WO2023116390A1 - 具有mat2a抑制活性的嘧啶-2（1h）-酮并二环类化合物及其用途 - Google Patents

具有mat2a抑制活性的嘧啶-2（1h）-酮并二环类化合物及其用途 Download PDF

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WO2023116390A1
WO2023116390A1 PCT/CN2022/136109 CN2022136109W WO2023116390A1 WO 2023116390 A1 WO2023116390 A1 WO 2023116390A1 CN 2022136109 W CN2022136109 W CN 2022136109W WO 2023116390 A1 WO2023116390 A1 WO 2023116390A1
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substituted
unsubstituted
compound
alkyl
cycloalkyl
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李征
郭红亮
杨君宇
屠汪洋
于冰
张毅翔
李乐平
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上海海和药物研究开发股份有限公司
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Priority to CN202280069707.0A priority Critical patent/CN118119625A/zh
Publication of WO2023116390A1 publication Critical patent/WO2023116390A1/zh

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • 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
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    • A61P35/00—Antineoplastic agents
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    • 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
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a pyrimidin-2(1H)-ketobicyclic compound, its stereoisomer or a pharmaceutically acceptable salt thereof, and its use for preparing a MAT2A inhibitor for treating and/or preventing tumors.
  • Cancer treatment is a huge challenge facing the world today.
  • existing common therapies such as chemotherapy and immunotherapy
  • the biggest problem is that the cell killing effect often not only targets cancer cells, but also has great side effects on normal cells and tissues. Therefore, there is an urgent need to develop new therapeutic approaches to better target cancer cells.
  • Synthetic lethality is defined as deletion of two or more genes that results in cell death, whereas deletion of any one of these genes alone has no effect.
  • Synthetic lethality is defined as deletion of two or more genes that results in cell death, whereas deletion of any one of these genes alone has no effect.
  • a large number of studies have shown that there are multiple genetic mutations in cancer cells that make them more sensitive to synthetic lethal treatments. These tumor-specific genetic mutations can prompt us to use appropriate targeted therapy drugs to kill cancer cells, while having no effect on normal cells.
  • Methionine adenosyltransferase 2A is a kind of enzyme that can catalyze the reaction between methionine (Met) and ATP to generate S-adenosylmethionine (S-Adenosyl-L-methionine).
  • SAM S-adenosylmethionine
  • SAM is the main methyl donor in the body, which can regulate the expression of genes through the transmethylation reaction of DNA, RNA and protein, and then have an important impact on cell differentiation, growth and death.
  • Arginine N-methyltransferase 5 PRMT5 is a methylase that uses SAM as a methyl donor.
  • SAM is essential for the activity of PRMT5, and methylthioadenosine (5'methylthioadenosine, MTA) can inhibit the activity of PRMT5.
  • MTA is the product of the methionine compensation pathway, which is catalyzed by methylthioadenosine phosphorylase (MTAP) to generate 5-methylthioribose-1-phosphate and adenine in the cell and maintained at a low level. level.
  • the MTAP gene is located on chromosome 9, which is deleted in the cells of various cancer patients, including pancreatic cancer, esophageal cancer, bladder cancer and lung cancer (cBioPortal database). Loss of MTAP leads to enrichment of intracellular MTA, making these cells more dependent on SAM production and MAT2A activity than normal cells. Studies have shown that inhibiting the expression of MAT2A in MTAP-deficient cancer cells can selectively inhibit cell viability compared with MTAP-normal cancer cells (McDonald et.al., 2017 Cell 170, 577-592).
  • MAT2A inhibitors may provide a new and effective therapeutic approach for cancer patients, especially those whose tumors contain MTAP deletion.
  • the present invention provides the compound of formula (I), its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutical composition and combination thereof.
  • the inventors have surprisingly found that the compounds of formula (I) are good MAT2A inhibitors.
  • X 1 is CR 3 or N
  • X 2 is CR 4 or N
  • X 3 is CR 5 or N
  • X 4 is CR 6 or N
  • at most two of X 1 , X 2 , X 3 , and X 4 are simultaneously N;
  • R 3 , R 4 , R 5 , R 6 are independently selected from H, D, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfonyl, C 3 -C 7 cycloalkyl, cyano, hydroxyl, mercapto, C 1 -C 6 alkylamino, amino, nitro, carboxyl, NHCOR a ,
  • the alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl are unsubstituted or optionally substituted by one or more substituents selected from D and halogen, and R a is selected from C 1 -C 10 Alkyl, C 3 -C 10 cycloalkyl;
  • R 3 , R 4 , R 5 , and R 6 are each independently selected from H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 alkoxy, C 3 -C 7 cycloalkyl, cyano, hydroxyl, amino, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl are unsubstituted or optionally replaced by one or Multiple substituents selected from D and halogen are substituted;
  • R 3 , R 5 , R 6 are each independently selected from H and halogen, and R 4 is selected from H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, cyano, hydroxyl, amino, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl are unsubstituted or optionally substituted with one or more substituents selected from D, halogen;
  • R 3 , R 5 , and R 6 are all H, and R 4 is selected from H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, cyano, hydroxyl, amino, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl are unsubstituted or optionally replaced by one Or a plurality of substituents selected from D and halogen are substituted;
  • X 1 is CH or N
  • X 2 is CR 4 or N
  • X 3 is CH or N
  • X 4 is CH or N
  • at most two of X 1 , X 2 , X 3 , and X 4 are N at the same time;
  • the R 4 is selected from F, Cl, Br, CH 3 , CD 3 , CF 3 , CF 2 H, CF 2 D, OH, SH, NH 2 , CN, OCH 3 , CH 3 CH 2 , -CH 2 CH 2 CH 3 , cyclopropyl, -CH 2 ( CH 3 )CH 3 , NO 2 .
  • At most one of X 1 , X 2 , X 3 , X 4 is N.
  • X 1 is CR 3
  • X 2 is CR 4
  • X 3 is CR 5
  • X 4 is CR 6
  • R 3 , R 4 , R 5 , and R 6 are as defined above.
  • W is selected from O, NR b , S, CHR b ;
  • the R b is selected from H, D, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and the alkyl and cycloalkyl are unsubstituted Or be substituted by one or more substituents selected from D, halogen, -OH;
  • the R b is selected from H, D, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl , the alkyl and cycloalkyl are unsubstituted or substituted by one or more substituents selected from halogen, -OH;
  • the R b is selected from H, D, methyl, ethyl, N-propyl, isopropyl, cyclopropyl, cyclobutyl, wherein methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cycl
  • W is selected from O, NH, NCH 3 , NC 2 H 4 OH, NCH(CH 3 ) 2 , NC 2 H 5 , S, CH 2 ;
  • R 1 is selected from unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, wherein, the substitution described in R1 refers to being substituted by one or more substituents selected from Group A, and Group A substituents include: halogen, CN, OH, oxo, SH, NH 2 , NO 2 , C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl (such as CF 3 , CF 2 H), COOH , CONHR c , NHCOR c , NHSO 2 R c , R c is selected from H, C 1 -C 4 alkyl, C 3 -C 10
  • R 1 is selected from unsubstituted or substituted phenyl, unsubstituted or substituted C 3 -C 7 cycloalkyl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5- 10-membered heteroaryl, wherein, the replacement described in R 1 and the limitations of heteroaryl and heterocycloalkyl are as above;
  • R 1 is selected from unsubstituted or substituted phenyl, unsubstituted or substituted C 3 -C 7 cycloalkyl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5- 10-membered heteroaryl, wherein, the substitution in R1 refers to being substituted by one or more substituents selected from Group A, and the substituents in Group A include: halogen, CN, OH, oxo, SH, NH2 , NO 2 , C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl (such as CF 3 , CF 2 H), the hetero Aryl and heterocycloalkyl contain one or more heteroatoms selected from N, O and S respectively;
  • R 1 is selected from unsubstituted or substituted phenyl, unsubstituted or substituted C 3 -C 7 cycloalkyl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5- 10-membered heteroaryl; the 5-10-membered heteroaryl is selected from the following groups:
  • said R 1 is selected from
  • R 10 and R 11 are each independently selected from halogen, CN, OH, SH, NH 2 , C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, COOH, CONH 2 , CONHR c , NHCOR c , R c is selected from unsubstituted or substituted C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy or phenyl.
  • said R 1 is selected from
  • R 2 is selected from NR 7 R 8 , -OR 9 , or -SR 9 ;
  • R 7 , R 8 , and R 9 are each independently selected from H, D, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C 3 -C 7 cycloalkyl, unsubstituted or substituted C 5 -C 10 aryl, unsubstituted or Substituted 3-7 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, -NHCO-(C 1 -C 6 alkyl), -NHSO 2 -(C 1 -C 6 alkyl) ; Wherein, the substitution described in R 7 , R 8 , and R 9 refers to being substituted by one or more substituents selected from the following group
  • R 7 , R 8 together with their connected N atoms form a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more substituents selected from the following: OH, halogen, C 1 -C 10 alkane Group, C 3 -C 10 cycloalkyl;
  • heteroaryl group and heterocycloalkyl group respectively contain one or more heteroatoms selected from N, O and S.
