烷基、-OR d、-NR eR f和卤素；R d、R e和R f各自独立地选自氢和C 1-3烷基；m选自1和2。
本发明第一方面的一些实施方式中，B环选自环戊烷基、氧代环戊烷基、氧杂环戊烷基、氧代的氮杂环戊烷基、氮杂环戊烷基和吡唑基，其中，所述环戊烷基、氧代环戊烷基、氧杂环戊烷基、氧代的氮杂环戊烷基和氮杂环戊烷基各自独立地任选被R 5范围内的一个或多个基团所取代；R 5范围的基团包括氢、C 1-3烷基、-OR d和-NR eR f；R d、R e和R f各自独立地选自氢和C 1-3烷基；m选自1和2。
本发明第一方面的一些实施方式中，B环选自环戊烷基、氧代环戊烷基、氧杂环戊烷基和氮杂环戊烷基，其中，所述环戊烷基、氧代环戊烷基、氧杂环戊烷基和氮杂环戊烷基各自独立地任选被R 5范围内的一个或多个基团所取代；R 5范围的基团包括氢、C 1-3烷基、-OR d和-NR eR f；R d、R e和R f各自独立地选自氢和C 1-3烷基；m选自1和2。
本发明第一方面的一些实施方式中，B环选自环戊烷基、氧代环戊烷基、氧杂环戊烷基、2-吡咯烷酮基和氮杂环戊烷基和吡唑基，其中，所述环戊烷基、氧代环戊烷基、氧杂环戊烷基、2-吡咯烷酮基、氮杂环戊烷基各自独立地任选被R 5范围内的一个或多个基团所取代；R 5范围的基团包括氢、甲基、-OH、氨基、-NHCH 3和-N(CH 3) 2；m选自1和2。
本发明第一方面的一些实施方式中，B环选自环戊烷基、氧代环戊烷基、氧杂环戊烷基和氮杂环戊烷基，其中，所述环戊烷基、氧代环戊烷基、氧杂环戊烷基、氮杂环戊烷基各自独立地任选被R 5范围内的一个或多个基团所取代；R 5范围的基团包括氢、甲基、-OH、氨基、-NHCH 3和-N(CH 3) 2；m选自1和2。
本发明第一方面的一些实施方式中，B环选自环戊烷基、氧代环戊烷基、2-吡咯烷酮基、氮杂环戊烷基和吡唑基，其中，所述环戊烷基、氧代环戊烷基、2-吡咯烷酮基、氮杂环戊烷基和吡唑基各自独立地任选被R 5范围内的一个或多个基团所取代；R 5范围的基团包括甲基、-OH、氨基、-NHCH 3和-N(CH 3) 2；m选自1和2。
本发明第一方面的一些实施方式中，B环选自环戊烷基、氧代环戊烷基和氮杂环戊烷基，其中，所述环戊烷基、氧代环戊烷基和氮杂环戊烷基各自独立地任选被R 5范围内的一个或多个基团所取代；R 5范围的基团包括甲基、-OH、氨基、-NHCH 3和-N(CH 3) 2；m选自1和2。
本发明第一方面的一些实施方式中，R 1选自
Figure PCTCN2020083270-appb-000022
Figure PCTCN2020083270-appb-000023
Figure PCTCN2020083270-appb-000024
本发明第一方面的一些实施方式中，R 1选自如下结构：
Figure PCTCN2020083270-appb-000025
Figure PCTCN2020083270-appb-000026
本发明第一方面的一些实施方式中，R 2选自氢、氰基、卤素、C 1-6烷基和卤代的C 1-6烷基；优选地，R 2选自氢、氰基、卤素和C 1-3烷基；优选地，R 2选自氢、氰基和氯；更优选地，R 2为氢。
本发明第一方面的一些实施方式中，R 3选自-C(O) qR 12、-C(O)NR gR h、-S(O) qR 12和- S(O) qNR gR h；
R 12选自氨基、C 1-6烷基、C 2-6烯基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基、C 3-8环烷基并C 6-10芳基、C 3-8环烷基并5-12元芳杂环基、5-12元脂杂环基并C 6-10芳基和5-12元脂杂环基并5-12元芳杂环基，其中，所述氨基、C 1-6烷基、C 2-6烯基、C 3-8环烷基、5-12元脂杂环基、5-12元芳杂环基、C 6-10芳基、C 3-8环烷基并C 6-10芳基、C 3- 8环烷基并5-12元芳杂环基、5-12元脂杂环基并C 5-10芳基、5-12元脂杂环基并5-12元芳杂环基各自独立地任选被R 13范围内的一个或多个基团取代；
R 13范围的基团包括氢、氨基、氰基、卤素、-OR j、-NR kR m、-C(O) qR 14、-C(O)NR kR m、-S(O) qR 14、-S(O) qNR kR m、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 6-10芳基、-C 1-6亚烷基-(C 6-10芳基)、5-12元芳杂环基和-C 1-6烷基-(5-12元芳杂环基)，其中，所述氨基、C 1- 6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 6-10芳基、-C 1-6亚烷基-(C 6-10芳基)、5-12元芳杂环基、-C 1-6烷基-(5-12元芳杂环基)各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氰基、C 1-6烷基、C 6-10芳基、任选被C 1-6烷基或卤素取代的5-12元芳杂环基；
R 14选自氢、C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基和C 2-6烯基，其中，所述C 1-6烷基、C 2-6烯基、5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1-6烷基、C 6-10芳基和任选被C 1-6烷基取代的5-12元芳杂环基；
R g、R h、R j、R k、R m各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2- 6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被一个或多个如下的取代基所取代：氢、卤素、氨基、羟基；q选自1和2。
本发明第一方面的一些实施方式中，R 3选自-C(O) qR 12、-C(O)NR gR h、-S(O) qR 12和-S(O) qNR gR h；
R 12选自氨基、C 1-6烷基、C 2-6烯基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基、C 3-8环烷基并C 6-10芳基、C 3-8环烷基并5-12元芳杂环基、5-12元脂杂环基并C 6-10芳基和5-12元脂杂环基并5-12元芳杂环基，其中，所述氨基、C 1-6烷基、C 2-6烯基、C 3-8环烷基、5-12元脂杂环基、5-12元芳杂环基、C 6-10芳基、C 3-8环烷基并C 6-10芳基、C 3- 8环烷基并5-12元芳杂环基、5-12元脂杂环基并C 5-10芳基和5-12元脂杂环基并5-12元芳杂环基各自独立地任选被R 13范围内的一个或多个基团所取代；
R 13范围的基团包括氢、氨基、卤素、-OR j、-NR kR m、-C(O) qR 14、-C(O)NR kR m、-S(O) qR 14、-S(O) qNR kR m、C 1-6烷基、C 3-8环烷基、-C 1-6亚烷基-(C 6-10芳基)、-C 1-6烷基-(5-12元芳杂环基)、C 6-10芳基和5-12元芳杂环基，其中，所述氨基、C 1-6烷基、C 3-8环烷基、C 6-10芳基、5-12元芳杂环基、-C 1-6亚烷基-(C 6-10芳基)和-C 1-6烷基-(5-12元芳杂环基)各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氰基、C 1-6烷基、C 6-10芳基、任选被C 1-6烷基取代的5-12元芳杂环基；
R 14选自氢、C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基和C 2-6烯基，其中，所述C 1-6烷基、C 2-6烯基、5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1-6烷基、C 6-10芳基、任选被C 1-6烷基取代的5-12元芳杂环基；
R g、R h、R j、R k、R m各自独立地选自氢、C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基；q选自1和2。
本发明第一方面的一些实施方式中，R 3选自-C(O) qR 12和-S(O) qR 12；
R 12选自C 1-6烷基、C 2-6烯基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基、C 3-8环烷基并C 6-10芳基、C 3-8环烷基并5-12元芳杂环基、5-12元脂杂环基并C 6-10 芳基和5-12元脂杂环基并5-12元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基、C 3-8环烷基并C 6-10芳基、C 3-8环烷基并5-12元芳杂环基、5-12元脂杂环基并C 5-10芳基、5-12元脂杂环基并5-12元芳杂环基各自独立地任选被R 13范围内的一个或多个基团所取代；
R 13范围的基团包括氢、氨基、卤素、-OR j、-NR kR m、-C(O) qR 14、-S(O) qR 14、C 1-6烷基、C 3-8环烷基、-C 1-6亚烷基-(C 6-10芳基)、-C 1-6烷基-(5-12元芳杂环基)、C 6-10芳基和5-12元芳杂环基，其中，所述氨基、C 1-6烷基、C 3-8环烷基、C 6-10芳基、5-12元芳杂环基、-C 1- 6亚烷基-(C 6-10芳基)、-C 1-6烷基-(5-12元芳杂环基)各自独立地任选被如下的一个或多个基团所取代：氢、卤素、C 1-6烷基、C 6-10芳基、C 6-10芳基、任选被C 1-6烷基或卤素取代的5-12元芳杂环基；
R 14选自氢、C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基和C 2-6烯基，其中，所述C 1-6烷基、C 2-6烯基、5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1-6烷基、C 6-10芳基、任选被C 1-6烷基取代的5-12元芳杂环基；
R j、R k、R m各自独立地选自氢、C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基；q选自1和2。
本发明第一方面的一些实施方式中，R 3为-C(O)R 12；
R 12选自C 1-6烷基、C 2-6烯基、C 3-8环烷基、5-10元脂杂环基、C 6-10芳基、5-10元芳杂环基、C 3-8环烷基并C 6-10芳基、C 3-8环烷基并5-10元芳杂环基、5-10元脂杂环基并C 6-10芳基和5-10元脂杂环基并5-10元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 3-8环烷基、5-10元脂杂环基、C 6-10芳基、5-10元芳杂环基、C 3-8环烷基并C 6-10芳基、C 3-8环烷基并5-10元芳杂环基、5-10元脂杂环基并C 5-10芳基和5-10元脂杂环基并5-10元芳杂环基各自独立地任选被R 13范围内的一个或多个基团所取代；
R 13范围的基团包括氢、氨基、卤素、-C(O)R 14、-OR j、C 1-6烷基、C 3-8环烷基、-C 1- 6亚烷基-(C 6-10芳基)、-C 1-6烷基-(5-10元芳杂环基)、C 6-10芳基和5-10元芳杂环基，其中，所述氨基、C 1-6烷基、C 3-8环烷基、-C 1-6亚烷基-(C 6-10芳基)、C 6-10芳基、5-10元芳杂环基和-C 1-6烷基-(5-10元芳杂环基)各自独立地任选被如下的一个或多个基团所取代：氢、卤素、C 1-6烷基、C 6-10芳基、任选被C 1-6烷基或卤素取代的5-10元芳杂环基；
R 14选自氢、C 1-6烷基、C 3-8环烷基、5-10元脂杂环基、C 6-10芳基、5-10元芳杂环基和C 2-6烯基，其中，所述C 1-6烷基、C 2-6烯基、5-10元芳杂环基各自独立地任选被一个或多个如下的取代基所取代：卤素、C 1-6烷基、C 6-10芳基、任选被C 1-6烷基取代的5-10元芳杂环基；
R j选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基、4-8元脂杂环基。
本发明第一方面的一些实施方式中，R 3为-C(O)R 12；
R 12选自C 1-6烷基、C 2-6烯基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基、5-8元芳杂环基、C 3-8环烷基并C 6-10芳基、C 3-8环烷基并5-8元芳杂环基、5-8元脂杂环基并C 6-10芳基和5-8元脂杂环基并5-8元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基、5-8元芳杂环基、C 3-8环烷基并C 6-10芳基、C 3-8环烷基并5-8元芳杂环基、5-8元脂杂环基并C 6-10芳基和5-8元脂杂环基并5-8元芳杂环基各自独立地任选被R 13范围内的一个或多个基团所取代；
R 13范围的基团包括氢、氨基、卤素、-C(O)R 14、-OR j、C 1-6烷基、C 3-6环烷基、-C 1-6亚烷基-(C 6-10芳基)、-C 1-6烷基-(5-8元芳杂环基)、C 6-10芳基和5-8元芳杂环基，其中，所述氨基、C 1-6烷基、-C 1-6亚烷基-(C 6-10芳基)、C 6-10芳基、5-8元芳杂环基、-C 1-6烷基-(5-8 元芳杂环基)各自独立地任选被一个或多个如下的取代基所取代：氢、卤素、C 1-6烷基、C 6- 10芳基、任选被C 1-3烷基或卤素取代的5-8元芳杂环基；
R 14选自氢、C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基、5-8元芳杂环基和C 2-6烯基，其中，所述C 1-6烷基、C 2-6烯基、5-8元芳杂环基各自独立地任选被一个或多个如下的取代基所取代：卤素、C 1-6烷基、C 6-10芳基和任选被C 1-6烷基取代的5-8元芳杂环基；
R j选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基、4-8元脂杂环基。
本发明第一方面的一些实施方式中，R 3为-C(O)R 12；
R 12选自C 1-6烷基、C 3-6环烷基、5-8元脂杂环基、5-8元脂杂环基并5-6元芳杂环基、C 6-10芳基和5-6元芳杂环基，其中，所述C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基、5-6元芳杂环基各自独立地任选被R 13范围内的一个或多个基团所取代；
R 13范围的基团包括氢、氨基、卤素、-C(O)R 14、-OR j、C 1-3烷基、C 3-6环烷基、苄基、-C 1-3亚烷基-(5-6元芳杂环基)、C 6-10芳基和5-6元芳杂环基，其中，所述氨基、C 1-3烷基、C 6-10芳基、5-6元芳杂环基、苄基、-C 1-3烷基-(5-6元芳杂环基)各自独立地任选被一个或多个如下的取代基所取代：卤素、C 1-3烷基、C 6-10芳基、任选被甲基或F取代的5-6元芳杂环基；
R 14选自氢、C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基、5-8元芳杂环基和C 2-6烯基，其中，所述C 1-6烷基、C 2-6烯基、5-8元芳杂环基各自独立地任选被一个或多个如下的取代基所取代：卤素、C 1-3烷基、C 6-10芳基和任选被C 1-3烷基取代的5-8元芳杂环基；
R j为5-8元芳杂环基，所述5-8元芳杂环基任选被一个或多个如下的取代基所取代：卤素、4-6元脂杂环基。
本发明第一方面的一些实施方式中，R 3为-C(O)R 12；其中，
R 12选自C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、5-8元芳杂环基和5-8元脂杂环基并5-6元芳杂环基，其中，所述C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、5-8元芳杂环基和5-8元脂杂环基并5-6元芳杂环基各自独立地任选被R 13范围内的一个或多个基团所取代；
R 13范围的基团包括氨基、卤素、-C(O)R 14、-OR j、C 1-3烷基、C 3-6环烷基、-C 1-3亚烷基-(C 6-8芳基)、-C 1-3亚烷基-(5-6元芳杂环基)、C 6-8芳基和5-8元芳杂环基，其中，所述氨基、C 1-3烷基、C 3-6环烷基、-C 1-3亚烷基-(C 6-8芳基)、C 6-8芳基、5-8元芳杂环基和-C 1-3亚烷基-(5-6元芳杂环基)各自独立地任选被如下的一个或多个基团所取代：卤素、C 1-3烷基、C 6-8芳基、任选被C 1-3烷基或卤素取代的5-8元芳杂环基；
R 14选自5-8元芳杂环基，5-8元芳杂环基任选被一个或多个如下的取代基所取代：C 1- 3烷基、任选被C 1-3烷基取代的5-8元芳杂环基；
R j为5-8元芳杂环基，5-8元芳杂环基任选被如下的一个或多个取代基所取代：氢、卤素、4-6元脂杂环基。
本发明第一方面的一些实施方式中，R 3为
Figure PCTCN2020083270-appb-000027
R 18为氢，R 19选自
Figure PCTCN2020083270-appb-000028
或者，R 18、R 19及与它们连接的碳原子共同形成
Figure PCTCN2020083270-appb-000029
其中，F’选自C 3-6环烷基、5-10元芳杂环基、5-10元脂杂环基、5-10元脂杂环基并5-10元芳杂环基；
t选自1、2和3；
R 17独立地选自氢、氨基、卤素、-OR j、C 6-10芳基、C 1-6烷基、-C 1-6烷基-C 6-10芳基、5-12元芳杂环基、-C 1-6烷基-C 6-10芳基、-C 1-6烷基-(5-12元芳杂环基)、-C(O)R 14和C 3-6环烷基，其中，所述氨基、C 6-10芳基、C 1-6烷基、5-12元芳杂环基、-C 1-6烷基-C 6-10芳基、-C 1-6烷基-(5-12元芳杂环基)各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1- 6烷基、C 1-6烷氧基、C 6-10芳基、任选被卤素取代的5-6元芳杂环基；
R j为5-6元芳杂环基，其中，所述5-6元芳杂环基任选如下的一个或多个基团所取代：F、
Figure PCTCN2020083270-appb-000030
R 14为5-6元芳杂环基，其中，所述的5-6元芳杂环基任选被如下的一个或多个基团所取代：C 1-3烷基、任选被C 1-3烷基取代的5-6元芳杂环基。
本发明第一方面的一些实施方式中，R 3为
Figure PCTCN2020083270-appb-000031
R 17选自氢、甲基、二氟甲基、环丙基和三氟甲基，R 18为氢，R 19选自
Figure PCTCN2020083270-appb-000032
Figure PCTCN2020083270-appb-000033
或者，R 18、R 19及与它们连接的碳原子共同形成
Figure PCTCN2020083270-appb-000034
F’选自
Figure PCTCN2020083270-appb-000035
t选自1、2和3；
R 17独立地选自氨基、
Figure PCTCN2020083270-appb-000036
苯基、甲基、苄基、
Figure PCTCN2020083270-appb-000037
Figure PCTCN2020083270-appb-000038
-OR j和环丙基，其中，所述氨基、
Figure PCTCN2020083270-appb-000039
各自独立地任选被如下的一个或多个取代基所取代：甲基、苯基、吡啶基、氟吡啶基、甲基 吡啶基、吡嗪基；优选地，R 17独立地选自氨基、
Figure PCTCN2020083270-appb-000040
苯基、甲基、苄基、
Figure PCTCN2020083270-appb-000041
-OR j和环丙基，其中，所述氨基、
Figure PCTCN2020083270-appb-000042
Figure PCTCN2020083270-appb-000043
各自独立地任选被如下的一个或多个取代基所取代：甲基、苯基、吡啶基、氟吡啶基、甲基吡啶基、吡嗪基；
R j选自吡啶基和吡嗪基，所述吡啶基任选被如下的一个或多个取代基所取代：F、
Figure PCTCN2020083270-appb-000044
本发明第一方面的一些实施方式中，R 3为
Figure PCTCN2020083270-appb-000045
R 19选自苯基、吡咯基和任选被一个或多个卤素(例如F、Cl)取代的1-吡唑基；
R 17为任选被一个或多个卤素所取代的C 1-6烷基；
优选地，R 3为
Figure PCTCN2020083270-appb-000046
R 19选自苯基和被一个或多个卤素(例如F、Cl)取代的1-吡唑基；
R 17为任选被一个或多个卤素所取代的C 1-6烷基。
本发明第一方面的一些实施方式中，R 3为
Figure PCTCN2020083270-appb-000047
R 19选自
Figure PCTCN2020083270-appb-000048
Figure PCTCN2020083270-appb-000049
R 17选自甲基、二氟甲基和三氟甲基。
本发明第一方面的一些实施方式中，R 3为
Figure PCTCN2020083270-appb-000050
F’选自C 3-6环烷基、取代或未取代的5-6元芳杂环基，其中，所述取代为被如下的一个或多个取代基所取代：卤素、C 1-6烷基和C 3-6环烷基；
R 17选自氢、C 3-6环烷基、取代或未取代的-C 1-3烷基-C 6-10芳基和取代或未取代的C 1-3烷基-(5-6元芳杂环基)，其中，所述取代为任选地被一个或多个如下的取代基所取代：卤素、C 1-3烷基、C 1-3烷氧基；
优选地，R 17选自
Figure PCTCN2020083270-appb-000051
优选地，R 17选自
Figure PCTCN2020083270-appb-000052
Figure PCTCN2020083270-appb-000053
在优选的实施方式中，R 3为
Figure PCTCN2020083270-appb-000054
F’选自任选被一个或多个C 1-3烷基(例如甲基)、C 3-6环烷基(例如环丙基)取代的
Figure PCTCN2020083270-appb-000055
Figure PCTCN2020083270-appb-000056
R 17选自
Figure PCTCN2020083270-appb-000057
优选地，R 17选自
Figure PCTCN2020083270-appb-000058
Figure PCTCN2020083270-appb-000059
本发明第一方面的一些实施方式中，R 3为-C(O)R 12；R 12选自下列基团：
Figure PCTCN2020083270-appb-000060
Figure PCTCN2020083270-appb-000061
本发明第一方面的一些实施方式中，R 3选自-C(O)R 12，R 12选自
Figure PCTCN2020083270-appb-000062
Figure PCTCN2020083270-appb-000063
本发明第一方面的一些实施方式中，R 3为-C(O)R 12；其中，
R 12选自C 1-6烷基、5-8元脂杂环基和5-8元芳杂环基，其中，所述C 1-6烷基、5-8元脂杂环基和5-8元芳杂环基各自独立地任选被R 13范围内的一个或多个基团所取代；
R 13范围的基团包括-C(O)R 14、C 1-3烷基、C 3-6环烷基、C 6-8芳基和5-8元芳杂环基，其中，所述C 1-3烷基、C 3-6环烷基、C 6-8芳基和5-8元芳杂环基各自独立地任选被如下的一个或多个基团所取代：卤素和C 6-8芳基；
R 14选自5-8元芳杂环基，5-8元芳杂环基任选被一个或多个如下的取代基所取代：C 1- 3烷基、任选被C 1-3烷基取代的5-8元芳杂环基。
本发明第一方面的一些实施方式中，R 3选自-C(O)R 12；R 12选自
Figure PCTCN2020083270-appb-000064
Figure PCTCN2020083270-appb-000065
本发明第一方面的一些实施方式中，R 3选自-C(O)R 12；R 12选自下列基团：
Figure PCTCN2020083270-appb-000066
Figure PCTCN2020083270-appb-000067
本发明第一方面的一些实施方式中，R 3为-C(O)R 12；其中，
R 12选自C 1-6烷基、5-8元脂杂环基和5-8元芳杂环基，其中，所述C 1-6烷基、5-8元脂杂环基和5-8元芳杂环基各自独立地任选被R 13范围内的一个或多个基团所取代；
R 13范围的基团包括-C(O)R 14、C 1-3烷基、C 6-8芳基和5-8元芳杂环基，其中，所述C 1- 3烷基、C 6-8芳基和5-8元芳杂环基各自独立地任选被如下的一个或多个基团所取代：卤素和C 6-8芳基；
R 14选自5-8元芳杂环基，5-8元芳杂环基任选被一个或多个如下的取代基所取代：C 1- 3烷基、任选被C 1-3烷基取代的5-8元芳杂环基。
本发明第一方面的一些实施方式中，R 3选自-C(O)R 12；R 12选自下列基团：
Figure PCTCN2020083270-appb-000068
Figure PCTCN2020083270-appb-000069
本发明第一方面的一些实施方式中，R 3选自-C(O)R 12；R 12选自下列基团：
Figure PCTCN2020083270-appb-000070
Figure PCTCN2020083270-appb-000071
本发明第一方面的一些实施方式中，n 1和n 2均为1。
本发明第二方面涉及式Ⅱ所示的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物：
Figure PCTCN2020083270-appb-000072
其中，
Y 1选自CH和N；
Y 2选自C和N，且当Y 2为N时，R 16不存在；
Y 3选自CH和N；
Z 1选自CH和N；
R 15选自氢、卤素、-C 1-6亚烷基-NR nR q、C 1-6烷氧基、羟基和5-12元脂杂环基，R 16选自氢、C 1-6烷氧基、5-12元脂杂环基和5-10元芳杂环基，其中，所述5-12元脂杂环基和5-10元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：羟基、C 1-6烷基、卤素；或者，R 15、R 16及与它们相连的芳基形成如下任一基团：C 6-12芳基并5-12元氧代环烷基、C 6-12芳基并5-12元环烷基、C 6-12芳基并5-10元脂杂环基、C 6-12芳基并氧代5-10元脂杂环基、C 6-12芳基并5-10元芳杂环基，其中，所述C 6-12芳基并5-12元氧代环烷基、C 6-12芳基并5-12元环烷基和C 6-12芳基并5-10元脂杂环基各自独立地任选被如下的一个或多个取代基所取代：-NR nR q、羟基、C 1-6烷基；
R n和R q各自独立地选自H和C 1-6烷基；
R 2选自氢、卤素和-CN；
R 18为氢，Z 2为CH，R 19为C 6-12芳基或5-10元芳杂环基，其中，所述C 6-12芳基和5-10元芳杂环基各自独立地任选被一个或多个卤素所取代；或者，R 18、Z 1、Z 2及R 19形成如下任一基团：6-12元亚脂杂环基、5-10元亚芳杂环基、3-12元亚环烷基、5-10元芳杂环并6-12元亚脂杂环基，其中，所述6-12元亚脂杂环基、5-10元亚芳杂环基和3-12元亚环烷基各自独立地任选被如下的一个或多个取代基所取代：5-10元芳杂环基C 1-6亚烷基、取代的5-10元芳杂环基C 1-6亚烷基、取代的5-10元芳杂环基羰基、C 1-6烷基、取代的5-10元芳杂环基亚氨基、3-8元环烷基、5-10元芳杂环基氧基、取代的5-10元芳杂环基氧基、C 6-12芳基亚氨基，并且，所述取代为各自独立地被如下的一个或多个取代基取代：C 1-6烷基、C 1-6烷基5-10元亚芳杂环基、卤素、3-8元脂杂环基；
R 17选自氢、C 1-6烷基、C 3-8环烷基、C 6-12芳基和C 6-12芳基C 1-6亚烷基，其中，所述C 1-6烷基和C 6-12芳基C 1-6亚烷基各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1-6烷基。
本发明第二方面的一些实施方式中，所述化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物包括如下(A)至(F)中的任一项：
(A)Y 1为CH，Y 2为C，Y 3为CH，Z 1为CH；
(B)Y 1为CH，Y 2为C，Y 3为N，Z 1为CH；
(C)Y 1为CH，Y 2为N，Y 3为N，Z 1为CH；
(D)Y 1为N，Y 2为C，Y 3为CH，Z 1为CH；
(E)Y 1为N，Y 2为C，Y 3为N，Z 1为CH；
(F)Y 1为CH，Y 2为C，Y 3为CH，Z 1为N。
本发明第三方面涉及式Ⅲ所示的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物：
Figure PCTCN2020083270-appb-000073
其中，
R 15选自氢、卤素、-C 1-6亚烷基-NR nR q、C 1-6烷氧基、羟基和5-12元脂杂环基，R 16选自氢、C 1-6烷氧基、5-12元脂杂环基和5-10元芳杂环基，其中，所述5-12元脂杂环基和5-10元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：羟基、C 1-6烷基、卤素；或者，R 15、R 16及与它们相连的苯基形成如下任一基团：C 6-12芳基并5-12元氧代环烷基、C 6-12芳基并5-12元环烷基、C 6-12芳基并5-10元脂杂环基、C 6-12芳基并氧代5-10元脂杂环基、C 6-12芳基并5-10元芳杂环基，其中，所述C 6-12芳基并5-12元氧代环烷基、C 6-12芳基并5-12元环烷基和C 6-12芳基并5-10元脂杂环基各自独立地任选被如下的一个或多个取代基所取代：-NR nR q、羟基、C 1-6烷基；
R n和R q各自独立地选自H和C 1-6烷基；
R 2选自氢、卤素和-CN；
R 18为氢，Z 2为CH，R 19为C 6-12芳基或5-10元芳杂环基，其中，所述5-10元芳杂环基任选地被一个或多个卤素所取代；或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：6-12元亚脂杂环基、5-10元亚芳杂环基、3-12元亚环烷基、5-10元芳杂环并6-12元亚脂杂环基，其中，所述6-12元亚脂杂环基、5-10元亚芳杂环基和3-12元亚环烷基各自独立地任选被如下的一个或多个取代基所取代：5-10元芳杂环基C 1-6亚烷基、取代的5-10元芳杂环基C 1-6亚烷基、取代的5-10元芳杂环基羰基、C 1-6烷基、取代的5-10元芳杂环基亚氨基、3-8元环烷基、5-10元芳杂环基氧基、取代的5-10元芳杂环基氧基、C 6-12芳基亚氨基，并且，所述取代为各自独立地被如下的一个或多个取代基取代：C 1-6烷基、C 1-6烷基5-10元亚芳杂环基、卤素、3-8元脂杂环基；
R 17选自氢、C 1-6烷基、C 3-8环烷基、C 6-12芳基和C 6-12芳基C 1-6亚烷基，其中，所述C 1-6烷基和C 6-12芳基C 1-6亚烷基各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1-6烷基。
本发明第三方面的一些实施方式中，R 15选自氢、卤素、-C 1-6亚烷基-NH 2、-C 1-6亚烷 基-NH-C 1-6烷基、-C 1-6亚烷基-N(C 1-6烷基) 2、C 1-6烷氧基、羟基和5-10元脂杂环基，其中，所述5-10元脂杂环基任选地被如下的一个或多个取代基所取代：羟基、C 1-6烷基；R 16选自氢、C 1-6烷氧基、6-12元脂杂环基和5-10元芳杂环基，其中，所述6-12元脂杂环基和5-10元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：C 1-6烷基、卤素；或者，R 15、R 16及与它们相连的苯基形成如下任一基团：茚酮基、苯并5-12元环烷基、苯并5-10元脂杂环基、苯并氧代5-10元脂杂环基、苯并5-10元芳杂环基，其中，所述茚酮基、苯并5-12元环烷基和苯并5-10元脂杂环基各自独立地任选被如下的一个或多个取代基所取代：C 1-6伯胺基、羟基、氨基、C 1-6仲胺基、C 1-6烷基。
本发明第三方面的一些实施方式中，R 15选自氢、卤素、NH 2-C 1-6亚烷基-、CH 3-NH-C 1-6亚烷基-、(CH 3) 2N-C 1-6亚烷基-、C 1-6烷氧基、羟基和吡咯烷基，其中，所述吡咯烷基任选地被如下的一个或多个取代基所取代：羟基、C 1-6烷基；R 16选自氢、C 1-6烷氧基、哌嗪基、吡唑基和N-吗啉基，其中，所述哌嗪基和吡唑基各自独立地任选被如下的一个或多个取代基所取代：C 1-6烷基、卤素；或者，R 15、R 16及与它们相连的苯基形成如下任一基团：1-茚酮基、苯并环戊烷基、苯并吡咯烷基、2-茚酮基、苯并吡咯烷酮基、苯并吡唑基，其中，所述苯并环戊烷基任选地被如下的一个或多个取代基所取代：C 1-6伯胺基、羟基、氨基、C 1-6仲胺基、C 1-6烷基。