  • R 2 is selected from NR 7 R 8 , -OR 9 , or -SR 9 ;
  • R 7 , R 8 , and R 9 are each independently selected from H, unsubstituted or substituted C 1 -C 3 alkyl, unsubstituted or substituted C 1 -C 3 alkoxy, unsubstituted or substituted C 3 - C 7 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, -NHCO-(C 1 -C 3 Alkyl), -NHSO 2 -(C 1 -C 3 alkyl); Wherein, the substitution in R 7 , R 8 , R 9 refers to being substituted by one or more substituents selected from the following groups: halogen, -NHR d , -N(R d ) 2 , -OR d , -SR d , C 1 -C 3 alkyl unsubstituted or
  • R 7 , R 8 together with their connected N atoms form a 5-6 membered heterocycloalkyl group that is unsubstituted or substituted by one or more substituents selected from the following: OH, halogen, C 1 -C 3 alkane Group, C 3 -C 6 cycloalkyl;
  • heteroaryl group and heterocycloalkyl group respectively contain one or more heteroatoms selected from N, O and S.
  • R 2 is selected from NH 2 ,
  • X 1 is CR 3 or N
  • X 2 is CR 4 or N
  • X 3 is CR 5 or N
  • X 4 is CR 6 or N
  • R 3 , R 5 , R 6 are each independently selected from H and halogen
  • R 4 is selected from H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, cyano, hydroxyl, amino, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl are unsubstituted or optionally replaced by One or more substituents selected from D and halogen are substituted;
  • W is selected from O, NH, NCH 3 , NC 2 H 4 OH, NCH(CH 3 ) 2 , NC 2 H 5 , S, CH 2 ;
  • R 1 is selected from unsubstituted or substituted phenyl, unsubstituted or substituted C 3 -C 7 cycloalkyl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heterocycloalkyl, Aryl; the 5-10 membered heteroaryl is selected from the following groups:
  • R 1 refers to being substituted by one or more substituents selected from group A;
  • substituents in group A include: halogen, CN, OH, oxo, SH, NH 2 , NO 2 , C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl (such as CF 3 , CF 2 H), COOH, CONHR c , NHCOR c , NHSO 2 R c , R c is selected from H, C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy or C 6 -C 10 aryl, wherein C in R c 1 -C 4 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, C 6 -C 10 aryl are unsubstituted or are selected from one or more
  • R 2 is selected from NR 7 R 8 , -OR 9 , or -SR 9 ;
  • R 7 , R 8 , and R 9 are each independently selected from H, unsubstituted or substituted C 1 -C 3 alkyl, unsubstituted or substituted C 1 -C 3 alkoxy, unsubstituted or substituted C 3 - C 7 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, -NHCO-(C 1 -C 3 Alkyl), -NHSO 2 -(C 1 -C 3 alkyl); Wherein, the substitution in R 7 , R 8 , R 9 refers to being substituted by one or more substituents selected from the following groups: halogen, -NHR d , -N(R d ) 2 , -OR d , -SR d , C 1 -C 3 alkyl unsubstituted or
  • R 7 , R 8 together with their connected N atoms form a 5-6 membered heterocycloalkyl group that is unsubstituted or substituted by one or more substituents selected from the following: OH, halogen, C 1 -C 3 alkane Group, C 3 -C 6 cycloalkyl;
  • heteroaryl group and heterocycloalkyl group respectively contain one or more heteroatoms selected from N, O and S.
  • the compound represented by formula (I) is represented by the following formula I-A,
  • W, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are respectively as above.
  • the compound represented by formula (I) is represented by the following formula I-A,
  • W is selected from O, NR b , S, CHR b ; said R b is selected from H, D, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, said alkyl and cycloalkyl Unsubstituted or substituted by one or more substituents selected from D, halogen, -OH;
  • R 3 , R 5 , R 6 are each independently selected from H and halogen
  • R 4 is selected from H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, cyano, hydroxyl, amino, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl are unsubstituted or optionally replaced by One or more substituents selected from D and halogen are substituted;
  • R 1 is selected from unsubstituted or substituted phenyl, unsubstituted or substituted C 3 -C 7 cycloalkyl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heterocycloalkyl, Aryl, wherein, the substitution mentioned in R 1 refers to being substituted by one or more substituents selected from group A, group A substituents include: halogen, CN, OH, oxo, SH, NH 2 , NO 2 , C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl;
  • R 2 is selected from NR 7 R 8 , -OR 9 , or -SR 9 ;
  • R 7 , R 8 , and R 9 are each independently selected from H, unsubstituted or substituted C 1 -C 3 alkyl, unsubstituted or substituted C 1 -C 3 alkoxy, unsubstituted or substituted C 3 - C 7 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, -NHCO-(C 1 -C 3 Alkyl), -NHSO 2 -(C 1 -C 3 alkyl); Wherein, the substitution in R 7 , R 8 , R 9 refers to being substituted by one or more substituents selected from the following groups: halogen, -NHR d , -N(R d ) 2 , -OR d , -SR d , C 1 -C 3 alkyl unsubstituted or
  • R 7 , R 8 together with their connected N atoms form a 5-6 membered heterocycloalkyl group that is unsubstituted or substituted by one or more substituents selected from the following: OH, halogen, C 1 -C 3 alkane Group, C 3 -C 6 cycloalkyl;
  • heteroaryl group and heterocycloalkyl group respectively contain one or more heteroatoms selected from N, O and S.
  • the compound represented by the described formula (I) of the present invention can specifically be selected from the following structures:
  • the present invention also provides a composition comprising at least one compound represented by formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical preparation, comprising a therapeutically effective amount of a compound represented by formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and diluents or excipients.
  • a pharmaceutical preparation comprising a therapeutically effective amount of a compound represented by formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and diluents or excipients.
  • the invention provides a combination, especially a pharmaceutical combination, comprising a therapeutically effective amount of a compound of the invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents.
  • the compounds according to the invention can be used alone, in combination with other compounds according to the invention or in combination with one or more, preferably one or two other substances, simultaneously or sequentially.
  • the present invention also provides the compound described in formula (I), its stereoisomer or its pharmaceutically acceptable salt, or the composition containing it, the pharmaceutical preparation, and the pharmaceutical combination in the preparation of treatment and/or prevention of tumor use in medicines.
  • the tumors include: MTAP-deficient tumors; MTAP low-expression tumors; MAT2A abnormal expression tumors; other MAT2A-dependent tumors.
  • the tumors include: breast cancer, lung cancer, glioblastoma, brain and spine cancer, head and neck cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, Rectal cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumors, germ cell Tumors, malignant neuroendocrine tumors, malignant rhabdoid tumors, soft tissue sarcomas, midline bundle carcinomas, and carcinomas of unknown primary.
  • the present invention provides a method for treating or preventing MAT2A-related tumors, the method comprising administering an effective amount of a first therapeutic agent and an optional second therapeutic agent to a patient in need thereof, wherein said first therapeutic agent is a compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and said second therapeutic agent is one or more other therapeutic agents.
  • the present invention provides a product or kit comprising a compound of the present invention as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and one or more other active agents simultaneously, separately or Combination preparations used sequentially.
  • a dash ("-") not between two letters or symbols indicates the point of attachment of a substituent.
  • -O(C 1 -C 3 alkyl) means that the group is attached to the rest of the molecule through an oxygen atom.
  • "-" can be omitted.
  • the wavy line indicates where the group is attached to the rest of the molecule.
  • heteroatom refers to a nitrogen (N), oxygen (O) or sulfur (S) atom, especially nitrogen or oxygen, each of which may be substituted or unsubstituted, including oxidized forms thereof.
  • halogen refers to fluoro, chloro, bromo and iodo. Preferred halogens as substituents are fluorine and chlorine.
  • alkyl refers to a fully saturated straight or branched chain monovalent hydrocarbon group.
  • the alkyl group preferably contains 1-20 carbon atoms, more preferably 1-16 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms or 1- 3 carbon atoms.
  • the number before the alkyl indicates the number of carbon atoms.
  • C 1 -C 6 alkyl means an alkyl group with 1-6 carbon atoms
  • C 1 -C 4 alkyl means an alkyl group with 1-4 carbon atoms
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, Base, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. This definition applies whether the term "alkyl" appears by itself or as part of another group such as haloalkyl, alkoxy, etc.
  • alkenyl refers to a linear or branched monovalent hydrocarbon group containing at least one double bond.
  • the alkenyl group preferably contains 2-20 carbon atoms, more preferably 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms or 2-4 carbon atoms.
  • the number before the alkenyl group indicates the number of carbon atoms.
  • Representative examples of alkenyl include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, heptenyl, octenyl, and the like.
  • alkynyl refers to a linear or branched monovalent hydrocarbon group comprising at least one triple bond.
  • the alkynyl group preferably contains 2-20 carbon atoms, more preferably 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms or 2-4 carbon atoms. The number before the alkynyl group indicates the number of carbon atoms.
  • alkynyl include, but are not limited to, ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, isopentynyl, hexynyl, heptynyl, octynyl Base etc.
  • alkoxy refers to an alkyl group as defined herein attached through an oxygen bridge, ie, an alkyl-O- group, the number preceding the alkoxy group indicating the number of carbon atoms.
  • C 1- C 6 alkoxy means an alkoxy group with 1-6 carbon atoms, namely -OC 1-6 alkyl
  • C 1- C 4 alkoxy means an alkoxy group with 1-4
  • C 1- C 3 alkoxy means an alkoxy group with 1-3 carbon atoms, that is -OC 1-3 alkyl.
  • alkoxy examples include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.
  • the alkoxy group contains about 1-6 carbons, or about 1-4 carbons, etc.