本发明第三方面的一些实施方式中，R 15选自氢、氟、氯、NH 2CH 2-、CH 3NHCH 2-、(CH 3) 2NCH 2-、甲氧基、羟基和
Figure PCTCN2020083270-appb-000074
R 16选自氢、甲氧基、
Figure PCTCN2020083270-appb-000075
或者，R 15、R 16及与它们相连的苯基形成如下任一基团：
Figure PCTCN2020083270-appb-000076
Figure PCTCN2020083270-appb-000077
本发明第三方面的一些实施方式中，R 15选自-C 1-6亚烷基-NH 2、羟基、卤素、C 1-6烷氧基、5-10元脂杂环基，其中，所述5-10元脂杂环基任选地被如下的一个或多个取代基所取代：羟基、C 1-6烷基，R 16选自氢和C 1-6烷氧基；或者，R 15、R 16及与它们相连的苯基形成如下任一基团：茚酮基、苯并5-12元环烷基、苯并5-10元脂杂环基、苯并氧代5-10元脂杂环基、苯并5-10元芳杂环基，其中，所述苯并5-12元环烷基和苯并5-10元脂杂环基各自独立地任选被如下的一个或多个取代基所取代：C 1-6伯胺基、C 1-6仲胺基、羟基、氨基。
本发明第三方面的一些实施方式中，R 15选自-C 1-6亚烷基-NH 2、羟基、卤素、C 1-6烷氧基、吡咯烷基，其中，所述吡咯烷基任选地被如下的一个或多个取代基所取代：羟基、C 1-6烷基，R 16选自氢和C 1-6烷氧基；或者，R 15、R 16及与它们相连的苯基形成如下任一基团：1-茚酮基、苯并环戊烷基、苯并吡咯烷基、2-茚酮基、苯并吡咯烷酮基、苯并吡唑基，其中，所述苯并环戊烷基任选地被如下的一个或多个取代基所取代：C 1-6伯胺基、C 1-6仲 胺基、羟基、氨基。
本发明第三方面的一些实施方式中，R 15选自NH 2CH 2-、CH 3NHCH 2-、(CH 3) 2NCH 2-、羟基、氟和
Figure PCTCN2020083270-appb-000078
R 16为氢；或者，R 15、R 16及与它们相连的苯基形成如下任一基团：
Figure PCTCN2020083270-appb-000079
本发明第三方面的一些实施方式中，R 15选自NH 2CH 2-、羟基、氟、甲氧基和
Figure PCTCN2020083270-appb-000080
R 16选自氢和甲氧基；或者，R 15、R 16及与它们相连的苯基形成如下任一基团：
Figure PCTCN2020083270-appb-000081
Figure PCTCN2020083270-appb-000082
本发明第三方面的一些实施方式中，R 15为-C 1-6亚烷基-NH 2或羟基，R 16选自氢；或者R 15、R 16及与它们相连的苯基形成如下任一基团：苯并5-12元环烷基、苯并5-10元脂杂环基，其中，所述苯并5-12元环烷基和苯并5-10元脂杂环基各自独立地任选被如下的一个或多个取代基所取代：C 1-6伯胺基、氨基。
本发明第三方面的一些实施方式中，R 15为-C 1-6亚烷基-NH 2或羟基，R 16为氢；或者R 15、R 16及与它们相连的苯基形成如下任一基团：苯并环戊烷基、苯并吡咯烷基，其中，所述苯并环戊烷基任选地被如下的一个或多个取代基所取代：C 1-6伯胺基、氨基。
本发明第三方面的一些实施方式中，R 15为NH 2CH 2-或羟基，R 16为氢；或者，R 15、R 16及与它们相连的苯基形成如下任一基团：
Figure PCTCN2020083270-appb-000083
本发明第三方面的一些实施方式中，R 15为NH 2CH 2-，R 16为氢；或者，R 15、R 16及与它们相连的苯基形成如下任一基团：
Figure PCTCN2020083270-appb-000084
本发明第三方面的一些实施方式中，R 2选自氢、氰基、卤素、C 1-6烷基和卤代的C 1- 6烷基；优选地，R 2选自氢、氰基、卤素和C 1-3烷基；更优选地，R 2选自氢、氯和-CN。
本发明第三方面的一些实施方式中，R 2为氢。
本发明第三方面的一些实施方式中，R 18为氢，Z 2为CH，R 19为C 6-12芳基或5-10元芳杂环基，其中，所述C 6-12芳基和5-10元芳杂环基各自独立地任选被一个或多个卤素所取代；或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：6-12元亚脂杂环基、5-10元亚芳杂环基、3-12元亚环烷基、5-10元芳杂环并6-12元亚脂杂环基，其中，所述6-12元亚脂杂环基、5-10元亚芳杂环基和3-12元亚环烷基各自独立地任选被如下的一个或多个取代基所取代：5-10元芳杂环基C 1-6亚烷基、取代的5-10元芳杂环基C 1-6亚烷基、取代的5-10元芳杂环基羰基、C 1-6烷基、取代的5-10元芳杂环基亚氨基、3-8元环烷基、5-10元芳杂环基氧基、取代的5-10元芳杂环基氧基、C 6-12芳基亚氨基，并且，所述取代为各自独立地被如下的一个或多个取代基取代：C 1-6烷基、C 1-6烷基亚吡啶基、卤素、氮杂环丁烷基。
本发明第三方面的一些实施方式中，R 18为氢，Z 2为CH，R 19为C 6-12芳基或5-10元芳杂环基，其中，所述C 6-12芳基和5-10元芳杂环基各自独立地任选被一个或多个卤素所取代；或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：6-12元亚脂杂环基、5-10元亚芳杂环基、3-12元亚环烷基、5-10元芳杂环并6-12元亚脂杂环基，其中，所述6-12元亚脂杂环基、5-10元亚芳杂环基和3-12元亚环烷基各自独立地任选被如下的一个或多个取代基所取代：吡嗪基C 1-6亚烷基、取代的噻唑基羰基、取代的噻唑基C 1-6亚烷基、取代的吡啶基C 1-6亚烷基、取代的吡啶基羰基、C 1-6烷基、取代的吡啶基亚氨基、3-6元环烷基、吡啶基氧基、吡嗪基氧基、苯基亚氨基、取代的吡啶基氧基，并且，所述取代为各自独立地被如下的一个或多个取代基取代：C 1-6烷基、
Figure PCTCN2020083270-appb-000085
卤素、
Figure PCTCN2020083270-appb-000086
本发明第三方面的一些实施方式中，R 18为氢，Z 2为CH，R 19为苯基或吡唑基，其中，所述苯基和吡唑基各自独立地任选被一个或多个卤素所取代；或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：亚哌啶基、亚吡唑基、亚吡咯基、亚异恶唑基、亚环己烷基、亚异噻唑基、亚环丙烷基、亚恶唑基、吡唑并亚哌啶基，其中，所述亚哌啶基、亚吡唑基、亚异恶唑基、亚环己烷基、亚异噻唑基、亚环丙烷基和亚恶唑基各自独立地任选被如下的一个或多个取代基所取代：吡嗪基C 1-6亚烷基、
Figure PCTCN2020083270-appb-000087
C 1-6烷基、
Figure PCTCN2020083270-appb-000088
环丙烷基、
Figure PCTCN2020083270-appb-000089
Figure PCTCN2020083270-appb-000090
Figure PCTCN2020083270-appb-000091
优选地，所述亚哌啶基、亚吡唑基、亚异恶唑基、亚环己烷基、亚异噻唑基、亚环丙烷基和亚恶唑基各自独立地任选被如下的一个或多个取代基所取代：吡嗪基C 1-6亚烷基、
Figure PCTCN2020083270-appb-000092
Figure PCTCN2020083270-appb-000093
C 1-6烷基、
Figure PCTCN2020083270-appb-000094
环丙烷基、
Figure PCTCN2020083270-appb-000095
Figure PCTCN2020083270-appb-000096
本发明第三方面的一些实施方式中，R 18为氢，Z 2为CH，R 19选自苯基、
Figure PCTCN2020083270-appb-000097
Figure PCTCN2020083270-appb-000098
其中，所述苯基任选地被一个卤素取代；或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：
Figure PCTCN2020083270-appb-000099
Figure PCTCN2020083270-appb-000100
本发明第三方面的一些实施方式中，R 18为氢，Z 2为CH，R 19为C 6-12芳基或被一个或多个卤素取代的5-10元芳杂环基；或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：6-12元亚脂杂环基、5-10元亚芳杂环基，其中，所述6-12元亚脂杂环基和5-10元亚芳杂环基各自独立地任选被如下的一个或多个取代基所取代：取代的噻唑基羰基、C 1- 6烷基，并且，所述取代为被如下的一个或多个取代基取代：C 1-6烷基、
Figure PCTCN2020083270-appb-000101
本发明第三方面的一些实施方式中，R 18为氢，Z 2为CH，R 19为C 6-12芳基或被一个或多个卤素取代的5-10元芳杂环基；或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：6-12元亚脂杂环基、5-10元亚芳杂环基，其中，所述6-12元亚脂杂环基和5-10 元亚芳杂环基各自独立地任选被如下的一个或多个取代基所取代：
Figure PCTCN2020083270-appb-000102
C 1-6烷基。
本发明第三方面的一些实施方式中，R 18为氢，Z 2为CH，R 19为苯基或被一个或多个卤素取代的吡唑基；或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：亚哌啶基、亚吡唑基、亚异恶唑基，其中，所述亚哌啶基、亚吡唑基和亚异恶唑各自独立地任选被如下的一个或多个取代基所取代：
Figure PCTCN2020083270-appb-000103
C 1-6烷基。
本发明第三方面的一些实施方式中，R 18为氢，Z 2为CH，R 19选自苯基、
Figure PCTCN2020083270-appb-000104
Figure PCTCN2020083270-appb-000105
或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：
Figure PCTCN2020083270-appb-000106
Figure PCTCN2020083270-appb-000107
本发明第三方面的一些实施方式中，R 18为氢，Z 2为CH，R 19为苯基或
Figure PCTCN2020083270-appb-000108
或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：
Figure PCTCN2020083270-appb-000109
本发明第三方面的一些实施方式中，R 18为氢，Z 2为CH，R 19为苯基或
Figure PCTCN2020083270-appb-000110
本发明第三方面的一些实施方式中，R 17选自氢、C 1-6烷基、C 3-8环烷基、C 6-12芳基和C 6-12芳基C 1-6亚烷基，其中，所述C 1-6烷基、C 3-8环烷基和C 6-12芳基C 1-6亚烷基各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1-6烷基。优选地，R 17选自氢、C 1-6烷基、C 6-12芳基和C 6-12芳基C 1-6亚烷基，其中，所述C 1-6烷基和C 6-12芳基C 1-6亚烷基各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1-6烷基。
本发明第三方面的一些实施方式中，R 17选自氢、C 1-6烷基、C 3-6环烷基、苯基和苯基C 1-6亚烷基，其中，所述C 1-6烷基、C 3-6环烷基和苯基C 1-6亚烷基各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1-6烷基；优选地，R 17选自氢、C 1-6烷基、苯基和苯基C 1-6亚烷基，其中，所述C 1-6烷基和苯基C 1-6亚烷基各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1-6烷基。本发明第三方面的一些实施方式中，R 17选自氢、甲基、二氟甲基、环丙基、苯基、苄基、
Figure PCTCN2020083270-appb-000111
和三氟甲基；优选地， 17选自氢、甲基、二氟甲基、苯基、苄基、
Figure PCTCN2020083270-appb-000112
和三氟甲基。
本发明第三方面的一些实施方式中，R 17选自C 1-6烷基、C 6-12芳基和C 6-12芳基C 1-6亚 烷基，其中，所述C 1-6烷基任选被一个或多个卤素所取代。
本发明第三方面的一些实施方式中，R 17选自C 1-6烷基、苯基和苯基C 1-6亚烷基，其中，所述C 1-6烷基任选被一个或多个卤素所取代。
本发明第三方面的一些实施方式中，R 17选自甲基、二氟甲基、苯基和苄基。
本发明第三方面的一些实施方式中，R 17选自甲基和二氟甲基。
本发明第一至第三方面的一些实施方式中，所述化合物选自下表中的化合物以及化合物64-68、76：
Figure PCTCN2020083270-appb-000113
Figure PCTCN2020083270-appb-000114
Figure PCTCN2020083270-appb-000115
Figure PCTCN2020083270-appb-000116
Figure PCTCN2020083270-appb-000117
Figure PCTCN2020083270-appb-000118
Figure PCTCN2020083270-appb-000119
Figure PCTCN2020083270-appb-000120
Figure PCTCN2020083270-appb-000121
Figure PCTCN2020083270-appb-000122
Figure PCTCN2020083270-appb-000123
Figure PCTCN2020083270-appb-000124
Figure PCTCN2020083270-appb-000125
本发明所述化合物中的原子可以被其同位素替代。例如 12C可被其同位素 13C或 14C替代； 1H可被 2H(D，氘)或 3H(T，氚)替代等。本发明化合物中任意原子经其同位素替换后得到同位素标记的化合物。
本发明化合物可使用下文所述方法、以及在合成有机化学领域中己知的合成方法、或者本领域技术人员所了解的关于其的变化形式来合成。优选方法包括但并不限于下文所述的那些方法。
本发明还涉及制备式I至式III中任一化合物的方法，其包括以下两条合成路线：
合成路线一：
Figure PCTCN2020083270-appb-000126
其中，R 1、R 2、R 3、n 1、n 2如上文中所定义。X选自卤素、-OTf，优选地，X为溴；PG选自C 1-6直链或支链烷基氧羰基、卤素取代C 1-6直链或支链烷基氧羰基、C 2-6烯基-烷氧羰基、Cbz、苄基和9-芴甲氧羰基，优选地，PG选自Boc和Cbz；R 20选自羟基和卤素，优选的，R 20为羟基；R 21选自硼酸酯和硼酸。
具体地，所述方法包括以下步骤：
步骤一：化合物a得到化合物b；
所述反应优选在适合的有机溶剂中进行，所述有机溶剂可选自醋酸、卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、醇类(例如甲醇、乙醇)、腈类(例如乙腈等)、N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺，优选N,N-二甲基甲酰胺。所述反应优选在适合的试剂存在下进行，所述试剂可选自溴素、卤代丁二酰亚胺，优选溴素、溴代丁二酰亚胺。所述反应优选在适合的温度下进行，优选反应温度为0-200℃，优选25-80℃。
步骤二：化合物b与化合物g反应得到化合物c；
所述反应优选在适合的有机溶剂中进行，所述有机溶剂可选自DMSO、DMF、DMA、碱类(例如三乙胺、DIPEA、NMP、吡啶、氨水等)、醇类(例如甲醇、乙醇、异丙醇、叔丁醇)、醚类(例如乙醚、THF、二氧六环等)、卤代烃(例如二氯甲烷、氯仿、四氯化碳)、 乙腈、水、苯甲醚，优选DMSO、DMF。所述反应优选在适合的酸性或碱性条件下进行，所述的酸或碱为有机酸/碱或无机酸/碱，所述有机酸选自醋酸、三氟乙酸，三氟化硼乙醚，所述无机酸选自盐酸、氢溴酸，所述有机碱选自三乙胺、DIPEA、吡啶、NMM、DMAP、醋酸钠、醋酸钾、醋酸铵、叔丁醇钠，所述无机碱选自碳酸钾、氢氧化钠、碳酸氢钠、碳酸铯、磷酸钾、氢氧化锂，优选地，所述碱选自吡啶、碳酸铯、碳酸钾。所述反应优选在适合的温度下进行，优选反应温度为0-200℃，优选50-150℃。
步骤三：化合物c经过脱除保护基得到化合物d；
所述反应优选在适合的有机溶剂中进行，所述有机溶剂可选自水、DMF、DMA、N-甲基吡咯烷酮、醇类(例如甲醇、乙醇、异丙醇等)、醚类(例如乙醚、THF、二氧六环等)、卤代烃(例如二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷等)、乙腈，优选二氯甲烷、甲醇、四氢呋喃。针对苄基和苄氧羰基保护基，所述反应在氢气存在下进行。所述反应优选在适合的酸性或碱性条件下进行，所述的酸或碱为有机酸/碱或无机酸/碱，优选地，所述有机酸选自醋酸、三氟乙酸、三氟化硼乙醚、盐酸、盐酸/二氧六环溶液、盐酸/乙酸乙酯溶液，所述无机酸选自盐酸、氢溴酸，所述无机碱选自碳酸钾、碳酸氢钠、氢氧化锂、氢氧化钠，优选地，所述有机碱选自二乙胺、哌啶、氨水。所述反应优选在适合的温度下进行，优选反应温度为0-200℃，优选0-50℃。
步骤四：化合物d与化合物h反应，得到化合物e；
所述反应优选在适合的有机溶剂中进行，所述有机溶剂可选自卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、腈类(例如乙腈等)、N-甲基吡咯烷酮、DMF、DMA、二氧六环、DMSO及其任意组合，优选二氯甲烷、DMF。所述反应优选在适合的缩合剂存在下进行，所述缩合剂可选自氯化亚砜、草酰氯、三氯氧磷、三氯化磷、五氯化磷、氯甲酸乙酯、氯甲酸异丙酯、HATU、HBTU、EEDQ、DEPC、DCC、DIC、EDC、BOP、PyAOP或PyBOP，优选地，所述缩合剂为HATU、EDC。所述反应优选在适合的碱性条件下进行，所述的有机碱选自三乙胺、DIPEA、吡啶、NMM或DMAP，所述的无机碱选自氢化钠、氢氧化钠、碳酸钠、碳酸钾，优选地，所述碱选自DIPEA。所述反应优选在适合的温度下进行，优选反应温度为0-100℃，更优选15-50℃。
步骤五：化合物e与化合物j反应得到式I；
所述反应优选在适合的有机溶剂中进行，所述有机溶剂可选自卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、甲醇、乙醇、DMF、乙腈、醚类(例如乙二醇二甲醚、四氢呋喃、二氧六环)、芳烃类(例如甲苯、苯、二甲苯)、水及其任意组合，优选二氧六环/水、乙二醇二甲醚/水。所述反应优选在适合的碱性条件下进行，所述的碱为有机碱或无机碱，优选地，所述有机碱选自三乙胺、DIPEA、吡啶、NMM、叔丁醇钠、醋酸钾、醋酸钠，所述无机碱选自碳酸钾、碳酸钠、碳酸氢钠、碳酸铯、磷酸钾、磷酸二氢钾，优选地，所述碱选自碳酸钾、磷酸钾、碳酸铯。所述反应优选在有催化剂催化下进行，所述催化剂选自四三苯基膦钯、醋酸钯、Pd 2(dba) 3、Pd(PPh 3) 2Cl 2、Pd(PPh 3) 2Cl 2二氯甲烷络合物、Pd(dppf)Cl 2，优选醋酸钯、Pd(dppf)Cl 2、四三苯基膦钯。所述反应在配体存在下进行，所述配体选自BINAP、三(邻甲基苯基)磷、三苯基膦、三环己基膦四氟硼酸盐、X-PHOS。所述反应优选在适合的温度下进行，优选反应温度为0-200℃，优选50-150℃。
合成路线二：
Figure PCTCN2020083270-appb-000127
其中，R 1、R 2、R 3、n 1、n 2如上文中所定义；X选自卤素和-OTf，优选地，X为溴；PG选自C 1-6直链或支链烷基氧羰基、卤素取代C 1-6直链或支链烷基氧羰基、C 2-6烯基-烷氧羰基、Cbz、苄基和9-芴甲氧羰基，优选地，PG选自Boc和Cbz；R 20选自羟基和卤素，优选地，LG为羟基；R 21选自硼酸酯和硼酸。
具体地，所述方法包括以下步骤：
步骤一：化合物a得到化合物b；方法同路线一的步骤一。
步骤二：化合物b得到化合物k；方法同路线一的步骤五。
步骤三：化合物k与化合物g反应得到化合物p；方法同路线一的步骤二。
步骤四：化合物p得到化合物s；方法同路线一的步骤三。
步骤五：化合物s与化合物h得到式I；方法同路线一的步骤四。
本发明第四方面涉及一种药物组合物，其包含本发明第一至三方面中任一方面所述的化合物其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，以及任选的药用辅料。
本发明第四方面的一些实施方式中，所述药物组合物为片剂、丸剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂或糖浆剂。
本发明第四方面的一些实施方式中，药物组合物可通过胃肠外、局部、静脉内、口服、皮下、动脉内、真皮内、经皮、直肠、颅内、腹膜内、鼻内、肌内途径或作为吸入剂给药，还可通过医药领域技术人员熟知的所有使用形式施用给药。
本发明第四方面的一些实施方式中，药用辅料选自稀释剂、润滑剂、粘合剂、崩解剂、吸收剂、着色剂、调味剂、甜味剂、乳化剂、分散剂、增强化合物的吸收的试剂及填充剂等。稀释剂包括但不限于水、甘油三酯类诸如氢化或部分氢化的植物油或其混合物、玉米油、橄榄油、向日葵油、红花油、鱼油诸诸如二十二碳六烯酸或其酯或甘油三酯或混合物、ω-3脂肪酸或其衍生物、乳糖、右旋糖、蔗糖、甘露醇、山梨糖醇、纤维素、钠、葡萄糖和/或甘氨酸；润滑剂包括但不限于二氧化硅、滑石、硬脂酸、其镁或钙盐、油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠和/或聚乙二醇；粘合剂包括但不限于硅酸镁铝、淀粉糊、明胶、甲基纤维素、羧甲基纤维素钠、碳酸镁、天然糖诸如葡萄糖或β-乳糖、玉米甜味剂、天然和合成树胶(诸如阿拉伯胶、海藻酸钠)、蜡和/或聚乙烯吡咯烷酮(如果需要)；崩解剂包括但不限于淀粉、琼脂、甲基纤维素、膨润土、黄原胶、海藻酸或其钠盐、或泡腾剂混合物；乳化剂或分散剂包括但不限于辛酸葵酸聚乙二醇甘油酯、油酸聚乙二醇甘油酯、油酸甘油酯、二乙二醇单乙基，或其他可接受的乳化剂；增强化合物的吸收的试剂包括但不限于环糊精、羟丙基-环糊精、聚乙二醇200、聚乙二醇400。
本发明第四方面的一些实施方式中，所述药物组合物还包含抑制去泛素化酶USP7活性的其它有效成分或者预防或治疗癌症的其它有效成分。
本发明第四方面的一些实施方式中，所述药物组合物还包含预防或治疗与USP7调节 相关疾病或病症的其它药物活性成分，所述与USP7调节相关疾病或病症选自癌症、神经退行性疾病(例如阿尔兹海默氏症和帕金森症)、糖尿病、骨关节病、关节炎炎性病症、骨质疏松症、免疫病症、心血管疾病、局部缺血性疾病、病毒感染性和/或潜伏、病毒性感染或疾病及细菌性感染或疾病。
本发明第四方面的一些实施方式中，所述药物组合物或适宜的剂型可以含有0.01mg至1000mg的本发明化合物。
当口服用药时，本发明所述化合物或其药学可接受的盐或者药物组合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。其中，片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。任选地，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当皮肤局部施用时，本发明所述化合物或其药学可接受的盐或者药物组合物可制成适当的软膏、洗剂或霜剂制剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
本发明所述化合物或其药学可接受的盐或者药物组合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。其中，可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
在本发明的实施方案中，进行合适的体外或体内测定来确定本发明药物组合物的效果以及给药是否适用于治疗个体所患疾病或医学疾病状态。这些测定的实例在下文非限制性实施例结合具体疾病或医学治疗进行了描述。通常，足以实现预防或治疗效果的本发明组合物的有效量为约0.001mg/千克体重/天至约10,000mg/千克体重/天。合适的情况下，剂量为约0.01mg/千克体重/天至约1000mg/千克体重/天。剂量范围可以为每天、每两天或每三天约0.01至1000mg/kg受试者体重，更通常为0.1至500mg/kg受试者体重。示例性的治疗方案为每两天一次或每周一次或每月一次给药。通常多次给予所述制剂，单次剂量之间的间隔可以是每天、每周、每月或每年。或者，可以以缓释制剂的形式给予所述制剂，在这种情况下，需要较少的给药频率。剂量和频率根据制剂在受试者中的半衰期而不同。也可以根据是预防性处理还是治疗性处理而不同。在预防性应用中，以相对低频率的间隔长期给予相对低的剂量。在治疗性应用中，有时需要以相对短的间隔给予相对高的剂量，直至疾病的进展被延缓或停止，并优选地直至个体表现出疾病症状的部分或完全改善，在此之后，可以给予患者预防方案。
本发明第五方面涉及一种药盒产品，其包括：
a)第一容器，其包括作为第一治疗剂的至少一种本发明第一至三方面的所述化合物或其药学上可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，或本发明第四方面的药物组合物；
b)任选存在的第二容器，其包括作为第二治疗剂的至少一种其他治疗剂，或者其他治疗剂的药物组合物；和
c)任选存在的包装说明书。
在一些优选的实施方案中，所述其他治疗剂选自可用于预防或治疗与USP7调节相关疾病或病症(尤其是癌症等疾病)的除本发明所述化合物之外的其他药物。
本发明第六方面涉及本发明第一至三方面所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物或者本发明第四方面所述的药物组合物在抑制去泛素化酶USP7的活性中的用途。
本发明第七方面涉及一种在体外或体内抑制去泛素化酶USP7活性的方法，包括将本 发明第一至三方面所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物或者本发明第四方面所述的药物组合物作用于(有需求的)受试体。
本发明第八方面涉及本发明第一至三方面所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物或者本发明第四方面所述的药物组合物在制备去泛素化酶USP7抑制剂或者在制备预防或治疗癌症的药物中的用途。
本发明第九方面涉及一种预防或治疗癌症的方法，包括将本发明第一至三方面所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物或者本发明第四方面所述的药物组合物施用于(有需求的)受试者；
优选地，所述癌症选自肝细胞癌、多发性骨髓瘤、结肠癌、肺癌、前列腺癌和膀胱癌中的至少一种。
本发明第一至三方面所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物或者本发明第四方面所述的药物组合物，用于抑制去泛素化酶USP7活性或者用于预防或治疗癌症。
本发明的一些实施方式中，所述癌症选自肝细胞癌、多发性骨髓瘤、结肠癌、肺癌、前列腺癌和膀胱癌中的至少一种。
本发明中，如无特别说明，其中：
术语“可药用盐”是指，(1)本发明化合物中存在的酸性官能团(例如-COOH、-OH、-SO 3H等)与适当的无机或者有机阳离子(碱)形成的盐，例如本发明化合物与碱金属或碱土金属形成的盐、本发明化合物的铵盐，和本发明化合物与含氮有机碱形成的盐；以及(2)本发明化合物中存在的碱性官能团(例如-NH 2等)与适当的无机或者有机阴离子(酸)形成的盐，例如本发明化合物与无机酸或有机羧酸形成的盐。
术语“卤素”是指氟、氯、溴和碘。
术语“C 1- 6烷基”是指具有1-6个碳原子的直链或支链烷基，例如C 1-4烷基、C 1-2烷基、C 1烷基、C 2烷基、C 3烷基、C 4烷基、C 5烷基。具体的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。
术语“C 1- 6亚烷基”是指C 1- 6烷基上去掉一个氢原子剩下的二价基团，其中“C 1- 6烷基”定义如上所述。例如C 1-4亚烷基、C 1-2亚烷基、C 1亚烷基、C 2亚烷基、C 3亚烷基、C 4亚烷基、C 5亚烷基、C 6亚烷基。
术语“烯基”是指含有至少一个碳-碳双键并且其一个氢原子被键代替的脂肪烃基团。烯基可以是直链或支链烯基，并且含有2至15个碳原子。例如本文中“C 2-6烯基”指含有2至6个碳原子的烯基。烯基的非限制性例子包括乙烯基，丙烯基，正丁烯基，3-甲基丁-2-烯基，正戊烯基，辛烯基和癸烯基。烯基可以是未取代的烯基，或被一个或多个相同或不同的取代基取代，每个取代基独立地选自卤素，烯基，炔基，芳基，环烷基，氰基，羟基，-O-烷基，-O-芳基，-亚烷基-O-烷基，烷硫基，-NH 2，-NH(烷基)，-N(烷基) 2，-NH(环烷基)，-O-C(O)-烷基，-O-C(O)-芳基，-O-C(O)-环烷基，-C(O)OH和-C(O)O-烷基。
术语“环烯基”是指含有至少一个碳-碳双键的不饱和的非芳族单环或多环(诸如双环)烃环。例如，如本文中所使用，术语“C 4-6环烯基”指具有4至6个碳原子的至少具有一个碳-碳双键的不饱和的非芳族单环或多环(诸如双环)烃环，其任选地被一个或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丁烯基。
术语“炔基”是指具有一个或多个C≡C三键的烃基。所述炔基具有但不限于2-18个碳原子，例如其具有2-10个碳原子，例如2-6个碳原子。“低级炔基”是指碳数较少的炔基，例如其具有2-8个碳原子，例如2-6个碳原子，例如2-4个碳原子。本文的炔 基实例包括但不限于乙炔基、2-丙炔基、2-丁炔基和1,3-丁二炔基等。本文定义的炔基出现数字范围时，例如“C 2-6炔基”是指可由2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子构成的炔基基团，本文的炔基也涵盖未指定数字范围的情况。
术语“C 1- 6烷氧基”是指以C 1-6烷基-O-方式形成的基团，其中“C 1-6烷基”的定义如前文所述。例如C 1-4烷氧基。具体的实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、2-丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、己氧基等。
术语“胺”是指氨分子中的一个或多个氢原子被烃基取代后的产物，可分成伯胺、仲胺、叔胺。术语“胺基”指去掉胺分子中氮连接的一个氢原子后，剩下的一价基团，包括伯胺基、仲胺基、叔胺基。具体例子包括甲胺基、二甲胺基、乙胺基、二乙胺基等。
术语“脂杂环基”是指至少含有一个N、O或S杂原子的不具有芳香性的单环或多环化合物形成的一价基团，例如5-20元脂杂环基、5-10元(5-8元、5-7元)脂杂环基、5-12元脂杂环基、5-20元(5-8元、5-7元、5-10元、5-12元)含氮脂杂环基、5-20元(5-8元、5-7元、5-10元、5-12元)元含氧脂杂环基、6-12元含氮脂杂环基。其中，脂杂环基的具体例子包括但不限于1-吡咯烷基、1-哌嗪基、N-吗啉基、1-哌啶基、吖丙啶基、己内酰胺基等。
术语“亚脂杂环基”是指由脂杂环基上去掉一个氢原子后剩下的二价基团。其中，“脂杂环基”的定义如前文所述。具体例子包括但不限于亚哌啶基、亚吡咯烷基、亚哌嗪基、亚吗啉基等。
术语“芳基”是指具有芳香性的单环或多环化合物形成的一价基团，例如5-20元芳基、5-12元芳基、6-12元(6-8元、6-9元)芳基、6-10元芳基等。
术语“C 6-10芳基”是指含有6-10个碳原子的上述芳基。具体的实例包括但不限于苯基、萘基、蒽基、菲基等。
术语“亚芳基”是指由芳基上去掉一个氢原子后剩下的二价基团。其中，“芳基”的定义如前文所述，例如C 6-10亚芳基、C 6-12亚芳基等。
术语“芳杂环基”是指至少含有一个N、O或S杂原子的有芳香性的单环或多环化合物形成的一价基团，例如5-20元芳杂环基、5-10元(5-8元、5-7元)芳杂环基、5-12元芳杂环基、6-10元芳杂环基、5-8元芳杂环基、5-20元(5-8元、5-7元、5-10元、5-12元)含氮芳杂环基、5-20元(5-8元、5-7元、5-10元、5-12元)含氧芳杂环基、6-12元含氮芳杂环基、5-20元(5-8元、5-7元、5-10元、5-12元)含氧、氮的芳杂环基。含氮芳杂环基的具体例子包括但不限于吡唑基、吡咯基、异恶唑基、异噻唑基、噻唑基、吡啶基、咪唑基、喹啉基、喋啶基。
术语“亚芳杂环基”是指由芳杂环基上去掉一个氢原子后剩下的二价基团。其中，“芳杂环基”的定义如前文所述。具体例子包括但不限于亚吡唑基、亚吡咯基、亚异恶唑基、亚异噻唑基、亚吡啶基、亚咪唑基、亚喹啉基、亚喋啶基。
术语“茚酮基”茚酮广泛存在于天然产物、药物、农药的活性分子中，其基本结构包括1-茚酮、2-茚酮、1,2-茚二酮、1,3-茚二酮、茚三酮。“茚酮基”是指茚酮分子去掉一个氢原子后剩下的一价基团，例如1-茚酮基、2-茚酮基等。
术语“环烷基”是指单环饱和烷基，3-12元环烷基含有3-12个环成员，例如2-10元环烷基、3元、4元、5元、6元、7元、8元、9元、10元环烷基。具体的实例包括但不限于：环丙基、环丁基、环戊基、环己基等。
术语“亚环烷基”是指由环烷基上去掉一个氢原子后，剩下的二价基团。其中，“环烷基”的定义如前文所述。例如2-10元亚环烷基、5-12元、5-10元、5-8元、3元、4元、5元、6元、7元、8元、9元、10元亚环烷基。具体实例包括但不限于亚环己烷基、亚环丙烷基。
术语“芳杂环基羰基”是指芳杂环基-C(O)-，其中，“芳杂环基”的定义如前述。例子有5-20元芳杂环基羰基、5-12元芳杂环基羰基、5-10元芳杂环基羰基、5-12元芳杂环基羰 基。具体例子包括但不限于吡唑基羰基、吡咯基羰基、异恶唑基羰基、异噻唑基羰基、噻唑基羰基、吡啶基羰基、咪唑基羰基、喹啉基羰基、喋啶基羰基。
术语“芳杂环基亚氨基”是指芳杂环基-NH-，其中，“芳杂环基”的定义如前述。例子有5-20元芳杂环基亚氨基、5-12元芳杂环基亚氨基、5-10元芳杂环基亚氨基、5-12元芳杂环基亚氨基。具体例子包括但不限于吡唑基亚氨基、吡咯基亚氨基、异恶唑基亚氨基、异噻唑基亚氨基、噻唑基亚氨基、吡啶基亚氨基、咪唑基亚氨基、喹啉基亚氨基、喋啶基亚氨基。
术语“芳杂环基亚烷基”是指芳杂环基-(CH 2) n-，其中，“芳杂环基”的定义如前述。例子有5-20元芳杂环基C 1-2亚烷基、5-12元芳杂环基C 1-4亚烷基、5-10元芳杂环基C 1-6亚烷基。具体例子包括但不限于吡唑基亚甲基、吡咯基亚乙基、异恶唑基亚丙基、异噻唑基亚丁基。
术语“芳杂环基氧基”是指芳杂环基-O-，其中，“芳杂环基”的定义如前述。例子有5-20元芳杂环基氧基、5-12元芳杂环基氧基、5-10元芳杂环基氧基、5-12元芳杂环基氧基。具体例子包括但不限于吡唑基氧基、吡咯基氧基、异恶唑基氧基、异噻唑基氧基、噻唑基氧基、吡啶基氧基、咪唑基氧基、喹啉基氧基、喋啶基氧基。
术语“芳基亚氨基”是指芳基-NH-，其中，“芳基”的定义如前述。例子有C 5-20元芳基亚氨基、C 5-12元芳基亚氨基、C 5-10元芳基亚氨基、C 6-12元芳基亚氨基。具体例子包括但不限于苯基亚氨基。
术语“烷基亚芳杂环基”是指烷基-亚芳杂环基-，其中，“亚芳杂环基”的定义如前述。例子有C 1-2烷基5-20元亚芳杂环基、C 1-4烷基5-12元亚芳杂环基、C 1-6烷基5-10元亚芳杂环基。具体例子包括但不限于甲基亚吡唑基、乙基亚吡咯基、丙基亚异恶唑基、丁基亚异噻唑基。
术语“1-吡咯烷基”的结构式为
Figure PCTCN2020083270-appb-000128
术语“1-哌嗪基”的结构式为
Figure PCTCN2020083270-appb-000129
术语“1-吡唑基”的结构式为
Figure PCTCN2020083270-appb-000130
术语“N-吗啉基”的结构式为
Figure PCTCN2020083270-appb-000131
术语“取代的”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
术语“任选被……取代”指被特定的基团、原子团或部分取代或者未取代。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋体、外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯 醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
本发明的化合物或其药学上可接受的盐还可以形成溶剂合物，例如醇合物等。
本发明的化合物还可以是前药或可在体内代谢变化后释放出所述活性成分的形式。选择和制备适当的前药衍生物是本领域技术人员公知技术。
本发明的化合物还可以是化学保护的形式，所述保护基可保护在化合物的活性基团(如氨基)上，所述保护基可在体内代谢释放出活性成分。选择和制备适当的化学保护的形式是本领域技术人员公知技术。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。根据在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、溶剂合物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。
本发明的化合物可以水合物或溶剂合物的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药药物时体内形成的化合物。
本发明所用术语“药物组合物”包括包含治疗有效量的本发明的化合物的产品，以及直接地或间接地由本发明的化合物的组合产生的任何产品。
本发明所用术语“有效量”是指足以实现所需治疗效果的量，例如，实现减轻与待治疗疾病相关的症状的量。
本发明所用的术语“治疗”目的是减轻或消除所针对的疾病状态或病症。如果受试者按照本文所述方法接受了治疗量的化合物、其光学异构体或其药学上可接受的盐或其药物组合物，该受试者一种或多种指征和症状表现出可观察到的和/或可检测出的降低或改善，则受试者被成功地“治疗”了。还应当理解，所述的疾病状态或病症的治疗的不仅包括完全地治疗，还包括未达到完全地治疗，但实现了一些生物学或医学相关的结果。
“治疗”表示本发明化合物的任何给药，包括：
(1)在可能有疾病倾向、但是尚未经历或显示疾病病理学或症状学的动物中防止疾病发生；
(2)在正在经历或显示疾病病理学或症状学的动物中抑制疾病(也就是阻止病理学和/或症状学的进一步发展)；或者
(3)在正在经历或显示疾病病理学或症状学的动物中改善疾病(也就是逆转病理学和/或症状学)。
本发明取得了如下的有益效果：
本发明化合物或药物组合物对去泛素化酶USP7的活性有较强抑制作用，药代动力学性质良好，入脑量极低，可用于预防或治疗癌症疾病。
具体实施方式
下面将结合实施例对本发明实施方案进行详细描述，但是，本领域技术人员应该理解，下列实施例仅用于说明本发明，而不对本发明保护范围构成任何的限定。
实施例中未注明的具体条件按照常规条件或制造商建议条件进行。所用试剂或仪器未 注明生产厂商者，均为可通过市购获得的常规试剂或仪器。
实施例中字母缩写所表达的含义如表1所示。
表1
Figure PCTCN2020083270-appb-000132
实施例中核磁共振( 1H NMR)检测的仪器为Bruker 400MHz核磁共振仪，检测溶剂为氘代甲醇(CD 3OD)、氘代氯仿(CDCl 3)、六氘代二甲基亚砜(DMSO-d 6)、氘代水(D 2O)，内标物质为四甲基硅烷(TMS)。全部δ值用ppm值表示。
核磁共振(NMR)图谱中字母缩写所表达的意思如下：
s：单峰(singlet)；d：二重峰(doublet)；t：三重峰(triplet)；q：四重峰(quartet)；dd：双二重峰(double doublet)；qd：四二重峰(quartet doublet)；ddd：双双二重峰(double double doublet)；ddt：双双三重峰(double double triplet)；dddd：双双双二重峰(double double double doublet)；m：多重峰(multiplet)；br：宽峰(broad)；J：偶合常数；Hz：赫兹；DMSO- d6：氘化二甲基亚砜。
实施例中质谱(MS)检测的仪器为Agilent(ESI)质谱仪，型号为Agilent 6120B。
以下实施例使用的制备薄层色谱采用烟台新诺化工有限公司生产的薄层层析硅胶板(厚度为1mm，规格为200x 200mm，粘结剂为羧甲基纤维素钠)，检测仪器为ZF-20D暗箱式紫外分析仪，检测波长为254nm、365nm。
实施例中高效液相色谱的操作条件如下：
⑴操作条件A：
色谱柱为Waters XBridge Prep C18 OBD，规格为5μm,19×150mm；
流动相A为乙腈，流动相B为水(含有0.05％甲酸)；
洗脱程序如表2所示：
表2
Figure PCTCN2020083270-appb-000133
⑵操作条件B：
色谱柱为Waters SunFire Prep C18 OBD，规格为5μm,19×150mm；
流动相A为乙腈，流动相B为水(含有0.05％甲酸)；
洗脱程序如表3所示：
表3
Figure PCTCN2020083270-appb-000134
⑶操作条件C：
色谱柱为Waters XBridge Prep C18 OBD，规格为5μm,19×150mm；
流动相A为乙腈，流动相B为水(含有0.05％碳酸氢铵)；
洗脱程序如表4所示：
表4
Figure PCTCN2020083270-appb-000135
⑷操作条件D：
色谱柱为Waters SunFire Prep C18 OBD，规格为5μm,19×150mm；
流动相A为乙腈，流动相B为水(含有0.05％甲酸)；
洗脱程序如表5所示：
表5
Figure PCTCN2020083270-appb-000136
⑸操作条件E：
色谱柱：Waters SunFire Prep C18 OBD，规格为5μm,19×150mm；
流动相A：乙腈；流动相B：水(含有0.05％甲酸)；
洗脱程序如表6所示：
表6
Figure PCTCN2020083270-appb-000137
⑹操作条件F：
色谱柱：Waters SunFire Prep C18 OBD，规格为5μm,19×150mm；
流动相A：乙腈；流动相B：水(含有0.05％甲酸)；
洗脱程序如表7所示：
表7
Figure PCTCN2020083270-appb-000138
⑺操作条件G：
色谱柱：Waters SunFire Prep C18 OBD，规格为5μm,19×150mm；
流动相A：乙腈；流动相B：水(含有0.05％甲酸)；
洗脱程序如表8所示：
表8
Figure PCTCN2020083270-appb-000139
⑻操作条件H：
色谱柱：GeLai C18 ODS，规格为8μm,45×450mm；
流动相A：乙腈；流动相B：水(含有0.1％甲酸)；
洗脱程序如表9所示：
表9
Figure PCTCN2020083270-appb-000140
⑼操作条件I：
色谱柱：Waters SunFire Prep C18 OBD，规格为5μm,19×150mm；
流动相A：乙腈；流动相B：水(含有0.05％甲酸)；
洗脱程序如表10所示：
表10
Figure PCTCN2020083270-appb-000141
⑽操作条件J：
色谱柱：Waters SunFire Prep C18 OBD，规格为5μm,19×150mm；
流动相A：乙腈；流动相B：水(含有0.05％三氟乙酸)；
洗脱程序如表11所示：
表11
Figure PCTCN2020083270-appb-000142
⑾操作条件K：
色谱柱：Waters XBridge Prep C18 OBD，规格为5μm,19×150mm；
流动相A：乙腈；流动相B：水(含有0.05％甲酸)；
洗脱程序如表12所示：
表12
Figure PCTCN2020083270-appb-000143
Figure PCTCN2020083270-appb-000144
⑿操作条件L：
色谱柱：Waters SunFire Prep C18 OBD，规格为5μm,19×150mm；
流动相A：乙腈；流动相B：水(含有0.05％碳酸氢铵)；
洗脱程序如表13所示：
表13
Figure PCTCN2020083270-appb-000145
实施例1 (R)-7-(4-(氨甲基)苯基)-3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)咪唑 [2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物1盐酸盐)的合成
Figure PCTCN2020083270-appb-000146
步骤一：(R)-7-溴-3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物1-2)的合成
室温下，将化合物1-1(151.00mg,0.70mmol)和(R)-3-苯基-1-(1-氧杂-6-氮杂螺环[2.5]辛-6-基)丁-1-酮(合成方法参考文献ACS Med.Chem.Lett.2018,9(3),238-243.)(218.56mg,0.84mmol)溶解于二甲亚砜(10mL)中，加入吡啶(277.76mg,3.51mmol)，升温到80℃，反应20h。降至室温，将反应液倒入水(100mL)中，用乙酸乙酯(20mL×3)萃取，饱和氯化钠溶液(50mL×1)洗，无水硫酸钠干燥，减压抽滤，滤液减压浓缩，得到的粗品经乙酸乙酯(5mL)重结晶纯化，得到化合物1-2，135.00mg。ESI-MS(m/z):474.1,476.1[M+H] +。
步骤二：(R)-(4-(3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)苄基)氨基甲酸叔丁酯(化合物1-3)的合成
室温下，将4-(N-叔丁氧羰基氨甲基)苯硼酸(27.79mg,0.11mmol)和化合物1-2(35.00mg,0.07mmol)溶解于水(0.8mL)和二氧六环(4mL)中，依次加入碳酸钾(30.59mg,0.22mmol)、四三苯基膦钯(8.53mg,0.07mmol)，氮气置换三次，升温到80℃，反应5h。降至室温，减压浓缩，加水(20mL)后，乙酸乙酯(10mL x 3)萃取，饱和氯化钠溶液(20mL)反洗，无水硫酸钠干燥，减压抽滤，滤液减压浓缩，得到粗品，粗品经制备 薄层色谱分离(展开剂：乙酸乙酯/甲醇＝25/1(v/v))，得化合物1-3，20.00mg。ESI-MS(m/z):601.4[M+H] +。
步骤三：(R)-7-(4-(氨甲基)苯基)-3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物1盐酸盐)的合成
室温下，称取化合物1-3(20.00mg,0.03mmol)于反应瓶中，加入盐酸/二氧六环溶液(2mL,4.0mol/L)，室温搅拌反应2h。减压浓缩，得到化合物1的粗品，经制备高效液相色谱分离(操作条件A)，制备液加入盐酸，冷冻干燥，得到化合物1的盐酸盐，10.00mg。
其结构表征如下：
1H NMR(400MHz,Methanol-d 6)δ8.51(d,J＝17.8Hz,1H),8.42(s,1H),8.13(d,J＝8.2Hz,2H),7.68(d,J＝8.0Hz,2H),7.39–7.14(m,5H),4.23(s,2H),4.15(s,1H),4.05–3.91(m,1H),3.75–3.59(m,2H),3.27–3.20(m,2H),3.08–2.91(m,1H),2.87–2.73(m,1H),2.63–2.49(m,1H),1.66–1.48(m,2H),1.44–1.29(m,5H).ESI-MS(m/z):501.3[M+H] +。
本实施例的反应式中未表示出化合物1的盐酸盐，表示的是化合物1。
实施例2 (R)-3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)-7-(1-氧代-2,3-二氢-1H-茚- 5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物2)的合成
Figure PCTCN2020083270-appb-000147
以化合物1-2(100.00mg,0.21mmol)和5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2,3-二氢-1H-茚-1-酮(81.62mg,0.32mmol)为原料，根据实施例1步骤二所述操作制备得到粗品，粗品经制备薄层色谱分离(展开剂：乙酸乙酯/甲醇＝25/1(v/v))，得化合物2，85.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.31(d,J＝8.4Hz,1H),8.28(s,1H),8.14(s,1H),8.11(dd,J＝8.0Hz,1.5Hz,1H),7.77(d,J＝8.1Hz,1H),7.30–7.25(m,4H),7.18–7.13(m,1H),4.94(d,J＝1.4Hz,1H),4.19–3.84(m,3H),3.70–3.65(m,1H),3.27–3.10(m,4H),2.89–2.84(m,1H),2.75–2.67(m,2H),2.66–2.53(m,2H),1.67–1.26(m,4H),1.21(d,J＝6.9Hz,3H).ESI-MS(m/z):526.3[M+H] +。
实施例3 3-((4-羟基-1-((R)-3-苯基丁酰基)哌啶-4-基)甲基)-7-(1-(甲胺基)-2,3-二氢- 1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐(化合物3甲酸盐)的合成
Figure PCTCN2020083270-appb-000148
室温下，将化合物2(5.00mg,0.01mmol)加入到甲胺乙醇溶液(5mL)中，反应体系在20℃反应16h，减压浓缩，得到粗品，粗品溶解于甲醇(2mL)中，加入硼氢化钠(1.08mg,0.03mmol)，反应液20℃反应4h，得到化合物3的粗品，粗品经制备高效液相色谱分离(操作条件B)，得化合物3的甲酸盐，2.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.31(s,1H),8.24(d,J＝8.6Hz,1H),7.91(s,1H),7.87(s,1H),7.82(d,J＝7.9Hz,1H),7.50(d,J＝7.9Hz,1H),7.27–7.25(m,4H),7.18–7.12(m,1H),4.20(t,J＝6.6Hz,1H),4.11–4.01(m,1H),4.00–3.90(m,1H),3.88(s,1H),3.72–3.63(m,1H), 3.21–3.14(m,2H),3.07–2.96(m,2H),2.89–2.79(m,2H),2.68–2.54(m,2H),2.38(s,3H),2.36–2.32(m,1H),2.02–1.96(m,1H),1.90–1.81(m,1H),1.59–1.30(m,4H),1.21(d,J＝6.9Hz,3H).ESI-MS(m/z):541.3[M+H] +。
本实施例的反应式中未表示出化合物3的甲酸盐，表示的是化合物3。
实施例4 3-((4-羟基-1-((R)-3-苯基丁酰基)哌啶-4-基)甲基)-7-(1-羟基-2,3-二氢-1H-茚- 5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物4)的合成
Figure PCTCN2020083270-appb-000149
室温下，将化合物2(8.00mg，0.02mmol)加入到甲醇(5mL)中，加入硼氢化钠(1.73mg，0.05mmol)，反应液20℃反应4h，得到反应液，反应液经制备高效液相色谱分离(操作条件B)，得化合物4，4.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.24(d,J＝8.5Hz,1H),7.91(s,1H),7.85–7.82(m,2H),7.46(d,J＝7.8Hz,1H),7.30–7.23(m,4H),7.19–7.11(m,1H),5.34(d,J＝6.0Hz,1H),5.09(q,J＝6.4Hz,1H),4.94(s,1H),4.10–3.87(m,3H),3.70–3.64(m,1H),3.23–3.13(m,2H),3.02–2.96(m,1H),2.90–2.74(m,2H),2.66–2.53(m,2H),2.42–2.34(m,1H),1.87–1.78(m,1H),1.58–1.27(m,4H),1.21(d,J＝6.9Hz,3H).ESI-MS(m/z):528.3[M+H] +。
实施例5 (R)-3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)-7-(吲哚啉-5-基)咪唑[2,1- f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物5盐酸盐)的合成
Figure PCTCN2020083270-appb-000150
步骤一：(R)-5-(3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)吲哚啉-1-氨基甲酸叔丁酯(化合物5-1)的合成
以化合物1-2(50.00mg,0.11mmol)和5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吲哚啉-1-氨基甲酸叔丁酯(54.59mg,0.18mmol)为原料，根据实施例1步骤二所述操作合成化合物5的粗品，经制备薄层色谱分离(展开剂：二氯甲烷/甲醇＝10/1(v/v))，得化合物5-1，50.00mg。ESI-MS(m/z):613.3[M+H] +。
步骤二：(R)-3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)-7-(吲哚啉-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物5盐酸盐)的合成
以化合物5-1(50.00mg,0.08mmol)为原料，根据实施例1步骤三所述的操作，其中，制备高效液相色谱分离的操作条件为操作条件B，得化合物5盐酸盐，19.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.17(d,J＝8.7Hz,1H),7.78–7.50(m,3H),7.32–7.08(m,5H),6.58(d,J＝8.2Hz,1H),5.89(s,1H),4.92(d,J＝2.1Hz,1H),4.14–3.83(m,3H),3.72–3.60(m,1H),3.49(t,J＝8.5Hz,2H),3.28–3.11(m,2H),2.99(t,J＝8.5Hz,2H),2.86(t,J＝11.2Hz,1H),2.71–2.52(m,2H),1.60–1.23(m,4H),1.21(d,J＝6.9Hz,3H).ESI-MS(m/z):513.3[M+H] +。
本实施例的反应式中未表示出化合物5的盐酸盐，表示的是化合物5。
实施例6 7-(2-氨基-2,3-二氢-1H-茚-5-基)-3-((4-羟基-1-((R)-3-苯基丁酰基)哌啶-4-基) 甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物6盐酸盐)的合成
Figure PCTCN2020083270-appb-000151
步骤一：(5-(3-((4-羟基-1-((R)-3-苯基丁酰基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-2-基)氨基甲酸叔丁酯的合成
以化合物1-2(50.00mg,0.11mmol)和(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2,3-二氢-1H-茚-2-基)氨基甲酸叔丁酯(56.80mg,0.16mmol)为原料，根据实施例1步骤二所述操作合成粗品，粗品经制备薄层色谱分离(展开剂：二氯甲烷/甲醇＝10/1(v/v))，得化合物6-1，58.00mg。ESI-MS(m/z):627.3[M+H] +。
步骤二：7-(2-氨基-2,3-二氢-1H-茚-5-基)-3-((4-羟基-1-((R)-3-苯基丁酰基)哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物6盐酸盐)的合成
利用化合物6-1(58.00mg,0.09mmol)为原料，根据实施例1步骤三所述的操作，其中，制备高效液相色谱分离的操作条件为操作条件B，得到化合物6盐酸盐，33.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.27(d,J＝8.4Hz,1H),7.97–7.79(m,3H),7.62(s,2H),7.42(d,J＝8.0Hz,1H),7.34–7.05(m,5H),4.97(s,1H),4.13–3.82(m,4H),3.72–3.61(m,1H),3.32–3.25(m,2H),3.25–3.10(m,2H),3.04–2.79(m,3H),2.69–2.52(m,2H),1.61–1.23(m,4H),1.21(d,J＝6.9Hz,3H).ESI-MS(m/z):527.3[M+H] +。
本实施例的反应式中未表示出化合物6的盐酸盐，表示的是化合物6。
实施例7 3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7-(1- (甲胺基)-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐(化合物7的甲酸盐 ) 的合成
Figure PCTCN2020083270-appb-000152
步骤一：N-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2,3-二氢-1H-茚-1-胺(化合物7-2)的合成
将化合物7-1(2.00g，6.59mmol)加入到甲醇(80mL)中，再加入甲胺的乙醇溶液(7mL，19.76mmol，3.0mol/L)，室温反应12h后，加入甲酸(970.01mg，21.08mmol)调节反应液pH至5～6。再加入氰基硼氢化钠(1.24g，19.76mmol)，继续室温反应12h。减压浓缩反应液后，加入乙酸乙酯(30mL)，抽滤，浓缩滤液，得化合物7-2，2.08g。ESI-MS(m/z):274.3[M+H] +。
步骤二：甲基(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2,3-二氢-1H-茚-1-基)氨基甲酸 叔丁酯(化合物7-3)的合成
将化合物7-2(0.939g，2.94mmol)溶于四氢呋喃(20mL)中，依次加入饱和碳酸氢钠水溶液(20mL)、二碳酸二叔丁酯(770.42mg，3.53mmol)，室温反应6h。加入乙酸乙酯50mL萃取，合并有机相，无水硫酸钠干燥，抽滤，减压浓缩滤液，得到的粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝9/1(v/v))，得化合物7-3，0.913g。ESI-MS(m/z):318.2[M-56+H] +。
步骤三：4-((7-溴-4-氧代咪唑[2,1-f][1,2,4]三嗪-3(4H)-基)甲基)-4-羟基哌啶-1-羧酸苄酯(化合物7-4)的合成
利用化合物1-1(100.00mg，0.47mmol)和1-氧杂-6-氮螺[2.5]辛烷-6-甲酸苄酯(138.02mg，0.56mmol)为原料，根据实施例1步骤一所述的制备方法得到粗品，经制备薄层色谱分离(展开剂：二氯甲烷/甲醇＝10/1(v/v))，得化合物7-4，120.00mg。ESI-MS(m/z):462.0,464.0[M+H] +。
步骤四：4-((7-(1-((叔丁氧基羰基)(甲基)氨基)-2,3-二氢-1H-茚-5-基)-4-氧代咪唑[2,1-f][1,2,4]三嗪-3(4H)-基)甲基)-4-羟基哌啶-1-羧酸苄酯(化合物7-5)的合成
利用化合物7-4(60.00mg，0.13mmol)和7-3(72.67mg，0.19mmol)为原料，根据实施例1步骤二所述操作制备出粗品，粗品经制备薄层色谱分离(展开剂：乙酸乙酯/甲醇＝25/1(v/v))，得化合物7-5，70.00mg。ESI-MS(m/z):629.3[M+H] +。
步骤五：(5-(3-((4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-1-基)(甲基)氨基甲酸叔丁酯(化合物7-6)的合成
室温下，称取化合物7-5(70.00mg，0.11mmol)溶解于甲醇(5mL)中，加钯碳(10％钯，55％水)，氢气置换3次，氢气气氛下室温搅拌反应2h。减压抽滤，滤液减压浓缩，得化合物7-6，55mg。ESI-MS(m/z):495.3[M+H] +。
步骤六：(5-(3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-1-基)(甲基)氨基甲酸叔丁酯(化合物7-7)的合成
室温下，称取4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酸(合成方法参考文献Nature.2017,550,481-486.)(27.77mg，0.13mmol)溶解于二氯甲烷(5mL)中，依次加入HATU(63.42mg，0.17mmol)、DIPEA(64.68mg，0.50mmol)和化合物7-6(55.00mg，0.11mmol)，室温搅拌反应4h，反应液经制备薄层色谱分离(展开剂：乙酸乙酯＝100％)，得化合物7-7，30.00mg。ESI-MS(m/z):685.3[M+H] +。
步骤七：3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7-(1-(甲胺基)-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐(化合物7甲酸盐)的合成
利用化合物7-7(30.00mg，0.04mmol)为原料，根据实施例1步骤三所述的操作反应，其中，制备高效液相色谱分离的操作条件为操作条件A，得化合物7甲酸盐，10.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.28(s,1H),8.26(d,J＝3.6Hz,1H),7.92(s,1H),7.89(s,1H),7.85–7.80(m,2H),7.53(d,J＝7.9Hz,1H),6.26(td,J H-F＝55.07Hz,J＝3.59Hz,1H),6.01–5.97(m,1H),5.12–4.88(m,2H),4.27(t,J＝6.6Hz,1H),4.06–3.88(m,3H),3.70(d,J＝13.4Hz,1H),3.30–3.22(m,3H),3.07–3.00(m,1H),2.95–2.81(m,3H),2.41(s,3H),2.39–2.34(m,1H),1.94–1.86(m,1H),1.66–1.33(m,4H).ESI-MS(m/z):585.3[M+H] +。
本实施例的反应式中未表示出化合物7的甲酸盐，表示的是化合物7。
实施例8 7-(4-(氨甲基)苯基)-3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌 啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物8盐酸盐)的合成
Figure PCTCN2020083270-appb-000153
步骤一：4-((7-(4-((叔丁氧基羰基)氨基)甲基)苯基)-4-氧代咪唑[2,1-f][1,2,4]三嗪-3(4H)-基)甲基)-4-羟基哌啶-1-甲酸苄酯(化合物8-1)的合成
利用化合物7-4(60.00mg，0.13mmol)和4-(N-叔丁氧羰基氨甲基)苯硼酸(47.64mg，0.19mmol)为原料，根据实施例1步骤二所述操作制得粗品，粗品经制备薄层色谱纯化(展开剂：乙酸乙酯/甲醇＝25/1(v/v))，得化合物8-1，56.00mg。ESI-MS(m/z):589.2[M+H] +。
步骤二：4-((3-((4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)苄基)氨基甲酸叔丁酯(化合物8-2)的合成
利用化合物8-1(46.00mg，0.08mmol)为原料，根据实施例7步骤五所述操作，制得化合物8-2，35mg。ESI-MS(m/z):455.3[M+H] +。
步骤三：4-((3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)苄基)氨基甲酸叔丁酯(化合物8-3)的合成
利用化合物8-2(42.00mg，0.09mmol)和4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酸(23.08mg，0.11mmol)为原料，根据实施例7步骤六所述操作制得反应液，反应液经制备薄层色谱纯化(洗脱液：乙酸乙酯＝100％)，得化合物8-3，45.00mg。ESI-MS(m/z):645.3[M+H] +。
步骤四：7-(4-(氨甲基)苯基)-3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物8盐酸盐)的合成
利用化合物8-3(45.00mg，0.07mmol)为原料，根据实施例1步骤三所述的操作进行，其中，高效液相色谱分离的操作条件为操作条件B，得到化合物8盐酸盐，34.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.52(s,3H),8.41–8.40(m,1H),8.07(d,J＝8.1Hz,2H),8.04(s,1H),7.82(dt,J＝5.3Hz,2.5Hz,1H),7.65(d,J＝8.2Hz,2H),6.27(td,J H-F＝55.06Hz,J＝3.61Hz,1H),5.99(td,J＝5.5,2.5Hz,1H),5.04–4.95(m,1H),4.12–3.93(m,5H),3.73–3.66(m,1H),3.63–3.37(m,1H),3.35–3.20(m,2H),2.95–2.87(m,2H),1.66–1.31(m,4H).ESI-MS(m/z):545.3[M+H] +。