  • cycloalkyl refers to a saturated or partially saturated non-aromatic carbocyclic ring, including mono-, bi- or tricyclic, preferably having 3-12 ring carbon atoms, more preferably 3-10 ring carbon atoms , such as 3-8, 3-7, 3-6, 4-10, or 4-8 ring carbon atoms.
  • C 3 -C 8 cycloalkyl is intended to include C 3 , C 4 , C 5 , C 6 , C 7 and C 8 cycloalkyl groups;
  • C 3 -C 6 cycloalkyl is intended to include C 3 , C 4 , C 5 and C 6 cycloalkyl groups; and so on.
  • Exemplary monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like.
  • Exemplary bicyclic cycloalkyls include bornyl, tetrahydronaphthyl, decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptene base, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, etc.
  • Exemplary tricyclic cycloalkyls include adamantyl and the like.
  • haloalkyl refers to a group wherein one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms, such as 1, 2 or 3 hydrogen atoms, are replaced by a halogen as described herein alkyl as defined, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same or different from each other.
  • C 1 -C 4 haloalkyl is intended to include C 1 , C 2 , C 3 and C 4 haloalkyl groups
  • C 1 -C 3 haloalkyl is intended to include C 1 , C 2 and C 3 haloalkyl groups group.
  • haloalkyl examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 1,1-difluoroethyl, 1,1,-difluoropropyl, and 1,1, 1-Trifluoropropyl.
  • fluoroalkyl also include "fluoroalkyl", which is intended to include an alkyl group as defined herein wherein one or more hydrogen atoms are replaced by a fluorine atom.
  • Haloalkyl herein is preferably an alkyl group in which up to three hydrogen atoms are replaced by halogen.
  • haloalkoxy means a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge, wherein one or more hydrogen atoms, for example 1, 2, 3, 4, 5, 6 or 7 Hydrogen atoms, eg 1, 2 or 3 hydrogen atoms are replaced by halogen.
  • C 1 -C 6 haloalkoxy or “C 1 to C 6 haloalkoxy” is intended to include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 haloalkoxy groups.
  • haloalkoxy examples include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy. Examples of haloalkoxy also include "fluoroalkoxy”.
  • aryl is composed of one or more rings condensed and has 6-20, preferably 6-14, more preferably 6-12, most preferably 6-10, for example 6-9
  • Preferred aryl groups are aryl groups having 6-10 ring carbon atoms, i.e.
  • C 6 -C 10 aryl groups which include: monocyclic aryl groups (such as phenyl); or fused bicyclic ring systems in which one ring is An aromatic ring, while the other ring is aromatic (eg in naphthalene, biphenyl) or non-aromatic (eg in indene, tetrahydronaphthalene).
  • aryl groups include phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indenyl, indenyl, or anthracenyl, and the like.
  • heteroaryl refers to 5-14 ring heteroatoms containing 1-8, preferably 1-4, more preferably 1-3, more preferably 1 or 2 ring heteroatoms selected from N, O or S member, preferably 5-10 member, more preferably 5-7 member or 5-6 member aromatic ring system, including monocyclic or bicyclic or fused polycyclic rings, and the remaining ring atoms are carbon atoms.
  • Heteroaryl is preferably 5-10 membered heteroaryl, more preferably 5-7 membered heteroaryl or 5-6 membered heteroaryl, each containing 1, 2 or 3 ring heteroaryls selected from N, O or S atom.
  • heteroaryl groups include, but are not limited to: pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridyl, pyranyl, pyrazine Base, pyridazinyl, pyrimidinyl, oxazinyl, oxadiazinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzoxazinyl, 2H-color Alkenes, benzopyranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, 7-azaindolyl, 6-azaindyl Indolyl, 5-azaindolyl, 4-azaindolyl, 1H
  • heterocycloalkyl is a monocyclic, bicyclic or tricyclic saturated ring having 3-20 ring atoms, such as 3-12 ring atoms, such as 3-8 ring atoms, such as 3-6 ring atoms and partially unsaturated nonaromatic rings.
  • heterocycloalkyl is preferably 4- to 12-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, preferably 4- to 8-membered heterocycloalkyl, More preferred is 4- to 7-membered, 4- to 6-membered or 5- to 6-membered heterocycloalkyl, wherein the heteroatoms are substituted or unsubstituted, for example substituted by C 1 -C 4 alkyl.
  • heterocycloalkyl groups include, but are not limited to: oxiranyl, aziridinyl, azetidinyl, oxetanyl, aziridinyl (pyrrolidinyl), Tetrahydrofuryl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, pyrazolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, pyrrolidinyl-2-one , imidazolone, piperidinyl (hexahydropyridine), N-methylpiperidinyl, tetrahydropyranyl, oxazinyl, 1,3-oxazinyl, hexahydropyrimidinyl, piperazinyl , piperidinylone (piperidinylone), 1,4-dioxa-8-aza-s
  • partially or fully saturated heterocyclic ring refers to a partially or fully hydrogenated non-aromatic ring, which may exist as a monocyclic ring, bicyclic ring (including fused rings), or a spiro ring.
  • spirocycles examples include 2,6-diazaspiro[3.3]heptanyl, 3-azaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl, and the like.
  • Partially saturated heterocycles include such as dihydropyrrolyl, dihydrofuranyl, dihydrooxazolyl, dihydropyridyl, imidazolinyl, 1H-dihydroimidazolyl, 2H-pyranyl, 2H-chromenyl , Dihydrooxazinyl and other groups.
  • Partially saturated heterocycles also include heterocycles having fused aryl or heteroaryl rings, preferably having 9-10 ring members (e.g.
  • dihydrobenzofuranyl dihydroisobenzofuranyl, indoline Indolyl (or 2,3-dihydroindolyl), dihydrobenzothienyl, dihydrobenzothiazolyl, dihydrobenzopyranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, Tetrahydropyrido[3,4-b]pyrazinyl, etc.).
  • optionally substituted alkyl includes “unsubstituted alkyl” and “substituted alkyl” as defined herein.
  • Optionally substituted by halogen includes the case of "substituted by halogen” and the case of "not substituted by halogen", for example, substituted by 0-3 halogens.
  • ring structure When a dotted ring is used in a ring structure, this means that the ring structure may be saturated, partially saturated or unsaturated.
  • substituted means that one or more hydrogen atoms on a given atom or group are replaced by one or more hydrogen atoms selected from a given group of substituents Substitution of radicals, provided that the normal valence of the given atom is not exceeded.
  • two hydrogen atoms on a single atom are replaced by oxygen.
  • a chemically correct and stable compound means that the compound is sufficiently stable that it can be isolated from a reaction mixture and the chemical structure of the compound can be determined, and subsequently formulated into a preparation that is at least practical.
  • substituted means one or more hydrogen atoms on a given atom or group independently substituted by one or more, eg 1, 2, 3 or 4 substituents.
  • substituents may be the same or different.
  • the term "compound of the present invention” or “compound of the present invention” refers to one or more formula (I) or subforms thereof as defined herein, such as formula (I-1), ( The compound of I-2), or a pharmaceutically acceptable salt thereof, and all isomers such as stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, Conformational isomers (including rotamers and atropisomers), tautomers, internal addition products of isomers, prodrugs, and isotopically labeled compounds (including deuterium substitutions) and inherently formed moieties (eg polymorphs, solvates and/or hydrates).
  • isomers such as stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, Conformational isomers (including rotamers and atropisomers), tautomers, internal addition products of isomers, prodrugs, and isotopically labeled compounds (including deuter
  • Salts especially pharmaceutically acceptable salts, are also included when moieties capable of forming salts are present.
  • the presence of tautomers or internal addition products of isomers can be identified by those skilled in the art using tools such as NMR.
  • Compounds of formula (I) of the present invention are capable of readily forming internal addition products of tautomers and isomers as depicted herein.
  • enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other.
  • a 1:1 mixture of a pair of enantiomers is a “racemic” mixture.
  • the term is used to denote a racemic mixture, where appropriate.
  • the conventional RS system is used to designate a single stereoisomer with known relative and absolute configuration of two chiral centers (e.g.
  • Resolved compounds of unknown absolute configuration can be assigned (+) or (-) according to the direction (dextrorotatory or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line.
  • resolved compounds can be defined by the respective retention times of the corresponding enantiomers/diastereomers via chiral HPLC.
  • Some of the compounds described herein contain one or more asymmetric centers or axes and thus can give rise to enantiomers, diastereomers, and compounds that can be defined in absolute stereochemistry as (R)- or (S)- Other stereoisomers.
  • Geometric isomers can occur when a compound contains a double bond or some other feature that gives the molecule a certain amount of structural rigidity. If the compound contains a double bond, the substituent can be in the E or Z conformation. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have either the cis or trans configuration.
  • Conformational isomers are isomers that differ by rotation about one or more valency bonds. Rotamers are conformers that differ by the rotation of only a single bond.
  • Atropisomer refers to a structural isomer based on axial or planar chirality resulting from restricted rotation in a molecule.
  • the compounds of the present invention are intended to include all such possible isomers, including racemic mixtures, optically active forms and intermediate mixtures.
  • Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds of the invention can be isolated in optically active or racemic forms.
  • Optically active forms can be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare the compounds of the invention and intermediates prepared therein are considered to be part of the invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example by chromatography or fractional crystallization.
  • the end products of the invention are obtained in free (neutral) or salt form.
  • the free and salt forms of these end products are within the scope of the present invention.