本实施例的反应式中未表示出化合物8的盐酸盐，表示的是化合物8。
实施例9 3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7-(2- (甲胺基)-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物9盐酸盐)的 合成
Figure PCTCN2020083270-appb-000154
步骤一：4-((7-溴-4-氧代咪唑[2,1-f][1,2,4]三嗪-3(4H)-基)甲基)-4-羟基哌啶-1-甲酸叔丁酯(化合物9-1)的合成
室温下，将化合物1-1(500.00mg，2.33mmol)和1-氧杂-6-氮杂-螺[2.5]辛-6-甲酸叔丁基酯(991.93mg，4.65mmol)溶解于二甲亚砜(15mL)中，加入吡啶(919.74mg，11.63mmol)，升温到80℃反应20h，降至室温，将反应液倒入水(100mL)中，用乙酸乙酯(30mL×3)萃取，合并有机相，再用饱和氯化钠溶液(100mL)反洗，无水硫酸钠干燥，减压抽滤，滤液减压浓缩，得到的粗品，粗品经硅胶柱纯化(洗脱液：乙酸乙酯＝100％)，得化合物9-1，630.00mg。ESI-MS(m/z):428.2,430.2[M+H] +。
步骤二：7-溴-3-((4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物9-2)的合成
室温下，称取化合物9-1(630.00mg，1.47mmol)于反应瓶中，加入盐酸/二氧六环溶液(15mL，4.0mol/L)，室温搅拌反应2h。抽滤，滤饼用乙醚(50mL)洗涤，得化合物9-2盐酸盐，510.00mg。ESI-MS(m/z):328.0,330.0[M+H] +。
步骤三：7-溴-3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物9-3)的合成
室温下，称取4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酸(313.95mg，1.51mmol)溶解于二氯甲烷(30mL)中，依次加入HATU(782.09mg，2.06mmol)、DIPEA(531.68mg，4.11mmol)和化合物9-2盐酸盐(500.00mg，1.37mmol)室温搅拌反应3h，得反应液，反应液经硅胶柱纯化(洗脱液：乙酸乙酯＝100％)，得化合物9-3，520.00mg。ESI-MS(m/z):518.1,520.1[M+H] +。
步骤四：(5-溴-2,3-二氢-1H-茚-2-基)(甲基)氨基甲酸叔丁酯(化合物9-5)的合成
称取化合物9-4(0.70g，2.24mmol)溶于DMF(14mL)中，降温至0℃，加入氢化钠(134.53mg，3.36mmol，60％)，继续在该温度下反应1h。再加入碘甲烷(381.90mg,2.69mmol)，缓慢升至室温反应16h。反应液用饱和氯化铵水溶液淬灭后，乙酸乙酯(3×50mL)萃取，合并有机相，饱和食盐水洗涤(3×50ml)，无水硫酸钠干燥，过滤，滤液浓缩后，得化合物9-5，0.60g，未经纯化直接用于下一步反应。ESI-MS(m/z):272.0,274.0[M-56+H] +。
步骤五：5-((4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2,3-二氢-1H-茚-2-基)(甲基)氨基甲酸叔丁基酯(化合物9-6)的合成
称取化合物9-5(0.20g，0.61mmol)、联硼酸频那醇酯(186.82mg,0.74mmol)、醋酸钾(180.50mg,1.84mmol)于1,4-二氧六环(5mL)中，氮气置换三次后，加入Pd(dppf)Cl 2(22.43mg,0.031mmol)，氮气置换三次并继续在氮气氛围下升温至80℃反应 16h。反应液冷至室温后，减压浓缩得到的粗品，经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1(v/v))，得化合物9-6，0.20g。ESI-MS(m/z):318.2[M-56+H] +。
步骤六：5-((3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-2-基)(甲基)氨基甲酸叔丁基酯(化合物9-7)的合成
室温下，将化合物9-6(39.61mg，0.11mmol)和化合物9-3(50.00mg，0.10mmol)溶解于水(1mL)和二氧六环(5mL)中，依次加入碳酸钾(40.00mg，0.29mmol)、四三苯基膦钯(15.00mg，0.01mmol)，氮气置换三次，升温到80℃反应5h。降至室温，减压浓缩，得到的粗品经制备薄层色谱纯化(洗脱液：乙酸乙酯/甲醇＝25/1(v/v))，得化合物9-7，57.00mg。ESI-MS(m/z):685.3[M+H] +。
步骤七：3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7-(2-(甲胺基)-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物9盐酸盐)的合成
室温下，称取化合物9-7(57.00mg，0.08mmol)于反应瓶中，加入盐酸/二氧六环溶液(10mL，4.0mol/L)，室温搅拌反应2h。减压浓缩得到反应液，反应液经制备高效液相色谱分离(操作条件B)，制备液加入盐酸，冷冻干燥，得化合物9盐酸盐，38.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ9.33(s,2H),8.37(d,J＝2.4Hz,1H),7.95(s,1H),7.91(s,1H),7.86(d,J＝8.0Hz,1H),7.82(dt,J＝5.2,2.5Hz,1H),7.43(d,J＝8.0Hz,1H),6.27(td,J H-F＝55.1Hz,J＝3.6Hz,1H),6.01–5.98(m,1H),5.09–4.91(m,1H),4.14–3.87(m,4H),3.78–3.62(m,1H),3.43–3.14(m,6H),2.96–2.85(m,2H),2.61(t,J＝5.4Hz,3H),1.70–1.29(m,4H).ESI-MS(m/z):585.3[M+H] +。
本实施例的反应式中未表示出化合物9的盐酸盐，表示出的是化合物9。
实施例10 (R)-3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)-7-(异吲哚啉-5-基)咪唑 [2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物10盐酸盐)的合成
Figure PCTCN2020083270-appb-000155
步骤一：(R)-5-(3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[[2,1-f][1,2,4]]三嗪-7-基)异吲哚啉-2-甲酸叔丁酯(化合物10-1)的合成
利用化合物1-2(44mg，0.09mmol)和5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)异吲哚啉-2-甲酸叔丁酯(48.04mg，0.14mmol)为原料，根据实施例1步骤二所述操作进行，得到粗品，经制备液相色谱分离(操作条件C)，得化合物10-1，24.00mg。ESI-MS(m/z):613.3[M+H] +。
步骤二：(R)-3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)-7-(异吲哚啉-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物10盐酸盐)的合成
利用化合物10-1(24mg，0.04mmol)为原料，根据实施例1步骤三所述操作进行，得化合物10盐酸盐，16.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ9.76(s,2H),8.30(d,J＝8.3Hz,1H),8.06(s,1H),8.01(d,J＝8.02Hz,1H),7.98(s,1H),7.56(d,J＝8.1Hz,1H),7.27–7.25(m,4H),7.18–7.13(m,1H),4.98(br,1H),4.58(dt,J＝11.0,5.5Hz,4H),4.08–3.91(m,4H),3.29–3.13(m,2H),2.88–2.83(m,1H),2.70–2.52(m,2H),1.60–1.27(m,4H),1.21(d,J＝7.0Hz,3H).ESI-MS(m/z):513.2[M+H] +。
本实施例的反应式中未表示出化合物10的盐酸盐，表示出的是化合物10。
实施例11 3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7-(1- 氧代-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物11)的合成
Figure PCTCN2020083270-appb-000156
利用化合物9-3(30.00mg，0.06mmol)和5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吲哚-1-酮(16.43mg，0.06mmol)为原料，根据实施例1步骤二所述操作进行，得到粗品，经制备液相色谱分离(操作条件B)，得化合物11，13.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.31(d,J＝3.6Hz,1H),8.28(s,1H),8.14(d,J＝0.8Hz,1H),8.11(d,J＝8.1Hz,1H),7.82(dt,J＝5.1,2.5Hz,1H),7.77(d,J＝8.1Hz,1H),6.26(td,J H-F＝55.02,3.59Hz,1H),6.01–5.98(m,1H),5.05–4.94(m,2H),4.06–3.91(m,3H),3.71(d,J＝13.7Hz,1H),3.32–3.17(m,4H),2.95–2.87(m,2H),2.73–2.66(m,2H),1.67–1.32(m,4H).ESI-MS(m/z):570.3[M+H] +。
实施例12 3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7- (吲哚啉-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物12盐酸盐)的合成
Figure PCTCN2020083270-appb-000157
步骤一：5-(3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)吲哚啉-1-甲酸叔丁酯(化合物12-1)的合成
利用化合物9-3(30.00mg，0.06mmol)和化合物5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吲哚啉-1-甲酸叔丁酯(21.98mg，0.06mmol)为原料，根据实施例1步骤二所述操作制得粗品，粗品经制备薄层色谱纯化(展开剂：乙酸乙酯/甲醇＝25/1(v/v))，得化合物12-1，30.00mg。ESI-MS(m/z):657.3[M+H] +。
步骤二：3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7-(吲哚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物12盐酸盐)的合成
利用化合物12-1(30.00mg，0.08mmol)为原料，根据实施例1步骤三所述操作进行，得化合物12盐酸盐，8.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.38(d,J＝2.9Hz,1H),8.07(s,1H),8.03(s,1H),7.96(d,J＝7.8Hz,1H),7.82(dt,J＝5.2,2.5Hz,1H),7.59(d,J＝8.0Hz,1H),6.27(td,J H-F＝55.1,J＝3.6Hz,1H),6.00(dt,J＝6.1,3.0Hz,1H),5.05–4.94(m,1H),4.08–3.93(m,3H),3.76(t,J＝7.9Hz,2H),3.72–3.66(m,1H),3.32–3.22(m,4H),2.97–2.84(m,2H),1.63–1.32(m,4H).ESI-MS(m/z):557.3[M+H] +。
本实施例的反应式中未表示出化合物12的盐酸盐，表示的是化合物12。
实施例13 3-((4-羟基-1-((R)-3-苯基丁酰基)哌啶-4-基)甲基)-7-(2-(甲氨基)-2,3-二氢- 二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物13盐酸盐)的合成
Figure PCTCN2020083270-appb-000158
步骤一：5-溴-2,3-二氢-1H-茚-2-甲氨基甲酸叔丁酯(化合物9-5)的合成
称取化合物9-4(700mg，2.24mmol)溶于DMF(14mL)中，降温至0℃，加入氢化钠(134.53mg，3.36mmol，60％)，保持在该温度下搅拌1h。再加入碘甲烷(381.90mg，2.69mmol)，缓慢升至室温反应16h。反应液经饱和氯化铵水溶液(100ml)淬灭，乙酸乙酯萃取(3x 50ml)，合并有机相，饱和食盐水洗涤(3×50ml)。有机相用无水硫酸钠干燥，过滤，浓缩滤液，得化合物13-2，600.00mg，未经纯化直接用于下一步反应。ESI-MS(m/z):272.0,274.0[M-56+H] +。
步骤二：(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2,3-二氢-1H-茚-2-基)-甲氨基甲酸叔丁酯(化合物9-6)的合成
称取化合物9-5(200mg，0.61mmol)、联硼酸频哪醇酯(186.82mg，0.74mmol)和乙酸钾(180.50mg，1.84mmol)于1,4-二氧六环(5mL)中，氮气置换3次，加入Pd(dppf)Cl 2(22.43mg,0.03mmol)，氮气置换三次，并在氮气氛围下升温至80℃反应16h。反应液冷至室温后，减压浓缩反应液，经快速柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1(v/v))，得化合物9-6，200.00mg。ESI-MS(m/z):318.2[M-56+H] +。
步骤三：5-(3-((4-羟基-1-((R)-3-苯基丁酰基)哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-2-基)(甲基)氨基甲酸叔丁酯(化合物13-4)的合成
利用化合物1-2(50.00mg，0.11mmol)和化合物9-6(59.02mg，0.16mmol)为原料，根据实施例1步骤二所述操作制得粗品，粗品经制备薄层色谱分离(展开剂：二氯甲烷/甲醇＝10/1(v/v))，得化合物13-4，58.00mg。ESI-MS(m/z):641.3[M+H] +。
步骤四：3-((4-羟基-1-((R)-3-苯基丁酰基)哌啶-4-基)甲基)-7-(2-(甲氨基)-2,3-二氢-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物13盐酸盐)的合成
利用化合物13-4(58.00mg,0.09mmol)为原料，根据实施例1步骤三所述操作进行，其中，制备高效液相色谱分离的操作条件为操作条件B，得到化合物13盐酸盐，32.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.28–8.22(m,2H),7.89(s,1H),7.83(s,1H),7.78(d,J＝8.0Hz,1H),7.35(d,J＝7.9Hz,1H),7.31–7.23(m,4H),7.19–7.12(m,1H),4.11–3.84(m,3H),3.66–3.62(m,3H),3.20–3.11(m,4H),2.88–2.82(m,3H),2.70–2.52(m,2H),2.41(s,3H),1.60–1.24(m,4H),1.21(d,J＝6.9Hz,3H).ESI-MS(m/z):541.1[M+H] +。
本实施例的反应式中未表示出化合物13的盐酸盐，表示的是化合物13。
实施例14 3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7-(4- 氟苯)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物14)的合成
Figure PCTCN2020083270-appb-000159
利用化合物9-3(23mg,0.04mmol)和化合物对氟苯硼酸(9.31mg,0.07mmol)为原料，根据实施例1步骤二所述操作，得到粗品，经制备液相色谱分离(操作条件D)，得 标题化合物，23.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.26(d,J＝3.6Hz,1H),8.12–8.02(m,2H),7.95(d,J＝0.8Hz,1H),7.81(dt,J＝4.8,2.4Hz,1H),7.44–7.33(m,2H),6.26(td,J  H-F＝54.8Hz,J＝3.6Hz,1H),5.99(ddd,J＝5.9,4.6,2.5Hz,1H),4.98(d,J＝1.9Hz,2H),3.98(m,3H),3.70(d,J＝13.7Hz,1H),3.32–3.18(m,2H),2.90(ddd,J＝17.1,13.1,4.5Hz,2H),1.64–1.32(m,4H).ESI-MS(m/z):534.2[M+H] +。
实施例15 3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7-(4- (3-羟基-3-甲基吡咯烷-1-基)苯基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物15)的合成
Figure PCTCN2020083270-appb-000160
步骤一：3-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)吡咯烷-3-醇(化合物15-2)的合成
室温下，将3-羟基-3-甲基吡咯盐酸盐(123.94mg，0.9mmol)和化合物15-1(200.00mg，0.9mmol)溶解于N,N-二甲基乙酰胺(5mL)中，加入碳酸钾(311.19mg，2.25mmol)，氮气置换三次，升温到110℃反应18h。降至室温，反应液倒入水中(50mL)，用乙酸乙酯(30mL x 3)萃取，饱和氯化钠溶液(50mL)反洗，无水硫酸钠干燥，减压抽滤，滤液减压浓缩，得到的粗品经硅胶柱纯化(洗脱液：乙酸乙酯/石油醚＝1/2(v/v))，得化合物15-2，15.00mg。ESI-MS(m/z):304.2[M+H] +。
步骤二：3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7-(4-(3-羟基-3-甲基吡咯烷-1-基)苯基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物15)的合成
利用化合物9-3(25.64mg，0.05mmol)和化合物15-2(15.00mg，0.05mmol)为原料，根据实施例1步骤二所述操作，得到粗品，经制备液相色谱分离(操作条件B)，得化合物15，4.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.20(d,J＝4.0Hz,1H),7.84–7.80(m,3H),7.76(d,J＝1.1Hz,1H),6.67–6.52(m,2H),6.26(td,J H-F＝55.0,J＝3.6Hz,1H),6.01–5.97(m,1H),5.06–4.96(m,2H),4.84(s,1H),4.06–3.87(m,3H),3.70(d,J＝14.0Hz,1H),3.46–3.37(m,2H),3.29–3.19(m,4H),2.95–2.86(m,2H),2.00–1.87(m,2H),1.67–1.40(m,4H),1.37(s,3H).ESI-MS(m/z):615.3[M+H] +。
实施例16 7-(2-氨基-2,3-二氢-1H-茚-5-基)-3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰 基)-4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物17的盐酸盐)的 合成
Figure PCTCN2020083270-appb-000161
步骤一：4-((7-(2-((叔丁氧基羰基)氨基)-2,3-二氢-1H-茚-5-基)-4-氧代咪唑[2,1-f][1,2,4]三嗪-3(4H)-基)甲基)-4-羟基哌啶-1-羧酸苄酯(化合物17-1)的合成
根据实施例1步骤二所述的操作，利用化合物7-4(500.00mg，1.08mmol)和5-((4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2,3-二氢-1H-茚-2-基)氨基甲酸叔丁酯(466.28mg，1.30mmol)为原料，经快速柱层析纯化(洗脱剂：乙酸乙酯＝100％)，得化合物17-1，660.00mg。ESI-MS(m/z):615.3[M+H] +。
步骤二：5-((3-((4-羟基哌啶-4-基)甲基)-4-氧代-3,4-氧代咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-2-基)氨基甲酸叔丁酯(化合物17-2)的合成
根据实施例7步骤五所述的操作，利用化合物17-1(90.00mg，0.15mmol)为原料，得化合物17-2，70.00mg。ESI-MS(m/z):481.3[M+H] +。
步骤三：5-((3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-2-基)氨基甲酸叔丁基酯(化合物17-3)的合成
根据实施例7步骤六所述的操作，利用化合物17-2(50.00mg，0.1mmol)和化合物4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酸(23.82mg，0.11mmol)为原料，减压浓缩，得化合物17-3，60.00mg。ESI-MS(m/z):671.3[M+H] +。
步骤四：7-(2-氨基-2,3-二氢-1H-茚-5-基)-3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物17的盐酸盐)的合成
根据实施例1步骤三所述的操作，利用化合物17-3(60.00mg，0.09mmol)为原料，制备高效液相色谱分离(操作条件A)，加入0.5mL盐酸，冻干，得化合物17的盐酸盐，38.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.37(d,J＝2.4Hz,1H),8.33(d,J＝5.5Hz,3H),7.94(s,1H),7.91(s,1H),7.86(d,J＝8.1Hz,1H),7.82(dt,J＝5.2,2.5Hz,1H),7.44(d,J＝8.0Hz,1H),6.27(td,J H-F＝55.1Hz,J＝3.6Hz,1H),6.01–5.98(m,1H),5.08–4.93(m,1H),4.18–3.88(m,4H),3.74–3.66(m,1H),3.43–3.20(m,4H),3.10–3.02(m,2H),2.95–2.85(m,2H),1.68–1.29(m,4H).ESI-MS(m/z):571.3[M+H] +。
本实施例的反应式中未表示出化合物17的盐酸盐，表示出的是化合物17。
实施例17 7-(2-氨基-2,3-二氢-1H-茚-5-基)-3-((1-(1-苄基-1H-吡唑-5羰基)-4-羟基哌啶 -4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐(化合物43的甲酸盐)的合成
Figure PCTCN2020083270-appb-000162
步骤一：(5-(3-((1-(1-苄基-1H-吡唑-5羰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-2-基)氨基甲酸叔丁酯(化合物43-1)的合成
室温下，称取1-苄基-1H-吡唑-5-羧酸(18.94mg，0.094mmol)溶解于DMF(1mL)中，依次加入HATU(37.39mg，0.098mmol)，DIPEA(36.31mg，0.28mmol)和化合物17-2(45.00mg，0.094mmol)，室温反应1h。反应液经制备高效液相色谱分离(操作条件E)，得化合物43-1，30.00mg。ESI-MS(m/z):665.3[M+H] +。
步骤二：7-(2-氨基-2,3-二氢-1H-茚-5-基)-3-((1-(1-苄基-1H-吡唑-5羰基)-4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐(化合物43的甲酸盐)的合成
根据实施例1步骤三所述的操作，利用化合物43-1(60.00mg，0.09mmol)为原料，经制备高效液相色谱分离(操作条件B)，得化合物43的甲酸盐，26.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.36(s,1H),8.22(s,1H),7.89(s,1H),7.87–7.76(m,2H),7.53(d,J＝1.9Hz,1H),7.40–7.32(m,3H),7.31–7.23(m,1H),7.17–7.11(m,2H),6.49(d,J＝1.9Hz,1H),5.40(d,J＝6.2Hz,2H),5.00(s,1H),4.25–4.10(m,1H),3.99–3.77(m,3H),3.25–3.10(m,6H),2.89–2.70(m,3H),1.51–1.38(m,2H),1.28–1.21(m,1H),1.11–1.01(m,1H).ESI-MS(m/z):565.3[M+H] +。
本实施例的反应式中未表示出化合物43的甲酸盐，表示出的是化合物43。
实施例18 7-(2-氨基-2,3-二氢-1H-茚-5-基)-3-((1-(5-苄基-1-甲基-1H-吡唑-4-羰基)-4- 羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐(化合物58的甲酸盐)的合成
Figure PCTCN2020083270-appb-000163
步骤一：(5-(3-((1-(5-苄基-1-甲基-1H-吡唑-4-羰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-2-基)氨基甲酸叔丁酯(化合物58-1)合成
根据实施例17步骤一所述的操作，利用化合物58-1(33.34mg，0.069mmol)和5-苄基-1-甲基-1H-吡唑-4-羧酸(15.00mg，0.069mmol)为原料，经制备高效液相色谱分离(操作条件B)，得化合物58-1，25.00mg。ESI-MS(m/z):679.3[M+H] +。
步骤二：7-(2-氨基-2,3-二氢-1H-茚-5-基)-3-((1-(5-苄基-1-甲基-1H-吡唑-4-羰基)-4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐的合成
根据实施例1步骤三所述的操作，利用化合物58-1(25.00mg，0.037mmol)为原料，经制备高效液相色谱分离(操作条件B)，得化合物58的甲酸盐，23.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.36(s,1H),8.26(s,1H),7.89(s,1H),7.85(s,1H),7.82–7.78(m,1H),7.52(s,1H),7.37(d,J＝7.9Hz,1H),7.34–7.26(m,2H),7.25–7.15(m,3H),5.03(s,1H),4.16(s,2H),3.96(s,2H),3.92–3.84(m,1H),3.67(s,3H),3.58–3.38(m,4H),3.31-3.18(m,4H),2.86–2.79(m,2H),1.46(s,4H).ESI-MS(m/z):579.3[M+H] +。
本实施例的反应式中未表示出化合物58的甲酸盐，表示出的是化合物58。
实施例19 7-(4-(氨甲基)苯基)-3-((4-羟基-1-(1-(4-甲基-2-(6-甲基吡啶-3-基)噻唑-5-羰 基)-3-苯基哌啶-4-羰基)哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮-异构体A的甲酸盐 (化合物36-异构体A的甲酸盐)的合成
Figure PCTCN2020083270-appb-000164
步骤一：1-(4-甲基-2-(6-甲基吡啶-3-基)噻唑-5-羰基)-3-苯基吡啶-4-羧酸(化合物36-2)的合成
将化合物36-1(合成方法参考文献WO2017212010)(650.00mg，1.45mmol)溶解于四氢呋喃(10ml)和水(10ml)中，加入氢氧化锂(213.1mg,8.90mmol)，室温反应18h。减压浓缩反应液后，得到的化合物36-2粗品。ESI-MS(m/z):422.1[M+H] +。
步骤二：1-(4-甲基-2-(6-甲基吡啶-3-基)噻唑-5-羰基)-3-苯基吡啶-4-羧酸-异构体A(化合物36-2-异构体A)和1-(4-甲基-2-(6-甲基吡啶-3-基)噻唑-5-羰基)-3-苯基吡啶-4-羧酸-异构体B(化合物36-2-异构体B)的制备
将化合物36-2粗品经制备高效液相色谱分离(操作条件B)，得化合物36-2-异构体A和化合物36-2-异构体B。经LC-MS分析，化合物36-2-异构体A，保留时间：1.241min，160.00mg，ESI-MS(m/z):422.1[M+H] +；化合物36-2-异构体B，保留时间：1.261min，209.00mg，ESI-MS(m/z):422.1[M+H] +；LC-MS分析条件如下：色谱柱：Waters SunFire Prep C18 5μm 4.6×50mm，流动相A：水(含有0.05％甲酸)；流动相B：乙腈(含有0.05％甲酸)，流速：2.0mL/min。
步骤三：4-((7-(4-(((叔丁氧羰基)氨基)甲基)苯基)-4-氧代咪唑[2,1-f][1,2,4]三嗪-3(4H)-基)甲基)-4-羟基哌啶-1-羧酸苄酯(化合物8-1)的合成
根据实施例1步骤二所述的操作，利用化合物7-4(250mg，0.54mmol)和(4-(((叔丁氧羰基)氨基)甲基)苯基)硼酸(270.30mg，1.08mmol)为原料，硅胶柱层析(洗脱液：乙酸乙酯/甲醇＝25/1(v/v))纯化，得化合物8-1，260.00mg。ESI-MS(m/z):589.3[M+H] +。
步骤四：4-(3-((4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)苄基氨基甲酸叔丁酯(化合物8-2)的合成
根据实施例7步骤五所述的操作，利用化合物8-1(273.68mg,0.44mmol)为原料，减压浓缩反应液，得化合物8-2，200.76mg，直接用于下一步反应。ESI-MS(m/z):455.3[M+H] +。
步骤五：4-(3-((4-羟基-1-(1-(4-甲基-2-(6-甲基吡啶-3-基)噻唑-5-羰基)-3-苯基哌啶-4-羰基)哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)苄基氨基甲酸叔丁酯-异构体A(化合物36-3-异构体A)的合成
根据实施例17步骤一所述的操作，利用化合物8-2(34.05mg，0.071mmol)与化合物36-2-异构体A(30.00mg，0.071mmol)为原料，制备高效液相色谱分离(操作条件E)，得标题化合物45.00mg。ESI-MS(m/z):858.4[M+H] +。
步骤六：7-(4-(氨甲基)苯基)-3-((4-羟基-1-(1-(4-甲基-2-(6-甲基吡啶-3-基)噻唑-5-羰基)- 3-苯基哌啶-4-羰基)哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮-异构体A的甲酸盐(化合物36-异构体A的甲酸盐)的合成
根据实施例1步骤三所述的操作，利用化合物36-3-异构体A(35.00mg，0.041mmol)为原料，制备高效液相色谱分离(操作条件B)，得化合物36-异构体A的甲酸盐，24.00mg。保留时间：1.980min。将产物进行LC-MS分析，条件如下：色谱柱：Waters XBridge C18，规格为5μm，4.6×50mm；流动相A：5mmol/L甲酸铵水溶液；流动相B：乙腈；流速：2.0mL/min。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.96(s,1H),8.25–8.08(m,2H),8.05–7.90(m,3H),7.61–7.48(m,2H),7.39(d,J＝8Hz,1H),7.35–7.08(m,5H),4.90(s,1H),4.23–4.04(m,2H),4.03–3.82(m,5H),3.79–3.58(m,3H),3.19–3.03(m,3H),2.75–2.60(m,3H),2.53(s,3H),2.43(s,3H),1.80(s,2H),1.59–0.87(m,5H).ESI-MS(m/z):758.3[M+H] +。
本实施例的反应式中未表示出化合物36-异构体A的甲酸盐，表示出的是化合物36-异构体A，即发明内容部分的表格中化合物36的异构体。
实施例20 7-(4-(氨甲基)苯基)-3-((4-羟基-1-(1-(4-甲基-2-(6-甲基吡啶-3-基)噻唑-5-羰 基)-3-苯基哌啶-4-羰基)哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮-异构体B的甲酸盐 (化合物36-异构体B的甲酸盐)的合成
Figure PCTCN2020083270-appb-000165
步骤一：4-(3-((4-羟基-1-(1-(4-甲基-2-(6-甲基吡啶-3-基)噻唑-5-羰基)-3-苯基哌啶-4-羰基)哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)苄基氨基甲酸叔丁酯-异构体B(化合物36-3-异构体B)的合成
根据实施例19步骤五所述的制备方法，利用化合物8-2(34.05mg，0.071mmol)和化合物36-2-异构体B(30.00mg，0.071mmol)为原料，制备高效液相色谱分离(操作条件E)，得化合物36-3-异构体B 45.00mg。ESI-MS(m/z):858.4[M+H] +。
步骤二：7-(4-(氨甲基)苯基)-3-((4-羟基-1-(1-(4-甲基-2-(6-甲基吡啶-3-基)噻唑-5-羰基)-3-苯基哌啶-4-羰基)哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮-异构体B的甲酸盐(化合物36-异构体B的甲酸盐)的合成
根据实施例19步骤六所述的操作，利用化合物36-3-异构体B(35.00mg，0.041mmol)为原料，制备高效液相色谱分离(操作条件B)，得化合物36-异构体B的甲酸盐，17.00mg。保留时间：1.967min。将产物进行LC-MS分析，条件如下：色谱柱：Waters XBridge C18 5μm 4.6x50mm，流动相A：5mmol/L甲酸铵水溶液；流动相B：乙腈，流速：2.0mL/min。
其结构表征如下：
1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.36(s,1H),8.26–8.14(m,3H),8.05–7.93(m,3H),7.57–7.50(m,2H),7.40(d,J＝8.0Hz,2H),7.31–7.04(m,5H),4.96(s,3H),3.99(d,J＝12.0Hz,2H),3.90(s,3H),3.82–3.64(m,2H),3.59–3.38(m,2H),3.16(t,J＝12.0Hz,1H),3.03–2.89(m,2H),2.75–2.63(m,1H),2.53(s,3H),2.50(t,J＝1.9Hz,27H),2.44(d,J＝2.8Hz,3H),1.93–1.21(m,6H).ESI-MS(m/z):758.3[M+H] +。
本实施例的反应式中未表示出化合物36-异构体B的甲酸盐，表示出的是化合物36-异构体B，即发明内容部分的表格中化合物36的又一异构体。
实施例21 3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7-(2- 羟基-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物23)的合成
Figure PCTCN2020083270-appb-000166
步骤一：3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7-(2-氧代-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮的合成
室温下，将联硼酸频那醇酯(101.07mg，0.40mmol)和化合物23-1(70.00mg，0.33mmol)溶解于1,4-二氧六环(5mL)中，加入醋酸钾(209.25mg，1.00mmol)，氮气置换三次后，再加入Pd(dppf)Cl 2(24.27mg，0.03mmol)，氮气置换三次，并升温到80℃反应4h。降至室温，向反应体系中加入化合物9-3(157.00mg，0.30mmol)、碳酸钾(125.58mg，0.91mmol)、四三苯基膦钯(35.00mg，0.03mmol)和水(1mL)，氮气置换三次并升温到80℃反应4h。反应液倒入水中(50mL)，用乙酸乙酯(30mL x 3)萃取，饱和氯化钠水溶液(50mL)反洗，无水硫酸钠干燥，减压抽滤，滤液减压浓缩，得到的粗品经制备薄层色谱纯化(洗脱液：乙酸乙酯/甲醇＝30/1(v/v))，得标题化合物，25.00mg。ESI-MS(m/z):570.2[M+H] +。
实施例22 3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7-(2- 羟基-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物24)的合成
Figure PCTCN2020083270-appb-000167
步骤一：3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7-(2-羟基-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮的合成
根据实施例4所述的制备方法，利用化合物23(8.00mg，0.02mmol)为原料，经制备高效液相色谱分离(操作条件B)，得标题化合物，4.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.24(d,J＝3.8Hz,1H),7.88(s,1H),7.86–7.80(m,2H),7.77(d,J＝7.9Hz,1H),7.35(d,J＝7.9Hz,1H),6.26(td,J H-F＝55.1Hz,J＝3.6Hz,1H),6.02–5.96(m,1H),5.07–4.95(m,2H),4.92(d,J＝3.9Hz,1H),4.58–4.52(m,1H),4.10–3.87(m,3H),3.78–3.64(m,1H),3.30–3.22(m,2H),3.16–3.08(m,2H),2.95–2.86(m,2H),2.84–2.77(m,2H),1.68–1.31(m,4H).ESI-MS(m/z):572.3[M+H] +。
实施例23 7-(4-(氨甲基)苯基)-3-((1-(3-苄基-1-甲基-1H-吡唑-4-羰基)-4-羟基哌啶-4- 基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物59的盐酸盐)的合成
Figure PCTCN2020083270-appb-000168
步骤一：(4-(3-((1-(3-苄基-1-甲基-1H-吡唑-4-羰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)苄基)氨基甲酸叔丁酯(化合物59-1)的合成
根据实施例7步骤六所述的操作，利用化合物8-2(30.00mg，0.07mmol)和化合物3-苄基-1-甲基-1H-吡唑-4-羧酸(16.53mg,0.07mmol)为原料，硅胶柱层析(洗脱液：二 氯甲烷/甲醇＝10/1(v/v))纯化，得化合物59-1，32.00mg。ESI-MS(m/z):653.3[M+H] +。
步骤二：7-(4-(氨甲基)苯基)-3-((1-(3-苄基-1-甲基-1H-吡唑-4-羰基)-4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物59的盐酸盐)的合成
根据实施例一步骤三所述的操作，利用化合物59-1(32.00mg，0.05mmol)为原料，制备高效液相色谱分离(操作条件B)，加0.5mL盐酸冻干，得化合物59的盐酸盐，12.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.66–8.30(m,4H),8.11–8.00(m,3H),7.81(s,1H),7.65(d,J＝8.0Hz,2H),7.26(t,J＝7.5Hz,2H),7.20–7.12(m,3H),4.08(d,J＝5.8Hz,2H),3.95(d,J＝5.3Hz,4H),3.78(s,3H),3.20–2.85(m,2H),1.76(s,1H),1.50–1.17(m,4H).ESI-MS(m/z):553.3[M+H] +。
本实施例的反应式中未表示出化合物59的盐酸盐，表示出的是化合物59。
实施例24 7-(4-(氨甲基)苯基)-3-((1-(4,4-二氟-3-苯基丁酰基)-4-羟基哌啶-4-基)甲基) 咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物60的盐酸盐)的合成
Figure PCTCN2020083270-appb-000169
步骤一：4-(3-((1-(4,4-二氟-3-苯基丁酰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)苄基氨基甲酸叔丁酯(化合物60-1)的合成
根据实施例七步骤六所述的操作，利用化合物8-2(31.58mg,0.07mmol)和4,4-二氟-3-苯基丁酸(15.30mg,0.07mmol)为原料，硅胶柱层析(洗脱液：二氯甲烷/甲醇＝30/1(v/v))纯化，得化合物60-1，41.00mg。ESI-MS(m/z):637.3[M+H] +。
步骤二：7-(4-(氨甲基)苯基)-3-((1-(4,4-二氟-3-苯基丁酰基)-4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物60的盐酸盐)的合成
根据实施例一步骤三所述的操作，利用化合物60-1(41.67mg，0.06mmol)为原料，制备高效液相色谱分离(操作条件B)，加0.5mL稀盐酸冻干，得化合物60的盐酸盐，12.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.50(s,3H),8.42–8.34(m,,1H),8.11–7.99(m,3H),7.64(d,J＝8.1Hz,2H),7.38–7.17(m,5H),6.24(td,J H-F＝56.6Hz,J＝3.9Hz,1H),4.11–3.86(m,5H),3.80–3.55(m,2H),3.30–3.15(m,1H),3.05–2.79(m,3H),1.64–1.36(m,3H),1.36–1.23(m,1H).ESI-MS(m/z):537.2[M+H] +。
本实施例的反应式中未表示出化合物60的盐酸盐，表示出的是化合物60。
实施例25 3-((4-羟基-1-(1-(4-甲基-2-(6-甲基吡啶-3-基)噻唑-5-羰基)-3-苯基哌啶-4-羰 基)哌啶-4-基)甲基)-7-(4-羟基苯基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮-异构体A(化合物38-异 构体A)的合成
Figure PCTCN2020083270-appb-000170
步骤一：7-溴-3-((4-羟基-1-(1-(4-甲基-2-(6-甲基吡啶-3-基)噻唑-5-羰基)-3-苯基哌啶-4-羰基)哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮-异构体A(化合物38-1-异构体A)的 合成
根据实施例17步骤一所述的操作，利用化合物9-2(25.95mg，0.07mmol)和化合物36-2-异构体A(30.00mg，0.07mmol)为原料，制备高效液相色谱分离(操作条件A)，得化合物38-1-异构体A，36.00mg。ESI-MS(m/z):731.2[M+H] +。
步骤二：3-((4-羟基-1-(1-(4-甲基-2-(6-甲基吡啶-3-基)噻唑-5-羰基)-3-苯基哌啶-4-羰基)哌啶-4-基)甲基)-7-(4-羟基苯基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮-异构体A(化合物38-异构体A)的合成
根据实施例1步骤二所述的操作，利用化合物38-1-异构体A(26.32mg，0.03mmol)和4-羟基-苯硼酸(7.44mg，0.05mmol)为原料，制备高效液相色谱分离(操作条件E)，得化合物38-异构体A，20.00mg，保留时间：2.369min。将产物进行LC-MS分析，条件如下：色谱柱：Waters XBridge C18 5μm 4.6x50mm，流动相A：5mmol/L甲酸铵水溶液；流动相B：乙腈，流速：2.0mL/min。化合物38-异构体A为发明内容部分的表格中化合物38的异构体。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ9.82(s,1H),8.98(s,1H),8.30–8.09(m,2H),7.92–7.73(m,3H),7.40(d,J＝8.0Hz,1H),7.31–7.03(m,5H),4.91–4.82(m,1H),4.07–3.62(m,6H),3.58–3.42(m,2H),3.16(t,J＝12.0Hz,2H),3.03–2.89(m,1H),2.77–2.61(m,3H),2.44(s,3H),1.95–1.15(m,6H).ESI-MS(m/z):745.3[M+H] +。
实施例26 3-((4-羟基-1-(1-(4-甲基-2-(6-甲基吡啶-3-基)噻唑-5-羰基)-3-苯基哌啶-4-羰 基)哌啶-4-基)甲基)-7-(4-羟基苯基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮-异构体B(化合物38-异 构体B)的合成
Figure PCTCN2020083270-appb-000171
步骤一：7-溴-3-((4-羟基-1-(1-(4-甲基-2-(6-甲基吡啶-3-基)噻唑-5-羰基)-3-苯基哌啶-4-羰基)哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮-异构体B(化合物38-1-异构体B)的合成
根据实施例24步骤一所述的操作，利用化合物9-2(25.95mg，0.07mmol)和化合物36-2-异构体B(30.00mg，0.07mmol)为原料，制备高效液相色谱分离(操作条件A)，得化合物38-1-异构体B，36.00mg。ESI-MS(m/z):731.2[M+H] +。
步骤二：3-((4-羟基-1-(1-(4-甲基-2-(6-甲基吡啶-3-基)噻唑-5-羰基)-3-苯基哌啶-4-羰基)哌啶-4-基)甲基)-7-(4-羟基苯基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮-异构体B(化合物38-异构体B)的合成
根据实施例一步骤二所述的操作，利用化合物38-1-异构体B(31.58mg，0.04mmol)和4-羟基-苯硼酸(8.93mg，0.06mmol)为原料，制备高效液相色谱分离(操作条件E)，得化合物38-异构体B，保留时间：2.397min，22.00mg。将产物进行LC-MS分析，条件如下：色谱柱：Waters XBridge C18，规格为5μm，4.6×50mm；流动相A：5mmol/L甲酸铵水溶液；流动相B：乙腈；流速：2.0mL/min。化合物38-异构体B为发明内容部分的表格中化合物38的又一异构体。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ9.82(s,1H),8.96(s,1H),8.15(d,J＝12.0Hz,2H),7.87–7.75(m,3H),7.39(d,J＝8.0Hz,1H),7.34–7.07(m,5H),6.97–6.84(m,2H),4.83(d,J＝12.0Hz,1H),4.36–3.81(m,5H),3.79–3.57(m,2H),3.56–3.44(m,2H),3.20–3.03(m,2H),2.74–2.60(m,1H),2.53(s,3H),2.43(s,3H),1.80(s,2H),1.57–0.92(m,4H).ESI-MS(m/z): 745.3[M+H] +。
实施例27 3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7-(2- (二甲胺基)-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐(化合物18的甲酸 盐)的合成
Figure PCTCN2020083270-appb-000172
室温下，将化合物23(15.00mg，0.01mmol)加入到甲醇(5mL)中，加入二甲胺甲醇溶液(5mL，30％wt)，室温反应20h。减压浓缩，将得到的粗品溶解于甲醇(2mL)中，加入硼氢化钠(2.91mg，0.08mmol)，室温反应2h。反应液经制备高效液相色谱分离(操作条件B)，得化合物18的甲酸盐，3.85mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.24(d,J＝3.8Hz,1H),8.20(s,1H),7.87(s,1H),7.82–7.80(m,2H),7.76(d,J＝7.8Hz,1H),7.33(d,J＝7.9Hz,1H),6.26(td,J H-F＝55.0Hz,J＝3.6Hz,1H),6.00–5.97(m,1H),5.30–4.65(m,2H),4.05–4.01(m,1H),4.00–3.88(m,2H),3.70(d,J＝13.4Hz,1H),3.28–3.21(m,2H),3.11–3.02(m,3H),2.96–2.76(m,4H),2.22(s,6H),1.68–1.31(m,4H).ESI-MS(m/z):599.3[M+H] +。
本实施例的反应式中未表示出化合物18的甲酸盐，表示的是化合物18。
实施例28 7-(4-(氨甲基)苯基)-3-((1-(3-苄基-5-甲基异恶唑-4-羰基)-4-羟基哌啶-4-基) 甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物63的盐酸盐)的合成
Figure PCTCN2020083270-appb-000173
步骤一：4-(3-((1-(3-苄基-5-甲基异恶唑-4-羰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7基)苄基氨基甲酸叔丁酯(化合物63-1)的合成
根据实施例7步骤六所述的操作，利用化合物8-2(50.00mg，0.11mmol)和化合物3-苄基-5-甲基异恶唑-4-甲酸(26.29mg，0.12mmol)为原料，制备高效液相色谱分离(操作条件C)，得化合物63-1，36.00mg。ESI-MS(m/z):654.3[M+H] +。
步骤二：7-(4-(氨甲基)苯基)-3-((1-(3-苄基-5-甲基异恶唑-4-羰基)-4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物63的盐酸盐)的合成
室温下，称取化合物63-1(36.00mg，0.055mmol)溶于二氧六环(4mL)中，再加入盐酸/二氧六环(2mL，4mol/L)，继续室温反应5h。反应液中有固体析出，过滤，将滤饼溶于水，加入0.5mL稀盐酸，冻干，得化合物63的盐酸盐，26.00mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.38(s,3H),8.29(s,1H),8.07(d,J＝8.0Hz,3H),8.01(s,1H),7.62(d,J＝8.0Hz,2H),7.34(t,J＝8.0Hz,2H),7.25(t,J＝7.3Hz,1H),7.17(d,J＝7.5Hz,2H),4.97(s,1H),4.09(q,J＝5.9Hz,3H),3.96(s,2H),3.92(s,1H),3.12(s,2H),2.91(t,J＝12Hz,2H),2.34(s,3H),1.40–1.15(m,4H).ESI-MS(m/z):554.3[M+H] +。本实施例的反应式中未表示出化合物63的盐酸盐，表示出的是化合物63。
本实施例的反应式中未表示出化合物63的盐酸盐，表示的是化合物63。
实施例29 7-(2-(二甲胺基)-2,3-二氢-1H-茚-5-基)-3-((4-羟基-1-((R)-3-苯基丁酰基)哌 啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐(化合物16的甲酸盐)的合成
Figure PCTCN2020083270-appb-000174
利用化合物1-2(20mg，0.04mmol)和2-((二甲胺基)-2,3-二氢-1H-茚-5-基)硼酸(10mg，0.05mmol)为原料，根据实施例1步骤二所述操作进行，反应完后将反应液直接减压浓缩得到粗品，经制备高效液相色谱分离(操作条件B)，得化合物16的甲酸盐，7mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.23(d,J＝8.5Hz,1H),8.18(s,0H),7.88(s,1H),7.81(s,1H),7.76(d,J＝7.9Hz,1H),7.33(d,J＝7.9Hz,1H),7.30-7.21(m,4H),7.18-7.12(m,1H),4.93(s,2H),4.08-4.04(m,1H),4.02-3.90(m,1H),3.88(s,1H),3.70-3.64(m,1H),3.26-3.15(m,2H),3.11-3.03(m,3H),2.89-2.79(m,3H),2.69-2.56(m,2H),2.24(s,6H),1.59-1.26(m,4H),1.21(d,J＝6.9Hz,3H).ESI-MS(m/z):571.3[M+H] +。
本实施例的反应式中未表示出化合物16的甲酸盐，表示的是化合物16。
实施例30 3-((4-羟基-1-((R)-3-苯基丁酰基)哌啶-4-基)甲基)-7-(2-羟基-2,3-二氢-1H-茚 -5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物20)的合成
Figure PCTCN2020083270-appb-000175
利用化合物1-2(20mg，0.04mmol)和5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2,3-二氢-1H-茚-2-醇(13mg，0.05mmol)为原料，根据实施例1步骤二所述操作进行，反应完后将反应液直接减压浓缩得到粗品，经制备高效液相色谱分离(操作条件E)，得化合物20，20mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.23(d,J＝8.6Hz,1H),7.88(s,1H),7.83(s,1H),7.77(d,J＝7.8Hz,1H),7.35(d,J＝7.9Hz,1H),7.29-7.25(m,4H),7.18-7.12(m,1H),4.92(d,J＝4.2Hz,2H),4.58-4.52(m,1H),4.08-4.03(m,1H),4.02-3.90(m,1H),3.88(s,1H),3.72-3.61(m,1H),3.26-3.08(m,4H),2.92-2.76(m,3H),2.65-2.56(m,2H),1.59-1.25(m,4H),1.21(d,J＝6.9Hz,3H).ESI-MS(m/z):528.3[M+H] +。
实施例31 (R)-6-氯-7-(3,4-二甲氧基苯基)-3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲 基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物53)的合成
Figure PCTCN2020083270-appb-000176
步骤一：4-((7-溴-6-氯-4-氧代咪唑[2,1-f][1,2,4]三嗪-3(4H)-基)甲基)-4-羟基哌啶-1-甲酸叔丁酯(化合物53-1)的合成
室温下，将化合物9-1(200mg，0.47mmol)溶解于N,N-二甲基甲酰胺(3mL)中，加入N-氯代丁二酰亚胺(95mg，0.70mmol)，升温到70℃反应3h。降至室温，将反应液倒入水中，乙酸乙酯(10mL x 3)萃取，饱和氯化钠溶液反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得到粗品，经制备薄层色谱纯化(展开剂：乙酸乙酯＝100％)，得化合物53-1，70mg。ESI-MS(m/z):462.1,464.1[M+H] +。
步骤二：4-((6-氯-7-(3,4-二甲氧基苯基)-4-氧代咪唑[2,1-f][1,2,4]三嗪-3(4H)-基)甲基)-4-羟基哌啶-1-甲酸叔丁酯(化合物53-2)的合成
利用化合物53-1(60mg，0.13mmol)和(3,4-二甲氧基苯基)硼酸(28mg，0.16mmol)为原料，根据实施例1步骤二所述操作进行，反应完后将反应液直接减压浓缩得到粗品，经制备薄层色谱纯化(展开剂：二氯甲烷/乙酸乙酯＝2/1)，得化合物53-2，60mg。ESI-MS(m/z):464.1,466.1[M+H-56] +。
步骤三：6-氯-7-(3,4-二甲氧基苯基)-3-((4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物53-3的盐酸盐)的合成
室温下，称取化合物53-2(60mg，0.09mmol)于反应瓶中，加入盐酸/二氧六环溶液(2mL，4.0mol/L)，室温搅拌反应10min。反应液经减压浓缩，得化合物53-3的盐酸盐，50mg。ESI-MS(m/z):420.0,422.0[M+H] +。
步骤四：(R)-6-氯-7-(3,4-二甲氧基苯基)-3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物53)的合成
利用化合物53-3的盐酸盐(10mg，0.02mmol)和4(R)-3-苯基丁酸(5mg，0.03mmol)为原料，根据实施例7步骤六所述操作制得反应液，反应液经硅胶柱层析纯化(洗脱液：乙酸乙酯＝100％)，得化合物53，3mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d6)δ8.23(d,J＝8.2Hz,1H),7.30-7.25(m,6H),7.18-7.14(m,2H),4.91(s,1H),4.10-4.02(m,1H),4.01-3.90(m,1H),3.87(s,1H),3.84(s,3H),3.79(s,3H),3.71-3.62(m,1H),3.22-3.11(m,2H),2.91-2.82(m,1H),2.64-2.57(m,2H),1.55-1.35(m,4H),1.21(d,J＝6.9Hz,3H).ESI-MS(m/z):566.2[M+H] +。
实施例32 (R)-7-(4-氟苯基)-3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)咪唑并[2,1- f][1,2,4]三嗪-4(3H)-酮(化合物75)的合成
Figure PCTCN2020083270-appb-000177
利用化合物1-2(30mg，0.063mmol)和4-氟苯硼酸(13mg，0.095mmol)为原料，根据实施例1步骤二所述操作进行，反应液冷却至室温，垫硅藻土过滤，滤液浓缩，得粗品，经制备高效液相色谱分离(操作条件E)，得化合物75，20mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d6)δ8.25(d,J＝8.5Hz,1H),8.10-8.01(m,2H),7.94(s,1H),7.42-7.33(m,2H),7.29-7.21(m,4H),7.18-7.12(m,1H),4.91(s,1H),4.13-3.83(m,3H),3.75-3.61(m,1H),3.28–3.10(m,2H),2.91-2.82(m,1H),2.74-2.52(m,2H),1.65-1.35(m,3H),1.35-1.23(m,1H),1.23-1.18(m,3H).ESI-MS(m/z):490.1[M+H] +。
实施例33 7-(4-氟苯)-3-((4-羟基-1-(3-(1-苯乙基)-1H-吡唑-4-羰基)哌啶-4-基)甲基)咪 唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物102)的合成
Figure PCTCN2020083270-appb-000178
步骤一：4-((7-(4-氟苯基)-4-氧代咪唑[2,1-f][1,2,4]三嗪-3(4H)-基)甲基)-4-羟基哌啶-1-羧酸苄酯(化合物102-1)的合成
利用化合物7-4(1.00g，2.16mmol)和(4-氟苯)硼酸(454mg，3.25mmol)为原料，根据实施例1步骤二所述操作制备出粗品，粗品经制备高效液相色谱分离(操作条件B)，得化合物102-1，740mg。ESI-MS(m/z):478.2[M+H] +。
步骤二：7-(4-氟苯基)-3-((4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物102-2)的合成
利用化合物102-1(700mg，147mmol)为原料，根据实施例7步骤五所述操作，得化合物102-2的粗品，490mg。ESI-MS(m/z):344.1[M+H] +。
步骤三：7-(4-氟苯)-3-((4-羟基-1-(3-(1-苯乙基)-1H-吡唑-4-羰基)哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物102)的合成
利用化合物102-2(30mg,0.087mmol)和3-(1-苯乙基)-1H-吡唑-4-羧酸(21mg,0.10mmol)为原料，根据实施例7步骤六所述的操作制得粗品，粗品经制备高效液相色谱分离(操作条件B)，制备液冷冻干燥，得化合物102，13mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ13.21-12.61(m,1H),8.23(s,1H),8.08-8.03(m,2H),7.95(s,1H),7.83-7.44(m,1H),7.41-7.35(m,2H),7.27(s,2H),7.17(s,3H),4.89(s,1H),4.54-4.29(m,1H),4.26-3.61(m,3H),3.20-2.84(m,2H),1.56(s,3H),1.50-1.05(m,5H).ESI-MS(m/z):537.2[M+H] +。
实施例34 (R)-3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)-7-(1H-吲唑-6-基)咪唑 [2,1-f][1,2,4]三嗪-4(3H)-酮(化合物90)的合成
Figure PCTCN2020083270-appb-000179
步骤一：6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吲唑(化合物90-2)的合成
以化合物90-1(200mg,1.02mmol)替换化合物9-5作为原料，根据实施例9步骤五所述操作制备得到粗品，粗品经制备高效液相色谱分离(操作条件G)，得化合物90-2，42mg。ESI-MS(m/z):245.1[M+H] +。
步骤二：(R)-3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)-7-(1H-吲唑-6-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物90)的合成
以化合物1-2(30mg,0.063mmol)和化合物90-2(19mg,0.076mmol)为原料，根据实施例1步骤二所述操作，反应温度为100℃，制备得到粗品，粗品过滤，滤液经制备高效液相色谱分离(操作条件E)，得化合物90，11mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ13.26(s,1H),8.35(s,1H),8.29(d,J＝8.4Hz,1H),8.13(s,1H),8.06(s,1H),7.89(d,J＝8.4Hz,1H),7.71-7.66(m,1H),7.29-7.24(m,4H),7.18-7.13(m,1H),4.94(s,1H),4.12-4.04(m,1H),3.98-3.82(m,2H),3.72-3.63(m,1H),3.22-3.12(m,2H),2.91-2.83(m,1H),2.68-2.57(m,2H),1.51-1.27(m,4H),1.23-1.18(m,3H).ESI-MS(m/z):512.3[M+H] +。