  • One form of a compound can be converted to the other, if desired. Free bases or acids can be converted into salts; salts can be converted into free compounds or other salts; mixtures of isomeric compounds of the invention can be separated into the individual isomers.
  • pharmaceutically acceptable salt refers to a salt that retains the biological effects and properties of the compounds of the present invention, and which is not biologically or otherwise undesirable.
  • Non-limiting examples of such salts include non-toxic, inorganic or organic base or acid addition salts of the compounds of the present invention.
  • the compounds of the invention are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like.
  • Organic acids from which salts can be derived include, for example, acetic, propionic, glycolic, pyruvic, oxalic, maleic, malonic, succinic, fumaric, tartaric, citric, benzoic, cinnamic, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, such as, inter alia, isopropylamine, Trimethylamine, Diethylamine, Triethylamine, Tripropylamine, and Ethanolamine.
  • salts of the invention can be synthesized from the parent compound (basic or acidic moiety) by conventional chemical methods.
  • such salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of an appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc. ) reaction or reacting the free base form of the compound with a stoichiometric amount of the appropriate acid.
  • Such reactions are usually carried out in water or organic solvents or a mixed solvent of the two.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred where practicable.
  • Other suitable salts can be found in Remington's Pharmaceutical Sciences, 20th Edition, Mack Publishing Company, Easton, Pa., (1985), which is incorporated herein by reference.
  • pharmaceutically acceptable excipient includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, antibacterial, antifungal), isotonic agents, Absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, said similar substances and combinations thereof, are known to those of ordinary skill in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company (Mack Printing Company), 1990, pp. 1289-1329, incorporated herein by reference) . Unless any conventional carrier is incompatible with the active ingredient, it can be considered for use in therapeutic or pharmaceutical compositions.
  • any formula given herein is also intended to represent unlabeled as well as isotopically labeled forms of the compound.
  • Isotopically labeled compounds have structures described by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number.
  • isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H (ie D), 3 H (ie T), 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, 125 I.
  • the invention includes various isotopically labeled compounds as defined herein, for example those in which radioactive isotopes such as3H , 13C and14C are present.
  • isotopically labeled compounds are useful in metabolic studies (with 14 C), reaction kinetics studies (for example with 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computer Tomography (SPECT), including drug or substrate tissue distribution assays, or radiation therapy may be used in patients.
  • PET positron emission tomography
  • SPECT single photon emission computer Tomography
  • drug or substrate tissue distribution assays or radiation therapy may be used in patients.
  • 18F or labeled compounds may be particularly desirable for PET or SPECT studies.
  • Isotopically-labeled compounds of the invention can generally be prepared by carrying out those procedures described in the schemes described hereinafter or in the Examples and Preparations, substituting readily available isotopically-labeled reagents for non-isotopically-labeled reagents.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a “therapeutically effective amount” of a compound of the present invention refers to the amount of the compound of the present invention that can elicit a biological or medical response in an individual or improve symptoms, slow down or delay disease progression, or prevent disease and the like.
  • a “therapeutically effective amount” can be determined by the participating physician or veterinary practitioner and will vary with the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the individual, the route and form of administration, the attending physician Vary depending on factors such as the judgment of the physician or veterinary practitioner.
  • individual refers to an animal.
  • the animal is a mammal.
  • a subject also refers to, for example, primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like.
  • the individual is a human.
  • inhibitor refers to the alleviation or inhibition of a particular condition, symptom or disorder or disease, or a significant reduction in the baseline activity of a biological activity or process.
  • any disease or condition refers in one embodiment to ameliorating the disease or condition (ie arresting or slowing the progression of the disease or at least one clinical symptom thereof). In another embodiment, “treating” refers to improving at least one physical parameter, which may not be perceived by the patient. In another embodiment, “treating” refers to modulating a disease or disorder either physically (eg, stabilizing a perceived symptom) or physiologically (eg, stabilizing a parameter of the body), or both.
  • prevention refers to the administration of one or more drug substances, particularly the compounds of the present invention and/or pharmaceutically acceptable salts thereof, to individuals having a predisposition to the disease in order to prevent the individual from suffering from the disease .
  • the term "about” is used herein to adjust a given numerical value by 20%, such as 10%, such as 5%, above or below the numerical value.
  • the sources and trade names of the reagents and equipment used are all indicated when they appear for the first time. Unless otherwise specified, the same reagents used thereafter are the same as those indicated for the first time. Conventional unmarked reagents are purchased from Sinopharm Chemical Reagent Co., Ltd. company.
  • Compound 5-a reacts with a nucleophilic nucleophile containing R2 under the action of an organic base and a condensation reagent such as 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate in a polar solvent such as acetonitrile.
  • a condensation reagent such as 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate in a polar solvent such as acetonitrile.
  • the reagents are reacted to obtain the compound I of general formula.
  • Compound 5-a is dissolved in an organic solvent, under the protection of an inert gas, and phosphorus oxychloride under the action of an organic base such as triethylamine, to obtain a chlorinated intermediate 6-a;
  • Compound 1-b is dissolved in a polar aprotic solvent such as dimethyl sulfoxide, reacts with an ester containing a W moiety such as glycine methyl ester under heating conditions to obtain intermediate 2-a; compound 2-a and halogenated R 1 Reagent Under the action of a catalyst containing Pd and other metals and a ligand containing P, the intermediate compound 3-a is obtained through a coupling reaction; the compound 3-a is reacted with chlorosulfonyl isocyanate at low temperature to obtain the intermediate compound 4 -a; compound 4-a is ring-closed under basic conditions to obtain compound 5-a.
  • a polar aprotic solvent such as dimethyl sulfoxide
  • the first step the synthesis of intermediate compound 2-1
  • reaction was carried out in a 100mL three-neck flask. Dissolve 5-chloro-2-hydroxybenzonitrile 1-1 (5.0 g, 32.47 mmol), methyl chloroacetate (3.5 g, 32.47 mmol), potassium carbonate (9.0 g, 64.94 mmol) in DMF (15 mL), nitrogen Stir at 80°C for 6h under protection until the reaction is complete.
  • reaction solution was filtered with diatomaceous earth, the filter cake was washed several times with dichloromethane, the filtrate was combined, mixed with silica gel, spin-dried, and then passed through the column with petroleum ether:ethyl acetate (50:1) to obtain compound 3- 1 is an orange-red oil (2.12 g, yield: 76%).
  • Compound 1-B replace the starting material 5-chloro-2-hydroxybenzonitrile 1-1 in the first step of the synthesis step in Example 1 with 4-chloro-2-hydroxybenzonitrile, with reference to Example 1 method, prepared.
  • the m-tolylboronic acid in the second step of the synthesis step was replaced with m-chlorophenylboronic acid, m-fluorophenylboronic acid, o-tolylboronic acid, and p-tolylboronic acid, respectively, to prepare compound 1 -E , Compound 1-F, Compound 1-G, Compound 1-H.
  • Example 17 replace the 2-aminoethane-1-ol in Example 2 with methylamine, and react with 1-B, 1-C, and 1-D respectively, and the compounds can be prepared respectively 6.
  • the first step the synthesis of intermediate compound 1-A-1
  • reaction was carried out in a 25ml one-necked flask.
  • Compound 1-A 100mg, 0.3mmol
  • Pd/C 10mg
  • methanol 5ml
  • Post-processing the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 1-A-1 (80.0 mg, yield: 89.5%) as a white solid, which was directly carried out to the next step without purification.
  • Post-processing spin the reaction solution to dryness, extract twice with dichloromethane (50ml), wash the organic layer twice with purified water and saturated brine, dry with anhydrous sodium sulfate, filter and concentrate to dryness under reduced pressure, Prep- Purified by HPLC (0.1% trifluoroacetic acid system) and lyophilized to obtain 4-(methylamino)1-(m-benzyl)benzofuro[3,2-d]pyrimidin 2(1H)-one (compound 2 ) as a white solid (5.7 mg, yield: 6.8%).
  • the first step the synthesis of intermediate compound 2-4
  • Example 4 Referring to the synthesis method of Example 4 (compound 4), the 2-hydroxy-5-trifluoromethylbenzonitrile in the first step of the synthesis step is replaced by 2-cyano-3-hydroxypyridine, and compound 7 can be prepared accordingly .
  • the first step the synthesis of intermediate compound 2-10
  • reaction was carried out in a 100mL three-neck flask. Add intermediate 3-10 (600mg, 2.1mmol) into 5ml tetrahydrofuran solution, replace with nitrogen three times, then cool down to -15°C, add chlorosulfonyl isocyanate (448mg, 3.1mmol) solution dropwise, after the dropwise addition is completed - The reaction was incubated at 15°C for 1 hour, 2 ml of purified water was added dropwise to the reaction solution, the pH value was adjusted to 13 with sodium hydroxide, and the temperature was raised to room temperature and stirred for 2 hours.
  • intermediate 3-10 600mg, 2.1mmol
  • chlorosulfonyl isocyanate 448mg, 3.1mmol
  • Post-processing spin the reaction solution to dryness, extract three times with ethyl acetate (50ml ⁇ 3), wash the organic layer twice with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to dryness, prep-HPLC (H 2 O: CAN, 0.1% NH 3 .H 2 O) prepared 20.17 mg of 10 as a yellow solid (purity 99.0%, yield 6.5%).