实施例35 (R)-3-((4-羟基-1-(3-苯基丁酰基)哌啶-4-基)甲基)-7-(2-氧代苯胺-6-基)咪唑 [2,1-f][1,2,4]三嗪-4(3H)-酮(化合物91)的合成
Figure PCTCN2020083270-appb-000180
利用化合物1-2(30mg，0.06mmol)和6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吲哚-2-酮(25mg，0.09mmol)为原料，根据实施例1步骤二所述操作进行，反应完后将反应液直接减压浓缩得到粗品，经制备高效液相色谱分离(操作条件E)，得化合物91，9mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ10.56(s,1H),8.25(d,J＝8.4Hz,1H),7.91(s,1H),7.57-7.49(m,2H),7.34(d,J＝7.7Hz,1H),7.29-7.24(m,4H),7.19-7.12(m,1H),4.96(s,1H),4.12-4.03(m,1H),4.03-3.91(m,1H),3.89(s,1H),3.72-3.62(m,1H),3.55(s,2H),3.24-3.11(m,2H),2.92-2.81(m,1H),2.66-2.53(m,2H),1.60-1.24(m,4H),1.21(d,J＝7.0Hz,3H).ESI-MS(m/z):527.2[M+H] +。
实施例36 3-((1-((S)-4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)- 7-(2-(甲胺基)2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐(化合物92的甲 酸盐)的合成
Figure PCTCN2020083270-appb-000181
步骤一：4-((7-(2-((叔丁氧羰基)(甲基)氨基)-2,3-二氢-1H-茚-5-基)-4-氧代咪唑[2,1-f][1,2,4]三嗪-3(4H)基)甲基)4-羟基哌啶-1-羧酸苄酯(化合物92-1)的合成
利用化合物7-4(0.30g,0.65mmol)和9-6(363mg,0.78mmol)为原料，根据实施例1步骤二所述操作进行，反应液抽滤，滤液经减压浓缩，得到的粗品经制备高效液相色谱分离(操作条件H)，制备液冷冻干燥，得化合物92-1，376mg。ESI-MS(m/z):629.3[M+H] +。
步骤二：(5-(3-((4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-2-基)(甲基)氨基甲酸叔丁酯(化合物92-2)的合成
利用化合物92-1(150mg,0.24mmol)为原料，根据实施例7步骤五所述操作，得化合物92-2的粗品，132mg。ESI-MS(m/z):495.3[M+H] +。
步骤三：5-(3-((1-((S)-4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑并[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-2-基)(甲基)氨基甲酸叔丁酯(化合物92-3)的合成
利用化合物92-2(17mg,0.03mmol)和(3S)-4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酸(6mg,0.03mmol)为原料，根据实施例17步骤一所述操作制备出粗品，粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1(v/v))，得化合物92-3，16mg。ESI-MS(m/z):685.3[M+H] +。
步骤四：3-((1-((S)-4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-7-(2-(甲胺基)2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐(化合物92的甲酸盐)的合成
利用化合物92-3(10mg，0.01mmol)为原料，根据实施例1步骤三所述的操作反应，经制备高效液相色谱分离(操作条件I)，得化合物92的甲酸盐，8mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.32(s,1H),8.26(d,J＝3.2Hz,1H),7.89(s,1H),7.85-7.77(m,3H),7.36(d,J＝8.0Hz,1H),6.26(td,J H-F＝55.2Hz,J＝3.2Hz,1H),6.01-5.97(m,1H),5.12-4.90(m,1H),4.10-3.87(m,3H),3.76-3.55(m,3H),3.35-3.10(m,4H),3.01-2.75(m,4H),2.43(s,3H),1.65-1.30(m,4H).ESI-MS(m/z):585.3[M+H] +。
本实施例的反应式中未表示出化合物92的甲酸盐，表示的是化合物92。
实施例37 3-((4-羟基-1-(4,4,4-三氟-3-苯基丁酰基)哌啶-4-基)甲基)-7-(2-(甲胺基)-2,3- 二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物93的盐酸盐)的合成
Figure PCTCN2020083270-appb-000182
步骤一：(5-(3-((4-羟基-1-(4,4,4-三氟-3-苯基丁醇)哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑并[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-2-基)(甲基)氨基甲酸叔丁酯(化合物93-1)的合 成
利用化合物92-2(30mg，0.06mmol)和4,4,4-三氟-3-苯丁酸(15mg，0.07mmol)为原料，根据实施例7步骤六所述操作制得反应液，反应液经制备薄层色谱纯化(展开剂：乙酸乙酯＝100％)，得化合物93-1，20mg。
步骤二：3-((4-羟基-1-(4,4,4-三氟-3-苯基丁醇)哌啶-4-基)甲基)-7-(2-(甲胺基)-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物93的盐酸盐)的合成
利用化合物93-1(20mg，0.03mmol)为原料，根据实施例1步骤三所述的操作反应，经制备高效液相色谱分离(操作条件J)，制备液加稀盐酸(0.5mL,1.0mol/L)，冷冻干燥，得化合物93的盐酸盐，12mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d6)δ9.30-9.11(m,2H),8.31(d,J＝7.3Hz,1H),7.92(d,J＝1.3Hz,1H),7.90(s,1H),7.86(d,J＝7.9Hz,1H),7.47-7.38(m,3H),7.38-7.28(m,3H),4.14-.08(m,1H),4.00-3.97(m,2H),3.81-3.77(m,1H),3.42-3.31(m,2H),3.29-3.10(m,4H),3.03-2.76(m,2H),2.61(t,J＝5.3Hz,3H),1.66-1.21(m,4H).ESI-MS(m/z):595.3[M+H] +。
本实施例的反应式中未表示出化合物93的盐酸盐，表示的是化合物93。
实施例38 7-(7-氯-2-(甲胺基)-2,3-二氢-1H-茚-5-基)-3-((1-(4,4-二氟-3-(3-氟-1H-吡唑- 1-基)丁酰基)-4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物94盐 酸盐)的合成
Figure PCTCN2020083270-appb-000183
步骤一：6-溴-4-氯-2,3-二氢-1H-茚-1-醇(化合物94-2)的合成：
室温下，将化合物94-1(600mg，2.44mmol)置于甲醇(4mL)中，加入硼氢化钠(185mg，4.89mmol)，室温搅拌2h。减压浓缩后，加水(30mL)稀释，用1.0mol/L的稀盐酸调节pH≈6，用二氯甲烷(30mL x 3)萃取，无水硫酸钠干燥，过滤，减压浓缩，得化合物94-2，605mg。
1H-NMR(400MHz,CDCl 3):δ7.43(s,1H),7.41(s,1H),5.25(t,J＝6.4Hz,1H),3.11-2.96(m,1H),2.82-2.70(m,1H),2.59-2.46(m,1H),2.02-1.94(m,1H)。
步骤二：5-溴-7-氯-1H-茚(化合物94-3)的合成：
室温下，将化合物94-2(605mg，2.44mmol)溶于甲苯(5mL)中，加入对甲苯磺酸(42mg，0.24mmol)，升温至120℃反应3h，减压浓缩反应液，粗品用石油醚洗涤，过滤，减压浓缩滤液，得化合物94-3，560mg,。
1H-NMR(400MHz,CDCl 3)：δ7.44(d,J＝1.6Hz,1H),7.33(d,J＝1.5Hz,1H),6.82(dt,J＝5.5,1.9Hz,1H),6.65(dt,J＝5.5,2.0Hz,1H),3.38(t,J＝1.9Hz,2H)。
步骤三：3-溴-5-氯-6,6a-二氢-1aH-茚并[1,2-b]环氧乙烷(化合物94-4)的合成：
室温下，将化合物94-3(560mg，2.44mmol)溶于二氯甲烷(10mL)中，加入间氯过氧苯甲酸(1.26g，7.32mmol)，室温反应16h。向反应液中加入石油醚稀释，过滤，滤液经硅胶柱层析分离纯化(洗脱液：石油醚/二氯甲烷＝2/1(v/v))，得化合物94-4，400mg。
1H-NMR(400MHz,CDCl 3)：δ7.53(d,J＝1.7Hz,1H),7.42(d,J＝1.7Hz,1H),4.26(dd,J＝2.7,1.4Hz,1H),4.15(t,J＝2.8Hz,1H),3.20(dd,J＝18.6,1.6Hz,1H),2.89(dd,J＝18.6,3.0Hz,1H)。
步骤四：6-溴-4-氯-1H-茚-2(3H)-酮(化合物94-5)的合成：
室温下，将化合物94-4(400mg，1.63mmol)溶于甲苯(10mL)中，加硅胶(2g)，于120℃反应6h。停止加热，冷至室温，减压浓缩反应液，经硅胶柱层析分离纯化(洗脱液：石油醚/二氯甲烷＝2/1(v/v))，得化合物94-5，300mg。
1H-NMR(400MHz,CDCl 3)：δ7.46(s,1H),7.37(s,1H),3.62(s,2H),3.52(s,2H)。
步骤五：N-(6-溴-4-氯-2,3-二氢-1H-茚-2-基)-N-甲基氨基甲酸叔丁酯(化合物94-6)的合成：
室温下，将94-5(330mg，1.34mmol)溶于甲醇(1.5mL)中，加甲胺/水溶液(1.5mL，40wt％)，室温反应5h。再加入硼氢化钠(60mg，1.61mmol)，继续反应1h。最后加入二碳酸二叔丁酯(4.40g，20.15mmol)，继续反应1h。将反应液倒入水中，乙酸乙酯(30mL x 3)萃取，饱和氯化钠溶液反洗，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶柱层析分离纯化(洗脱液：石油醚/四氢呋喃＝30/1(v/v))，得化合物94-6,310mg。
1H-NMR(400MHz,CDCl 3)：δ7.32(s,1H),7.24(s,1H),5.26-4.93(m,1H),3.25-3.12(m,2H),3.05-2.87(m,2H),2.72(s,3H),1.46(s,9H)。
步骤六：(4-氯-6-(3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑并[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-2-基)(甲基)氨基甲酸叔丁酯(化合物94-7)的合成
室温下，将化合物94-6(20mg，0.06mmol)、联硼酸频那醇酯(17mg，0.07mmol)、Pd(dppf)Cl 2(4mg，0.006mmol)和乙酸钾(11mg，0.11mmol)溶于1,4-二氧六环(2mL)中，反应体系氮气置换三次，升温到80℃反应16h。反应液冷却到室温，加入化合物9-3(10mg，0.02mmol)、碳酸钾(8mg，0.06mmol)、四(三苯基膦)钯(2mg，0.002mmol)和水(0.4mL)，氮气置换三次，升温到80℃反应5h。反应液降至室温，减压浓缩反应液，得到的粗品经制备薄层色谱分离(展开剂：乙酸乙酯/甲醇＝60/1(v/v))，得化合物94-7，12mg。ESI-MS(m/z):719.2,721.2[M+H] +。
步骤七：7-(7-氯-2-(甲胺基)-2,3-二氢-1H-茚-5-基)-3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物94盐酸盐)的合成
室温下，称取化合物94-7(12mg，0.02mmol)于盐酸/乙酸乙酯溶液(5mL，4.0mol/L)中，反应液室温搅拌0.5h。减压浓缩除去溶剂，粗品经制备高效液相色谱分离(操作条件B)，制备液加稀盐酸(0.5mL，1.0mol/L)，冷冻干燥，得化合物94的盐酸盐，10mg。
其结构表征如下：
1H NMR(400MHz,Methanol-d 4)：δ8.56(d,J＝5.0Hz,1H),8.41(s,1H),8.00(s,1H),7.91(s,1H),7.60(dt,J＝8.6,2.5Hz,1H),6.27-5.97(m,1H),5.88(ddd,J＝14.2,5.8,2.6Hz,1H),4.99-4.94(m,1H),4.25-4.07(m,4H),3.87-3.77(m,1H),3.68-3.56(m,2H),3.49-3.33(m,3H),3.29-3.23(m,1H),3.13-3.04(m,1H),2.97-2.85(m,1H),2.81(s,3H),1.82-1.46(m,4H).ESI-MS(m/z):619.3,621.3[M+H] +。
本实施例的反应式中未表示出化合物94的盐酸盐，表示的是化合物94。
实施例39 3-((1-(4,4-二氟-3-苯基丁酰基)-4-羟基哌啶-4-基)甲基)-7(2-(甲胺基)-2,3-二 氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物95盐酸盐)的合成
Figure PCTCN2020083270-appb-000184
步骤一：(5-(3-((1-(4,4-二氟-3-苯丁酰基)-4-羟基哌啶-4-基)甲基)4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-2-基)(甲基)氨基甲酸叔丁酯(化合物95-2)的合成
称取化合物95-1(8mg,0.04mmol)溶于二氯甲烷(0.75mL)中，依次加入HATU(16mg，0.04mmol)，DIPEA(0.02mL，0.12mmol)和化合物92-2(20mg，0.04mmol)，室温搅拌反应3h。减压浓缩反应液，得到的粗品经制备薄层色谱纯化(展开剂：乙酸乙酯＝100％)，得化合物95-2，10mg。ESI-MS(m/z):677.3[M+H] +。
步骤二：3-((1-(4,4-二氟-3-苯基丁酰基)-4-羟基哌啶-4-基)甲基)-7(2-(甲胺基)-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物95盐酸盐)的合成
利用化合物95-2(8mg,0.04mmol)为原料，根据实施例1步骤三所述的操作合成得化合物95粗品，粗品经制备高效液相色谱分离(操作条件B)，制备液加稀盐酸(0.5mL,1.0mol/L)，冷冻干燥，得化合物95的盐酸盐，8mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.23(d,J＝8.0Hz,1H),8.00-7.80(m,2H),7.85(d,J＝8.0Hz,1H),7.44(d,J＝8.0Hz,1H),7.36-7.01(m,5H),6.24(td,J H-F＝56.8,4.0Hz,1H),4.14-3.92(m,3H),3.89(s,1H),3.45-3.34(m,2H),3.31-3.20(m,1H),3.17-3.05(m,2H),2.97-2.89(m,1H),2.8-2.77(m,1H),2.64(s,2H),2.07-1.94(m,1H),1.63-1.50(m,1H),1.49-1.28(m,3H),1.27-1.18(m,3H).ESI-MS(m/z):577.3[M+H] +。
本实施例的反应式中未表示出化合物95的盐酸盐，表示出的是化合物95。
实施例40 3-((1-(4,4-二氟-3-苯丁酰基)-4-羟基哌啶-4-基)甲基)-7-(1-(甲胺)-2,3-二氢- 1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物96盐酸盐)的合成
Figure PCTCN2020083270-appb-000185
步骤一：7-溴-3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物96-2)的合成
室温下，称取4,4-二氟-3-苯丁酸(30mg，0.15mmol)溶解于二氯甲烷(1mL)中，依次加入化合物9-2盐酸盐(50mg，0.14mmol)、HATU(54mg，0.14mmol)和DIPEA(53mg，0.41mmol)，室温反应2h。反应液经硅胶柱纯化(洗脱液：二氯甲烷/甲醇＝95/5(v/v))，得化合物96-2，50mg。ESI-MS(m/z):509.8,511.7[M+H] +。
步骤二：(5-(3-((1-(4,4-二氟-3-苯丁酰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-1-基)甲基叔丁酯(化合物96-3)的合成
利用化合物96-2(30mg，0.058mmol)和化合物7-3(27mg，0.072mmol)为原料，根据实施例1步骤二所述操作合成化合物96-3粗品，粗品经制备薄层色谱纯化(洗脱液：二氯甲烷/甲醇＝95/5(v/v))，得化合物96-3，30mg。ESI-MS(m/z):676.8[M+H] +。
步骤三：3-((1-(4,4-二氟-3-苯丁酰基)-4-羟基哌啶-4-基)甲基)-7-(1-(甲胺)-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物96盐酸盐)的合成
利用化合物96-3(35mg，0.05mmol)为原料，根据实施例1步骤三所述的操作合成化合物96粗品，粗品经制备高效液相色谱分离(操作条件B)，制备液加稀盐酸(0.5mL,1.0mol/L)，冷冻干燥，得化合物96盐酸盐，12mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ9.45(s,1H),9.34-9.18(m,1H),8.34(d,J＝7.6Hz,1H),8.00(s,2H),7.95(dd,J＝8.0,1.6Hz,1H),7.83(d,J＝8.0Hz,1H),7.36-7.29(m,4H),7.29-7.22(m,1H),6.24(td,J H-F＝56.4,4.0Hz,1H),4.80-4.75(m,1H),3.90-3.80(m,3H),3.80-3.50(m,3H),3.25-3.13(m,2H),3.02-2.78(m,4H),2.59(t,J＝5.2Hz,3H),2.48-2.43(m,1H),2.32-2.18(m,1H),1.65-1.20(m,4H).ESI-MS(m/z):576.8[M+H] +。
本实施例的反应式中未表示出化合物96的盐酸盐，表示出的是化合物96。
实施例41 3-((1-(3-(3-氯-1H-吡唑-1-基)-4,4-二氟丁酰基)-4-羟基哌啶-4-基)甲基)-7-(2- (甲胺基)-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物97盐酸盐) 的合成
Figure PCTCN2020083270-appb-000186
步骤一：(5-(3-((3-(3-氯-1H-吡唑-1-基)-4,4-二氟丁酰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-2-基)(甲基)氨基甲酸叔丁酯(化合物97-2)的合成
称取化合物97-1(11mg,0.05mmol)溶于二氯甲烷(1mL)，依次加入HATU(16mg，0.04mmol)、DIPEA(0.02mL，0.12mmol)、化合物92-2(20mg,0.04mmol)，室温反应2h。减压浓缩反应液，得到的粗品经制备高效液相色谱分离(操作条件G)，得化合物97-2，9mg。ESI-MS(m/z):700.8,702.6[M+H] +。
步骤二：3-((1-(3-(3-氯-1H-吡唑-1-基)-4,4-二氟丁酰基)-4-羟基哌啶-4-基)甲基)-7-(2-(甲胺基)-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物97盐酸盐)的合成
利用化合物97-2(9mg,0.01mmol)为原料，根据实施例1步骤三所述的操作合成化合物97的粗品，粗品经制备高效液相色谱分离(操作条件F)，制备液加稀盐酸(0.5mL,1.0mol/L)，冷冻干燥，得化合物97的盐酸盐，2mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)9.02(s,2H),8.29(d,J＝2.4Hz,1H),8.03-7.89(m,3H),7.86(d,J＝7.6Hz,1H),7.43(d,J＝8.0Hz,1H),6.35(dd,J＝4.4,2.4Hz,1H),6.30(td,J H-F＝54.8,3.6Hz,1H),5.16-4.95(m,2H),4.07-3.90(m,4H),3.74-3.68(m,1H),3.42-3.30(m,3H),3.30-3.23(m,1H),3.19-3.08(m,2H),3.00-2.93(m,1H),2.93-2.85(m,1H),2.63(t,J＝5.6Hz,3H),1.69-1.55(m,1H),1.54-1.33(m,3H).ESI-MS(m/z):600.7,602.8[M+H] +。
本实施例的反应式中未表示出化合物97的盐酸盐，表示出的是化合物97。
实施例42 3-((1-(3-环丙基-3-苯基丙酰基)-4-羟基哌啶-4-基)甲基)-7-(2-(甲胺)-2,3-二 氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐(化合物98的甲酸盐)的合成
Figure PCTCN2020083270-appb-000187
步骤一：(5-(3-((1-(3-环丙基-3-苯基丙酰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪 唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-1-基)(甲基)氨基甲酸叔丁酯(化合物98-1)的合成
利用3-环丙基-3-苯基丙酸(10mg，0.05mmol)和化合物92-2(26mg，0.05mmol)为原料，根据实施例17步骤一所述操作合成化合物98-1粗品，粗品经硅胶柱纯化(洗脱液：二氯甲烷/甲醇＝15/1(v/v))，得化合物98-1，30mg。ESI-MS(m/z):667.3[M+H] +。
步骤二：3-((1-(3-环丙基-3-苯基丙酰基)-4-羟基哌啶-4-基)甲基)-7-(2-(甲胺)-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐(化合物98的甲酸盐)的合成
利用化合物98-1(32mg，0.045mmol)为原料，根据实施例1步骤三所述的操作合成化合物98粗品，粗品经制备高效液相色谱分离(操作条件B)，得化合物98的甲酸盐，8mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.32(s,0.5H),8.24(d,J＝10.4Hz,1H),7.89(d,J＝2.8Hz,1H),7.83(s,1H),7.78(d,J＝8.0Hz,1H),7.35(d,J＝8.0Hz,1H),7.28-7.22(m,4H),7.18-.10(m,1H),4.95(s,1H),4.05-3.92(m,2H),3.86(s,1H),3.75-3.70(m,1H),3.68-3.58(m,1H),3.27-3.12(m,4H),2.88-2.76(m,4H),2.75-2.63(m,1H),2.40(s,3H),2.34-2.28(m,1H),1.60-1.34(m,3H),1.25-1.00(m,1H),1.10-1.02(m,1H),0.53-0.49(m,1H),0.35-0.27(m,1H),0.25-0.17(m,1H),0.10-0.03(m,1H).ESI-MS(m/z):566.7[M+H] +。
本实施例的反应式中未表示出化合物98的甲酸盐，表示出的是化合物98。
实施例43 3-((1-(3-环丙基-3-苯基丙酰基)-4-羟基哌啶-4-基)甲基)-7-(1-(甲胺)-2,3-二 氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮三氟乙酸盐(化合物99的三氟乙酸盐)的合 成
Figure PCTCN2020083270-appb-000188
步骤一：7-溴-3-((1-(4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基)-4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮(化合物99-1)的合成
利用3-环丙基-3-苯基丙酸(18mg，0.10mmol)和化合物9-2的盐酸盐(30mg，0.08mmol)为原料，根据实施例7步骤六所述操作得化合物99-1粗品，粗品经硅胶柱纯化(洗脱液：二氯甲烷/甲醇＝95/5(v/v))，得化合物99-1，50mg。ESI-MS(m/z):500.1,502.3[M+H] +。
步骤二：(5-(3-((1-(3-环丙基-3-苯基丙酰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑并[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-1-基)(甲基)氨基甲酸叔丁酯(化合物99-2)的合成
利用化合物99-1(30mg，0.06mmol)和化合物7-3(27mg，0.07mmol)为原料，根据实施例1步骤二所述操作合成化合物99-2粗品，粗品经制备薄层色谱纯化(洗脱液：二氯甲烷/甲醇＝95/5(v/v))，得化合物99-2，20mg。ESI-MS(m/z):667.3[M+H] +。
步骤三：3-((1-(3-环丙基-3-苯基丙酰基)-4-羟基哌啶-4-基)甲基)-7-(1-(甲胺)-2,3-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐(化合物99的三氟乙酸盐)的合成
利用化合物99-2(20mg，0.03mmol)为原料，根据实施例1步骤三所述的操作合成化合物99粗品，粗品经制备高效液相色谱分离(操作条件J)，得化合物99的三氟乙酸盐，14mg。
其结构表征如下：
1H NMR(400MHz,Methanol-d 4)δ8.16(dd,J＝20.0,2.0Hz,1H),8.10-8.02(m,1H),8.02-7.92(m,1H),7.92-7.75(m,1H),7.66(d,J＝8.0Hz,1H),7.37-7.22(m,4H),7.22-7.13(m,1H),4.81(dd,J＝8.0,4.0Hz,1H),4.26-4.10(m,1H),4.09-3.81(m,2H),3.79-3.65(m,1H),3.30-2.85(m,5H),2.78(s,3H),2.77-2.54(m,2H),2.36-2.21(m,2H),1.68-1.52(m,1H),1.50- 1.40(m,1H),1.40-1.30(m,1H),1.30-1.15(m,1H),1.15-0.73(m,1H),0.67-.56(m,1H),0.45-0.35(m,1H),0.35-0.24(m,1H),0.13-0.04(m,1H).ESI-MS(m/z):566.7[M+H] +。
本实施例的反应式中未表示出化合物99的三氟乙酸盐，表示出的是化合物99。
实施例44 7-(4-氯-1-(甲胺基)-2,3-二氢-1H-茚-5-基)-3-((4-羟基-1-((R)-3-苯基丁酰基) 哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐(化合物100甲酸盐)的合成
Figure PCTCN2020083270-appb-000189
步骤一：(5-溴-4-氯-2,3-二氢-1H-茚-1-基)(甲基)氨基甲酸叔丁酯(化合物100-2)的合成
室温下，将化合物100-1(100mg，0.41mmol)用甲醇(2mL)溶解，加入甲胺/乙醇溶液(2mL，33％wt)，室温反应16h，将反应液旋干，浓缩物再用甲醇(2mL)溶解，加入硼氢化钠(30mg，0.81mmol)，室温反应1h后加入二碳酸二叔丁酯(0.44g，2.04mmol)，继续在室温反应1h。减压抽干溶剂，经硅胶柱层析分离纯化(洗脱液：石油醚/乙酸乙酯＝10/1(v/v))，得化合物100-2，0.13g。ESI-MS(m/z):304.3,306.3[M-56+H] +。
步骤二：4-氯-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2,3-二氢-1H-茚-1-基)(甲基)氨基甲酸叔丁酯(化合物100-3)的合成
利用化合物100-2(0.13g，0.36mmol)替换化合物9-5作为反应原料,根据实施例9步骤五中所述的操作合成化合物100-3粗品，粗品经制备薄层色谱分离(展开剂：石油醚/乙酸乙酯＝15/1(v/v))，得化合物100-3，100mg。ESI-MS(m/z):352.2,354.2[M-56+H] +。
步骤三：4-氯-5-(3-((4-羟基-1-((R)-3-苯基丁酰基)哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-1-基)(甲基)氨基甲酸叔丁酯(化合物100-4)的合成
利用化合物1-2(20mg，0.04mmol)和化合物100-3(21mg，0.05mmol)为反应原料，根据实施例1步骤二所述操作得化合物100-4粗品，粗品经制备薄层色谱纯化(展开剂：乙酸乙酯/甲醇＝60/1(v/v))，得化合物100-4，15mg。ESI-MS(m/z):675.3,677.3[M+H] +。
步骤四：7-(4-氯-1-(甲胺基)-2,3-二氢-1H-茚-5-基)-3-((4-羟基-1-((R)-3-苯基丁酰基)哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮甲酸盐(化合物100甲酸盐)的合成
将化合物100-4(15mg，0.02mmol)用盐酸/乙酸乙酯溶液(5mL,4.0mol/L)溶解，室温反应0.5h。反应液减压浓缩得化合物100粗品，粗品经制备高效液相色谱分离(操作条件K)，制备液冷冻干燥，得化合物100的甲酸盐，10mg。
其结构表征如下：
1H NMR(400MHz,Methanol-d 4)δ8.53(brs,1H),8.06(d,J＝19.2Hz,1H),7.69(d,J＝2.4Hz,1H),7.59(s,2H),7.36-7.12(m,5H),4.85-4.70(m,1H),4.27-4.12(m,1H),4.12-3.97(m,1H),3.95-3.82(m,1H),3.73-3.58(m,1H),3.30-3.15(m,3H),3.15-2.85(m,2H),2.85-2.73(m,1H),2.70(s,3H),2.65-2.41(m,2H),2.32-2.15(m,1H),1.65-1.25(m,7H).ESI-MS(m/z):575.3,577.3[M+H] +。
本实施例的反应式中未表示出化合物100的甲酸盐，表示的是化合物100。
实施例45 7-(7-氯-1-(甲胺基)-2,3-二氢-1H-茚-5-基)-3-((1-(3-环丙基-3-苯基丙酰基)-4- 羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物101的盐酸盐)的合成
Figure PCTCN2020083270-appb-000190
步骤一：N-(5-溴-7-氯-2,3-二氢-1H-茚-1-基)-N-甲基氨基甲酸叔丁酯(化合物101-2)的合成
室温下，将化合物101-1(300mg，1.2mmol)和甲胺盐酸盐(248mg，3.7mmol)溶于四氢呋喃(18mL)和甲醇(6mL)的混合溶剂中，加入甲胺/乙醇溶液(0.5mL，33wt％)和氰基硼氢化钠(421mg，18.33mmol)。氮气保护下，升温至65℃回流反应24h。终止加热，移至室温继续搅拌，待冷至室温后，加入碳酸二叔丁酯(533mg，0.6mL，2.44mmol)和DIPEA(316mg，0.4mL，2.44mmol)，继续搅拌反应3h。加水淬灭反应，用乙酸乙酯(30mL×3)萃取，有机相依次用饱和碳酸氢钠水溶液(20mL)和饱和食盐水(20mL)洗涤，用无水硫酸钠干燥，减压浓缩，剩余物经制备高效液相色谱分离(操作条件L)，制备液冷冻干燥，得化合物101-2，248mg。ESI-MS(m/z):304.0,306.0[M-56+H] +。
步骤二：N-(7-氯-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-2,3-二氢-1氢-茚-1-基)-N-甲基氨基甲酸叔丁酯(化合物101-3)的合成
根据实施例13步骤二所述操作，利用化合物101-2(248mg，0.69mmol)替换化合物9-5作为反应原料进行反应，联硼酸频那醇酯用量为218mg(0.86mmol)，反应液经硅胶柱层析分离纯化(洗脱液：石油醚/乙酸乙酯＝90/10(v/v))，得化合物101-3，211mg。ESI-MS(m/z):352.1,354.1[M-56+H] +。
步骤三：(7-氯-5-(3-((1-(3-环丙基-3-苯基丙酰基)-4-羟基哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-1-基)(甲基)氨基甲酸叔丁酯(化合物101-4)的合成
根据实施例1步骤二所述操作，利用化合物99-1(30mg，0.06mmol)、化合物101-3(27mg，0.07mmol)为反应原料，反应液经制备薄层色谱分离纯化(展开剂：二氯甲烷/甲醇＝30/1(v/v))得化合物101-4，30mg。ESI-MS(m/z):701.4,703.3[M+H] +。
步骤四：7-(7-氯-1-(甲胺基)-2,3-二氢-1H-茚-5-基)-3-((1-(3-环丙基-3-苯基丙酰基)-4-羟基哌啶-4-基)甲基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮盐酸盐(化合物101盐酸盐)的合成
室温下，称取化合物101-4(30mg，0.04mmol)于反应瓶中，加入盐酸/乙酸乙酯溶液(2mL，4.0mol/L)，室温搅拌反应1h。抽滤，滤饼用乙酸乙酯洗涤，干燥，得化合物101盐酸盐，14mg。
其结构表征如下：
1H NMR(400MHz,Methanol-d 4)δ8.45(d,J＝19.2Hz,1H),8.41-8.32(m,1H),8.12(s,1H),8.03(s,1H),7.45-7.09(m,5H),5.01(dd,J＝7.8,1.9Hz,1H),4.31-4.16(m,1H),4.13(s,1H),4.00-4.88(m,1H),3.73(t,J＝13.5Hz,1H),3.46-3.39(m,1H),3.28-3.13(m,2H),3.03-2.88(m,2H),2.85-2.75(m,3H),2.74-2.56(m,2H),2.49-2.41(m,1H),2.33-2.24(m,1H),1.67-1.48(m,2H),1.43-1.27(m,2H),1.25-1.15(m,1H),0.81-0.73(m,1H),0.67-0.59(m,1H),0.46-0.38(m,1H),0.35-0.27(m,1H),0.14-0.07(m,1H).ESI-MS(m/z):601.2,603.3[M+H] +。
本实施例的反应式中未表示出化合物101的盐酸盐，表示的是化合物101。
实施例46 3-((4-羟基-1-((R)-3-苯基丁酰基)哌啶-4-基)甲基)-7-(2-(甲氨基)-2,3-二氢- 二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮-异构体A盐酸盐(化合物13-异构体A 盐酸盐)的合成
Figure PCTCN2020083270-appb-000191
步骤一：5-(3-((4-羟基-1-((R)-3-苯基丁酰基)哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-2-基)(甲基)氨基甲酸叔丁酯-异构体A(化合物13-4-异构体A)和5-(3-((4-羟基-1-((R)-3-苯基丁酰基)哌啶-4-基)甲基)-4-氧代-3,4-二氢咪唑[2,1-f][1,2,4]三嗪-7-基)-2,3-二氢-1H-茚-2-基)(甲基)氨基甲酸叔丁酯-异构体B(化合物13-4-异构体B)的合成
通过手性高效液相，对化合物13-4(308mg，0.48mmol)进行分离，得到化合物13-4-异构体A(154mg)和化合物13-4-异构体B(154mg)。化合物13-4-异构体A和化合物13-4-异构体B的手性高效液相色谱条件如下：手性柱：CHIRALCEL OJ-H(OJH0CD-WB010)(0.46cm I.D.×15cm L)；进样量：5μL；流动相：MeOH＝100％；流速：1.0mL/min；波长：UV 214nm；温度：35℃；高效液相色谱设备：Shimadzu LC-20AD CP-HPLC-08；其中化合物13-4-异构体A的保留时间为：4.656min，ESI-MS(m/z):641.2[M+H] +。化合物13-4-异构体B的保留时间为6.631min,ESI-MS(m/z):641.2[M+H] +。
步骤二：3-((4-羟基-1-((R)-3-苯基丁酰基)哌啶-4-基)甲基)-7-(2-(甲氨基)-2,3-二氢-二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮-异构体A盐酸盐(化合物13-异构体A盐酸盐)的合成
向化合物13-4-异构体A(142mg，0.22mmol)中，加入盐酸/乙酸乙酯溶液(2mL,4.0mol/L)，室温反应1h。停止搅拌，将反应液过滤，收集滤饼。滤饼加水(30mL)溶解，冷冻干燥，得化合物13-异构体A盐酸盐，120mg。
其结构表征如下：
1H NMR(400MHz,Methanol-d 4)δ8.43(d,J＝17.5Hz,1H),8.22(s,1H),7.95(s,1H),7.87(d,J＝7.9Hz,1H),7.48(d,J＝8.0Hz,1H),7.35–7.16(m,5H),4.26–3.88(m,4H),3.68(t,J＝13.5Hz,1H),3.52(dt,J＝17.1,6.8Hz,2H),3.23(dt,J＝16.8,6.9Hz,4H),2.95(dt,J＝14.3,10.6Hz,1H),2.80(s,4H),2.55(ddd,J＝37.3,14.2,6.6Hz,1H),1.68–1.31(m,6.5H),0.91–0.82(m,0.5H).ESI-MS(m/z):541.2[M+H] +。
本实施例的反应式中未表示出化合物13-异构体A的盐酸盐，表示的是化合物13-异构体A，即发明内容部分的表格中化合物13的异构体。
实施例47 3-((4-羟基-1-((R)-3-苯基丁酰基)哌啶-4-基)甲基)-7-(2-(甲氨基)-2,3-二氢- 二氢-1H-茚-5-基)咪唑[2,1-f][1,2,4]三嗪-4(3H)-酮-异构体B盐酸盐(化合物13-异构体B盐 酸盐)的合成
13-4-异构体B→13-异构体B
室温下，称取化合物13-4-异构体B(144mg，0.21mmol)于反应瓶中，加入盐酸/乙酸乙酯溶液(2mL，4.0mol/L)，室温搅拌反应1h。将反应液过滤，收集滤饼。滤饼加水(10mL)溶解，冷冻干燥，得化合物13-异构体B盐酸盐，114mg。
其结构表征如下：
1H NMR(400MHz,Methanol-d 4)δ8.62–8.47(m,1H),8.41(s,1H),7.97(s,1H),7.89(d,J＝7.8Hz,1H),7.52(d,J＝7.9Hz,1H),7.36–7.15(m,5H),4.27–3.91(m,4H),3.69(t,J＝13.0Hz,1H),3.60–3.48(m,2H),3.30–3.17(m,4H),3.10–2.90(m,1H),2.85–2.70(m, 4H),2.65–2.58(m,1H),1.71–1.31(m,6.5H),0.90-0.78(m,0.5H).ESI-MS(m/z):541.2[M+H] +。
本实施例的反应式中未表示出化合物13-异构体B的盐酸盐，表示的是化合物13-异构体B，即发明内容部分的表格中化合物13的又一异构体。
药理活性测试
试验例一：USP7(去泛素化酶)体外酶学活性抑制试验
(1)试验系统：
试剂盒：USP7 Inhibitor Screening Assay Kit,(BPS Catalog:79256)；
去泛素化酶：USP7 HisFLAGtags enzyme,(BPS Catalog:80395)；
底物：Ub-AMC Substrate,(BPS Catalog:81150)；
缓冲液：5x USP7 Assay Buffer,(BPS Catalog:79274)；
(2)试验参数：
USP7浓度：3nM；
Ub-AMC浓度：100nM；
缓冲液体系：1.25x USP7 Assay Buffer；0.06％BSA；1mM DTT；ddH2O；
化合物和酶孵育时间：20min；
酶动力学反应时间：20min；
酶标仪参数：BMG PHERAstar Fluorescence，激发波长350nm，发射波长460nm；
(3)试验步骤：
将待测化合物和去泛素化酶USP7混合，得到混合物；将混合物在缓冲液体系下室温孵育20min，加入底物Ub-AMC启动反应，采用酶动力学方法，读取每个循环(1min)中各孔的荧光值，读取20个循环。
(4)数据处理：
以溶媒组(3nM USP7+100nM Ub-AMC+0.2％DMSO)为阳性对照，反应缓冲液组(100nM Ub-AMC+0.2％DMSO)为阴性对照，计算各浓度组的相对抑制活性，抑制率＝1-100％×(测试组荧光值-阴性组荧光值)/(阳性组荧光值-阴性组荧光值)。按照四参数模型拟合曲线，计算化合物对USP7活性的半数抑制浓度(IC 50)，结果如表14中所示。
表14 USP7酶活抑制试验结果
制备化合物的实施例 IC 50(nM)
实施例1 42.26±3.50
实施例3 39.54±3.81
实施例6 37.49±3.49
实施例9 46.76±7.30
实施例10 50.51±16.82
实施例13 6.73±1.10
实施例20 19.27±2.45
实施例23 1.92±3.24
实施例24 12.43±2.71
实施例25 1.18±0.19
实施例26 15.02±2.93
实施例28 1.91±1.59
实施例42 77.56±10.29
实施例46 55.87±6.81
实施例47 22.66±2.93
由表14可知，本发明化合物或其可药用盐能够抑制去泛素化酶USP7的活性，其中，实施例1、3、6、9、10、13、20、23、24、25、26、28、46、47的化合物对去泛素化酶USP7活性的抑制作用更加显著。
试验例二：MM.1S细胞(骨髓瘤细胞)增殖活性抑制试验
(1)试验系统：细胞名称：MM.1S(购买自南京科佰公司)；试剂盒：
Figure PCTCN2020083270-appb-000192
发光法细胞活力分析试剂盒(Promega)；
(2)试验参数：细胞数量：3000细胞/孔；铺板培养基：MM.1S:RPMI1640+10％FBS；加药培养基：MM.1S:RPMI1640+10％FBS；化合物孵育条件：37℃，5％CO 2；孵育时间：5d；检测温度：室温；BMG PHERAstar FS检测化学发光。
(3)试验方法：
将细胞培养在含有10％胎牛血清的培养基中，放置在37℃，5％CO 2培养条件下进行培养；向96孔板中铺入适量细胞，培养箱中过夜培养。次日，加入含有各浓度待测化合物(事先用溶媒DMSO配制)的完全培养基，37℃孵育5d；结束后，向每孔中加入检测试剂CellTiter-GLo，化学发光检测各孔的相对发光单位(RLU)。
(4)数据处理：将不含细胞的培养基的
Figure PCTCN2020083270-appb-000193
测定值作为背景值。细胞活率(％)＝(样品RLU-背景RLU)/(溶媒RLU-背景RLU)×100％，抑制率(％)＝100％-细胞活率(％)。按照四参数模型拟合曲线，计算化合物的半数抑制浓度(IC 50)。
(5)试验结果：
采用上述方法测定各化合物对MM.1S细胞增殖的抑制活性，结果如表15中所示。
表15 化合物对MM.1S细胞增殖活性抑制结果
实施例编号 MM.1S,IC 50(nM)
实施例1 65.73±3.95
实施例13 26.30±7.93
实施例25 58.88±9.53
实施例47 58.56±10.76
在MM.1S细胞增殖活性抑制试验中，本发明化合物表现出较强的细胞增殖抑制活性，尤其是实施例13中的化合物对MM.1S细胞增殖具有极强的抑制活性。
试验例三：生化hERG抑制试验
(1)试验系统：试剂盒：Predictor TM hERG荧光极化分析试剂盒，其含有：作为阳 性对照的化合物E4031；hERG细胞膜；亲和性示踪剂；和hERG缓冲液。
(2)试验参数：hERG浓度：1×；示踪剂浓度：1nM；孵育时间：2h；酶标仪参数：BMG PHERAstar FS荧光酶标仪。
(3)试验方法：
按照试剂盒说明书进行试验，步骤如下：
测试组：将不同浓度的待测化合物加入到含有hERG细胞膜的微孔板中，每孔中再加入具有高hERG亲和性示踪剂，将微孔板在室温孵育2小时后，使用多功能酶标仪检测荧光偏振(激发波长：540nm；发射波长：590nm)值的变化。
阳性对照组：用30μM的化合物E4031代替待测化合物，实验方法与测试组相同。
空白对照组：用hERG缓冲液代替待测化合物，并且不加hERG细胞膜，实验方法与测试组相同。
(4)数据处理：
根据数据比值，计算本发明化合物在不同浓度下对hERG百分比抑制率(％)，判断化合物的半数抑制浓度(IC 50)的范围。百分比抑制率(％)＝(1-(待测化合物的荧光偏振值-阳性对照组的荧光偏振值)/(空白对照组的荧光偏振值-阳性对照组的荧光偏振值))×100％。
(5)试验结果：
采用上述方法测定化合物对hERG的抑制，结果如表16中所示。
表16 hERG抑制试验结果
实施例编号 IC 50(μM)
实施例8 ＞10
实施例9 ＞10
实施例10 ＞10
实施例13 ＞10
实施例15 ＞10
实施例19 ＞10
实施例20 ＞10
实施例23 ＞10
实施例24 ＞10
实施例25 ＞10
实施例26 ＞10
实施例27 ＞10
实施例28 ＞10
实施例31 ＞10
实施例36 ＞10
实施例39 ＞10
实施例42 ＞10
实施例46 ＞10
实施例47 ＞10
测试结果表明，实施例8、9、10、13、15、19、20、23、24、25、26、27、28、31、36、39和42中的化合物与hERG亲和性低，与亲和性示踪剂竞争的IC 50均大于10μM。
试验例四：生化CYP酶(细胞色素P450)抑制试验
(1)试验系统：P450-Glo TM CYP1A2筛选系统；P450-Glo TM CYP2D6筛选系统；P450-Glo TM CYP3A4筛选系统；
(2)测试仪器：
BMG PHERAstar FS检测化学发光。
(3)试验方法：
(3.1)对CYP1A2的抑制：测试组：将不同浓度的待测化合物加入到微孔板中，向每孔中加入Luciferin-ME(100μM)、K 3PO 4(100mM)和CYP1A2(0.01pmol/μL)，在室温下预孵育10min，随后加入NADPH再生系统在室温下反应30min，最后加入等体积的检测缓冲液在室温下孵育20min后进行化学发光检测。阴性对照组：实验方法同测试组，除了不加待测化合物。空白对照组：实验方法同测试组，除了不加待测化合物，并且用CYP1A2膜(0.01pmol/μL)代替CYP1A2。
(3.2)对CYP2D6的抑制：测试组：将不同浓度的待测化合物加入到微孔板中，向每孔中加入Luciferin-ME EGE(30μM)、K 3PO 4(100mM)和CYP2D6(5nM)，在室温下预孵育10min，随后加入NADPH再生系统在37℃下反应30min，最后加入等体积的检测缓冲液在室温下孵育20min后进行化学发光检测。
阴性对照组：实验方法同测试组，除了不加待测化合物。
空白对照组：实验方法同测试组，除了不加待测化合物，并且用CYP2D6膜(5nM)代替CYP2D6。
(3.3)对CYP3A4的抑制：测试组：将不同浓度的待测化合物加入到微孔板中，向每孔中加入Luciferin-IPA(3μM)、K 3PO 4(100mM)和CYP3A4(2nM)，在室温下预孵育10min，随后加入NADPH再生系统在室温下反应30min，最后加入等体积的检测缓冲液在室温下孵育20min后进行化学发光检测。阴性对照组：实验方法同测试组，除了不加待测化合物。空白对照组：实验方法同测试组，除了不加待测化合物，并且用CYP3A4膜(2nM)代替CYP3A4。
(4)数据处理：百分比抑制率(％)＝(1-(待测化合物的化学发光值-空白对照组的化学发光值)/(阴性对照组的化学发光值-空白对照组的化学发光值))×100％。根据不同浓度下化合物对CYP酶的抑制率，估算化合物的半数抑制浓度(IC 50)或范围。
IC 50＝X×(1-百分比抑制率(％))/百分比抑制率(％)，其中X为化合物测试浓度。
(5)试验结果：
按照上述方法测定本发明化合物对三种CYPs的抑制，结果如表17中所示。
表17 CYPs抑制试验结果
Figure PCTCN2020083270-appb-000194
上述结果表明，实施例8、9、27和36中的化合物对3种主要CYP亚型均无明显抑制作用，表明其潜在的药物相互作用可能性相对较低，具有较好的成药性质。
试验例五：大鼠药代动力学(PK)研究
通过静脉(IV)给予雄性SD大鼠实施例13的化合物盐酸盐，考察药代动力学特点。给药剂量是1mg/kg，溶媒为5％DMSO:5％Solutol(聚乙二醇-15羟基硬脂酸酯):90％生理盐水。在给药前，给药后0.083、0.25、0.5、1、2、4、6、8和24h分别采集静脉血样；血液采用EDTA.K 2抗凝，离心后得到血浆样品，保存于-80℃。血浆样品经沉淀蛋白处理后进行LC-MS/MS分析。应用WinNonlin 6.3软件，采用非房室模型计算药代动力学参数，结果见表18。
表18 实施例13化合物盐酸盐在大鼠体内血液中的药代动力学参数
Figure PCTCN2020083270-appb-000195
实施例13化合物盐酸盐在大鼠体内的药代动力学性质良好。
试验例六：大鼠脑组织分布试验
通过静脉(IV)给予雄性SD大鼠实施例13化合物盐酸盐，考察其脑组织分布特点。给药剂量是10mg/kg，溶媒为5％DMSO:5％Solutol(聚乙二醇-15羟基硬脂酸酯):90％生理盐水，在给药前，给药后0.083、0.25、1、4、和8h分别收集血液和脑组织；血液采用EDTA.K2抗凝，离心后得到血浆样品；脑组织按1:2生理盐水(g:ml)匀浆；血浆与脑组织匀浆液均保存于-80℃，血浆和脑组织样品经沉淀蛋白处理后进行LC-MS/MS分析。应用WinNonlin 6.3软件，采用非房室模型计算药代动力学参数，结果见表19。
表19 实施例13化合物盐酸盐在大鼠体内血浆和脑组织中的药代动力学参数
Figure PCTCN2020083270-appb-000196
Figure PCTCN2020083270-appb-000197
注：“/”表示未测试。
SD大鼠静脉给予实施例13化合物盐酸盐(10mg/kg)后，化合物入脑情况为脑组织与血浆的浓度(C max)之比为0.01，药时曲线下面积(AUC last)比值为0.026，即化合物的入脑量极少，该化合物产生中枢副作用的风险较小。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。

Claims (21)

  1. 式I所示的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物：
    Figure PCTCN2020083270-appb-100001
    其中：
    R 1选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基和
    Figure PCTCN2020083270-appb-100002
    其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被R 4范围内的一个或多个基团所取代；
    R 4范围的基团包括氢、卤素、氧代基、-OR a、-NR bR c、-C(O) qR 7、-C(O)NR bR c、-S(O) qR 7、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a、-O-C 2-6亚烷基-NR bR c、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被R 6范围内的一个或多个基团所取代；
    R 6范围的基团包括氢、卤素、氰基、C 1-6烷基、卤代的C 1-6烷基、-OR a、-NR bR c、-C(O) qR 8、-C(O)NR bR c、-S(O) qR 8、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a、-O-C 2-6亚烷基-NR bR c、C 1-6烷基、-C 1-6亚烷基-OR a和-C 1-6亚烷基-NR bR c；
    A环选自C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被R范围内的一个或多个基团所取代；
    B环选自C 4-6环烯基、C 3-8环烷基、氧代的C 3-8环烷基、5-12元脂杂环基、氧代的5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 3-8环烷基、氧代的C 3-8环烷基、5-12元脂杂环基、氧代的5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；
    R范围的基团包括氢、C 1-6烷基、卤代的C 1-6烷基、卤素、氰基、-OR d和-NR eR f；
    R 5范围的基团包括氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基、-OR d、-NR eR f、卤素、氰基、-C(O) qR 9、-C(O)NR eR f、-S(O) qR 9、-S(O) qNR eR f、-O-(C 2-6亚烷基-O) t-R d和-O-C 2-6亚烷基-NR eR f，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被K范围内的一个或多个基团所取代；
    K范围的基团包括氢、卤素、氰基、C 1-6烷基、-OR d、-NR eR f、-C(O) qR 10、-C(O)NR eR f、-S(O) qR 10和-S(O) qNR eR f；
    R a、R b、R c、R d、R e和R f各自独立地选自氢、-C(O) qR 11、-S(O) qR 11、C 1-6烷基、C 2- 6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 6-10芳基和5-12元芳杂环基各自独立地任选被一个或多个如下的取代基 所取代：氢、卤素、氨基、羟基；
    R 7、R 8、R 9、R 10和R 11各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氰基、氨基、羟基、C 1-6烷基；
    R 2选自氢、氰基、卤素、C 1-6烷基、卤代的C 1-6烷基、C 3-8环烷基和5-12元脂杂环基；
    R 3选自氢、C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基、-C(O) qR 12、-C(O)NR gR h、-S(O) qR 12和-S(O) qNR gR h，其中，所述C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、C 1-6烷基、卤代的C 1-6烷基、C 6-10芳基、卤代的C 6-10芳基、5-12元芳杂环基、卤代的5-12元芳杂环基、C 3-8环烷基、卤代的C 3-8环烷基；
    R 12选自氢、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基、C 3-8环烷基并C 6-10芳基、C 3-8环烷基并5-12元芳杂环基、5-12元脂杂环基并C 6-10芳基、5-12元芳杂环并5-12元脂杂环基，其中，所述氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基、C 3-8环烷基并C 6-10芳基、C 3-8环烷基并5-12元芳杂环基、5-12元脂杂环基并C 6-10芳基和5-12元芳杂环并5-12元脂杂环基各自独立地任选被R 13范围内的一个或多个基团所取代；
    R 13范围的基团包括氢、氨基、氰基、卤素、-OR j、-NR kR m、-C(O) qR 14、-C(O)NR kR m、-S(O) qR 14、-S(O) qNR kR m、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、-C 1-6亚烷基-(C 6- 10芳基)、C 6-10芳基、5-12元芳杂环基和-C 1-6亚烷基-5-12元芳杂环基，其中，所述氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、-C 1-6亚烷基-(C 6-10芳基)、C 6-10芳基、5-12元芳杂环基和-C 1-6亚烷基-5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氰基、C 1-6烷基、C 6-10芳基、任选被C 1-6烷基或卤素取代的5-12元芳杂环基；
    R 14选自氢、C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基和C 2-6烯基，其中，所述的C 1-6烷基、C 2-6烯基和5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1-6烷基、C 6-10芳基和任选被C 1-6烷基取代的5-12元芳杂环基；
    R g、R h、R j、R k和R m各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2- 6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基、4-8元脂杂环基；
    m选自1、2、3、4、5、6、7和8；
    n 1和n 2各自独立地选自0、1和2；
    q选自1和2；
    r选自1、2和3；
    t选自1、2、3和4。
  2. 根据权利要求1所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，其中，
    R 1选自氢、C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基、5-8元芳杂环基和
    Figure PCTCN2020083270-appb-100003
    其中，所述的C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基各自独立地任选被R 4范围内的一个或多个基团所取代；
    R 4范围的基团包括氢、卤素、氧代基、-OR a、-NR bR c、-C(O) qR 7、-C(O)NR bR c、-S(O) qR 7、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a、-O-C 2-6亚烷基-NR bR c、C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述的C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基各自独立地任选被R 6范围内的一个或多个基团所取代；
    R 6范围的基团包括氢、卤素、氰基、C 1-6烷基、卤代的C 1-6烷基、-OR a、-NR bR c、-C(O) qR 8、-C(O)NR bR c、-S(O) qR 8、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a、-O-C 2-6亚烷基-NR bR c、-C 1-6亚烷基-OR a和-C 1-6亚烷基-NR bR c；
    A环选自C 6-10芳基和5-8元芳杂环基，所述C 6-10芳基、5-8元芳杂环基各自独立地任选被R范围内的一个或多个基团所取代；
    B环选自C 3-8环烷基、氧代的C 3-8环烷基、5-8元脂杂环基、氧代的5-8元脂杂环基和5-8元芳杂环基，其中，所述C 3-8环烷基、氧代的C 3-8环烷基、5-8元脂杂环基、氧代的5-8元脂杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；
    R范围的基团包括氢、C 1-6烷基、卤代的C 1-6烷基、卤素、氰基、-OR a和-NR bR c；
    R 5范围的基团包括氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基、5-8元芳杂环基、-OR d、-NR eR f、卤素、氰基、-C(O) qR 9、-C(O)NR eR f、-S(O) qR 9、-S(O) qNR eR f、-O-(C 2-6亚烷基-O) t-R d和-O-C 2-6亚烷基-NR eR f，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基、5-8元芳杂环基各自独立地任选被K范围内的一个或多个基团所取代；
    K范围的基团包括氢、卤素、氰基、C 1-6烷基、-OR d、-NR eR f、-C(O) qR 10、-C(O)NR eR f、-S(O) qR 10和-S(O) qNR eR f；
    R a、R b、R c、R d、R e和R f各自独立地选自氢、-C(O) qR 11、-S(O) qR 11、C 1-6烷基、C 2- 6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述C 1-6烷基、C 6-10芳基和5-8元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基；
    R 7、R 8、R 9、R 10和R 11各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2- 6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：卤素、氰基、氨基、羟基、C 1-6烷基；
    q选自1和2；
    t选自1、2、3和4；
    r选自1、2和3；
    m选自1、2、3、4、5、6、7和8；
    优选地，
    R 1选自C 6-10芳基、5-8元芳杂环基和
    Figure PCTCN2020083270-appb-100004
    其中，所述的C 6-10芳基和5-8元芳杂环基各自独立地任选被R 4范围内的一个或多个基团所取代；
    R 4范围的基团包括氢、卤素、-OR a、-NR bR c、-C(O) qR 7、-C(O)NR bR c、-S(O) qR 7、-S(O) qNR bR c、C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述的C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基、5-8元芳杂环基各自独立地任选被R 6范围内的一个或多个基团所取代；
    R 6范围的基团包括氢、卤素、C 1-6烷基、卤代的C 1-6烷基、-OR a、-NR bR c、-C(O) qR 8、-S(O) qR 8、-C 1-6亚烷基-OR a和-C 1-6亚烷基-NR bR c；
    A环为苯基，所述苯基任选的被R范围内的一个或多个基团所取代；
    R范围的基团包括氢、C 1-6烷基、卤代的C 1-6烷基、卤素、氰基；
    B环选自C 3-8环烷基、氧代的C 3-8环烷基、5-8元脂杂环基、氧代的5-8元脂杂环基和5-8元芳杂环基，其中，所述C 3-8环烷基、氧代的C 3-8环烷基、5-8元脂杂环基和氧代的5-8元脂杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；
    R 5范围的基团包括氢、C 1-6烷基、卤代的C 1-6烷基、-OR d、-NR eR f和卤素；
    R a、R b和R c各自独立地选自氢、-C(O) qR 11、-S(O) qR 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述C 1-6烷基、C 6- 10芳基、5-8元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基；
    R d、R e和R f各自独立地选自氢和C 1-6烷基；
    R 7、R 8和R 11各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3- 8环烷基、5-8元脂杂环基、C 6-10芳基、5-8元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氰基、氨基、羟基、C 1-6烷基；
    q选自1和2；
    t选自1、2、3和4；
    r选自1、2和3；
    m选自1和2；
    更优选地，R 1选自苯基、对氟苯基、对氯苯基、对氨基苯基、对羟基苯基、