  • the methylamine tetrahydrofuran solution in the fourth step of the synthesis step was replaced with dimethylamine tetrahydrofuran solution, methylethylamine, cyclopropylamine, 2,2-difluoroethylamine, 2,2 , 2-trifluoroethylamine, (1S,2R)-2-fluorocyclopropylamine can be prepared accordingly to obtain 15, 16, 23, 52, 53, 68.
  • the 3-bromopyridine in the first step of the synthesis step was replaced by 2-methyl-3-bromopyridine, 5-bromo-3-methylpyridine, 5-bromo-2-
  • the methylamine tetrahydrofuran solution in the fourth step is replaced by cyclopropylamine, and compounds 47, 49, and 50 can be prepared accordingly.
  • the first step the synthesis of intermediate compound 2-27
  • LCMS (ESI) m/z 481.1[M+H] + .
  • reaction was carried out in a 100mL three-neck flask. Dissolve 2-cyano-3-hydroxypyridine 1-22 (5g, 41.63mmol) in 50mL ACN:H 2 O (5:1), at 0°C, dissolve NBS (8.15g, 45.79mmol) in 50mL ACN :H 2 O (5:1) solution, and slowly added dropwise into the reaction solution, and reacted at low temperature for 6h.
  • reaction was carried out in a 50mL single-necked bottle. Put compound 1-A (2.00g, 6.12mmol) into a one-necked bottle, then add phosphorus oxychloride (20ml) and two drops of catalytic amount of DMF, reflux and stir for 12h under the protection of nitrogen, and the central control detects that the reaction is complete.
  • the reaction was carried out in a 250 mL eggplant flask. Dissolve 5-chloro-2-fluorobenzonitrile 1-11 (5.00g, 32.26mmol) in DMF (80mL), add methyl thioglycolate (3.76g, 35.48mmol), potassium carbonate (8.90g, 64.52mmol) , Stir at 80°C for 12h until the reaction is complete. Cool the reaction mixture to room temperature, add water (3 L) to precipitate a solid, filter, and dry the filter cake to obtain the product compound 2-51 (6.00 g, yield: 77.2%) as a yellow solid.
  • compound 69 can be prepared accordingly.
  • Example 9 Referring to the synthetic method of Example 9 Compound 12, the m-iodotoluene in the second step of the synthesis step was replaced by 3-bromopyridine, 2-iodotoluene, 1-chloro-2-iodobenzene, 2-methyl-3- Bromopyridine, replace the methylamine tetrahydrofuran solution in the sixth step of the synthesis step with cyclopropylamine, and compounds 89, 91, 92, and 87 can be prepared accordingly.
  • Example 9 compound 12 With reference to the synthetic method of Example 9 compound 12, the m-iodotoluene in the second step of the synthesis step is replaced by 2-methyl-3-bromopyridine, and the methyl iodide in the third step of the synthesis is replaced by ethyl iodide, which can be correspondingly Compound 72 was prepared.
  • Example 9 compound 12 With reference to the synthetic method of Example 9 compound 12, the m-iodotoluene in the second step of the synthetic step is replaced by 3-bromopyridine, the methylamine tetrahydrofuran solution in the sixth step of the synthetic step is replaced by the ethylamine tetrahydrofuran solution, and the sixth step The free base product obtained from the reaction was further treated with hydrochloric acid-dioxane solution to finally obtain the hydrochloride of compound 110.
  • reaction was carried out in a 100mL three-neck flask. Dissolve 5-chloro-2-hydroxybenzonitrile 1-1 (4.0g, 26.14mmol), methyl chloroacetate (3.1g, 28.76mmol), potassium carbonate (7.2g, 52.29mmol) in DMF (50mL), nitrogen Stir at 80°C for 12h under protection until the reaction is complete.
  • reaction was carried out in a 250mL three-neck flask. Put compound 4-47 (3.5g, 11.58mmol) into a three-necked flask, replace with nitrogen three times, add 100ml of DMF to dissolve, cool down to 0°C in ice bath, add sodium hydride (content 60%) (1.39g, 34.74mmol), and put in ice bath Stir for 30 min, add CDI (2.8 g, 17.47 mmol), and stir in ice bath for 2 h.
  • compound 59 can be prepared by replacing cyclopropylamine in the sixth step of the synthesis step with methylamine tetrahydrofuran solution.
  • the 2-methyl-3-bromopyridine in the second step of the synthesis step was replaced by 2-bromotoluene, 4-bromo-3-methylpyridine, 2-fluoroiodobenzene , 2,4-difluoroiodobenzene, 3-bromo-1-methyl-2-pyridone, 4-bromo-2-methylpyridine, 2-bromopyridine, 2-bromo-3-methylpyridine, 2 -Bromo-4-methylpyridine, 2-bromo-6-methylpyridine, 3-bromo-2-cyclopropylpyridine, the cyclopropylamine in the sixth step of the synthesis step is replaced by methylamine tetrahydrofuran solution, which can be respectively corresponding Compounds 64, 99, 100, 101, 102, 104, 105, 106, and 107 were prepared as formate salts (the compounds were separated from the formic acid-containing preparative liquid phase system), 108, and 116
  • Post-treatment Pour the reaction solution into water (100mL), extract twice with dichloromethane (50mL ⁇ 2), wash the combined organic layer with water and saline once, dry over sodium sulfate, filter and spin dry, and the crude product is flashed through silica gel.
  • LCMS (ESI) m/z 304.2[M+H] + .
  • the reaction was carried out in a 25mL single-necked bottle. Put Intermediate 4-54 (50mg, 0.16mmol), phosphorus oxychloride (74mg, 0.48mmol), DIPEA (62mg, 0.48mmol), and acetonitrile (5mL) into a reaction flask, heat up to 80°C and stir for 2 hours, then send the sample detection. Post-processing: the reaction solution was concentrated under reduced pressure to obtain the crude intermediate 5-54, which was directly carried out to the next step without purification.
  • the reaction was carried out in a 20mL single-necked bottle.
  • the crude intermediate 5-54 was dissolved in 5 mL of tetrahydrofuran, and cyclopropylamine (57 mg, 1 mmol) was added, reacted at room temperature for 1 hour, and sent for sample detection.
  • reaction was carried out in a 50ml single-necked bottle.
  • Compound 14 (2.12g, 6.49mmol) was added to 25mL hydrochloric acid-dioxane solution, stirred at room temperature for about 10 minutes, the reaction solution was filtered, and the filter cake was freeze-dried by adding water and acetonitrile to obtain the final product 14 hydrochloride 2.3 g, yellow solid, yield 98%.
  • compound 60 hydrochloride can be prepared accordingly.
  • the reaction was carried out in a 100mL three-neck flask. Put 2,3-difluoro-6-methoxybenzonitrile 1-114 (2.28g, 13.48mmol) and 30mL of dichloromethane into a three-necked flask, cool to -78°C and add dropwise BBr 3 (10.13g, 40.44), the dropwise addition was completed, and moved to room temperature to react for 20h. The reaction solution was quenched by adding ice water, extracted twice with dichloromethane, and concentrated to dryness to obtain compound 2-114 (2.05 g, yield: 44.1%) as a brown solid.
  • reaction was carried out in a 100mL single-necked bottle. Add intermediate 2-114 (2.04g, 13.15mmol), methyl chloroacetate (3.64g, 26.31mmol), K 2 CO 3 (1.57g, 14.47mmol) and 25mL DMF into a one-necked flask, N 2 protection, The temperature was raised to 80° C. and stirred for 18 hours. The reaction solution was filtered, then concentrated and mixed through a Flash column (mobile phase: 20% EtOAcin PE) to obtain 1.8 g of white solid 3-114 with a yield of 60%.
  • reaction was carried out in a 50mL single-necked bottle, and compound 3-114 (1.05g, 4.62mmol), 2-methyl-3 bromopyridine (1.19g, 6.93mmol), Pd 2 (dba) 3 (423mg, 0.46mmol), Xantphos (535mg, 0.92mmol), cesium carbonate (3.01g, 9.24mmol), and 1,4-dioxane (12ml) were put into a one-necked bottle, replaced with nitrogen three times, heated to 100°C and stirred for 15 hours.
  • reaction was carried out in a 100mL reactor. Add intermediate 4-114 (800mg, 2.51mmol) and 60mL of ammonia-methanol solution into the reaction kettle together, heat the oil pan to 100°C and stir for 18 hours, and filter the reaction liquid in the kettle directly to obtain 630mg of intermediate 5-114, gray Solid, yield 82.68%.
  • LCMS (ESI) m/z 304.00[M+H] + .
  • reaction was carried out in a 50mL three-necked bottle, and the inside of the bottle was ensured to be dry.
  • Compound 5-114 (630mg, 2.08mmol) was added to 10mL DMF, replaced with nitrogen three times, and after cooling down to 0°C, NaH (60%) (249mg, 6.24mmol) was added.
  • CDI 505 mg, 3.12 mmol was added and stirring was continued for 10 minutes.
  • the reaction liquid was quenched by adding saturated ammonium chloride aqueous solution, ten times the amount of water was added, suction filtered, and the filter cake was spin-dried to obtain 550 mg of compound 6-114, yield: 80.41%, off-white solid.
  • the reaction was carried out in a 50ml single-necked bottle.
  • MAT2A can catalyze the conversion of L-methionine and ATP into SAM, inorganic phosphate and inorganic diphosphate.
  • a chromogenic reagent added to the enzymatic reaction system, the content of inorganic phosphate in the sample can be quantitatively detected, and then the enzymatic activity of MAT2A can be characterized.
  • test compound concentration gradient the test compound test concentration is 10 ⁇ M starting, 3-fold dilution, 10 concentrations, repeated well test. 10 solutions with different concentrations were serially diluted to 100 times final concentration in a 384-well plate. Then use Echo550 to transfer 250nL to 384 reaction plate for later use. 250 nL of 100% DMSO was added to negative control wells and positive control wells, respectively.
  • Compound inhibition rate (%) (OD620_max-OD620_sample)/(OD620_max-OD620_min)X100
  • OD620_sample is the absorbance value of the sample well
  • OD620_min is the absorbance value of the positive control well, indicating the reading of the well without enzyme activity
  • OD620_max is the absorbance value of the negative control well, indicating the reading of the well without compound inhibition
  • the inhibitory effect of the test compound on the enzyme activity of MAT2A can be expressed by the IC 50 value of the inhibition of the level of phosphate production during the enzymatic reaction. See Table 1 for the MAT2A inhibitory activity of the compounds to be tested. Wherein, 0nM ⁇ A ⁇ 100nM, 100nM ⁇ B ⁇ 500nM, C ⁇ 500nM.
  • the cells After co-incubating the MAT2A inhibitor to be tested with the cells for a period of time, the cells are lysed with a lysate to quench the MAT2A enzyme activity.
  • the content of SAM in the cell lysate was detected by LC-MS/MS to characterize the MAT2A enzyme activity in the cell.
  • HCT116 MTAP -/- cells were cultured with RPMI-1640 containing 10% fetal bovine serum and 1% penicillin-streptomycin in a cell culture incubator at 37°C and 5% CO 2 , in logarithmic growth Cells at this stage can be used for subsequent experiments.
  • Compound inhibition rate (%) (SAM_max-SAM_sample)/(SAM_max-SAM_min)X100
  • SAM_sample is the SAM concentration of the sample well
  • SAM_min is the SAM concentration of the positive control well, indicating the reading without cells
  • SAM_max is the absorbance value of the negative control well, indicating the SAM concentration of the well without compound inhibition.
  • the IC 50 value of the test compound on the inhibition of HCT116MTAP -/- intracellular SAM production was used to characterize the inhibitory ability of the test compound to the intracellular MAT2A enzyme activity. See Table 2 for the inhibitory activity of the compounds to be tested on intracellular SAM production.
  • Test example 3 human pancreatic cancer KP-4 cell activity inhibition test
  • the cell activity measurement method based on the ATP content is used to characterize the effect of the test compound on the cell activity.
  • KP-4 cells (JCRB#JCRB0182)
  • KP-4 cells are cultured in IMDM containing 10% fetal bovine serum and 1% penicillin-streptomycin, and cultured in a cell incubator under the conditions of 37°C and 5% CO 2 , and the cells can only be used in the logarithmic growth phase in subsequent tests.
  • Compound inhibition rate (%) (Signal_max-Signal_sample)/(Signal_max-Signal_min)X100
  • Signal_sample is the reading of the sample well, indicating the cell activity of the well inhibited by the compound
  • Signal_min is the reading of the positive control well, indicating no background activity of the cells
  • Signal_max is the reading of the negative control well, indicating the cell activity of the well not inhibited by the compound.

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Abstract

提供了一种具有 MAT2A 抑制活性的嘧啶-2(1H)-酮并二环类化合物及其用途，具体地，提供了一种具有 MAT2A 抑制活性的式(I)化合物，其立体异构体、药物组合物，以及这些化合物用于预防或治疗肿瘤疾病的用途。

Description

具有MAT2A抑制活性的嘧啶-2(1H)-酮并二环类化合物及其用途 技术领域
本发明涉及一种嘧啶-2(1H)-酮并二环类化合物、其立体异构体或其可药用盐，以及其可以用于制备MAT2A抑制剂，治疗和/或预防肿瘤的用途。
背景技术
癌症治疗是当今世界面对的巨大挑战，对于现有的常用疗法，比如化疗和免疫治疗，最大的问题是细胞杀伤效果往往不仅针对癌症细胞，对于正常细胞和组织也会产生很大的副作用。因此，迫切需要开发新型治疗手段以更好的靶向癌症细胞。
合成致死被定义为两个或多个基因的缺失导致细胞死亡，而其中任何一个基因的单独缺失不会有影响。近年来，大量的研究显示在癌症细胞中存在着多种基因突变导致它们对于合成致死的治疗手段更加敏感。这些肿瘤特异性的基因突变可以促使我们使用合适的靶向治疗药物杀伤癌症细胞，而对于正常细胞没有影响。
甲硫氨酸腺苷转移酶2A(methionine adenosyltransferase 2A,MAT2A)是一种能够催化甲硫氨酸(methionine，Met)与ATP反应生成S-腺苷甲硫氨酸(S-Adenosyl-L-methionine，SAM)的酶。SAM是体内主要的甲基供体，能够通过对DNA，RNA和蛋白的转甲基反应，调控基因的表达，进而对细胞的分化、生长和死亡产生重要影响。精氨酸甲基转移酶5(arginine N-methyltransferase 5，PRMT5)是一种以SAM为甲基供体的甲基化酶。SAM对于PRMT5的活性至关重要，同时甲硫腺苷(5’methylthioadenosine，MTA)可以抑制PRMT5的活性。MTA是甲硫氨酸补偿途径的产物，其在细胞内通过甲硫腺苷转化酶(methylthioadenosine phosphorylase，MTAP)催化生成5-甲基硫代核糖-1-磷酸及腺嘌呤而维持在较低的水平。
MTAP基因位于9号染色体，该染色体在多种癌症病人的细胞中存在缺失，包括胰腺癌、食管癌、膀胱癌和肺癌等(cBioPortal数据库)。MTAP的缺失会导致细胞内MTA的富集，进而使这些细胞相比于正常细胞更加依赖于SAM的产量和MAT2A的活性。研究表明，在MTAP缺失的癌细胞中抑制MAT2A的表达相较于MTAP正常的癌细胞可以选择性的抑制细胞活性(McDonald et.al.,2017Cell 170,577-592)。同时，降低MAT2A表达可以选择性的抑制MTAP缺失的肿瘤细胞小鼠异种移植瘤模型中的肿瘤生长(Marjon et.al.,2016Cell Reports 15(3),574-587)。这些结果表明MAT2A抑制剂可以为癌症病人，尤其是肿瘤含有MTAP缺失的病人，提供一种新型有效的治疗手段。
发明内容