    Figure PCTCN2020083270-appb-100005
    Figure PCTCN2020083270-appb-100006
    Figure PCTCN2020083270-appb-100007
    进一步优选地，R 1选自苯基、对氟苯基、对氯苯基、对羟基苯基、
    Figure PCTCN2020083270-appb-100008
    Figure PCTCN2020083270-appb-100009
  3. 根据权利要求1所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，其中，
    R 1选自氢、C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述的C 1-6烷基、C 3-8环烷基、5-8元脂杂环基、C 6-10芳基和5-8元芳杂环基各自独立地任选被R 4范围内的一个或多个基团所取代；
    R 4范围的基团包括氢、卤素、氧代基、-OR a、-NR bR c、-C(O) qR 7、-C(O)NR bR c、-S(O) qR 7、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a、-O-C 2-6亚烷基-NR bR c、C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述的C 1-6烷基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被R 6范围内的一个或多个基团所取代；
    R 6范围的基团包括氢、卤素、氰基、C 1-6烷基、卤代的C 1-6烷基、-OR a、-NR bR c、-C(O) qR 8、-C(O)NR bR c、-S(O) qR 8、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a、-O-C 2-6亚烷基-NR bR c、-C 1-6亚烷基-OR a和-C 1-6亚烷基-NR bR c；
    R a、R b、R c各自独立地选自氢、-C(O) qR 11、-S(O) qR 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 6-10芳基、5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基；
    R 7、R 8和R 11各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12 元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：卤素、氰基、氨基、羟基、C 1-6烷基；
    q选自1和2；
    t选自1、2、3和4；
    优选地，
    R 1选自C 6-10芳基和5-8元芳杂环基，其中，所述的C 6-10芳基和5-8元芳杂环基各自独立地任选被R 4范围内的一个或多个基团所取代；
    R 4范围的基团包括氢、卤素、-OR a、-NR bR c、-C(O) qR 7、-C(O)NR bR c、-S(O) qR 7、-S(O) qNR bR c、C 1-6烷基、C 3-8环烷基、5-10元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述的C 1-6烷基、C 3-8环烷基、5-10元脂杂环基、C 6-10芳基、5-8元芳杂环基各自独立地任选被R 6范围内的一个或多个基团所取代；
    R 6范围的基团包括氢、卤素、C 1-6烷基、卤代的C 1-6烷基、-OR a、-NR bR c、-C(O) qR 8、-S(O) qR 8、-C 1-6亚烷基-OR a和-C 1-6亚烷基-NR bR c；
    R a、R b、R c各自独立地选自氢、-C(O) qR 11、-S(O) qR 11、C 1-3烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-10元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述C 1-6烷基、C 6-10芳基、5-8元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基；
    R 7、R 8和R 11各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-10元脂杂环基、C 6-10芳基和5-8元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-10元脂杂环基、C 6-10芳基、5-8元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氰基、氨基、羟基、C 1-6烷基；
    q选自1和2；
    t选自1、2、3和4；
    更优选地，R 1选自苯基、吡啶基、吡嗪基和嘧啶基，其中，所述的苯基、吡啶基、吡嗪基和嘧啶基各自独立地任选被如下的一个或多个基团所取代：氢、卤素、-OH、-OCH 3、-NH 2、-NHCH 3、-N(CH 3) 2、-CH 2NH 2、-CH 2NHCH 3、-CH 2N(CH 3) 2、
    Figure PCTCN2020083270-appb-100010
    Figure PCTCN2020083270-appb-100011
    进一步优选地，R 1选自苯基、吡啶基、吡嗪基和嘧啶基，其中，所述的苯基、吡啶基、吡嗪基和嘧啶基各自独立地任选被如下的一个或多个基团所取代：氢、卤素、-OH、-OCH 3、-NH 2、-CH 2NH 2、-CH 2NHCH 3、-CH 2N(CH 3) 2、
    Figure PCTCN2020083270-appb-100012
    更进一步优选地，R 1选自苯基、对氟苯基、对氯苯基、对氨基苯基、对羟基苯基、
    Figure PCTCN2020083270-appb-100013
    Figure PCTCN2020083270-appb-100014
  4. 根据权利要求1所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，其中，
    R 1为
    Figure PCTCN2020083270-appb-100015
    其中，
    A环选自C 6-10芳基和5-12元芳杂环基，所述C 6-10芳基、5-12元芳杂环基各自独立地任选被R范围内的一个或多个基团所取代；
    R范围的基团包括氢、C 1-6烷基、卤代的C 1-6烷基、卤素、氰基、-OR a和-NR bR c；
    R a、R b、R c各自独立地选自氢、-C(O) qR 11、-S(O) qR 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 6-10芳基、5-12元芳杂环基各自独立地任选被一个或多个如下的取代基所取代：氢、卤素、氨基、羟基；
    R 11选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基各自独立地任选被一个或多个如下的取代基所取代：氢、卤素、氰基、氨基、羟基、C 1-6烷基；
    q选自1和2；
    r选自1、2和3；
    优选地，A环为苯基，所述苯基任选的被R范围内的一个或多个基团所取代，R范围的基团包括：氢、C 1-6烷基、卤代的C 1-6烷基、卤素、氰基；r选自1、2和3；
    更优选地，A环选自苯基和氯代苯基；
    进一步优选地，A环为苯基。
  5. 根据权利要求1或4所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，其中，
    B环选自C 3-8环烷基、氧代的C 3-8环烷基、5-12元脂杂环基和氧代的5-12元脂杂环基，其中，所述C 3-8环烷基、氧代的C 3-8环烷基、5-12元脂杂环基、氧代的5-12元脂杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；
    R 5范围的基团包括氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基、-OR d、-NR eR f、卤素、氰基、-C(O) qR 9、-C(O)NR eR f、-S(O) qR 9、-S(O) qNR eR f、-O-(C 2-6亚烷基-O) t-R d和-O-C 2-6亚烷基-NR eR f，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基各自独立地任选被K范围内的一个或多个基团所取代；
    K范围的基团包括氢、卤素、氰基、C 1-6烷基、-OR d、-NR eR f、-C(O) qR 10、-C(O)NR eR f、 -S(O) qR 10和-S(O) qNR eR f；
    R d、R e和R f各自独立地选自氢、-C(O) qR 11、-S(O) qR 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 6-10芳基、5-12元芳杂环基各自独立地任选被一个或多个如下的取代基所取代：氢、卤素、氨基、羟基；
    R 9、R 10、R 11各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基、5-12元芳杂环基各自独立地任选被一个或多个如下的取代基所取代：氢、卤素、氰基、氨基、羟基、C 1-6烷基；
    m选自1、2、3、4、5、6、7和8；
    q选自1和2；
    t选自1、2、3和4；
    优选地，B环选自C 3-8环烷基、氧代的C 3-8环烷基、氧代的5-8元脂杂环基和5-8元脂杂环基，其中，所述C 3-8环烷基、氧代的C 3-8环烷基、5-8元脂杂环基和氧代的5-8元脂杂环基各自独立地任选被R 5范围内的一个或多个基团所取代；R 5范围的基团包括氢、C 1-6烷基、卤代的C 1-6烷基、-OR d、-NR eR f和卤素，其中，R d、R e、R f各自独立地选自氢和C 1-6烷基；m选自1和2；
    更优选地，B环选自环戊烷基、氧代环戊烷基、2-吡咯烷酮基、氮杂环戊烷基和吡唑基，其中，所述环戊烷基、氧代环戊烷基、2-吡咯烷酮基、氮杂环戊烷基和吡唑基各自独立地任选被R 5范围内的一个或多个基团所取代；R 5范围的基团包括甲基、-OH、氨基、-NHCH 3和-N(CH 3) 2；m选自1和2。
  6. 根据权利要求1所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，其中，
    R 1选自
    Figure PCTCN2020083270-appb-100016
    Figure PCTCN2020083270-appb-100017
  7. 根据权利要求1至6中任一项所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，其中，
    R 3为-C(O)R 12；其中，
    R 12选自C 1-6烷基、C 2-6烯基、C 3-8环烷基、5-10元脂杂环基、C 6-10芳基、5-10元芳杂环基、C 3-8环烷基并C 6-10芳基、C 3-8环烷基并5-10元芳杂环基、5-10元脂杂环基并C 6-10芳基和5-10元脂杂环基并5-10元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 3-8环烷基、5-10元脂杂环基、C 6-10芳基、5-10元芳杂环基、C 3-8环烷基并C 6-10芳基、C 3-8环烷基并5-10元芳杂环基、5-10元脂杂环基并C 5-10芳基和5-10元脂杂环基并5-10元芳杂环基各自独立地任选被R 13范围内的一个或多个基团所取代；
    R 13范围的基团包括氢、氨基、卤素、-C(O)R 14、-OR j、C 1-6烷基、C 3-8环烷基、-C 1- 6亚烷基-(C 6-10芳基)、-C 1-6亚烷基-(5-10元芳杂环基)、C 6-10芳基和5-10元芳杂环基，其中，所述氨基、C 1-6烷基、C 3-8环烷基、-C 1-6亚烷基-(C 6-10芳基)、C 6-10芳基、5-10元芳杂环基和-C 1-6亚烷基-(5-10元芳杂环基)各自独立地任选被如下的一个或多个基团所取代：氢、卤素、C 1-6烷基、C 6-10芳基、任选被C 1-6烷基或卤素取代的5-10元芳杂环基；
    R 14选自氢、C 1-6烷基、C 3-8环烷基、5-10元脂杂环基、C 6-10芳基、5-10元芳杂环基和C 2-6烯基，其中，所述C 1-6烷基、C 2-6烯基、5-10元芳杂环基各自独立地任选被一个或多个如下的取代基所取代：卤素、C 1-6烷基、C 6-10芳基、任选被C 1-6烷基取代的5-10元芳杂环基；
    R j选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基，其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-12元脂杂环基、C 6-10芳基和5-12元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：氢、卤素、氨基、羟基、4-8元脂杂环基；
    优选地，R 3为-C(O)R 12；其中，
    R 12选自C 1-6烷基、C 3-8环烷基、5-10元脂杂环基、5-10元芳杂环基和5-10元脂杂环基并5-10元芳杂环基，其中，所述C 1-6烷基、C 3-8环烷基、5-10元脂杂环基、5-10元芳杂环基和5-10元脂杂环基并5-10元芳杂环基各自独立地任选被R 13范围内的一个或多个基团所取代；
    R 13范围的基团包括氨基、卤素、-C(O)R 14、-OR j、C 1-6烷基、C 3-8环烷基、-C 1-6亚烷基-(C 6-10芳基)、-C 1-6亚烷基-(5-10元芳杂环基)、C 6-10芳基和5-10元芳杂环基，其中，所述氨基、C 1-6烷基、C 3-8环烷基、-C 1-6亚烷基-(C 6-10芳基)、C 6-10芳基、5-10元芳杂环基和-C 1-6亚烷基-(5-10元芳杂环基)各自独立地任选被如下的一个或多个基团所取代：卤素、C 1-6烷基、C 6-10芳基、任选被C 1-6烷基或卤素取代的5-10元芳杂环基；
    R 14选自5-10元芳杂环基，5-10元芳杂环基任选被一个或多个如下的取代基所取代：C 1-6烷基、任选被C 1-6烷基取代的5-10元芳杂环基；
    R j为5-12元芳杂环基，5-12元芳杂环基任选被如下的一个或多个取代基所取代：氢、卤素、4-8元脂杂环基；
    更优选地，
    R 3为-C(O)R 12；其中，R 12选自
    Figure PCTCN2020083270-appb-100018
    Figure PCTCN2020083270-appb-100019
    进一步优选地，R 12选自
    Figure PCTCN2020083270-appb-100020
    Figure PCTCN2020083270-appb-100021
    Figure PCTCN2020083270-appb-100022
  8. 式Ⅱ所示的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物：
    Figure PCTCN2020083270-appb-100023
    其中，
    Y 1选自CH和N；
    Y 2选自C和N，且当Y 2为N时，R 16不存在；
    Y 3选自CH和N；
    Z 1选自CH和N；
    R 15选自氢、卤素、-C 1-6亚烷基-NR nR q、C 1-6烷氧基、羟基和5-12元脂杂环基，R 16选自氢、C 1-6烷氧基、5-12元脂杂环基和5-10元芳杂环基，其中，所述5-12元脂杂环基和5-10元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：羟基、C 1-6烷基、卤素；或者，R 15、R 16及与它们相连的芳基形成如下任一基团：C 6-12芳基并5-12元氧代环烷基、C 6-12芳基并5-12元环烷基、C 6-12芳基并5-10元脂杂环基、C 6-12芳基并氧代5-10元脂杂环基、C 6-12芳基并5-10元芳杂环基，其中，所述C 6-12芳基并5-12元氧代环烷基、C 6-12芳基并5-12元环烷基和C 6-12芳基并5-10元脂杂环基各自独立地任选被如下的一个或多个取代基所取代：-NR nR q、羟基、C 1-6烷基；
    R n和R q各自独立地选自H和C 1-6烷基；
    R 2选自氢、卤素和-CN；
    R 18为氢，Z 2为CH，R 19为C 6-12芳基或5-10元芳杂环基，其中，所述C 6-12芳基和5-10元芳杂环基各自独立地任选被一个或多个卤素所取代；或者，R 18、Z 1、Z 2及R 19形成如下任一基团：6-12元亚脂杂环基、5-10元亚芳杂环基、3-12元亚环烷基、5-10元芳杂环并6-12元亚脂杂环基，其中，所述6-12元亚脂杂环基、5-10元亚芳杂环基和3-12元亚环烷基各自独立地任选被如下的一个或多个取代基所取代：5-10元芳杂环基C 1-6亚烷基、取代的5-10元芳杂环基C 1-6亚烷基、取代的5-10元芳杂环基羰基、C 1-6烷基、取代的5-10元芳杂环基亚氨基、3-8元环烷基、5-10元芳杂环基氧基、取代的5-10元芳杂环基氧基、C 6-12芳基亚氨基，并且，所述取代为各自独立地被如下的一个或多个取代基取代：C 1-6烷基、C 1-6烷基5-10元亚芳杂环基、卤素、3-8元脂杂环基；
    R 17选自氢、C 1-6烷基、C 6-12芳基和C 6-12芳基C 1-6亚烷基，其中，所述C 1-6烷基和C 6- 12芳基C 1-6亚烷基各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1-6烷基。
  9. 根据权利要求8所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，其特征在于如下(A)至(F)中的任一项：
    (A)Y 1为CH，Y 2为C，Y 3为CH，Z 1为CH；
    (B)Y 1为CH，Y 2为C，Y 3为N，Z 1为CH；
    (C)Y 1为CH，Y 2为N，Y 3为N，Z 1为CH；
    (D)Y 1为N，Y 2为C，Y 3为CH，Z 1为CH；
    (E)Y 1为N，Y 2为C，Y 3为N，Z 1为CH；
    (F)Y 1为CH，Y 2为C，Y 3为CH，Z 1为N。
  10. 式Ⅲ所示的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物：
    Figure PCTCN2020083270-appb-100024
    其中，
    R 15选自氢、卤素、-C 1-6亚烷基-NR nR q、C 1-6烷氧基、羟基和5-12元脂杂环基，R 16选自氢、C 1-6烷氧基、5-12元脂杂环基和5-10元芳杂环基，其中，所述5-12元脂杂环基和5-10元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：羟基、C 1-6烷基、卤素；或者，R 15、R 16及与它们相连的苯基形成如下任一基团：C 6-12芳基并5-12元氧代环烷基、C 6-12芳基并5-12元环烷基、C 6-12芳基并5-10元脂杂环基、C 6-12芳基并氧代5-10元脂杂环基、C 6-12芳基并5-10元芳杂环基，其中，所述C 6-12芳基并5-12元氧代环烷基、C 6-12芳基并5-12元环烷基和C 6-12芳基并5-10元脂杂环基各自独立地任选被如下的一个或多个取代基所取代：-NR nR q、羟基、C 1-6烷基；
    R n和R q各自独立地选自H和C 1-6烷基；
    R 2选自氢、卤素和-CN；
    R 18为氢，Z 2为CH，R 19为C 6-12芳基或5-10元芳杂环基，其中，所述5-10元芳杂环基任选地被一个或多个卤素所取代；或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：6-12元亚脂杂环基、5-10元亚芳杂环基、3-12元亚环烷基、5-10元芳杂环并6-12元亚脂杂环基，其中，所述6-12元亚脂杂环基、5-10元亚芳杂环基和3-12元亚环烷基 各自独立地任选被如下的一个或多个取代基所取代：5-10元芳杂环基C 1-6亚烷基、取代的5-10元芳杂环基C 1-6亚烷基、取代的5-10元芳杂环基羰基、C 1-6烷基、取代的5-10元芳杂环基亚氨基、3-8元环烷基、5-10元芳杂环基氧基、取代的5-10元芳杂环基氧基、C 6-12芳基亚氨基，并且，所述取代为各自独立地被如下的一个或多个取代基取代：C 1-6烷基、C 1-6烷基5-10元亚芳杂环基、卤素、3-8元脂杂环基；
    R 17选自氢、C 1-6烷基、C 3-8环烷基、C 6-12芳基和C 6-12芳基C 1-6亚烷基，其中，所述C 1-6烷基和C 6-12芳基C 1-6亚烷基各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1-6烷基。
  11. 根据权利要求8至10中任一项所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，其中，
    R 15选自氢、卤素、-C 1-6亚烷基-NH 2、-C 1-6亚烷基-NH-C 1-6烷基、-C 1-6亚烷基-N(C 1-6烷基) 2、C 1-6烷氧基、羟基和5-10元脂杂环基，其中，所述5-10元脂杂环基任选地被如下的一个或多个取代基所取代：羟基、C 1-6烷基；R 16选自氢、C 1-6烷氧基、6-12元脂杂环基和5-10元芳杂环基，其中，所述6-12元脂杂环基和5-10元芳杂环基各自独立地任选被如下的一个或多个取代基所取代：C 1-6烷基、卤素；或者，R 15、R 16及与它们相连的苯基形成如下任一基团：茚酮基、苯并5-12元环烷基、苯并5-10元脂杂环基、苯并氧代5-10元脂杂环基、苯并5-10元芳杂环基，其中，所述茚酮基、苯并5-12元环烷基和苯并5-10元脂杂环基各自独立地任选被如下的一个或多个取代基所取代：C 1-6伯胺基、羟基、氨基、C 1-6仲胺基、C 1-6烷基；
    优选地，R 15选自氢、卤素、NH 2-C 1-6亚烷基-、CH 3-NH-C 1-6亚烷基-、(CH 3) 2N-C 1-6亚烷基-、C 1-6烷氧基、羟基和吡咯烷基，其中，所述吡咯烷基任选地被如下的一个或多个取代基所取代：羟基、C 1-6烷基；R 16选自氢、C 1-6烷氧基、哌嗪基、吡唑基和N-吗啉基，其中，所述哌嗪基和吡唑基各自独立地任选被如下的一个或多个取代基所取代：C 1-6烷基、卤素；或者，R 15、R 16及与它们相连的苯基形成如下任一基团：1-茚酮基、苯并环戊烷基、苯并吡咯烷基、2-茚酮基、苯并吡咯烷酮基、苯并吡唑基，其中，所述苯并环戊烷基任选地被如下的一个或多个取代基所取代：C 1-6伯胺基、羟基、氨基、C 1-6仲胺基、C 1-6烷基；
    更优选地，R 15选自氢、氟、氯、NH 2CH 2-、CH 3NHCH 2-、(CH 3) 2NCH 2-、甲氧基、羟基和
    Figure PCTCN2020083270-appb-100025
    R 16选自氢、甲氧基、
    Figure PCTCN2020083270-appb-100026
    或者，R 15、R 16及与它们相连的苯基形成如下任一基团：
    Figure PCTCN2020083270-appb-100027
    Figure PCTCN2020083270-appb-100028
    进一步优选地，R 15选自NH 2CH 2-、羟基、氟、甲氧基和
    Figure PCTCN2020083270-appb-100029
    R 16选自氢和甲氧 基；或者，R 15、R 16及与它们相连的苯基形成如下任一基团：
    Figure PCTCN2020083270-appb-100030
    Figure PCTCN2020083270-appb-100031
    更进一步优选地，R 15为NH 2CH 2-或羟基，R 16为氢；或者，R 15、R 16及与它们相连的苯基形成如下任一基团：
    Figure PCTCN2020083270-appb-100032
    更加优选地，R 15为NH 2CH 2-，R 16为氢；或者，R 15、R 16及与它们相连的苯基形成如下任一基团：
    Figure PCTCN2020083270-appb-100033
  12. 根据权利要求1至11中任一项所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，其中，
    R 2选自氢、氰基、卤素和C 1-3烷基；
    优选地，R 2选自氢、氯和-CN；
    更优选地，R 2为氢。
  13. 根据权利要求8至12中任一项所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，其中，
    R 18为氢，Z 2为CH，R 19为C 6-12芳基或5-10元芳杂环基，其中，所述C 6-12芳基和5-10元芳杂环基各自独立地任选被一个或多个卤素所取代；或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：6-12元亚脂杂环基、5-10元亚芳杂环基、3-12元亚环烷基、5-10元芳杂环并6-12元亚脂杂环基，其中，所述6-12元亚脂杂环基、5-10元亚芳杂环基和3-12元亚环烷基各自独立地任选被如下的一个或多个取代基所取代：5-10元芳杂环基C 1-6亚烷基、取代的5-10元芳杂环基C 1-6亚烷基、取代的5-10元芳杂环基羰基、C 1- 6烷基、取代的5-10元芳杂环基亚氨基、3-8元环烷基、5-10元芳杂环基氧基、取代的5-10元芳杂环基氧基、C 6-12芳基亚氨基，并且，所述取代为各自独立地被如下的一个或多个取代基取代：C 1-6烷基、C 1-6烷基亚吡啶基、卤素、氮杂环丁烷基；
    优选地，R 18为氢，Z 2为CH，R 19为苯基或吡唑基，其中，所述苯基和吡唑基各自独立地任选被一个或多个卤素所取代；或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：亚哌啶基、亚吡唑基、亚吡咯基、亚异恶唑基、亚环己烷基、亚异噻唑基、亚环丙烷基、亚恶唑基、吡唑并亚哌啶基，其中，所述亚哌啶基、亚吡唑基、亚异恶唑基、亚环己烷基、亚异噻唑基、亚环丙烷基和亚恶唑基各自独立地任选被如下的一个或多个取 代基所取代：吡嗪基C 1-6亚烷基、
    Figure PCTCN2020083270-appb-100034
    C 1-6烷基、
    Figure PCTCN2020083270-appb-100035
    环丙烷基、
    Figure PCTCN2020083270-appb-100036
    Figure PCTCN2020083270-appb-100037
    更优选地，R 18为氢，Z 2为CH，R 19选自苯基、
    Figure PCTCN2020083270-appb-100038
    其中，所述苯基任选地被一个卤素取代；或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：
    Figure PCTCN2020083270-appb-100039
    Figure PCTCN2020083270-appb-100040
    进一步优选地，R 18为氢，Z 2为CH，R 19选自苯基、
    Figure PCTCN2020083270-appb-100041
    或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：
    Figure PCTCN2020083270-appb-100042
    Figure PCTCN2020083270-appb-100043
    更进一步优选地，R 18为氢，Z 2为CH，R 19为苯基或
    Figure PCTCN2020083270-appb-100044
    或者，R 18、Z 2、R 19及与R 18相连的碳原子形成如下任一基团：
    Figure PCTCN2020083270-appb-100045
    更加优选地，R 18为氢，Z 2为CH，R 19为苯基或
    Figure PCTCN2020083270-appb-100046
  14. 根据权利要求8至13中任一项所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，其中，
    R 17选自氢、C 1-6烷基、C 3-8环烷基、C 6-12芳基和C 6-12芳基C 1-6亚烷基，其中，所述C 1-6烷基和C 6-12芳基C 1-6亚烷基各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1-6烷基；
    优选地，R 17选自氢、C 1-6烷基、苯基和苯基C 1-6亚烷基，其中，所述C 1-6烷基和苯基C 1-6亚烷基各自独立地任选被如下的一个或多个取代基所取代：卤素、C 1-6烷基；
    更优选地，R 17选自氢、甲基、二氟甲基、环丙基、苯基、苄基、
    Figure PCTCN2020083270-appb-100047
    和三氟甲基；
    进一步优选地，R 17选自甲基、二氟甲基、苯基和苄基。
    更进一步优选地，R 17选自甲基和二氟甲基。
  15. 根据权利要求1至14中任一项所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，其中，所述化合物选自：
    Figure PCTCN2020083270-appb-100048
    Figure PCTCN2020083270-appb-100049
    Figure PCTCN2020083270-appb-100050
    Figure PCTCN2020083270-appb-100051
    Figure PCTCN2020083270-appb-100052
    优选地，所述化合物选自：
    Figure PCTCN2020083270-appb-100053
    Figure PCTCN2020083270-appb-100054
  16. 一种药物组合物，其包含权利要求1至15中任一项所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，以及任选的药用辅料；
    优选地，所述药物组合物还包含抑制去泛素化酶USP7活性的其它有效成分或者预防或治疗癌症的其它有效成分。
  17. 权利要求1至15中任一项所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物或者权利要求16所述的药物组合物在抑制去泛素化酶USP7的活性中的用途。
  18. 一种在体外抑制去泛素化酶USP7活性的方法，包括将权利要求1至15中任一项所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物或者权利要求16所述的药物组合物作用于受试体。
  19. 一种预防或治疗癌症的方法，包括将权利要求1至15中任一项所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，或者权利要求16所述的药物组合物施用于有需求的受试者；
    优选地，所述癌症选自肝细胞癌、多发性骨髓瘤、结肠癌、肺癌、前列腺癌和膀胱癌中的至少一种。
  20. 权利要求1至15中任一项所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物，或者权利要求16所述的药物组合物，用于抑制去泛素化酶USP7或者预防或治疗癌症；
    优选地，所述癌症选自肝细胞癌、多发性骨髓瘤、结肠癌、肺癌、前列腺癌和膀胱 癌中的至少一种。
  21. 权利要求1至15中任一项所述的化合物、其可药用盐、酯、溶剂化物、立体异构体、互变异构体、前药、任意晶型、代谢物或它们的混合物或者权利要求16所述的药物组合物在制备去泛素化酶USP7抑制剂或者在制备预防或治疗癌症的药物中的用途；优选地，所述癌症选自肝细胞癌、多发性骨髓瘤、结肠癌、肺癌、前列腺癌和膀胱癌中的至少一种。
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WO2016109480A1 (en) * 2014-12-30 2016-07-07 Forma Therapeutics, Inc. Pyrrolotriazinone and imidazotriazinone derivatives as ubiquitin-specific protease 7 (usp7) inhibitors for the treatment of cancer
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