本发明提供了式(I)化合物、其立体异构体、其可药用盐、其药物组合物及其组合。发明人出人意料地发现，所述式(I)化合物为良好的MAT2A抑制剂。
根据本发明，提供一种如式(I)所示的化合物、其立体异构体或其可药用盐，
Figure PCTCN2022136109-appb-000001
其中
X 1为，CR 3或N，X 2为CR 4或N，X 3为CR 5或N，X 4为CR 6或N；且X 1、X 2、X 3、X 4至多两个同时为N；
R 3，R 4，R 5，R 6各自独立的选自H、D、卤素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6烷基磺酰基、C 3-C 7环烷基、氰基、羟基、巯基、C 1-C 6烷基氨基、氨基、硝基、羧基、NHCOR a，所述烷基、烯基、炔基、烷氧基、环烷基为无取代或任选地被一个或多个选自D、卤素的取代基所取代，R a选自C 1-C 10烷基、C 3-C 10环烷基；
优选地，R 3，R 4，R 5，R 6各自独立的选自H、卤素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 3-C 7环烷基、氰基、羟基、氨基，所述烷基、烯基、炔基、烷氧基、环烷基为无取代或任选地被一个或多个选自D、卤素的取代基取代；
进一步优选地，R 3、R 5、R 6各自独立地选自H和卤素，R 4选自H、卤素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 3-C 7环烷基、氰基、羟基、氨基，所述烷基、烯基、炔基、烷氧基、环烷基为无取代或任选地被一个或多个选自D、卤素的取代基取代；
进一步优选地，R 3、R 5、R 6均为H，R 4选自H、卤素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 3-C 7环烷基、氰基、羟基、氨基，所述烷基、烯基、炔基、烷氧基、环烷基为无取代或任选地被一个或多个选自D、卤素的取代基取代；
例如，X 1为CH或N，X 2为CR 4或N，X 3为CH或N，X 4为CH或N；且X 1、X 2、X 3、X 4至多两个同时为N；所述R 4选自F、Cl、Br、CH 3、CD 3、CF 3、CF 2H、CF 2D、OH、SH、NH 2、CN、OCH 3、CH 3CH 2、-CH 2CH 2CH 3、环丙基、-CH 2(CH 3)CH 3、NO 2。
优选地，X 1、X 2、X 3、X 4中至多一个为N。
进一步优选地，X 1为CR 3，X 2为CR 4，X 3为CR 5，X 4为CR 6，R 3，R 4，R 5，R 6分别如上所定义。
W选自O、NR b、S、CHR b；所述R b选自H、D、C 1-C 4烷基、C 3-C 6环烷基，所述烷基和环烷基无取代或被选自D、卤素、-OH中的一个或多个取代基所取代；优选地，所述R b选自H、D、C 1-C 3烷基、C 3-C 6环烷基，所述烷基和环烷基无取代或被选自卤素、-OH中的一个或多个取代基所取代；更优选地，所述R b选自H、D、甲基、乙基、正丙基、异丙基、环丙基、环丁基，其中甲基、乙基、正丙基、异丙基、环丙基、环丁基为无取代或被选自D、卤素、-OH中的一个或多个取代基所取代；
优选地，W选自O、NH、NCH 3、NC 2H 4OH、NCH(CH 3) 2、NC 2H 5、S、CH 2；
R 1选自无取代或取代的C 3-C 10环烷基、无取代或取代的C 6-C 10芳基、无取代或取代的5-6元杂环烷基、无取代或取代的5-10元杂芳基，其中，R 1中所述取代是指被一个或多个 选自A组的取代基所取代，A组取代基包括：卤素、CN、OH、氧代、SH、NH 2、NO 2、C 1-C 4烷基、C 3-C 7环烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基(如CF 3、CF 2H)、COOH、CONHR c、NHCOR c、NHSO 2R c，R c选自H、C 1-C 4烷基、C 3-C 10环烷基、C 1-C 10烷氧基或C 6-C 10芳基(如苯基、吡啶)，其中R c中的C 1-C 4烷基、C 3-C 10环烷基、C 1-C 10烷氧基、C 6-C 10芳基为无取代的或被选自卤素、羟基、氰基的一个或多个取代，所述杂芳基和杂环烷基分别含有选自N、O、S中的一个或多个杂原子；
优选地，R 1选自无取代或取代的苯基、无取代或取代的C 3-C 7环烷基、无取代或取代的5-6元杂环烷基、无取代或取代的5-10元杂芳基，其中，R 1中所述取代以及杂芳基和杂环烷基的限定分别如上所述；
优选地，R 1选自无取代或取代的苯基、无取代或取代的C 3-C 7环烷基、无取代或取代的5-6元杂环烷基、无取代或取代的5-10元杂芳基，其中，R 1中所述取代是指被一个或多个选自A组的取代基所取代，A组取代基包括：卤素、CN、OH、氧代、SH、NH 2、NO 2、C 1-C 4烷基、C 3-C 7环烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基(如CF 3、CF 2H)，所述杂芳基和杂环烷基分别含有选自N、O、S中的一个或多个杂原子；
优选地，R 1选自无取代或取代的苯基、无取代或取代的C 3-C 7环烷基、无取代或取代的5-6元杂环烷基、无取代或取代的5-10元杂芳基；所述5-10元杂芳基选自如下基团：
Figure PCTCN2022136109-appb-000002
其中，R 1中所述取代是指被一个或多个选自A组的取代基所取代；A组取代基包括：卤素、CN、OH、氧代(＝O)、SH、NH 2、NO 2、C 1-C 4烷基、C 3-C 7环烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基(如CF 3、CF 2H)、COOH、CONHR c、NHCOR c、NHSO 2R c，R c选自H、C 1-C 4烷基、C 3-C 10环烷基、C 1-C 10烷氧基或C 6-C 10芳基(如苯基、吡啶)，其中R c中的C 1-C 4烷基、C 3-C 10环烷基、C 1-C 10烷氧基、C 6-C 10芳基为无取代或被选自卤素、羟基、氰基的一个或多个取代；
优选地，所述R 1选自
Figure PCTCN2022136109-appb-000003
Figure PCTCN2022136109-appb-000004
其中，R 10和R 11各自独立地选自卤素、CN、OH、SH、NH 2、C 1-C 4烷基、C 3-C 7环烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基、COOH、CONH 2、CONHR c、NHCOR c，R c选自无取代或被选自卤素、羟基、氰基的一个或多个取代的C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4烷氧基或苯基。
优选地，所述R 1选自
Figure PCTCN2022136109-appb-000005
Figure PCTCN2022136109-appb-000006
R 2选自NR 7R 8、-OR 9、或-SR 9；
R 7、R 8、R 9各自独立地选自H、D、无取代或取代的C 1-C 6烷基、无取代或取代的C 1-C 6烷氧基、无取代或取代的C 2-C 6烯基、无取代或取代的C 2-C 6炔基、无取代或取代的C 3-C 7环烷基、无取代或取代的C 5-C 10芳基、无取代或取代的3-7元杂环烷基、无取代或取代的5-10元杂芳基、-NHCO-(C 1-C 6烷基)、-NHSO 2-(C 1-C 6烷基)；其中，R 7、R 8、R 9中所述取代是指被一个或多个选自如下的取代基所取代：D、卤素、-NHR d、-N(R d) 2、-OR d、-SR d、无取代或被一个或多个选自B组的取代基所取代的C 1-C 3烷基、无取代或被一个或多个选自B组的取代基所取代的C 3-C 7环烷基、无取代或被一个或多个选自B组的取代基所取代的5-10元杂芳基；R d为H、COOH、Boc、无取代或被一个或多个选自B组的取代基所取代的C 1-C 3烷基、无取代或被一个或多个选自B组的取代基所取代的C 3-C 7环烷基、无取代或被一个或多个选自B组的取代基所取代的5-10元杂芳基；B组取代基包括：C 1-C 6烷基、卤素、OH、氨基；
或R 7、R 8与它们相连的N原子一起形成无取代或被选自如下的一个或多个取代基所取代的4-6元杂环烷基：OH、卤素、C 1-C 10烷基、C 3-C 10环烷基；
其中所述杂芳基和杂环烷基分别含有选自N、O、S中的一个或多个杂原子。
优选地，其中，R 2选自NR 7R 8、-OR 9、或-SR 9；
R 7、R 8、R 9各自独立地选自H、无取代或取代的C 1-C 3烷基、无取代或取代的C 1-C 3烷氧基、无取代或取代的C 3-C 7环烷基、无取代或取代的苯基、无取代或取代的3-6元杂环烷基、无取代或取代的5-10元杂芳基、-NHCO-(C 1-C 3烷基)、-NHSO 2-(C 1-C 3烷基)；其中，R 7、R 8、R 9中所述取代是指被一个或多个选自如下的取代基所取代：卤素、-NHR d、-N(R d) 2、-OR d、-SR d、无取代或被一个或多个选自B组的取代基所取代的C 1-C 3烷基、无取代或被一个或多个选自B组的取代基所取代的C 3-C 7环烷基、无取代或被一个或多个选自B组的取代基所取代的5-10元杂芳基，R d为H、COOH、Boc、无取代或被一个或多个选自B组的取代基所取代的C 1-C 3烷基、无取代或被一个或多个选自B组的取代基所取代的C 3-C 7环烷基、无取代或被一个或多个选自B组的取代基所取代的5-10元杂芳基；B组取代基包括：C 1-C 3烷基、卤素、OH、氨基；
或R 7、R 8与它们相连的N原子一起形成无取代或被选自如下的一个或多个取代基所取代的5-6元杂环烷基：OH、卤素、C 1-C 3烷基、C 3-C 6环烷基；
其中所述杂芳基和杂环烷基分别含有选自N、O、S中的一个或多个杂原子。
进一步优选地，R 2选自NH 2、
Figure PCTCN2022136109-appb-000007
Figure PCTCN2022136109-appb-000008
例如，在一个实施方式中，在式(I)所示的化合物中，
X 1为CR 3或N，X 2为CR 4或N，X 3为CR 5或N，X 4为CR 6或N，其X 1、X 2、X 3、X 4中至多一个为N，R 3、R 5、R 6各自独立地选自H和卤素，R 4选自H、卤素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 3-C 7环烷基、氰基、羟基、氨基，所述烷基、烯基、炔基、烷氧基、环烷基为无取代或任选地被一个或多个选自D、卤素的取代基取代；
W选自O、NH、NCH 3、NC 2H 4OH、NCH(CH 3) 2、NC 2H 5、S、CH 2；
R 1选自无取代或取代的苯基、无取代或取代的C 3-C 7环烷基、无取代或取代的5-6元杂环烷基、无取代或取代的5-10元杂芳基；所述5-10元杂芳基选自如下基团：
Figure PCTCN2022136109-appb-000009
其中，R 1中所述取代是指被一个或多个选自A组的取代基所取代；A组取代基包括：卤素、CN、OH、氧代、SH、NH 2、NO 2、C 1-C 4烷基、C 3-C 7环烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基(如CF 3、CF 2H)、COOH、CONHR c、NHCOR c、NHSO 2R c，R c选自H、C 1-C 4 烷基、C 3-C 10环烷基、C 1-C 10烷氧基或C 6-C 10芳基，其中R c中的C 1-C 4烷基、C 3-C 10环烷基、C 1-C 10烷氧基、C 6-C 10芳基为无取代或被选自卤素、羟基、氰基的一个或多个取代；
R 2选自NR 7R 8、-OR 9、或-SR 9；
R 7、R 8、R 9各自独立地选自H、无取代或取代的C 1-C 3烷基、无取代或取代的C 1-C 3烷氧基、无取代或取代的C 3-C 7环烷基、无取代或取代的苯基、无取代或取代的3-6元杂环烷基、无取代或取代的5-10元杂芳基、-NHCO-(C 1-C 3烷基)、-NHSO 2-(C 1-C 3烷基)；其中，R 7、R 8、R 9中所述取代是指被一个或多个选自如下的取代基所取代：卤素、-NHR d、-N(R d) 2、-OR d、-SR d、无取代或被一个或多个选自B组的取代基所取代的C 1-C 3烷基、无取代或被一个或多个选自B组的取代基所取代的C 3-C 7环烷基、无取代或被一个或多个选自B组的取代基所取代的5-10元杂芳基，R d为H、COOH、Boc、无取代或被一个或多个选自B组的取代基所取代的C 1-C 3烷基、无取代或被一个或多个选自B组的取代基所取代的C 3-C 7环烷基、无取代或被一个或多个选自B组的取代基所取代的5-10元杂芳基；B组取代基包括：C 1-C 3烷基、卤素、OH、氨基；
或R 7、R 8与它们相连的N原子一起形成无取代或被选自如下的一个或多个取代基所取代的5-6元杂环烷基：OH、卤素、C 1-C 3烷基、C 3-C 6环烷基；
其中所述杂芳基和杂环烷基分别含有选自N、O、S中的一个或多个杂原子。
例如，在一个实施方式中，式(I)所示的化合物如下式I-A所示，
Figure PCTCN2022136109-appb-000010
其中，W、R 1、R 2、R 3、R 4、R 5、R 6分别如上所述。
例如，在一个实施方式中，式(I)所示的化合物如下式I-A所示，
Figure PCTCN2022136109-appb-000011
其中，W选自O、NR b、S、CHR b；所述R b选自H、D、C 1-C 4烷基、C 3-C 6环烷基，所述烷基和环烷基无取代或被选自D、卤素、-OH中的一个或多个取代基所取代；
R 3、R 5、R 6各自独立地选自H和卤素，R 4选自H、卤素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 3-C 7环烷基、氰基、羟基、氨基，所述烷基、烯基、炔基、烷氧基、环烷基为无取代或任选地被一个或多个选自D、卤素的取代基取代；
R 1选自无取代或取代的苯基、无取代或取代的C 3-C 7环烷基、无取代或取代的5-6元杂环烷基、无取代或取代的5-10元杂芳基，其中，R 1中所述取代是指被一个或多个选自A组 的取代基所取代，A组取代基包括：卤素、CN、OH、氧代、SH、NH 2、NO 2、C 1-C 4烷基、C 3-C 7环烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基；
R 2选自NR 7R 8、-OR 9、或-SR 9；
R 7、R 8、R 9各自独立地选自H、无取代或取代的C 1-C 3烷基、无取代或取代的C 1-C 3烷氧基、无取代或取代的C 3-C 7环烷基、无取代或取代的苯基、无取代或取代的3-6元杂环烷基、无取代或取代的5-10元杂芳基、-NHCO-(C 1-C 3烷基)、-NHSO 2-(C 1-C 3烷基)；其中，R 7、R 8、R 9中所述取代是指被一个或多个选自如下的取代基所取代：卤素、-NHR d、-N(R d) 2、-OR d、-SR d、无取代或被一个或多个选自B组的取代基所取代的C 1-C 3烷基、无取代或被一个或多个选自B组的取代基所取代的C 3-C 7环烷基、无取代或被一个或多个选自B组的取代基所取代的5-10元杂芳基，R d为H、COOH、Boc、无取代或被一个或多个选自B组的取代基所取代的C 1-C 3烷基、无取代或被一个或多个选自B组的取代基所取代的C 3-C 7环烷基、无取代或被一个或多个选自B组的取代基所取代的5-10元杂芳基；B组取代基包括：C 1-C 3烷基、卤素、OH、氨基；
或R 7、R 8与它们相连的N原子一起形成无取代或被选自如下的一个或多个取代基所取代的5-6元杂环烷基：OH、卤素、C 1-C 3烷基、C 3-C 6环烷基；
其中所述杂芳基和杂环烷基分别含有选自N、O、S中的一个或多个杂原子。
本发明的所述的式(I)所示的化合物具体可以选自如下结构：
Figure PCTCN2022136109-appb-000012
Figure PCTCN2022136109-appb-000013
Figure PCTCN2022136109-appb-000014
Figure PCTCN2022136109-appb-000015
Figure PCTCN2022136109-appb-000016
Figure PCTCN2022136109-appb-000017
Figure PCTCN2022136109-appb-000018
Figure PCTCN2022136109-appb-000019
Figure PCTCN2022136109-appb-000020
Figure PCTCN2022136109-appb-000021
Figure PCTCN2022136109-appb-000022
本发明还提供了一种组合物，包含至少一种式(I)所示的化合物、其立体异构体或其可药用盐。
本发明还提供了一种药物制剂，包含治疗有效量的式(I)所示的化合物、其立体异构体或其可药用盐，以及一种或多种可药用的载体、稀释剂或赋形剂。
在另一个实施方案中，本发明提供组合，尤其是药物组合，其包含治疗有效量的本发明的化合物、其立体异构体或其可药用盐，及一种或多种其它治疗剂。
本发明的化合物可以单独地、与其它的本发明的化合物组合地或与一种或多种、优选一种或两种其它物质组合地同时或依次使用。
本发明还提供了式(I)所述的化合物、其立体异构体或其可药用盐、或包含其的组合物、所述药物制剂、所述药物组合在制备治疗和/或预防肿瘤的药物中的用途。
优选地，所述肿瘤包括：MTAP缺失的肿瘤；MTAP低表达的肿瘤；MAT2A异常表达的肿瘤；其他MAT2A依赖的肿瘤。
具体地，所述肿瘤包括：乳腺癌、肺癌、胶质母细胞瘤、脑癌和脊椎癌、头颈癌、皮肤癌、生殖系统癌症、胃肠系统癌症、食道癌、鼻咽癌、胰腺癌、直肠癌、肝细胞癌、胆管癌、胆囊癌、结肠癌、多发性骨髓瘤、肾脏和膀胱癌、骨癌、恶性间皮瘤、肉瘤、淋巴瘤、腺癌、甲状腺癌、心脏肿瘤、生殖细胞肿瘤、恶性神经内分泌肿瘤、恶性横纹肌样瘤、软组织肉瘤、中线束癌和未知原发癌。
在本发明的一个实施方案中，本发明提供了治疗或预防MAT2A相关的肿瘤的方法，该方法包括给有需要的患者施用有效量的第一种治疗剂和任选的第二种治疗剂，其中所述第一种治疗剂是本发明的化合物、其立体异构体或其可药用盐，并且所述第二种治疗剂是一种或多种其它治疗剂。
另外，本发明提供了产品或试剂盒，其包含如上定义的本发明的化合物或其可药用盐、或其药物组合物和一种或多种其它活性剂在抗癌疗法中同时、分开或依次使用的联合制剂。
术语说明
在本发明中，除非另外明确地说明，本发明所使用的术语具有下面所定义的含义。本发明未明确定义的术语具有本领域技术人员所普遍理解的一般含义。
在本发明的上下文中(尤其在权利要求的上下文中)使用的术语“一个”、“一种”、“该”和类似术语被理解为包括单数和复数，除非文中另外特别指出或根据上下文明显矛 盾。
不在两个字母或符号之间的短横(“-”)表示取代基的连接位点。例如，-O(C 1-C 3烷基)表示该基团通过氧原子与分子的其余部分连接。然而，当取代基的连接位点对本领域技术人员来说是显而易见的时候，例如对于卤素、羟基等取代基而言，“-”可以省略。
当基团带有波浪线“
Figure PCTCN2022136109-appb-000023
”时，波浪线表示该基团与分子其余部分的连接位置。
如本文所用，“杂原子”指氮(N)、氧(O)或硫(S)原子，特别是氮或氧，其各自可以是取代或未取代的，包括其氧化形式。杂原子的实例包括但不限于-O-、-N＝、-NR-、-S-、-S(O)-和-S(O) 2-，其中R是氢、C 1-C 4烷基或氮保护基(例如苄氧羰基、对甲氧基苄基羰基、叔丁氧基羰基、乙酰基、苯甲酰基、苄基、对甲氧基-苄基、对甲氧基-苯基、3,4-二甲氧基苄基等)。任何具有未满足的价键的杂原子被认为具有足以满足价键的氢原子，另有指示除外。
如本文所用，“卤素”或“卤代”指氟、氯、溴和碘。优选的作为取代基的卤素是氟和氯。
如本文所用，“烷基”指完全饱和的直链或支链的一价烃基团。烷基优选包含1-20个碳原子，更优选1-16个碳原子、1-10个碳原子、1-8个碳原子、1-6个碳原子、1-4个碳原子或1-3个碳原子。烷基前的数字表示碳原子的个数。例如，“C 1-C 6烷基”表示具有1-6个碳原子的烷基，“C 1-C 4烷基”表示具有1-4个碳原子的烷基，“C 1-C 3烷基”表示具有1-3个碳原子的烷基。烷基的代表性示例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基、正癸基等。无论术语“烷基”单独出现，还是作为其它基团如卤代烷基、烷氧基等的一部分出现，均适用该定义。
如本文所用，“烯基”指包含至少一个双键的直链或支链的一价烃基团。烯基优选包含2-20个碳原子，更优选2-10个碳原子、2-8个碳原子、2-6个碳原子或2-4个碳原子。烯基前的数字表示碳原子的个数。烯基的代表性示例包括但不限于乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基、戊烯基、异戊烯基、己烯基、庚烯基、辛烯基等。
如本文所用，“炔基”指包含至少一个叁键的直链或支链的一价烃基团。炔基优选包含2-20个碳原子，更优选2-10个碳原子、2-8个碳原子、2-6个碳原子或2-4个碳原子。炔基前的数字表示碳原子的个数。炔基的代表性示例包括但不限于乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、戊炔基、异戊炔基、己炔基、庚炔基、辛炔基等。
如本文所用，“烷氧基”指通过氧桥连接的如本文所定义的烷基，即，烷基-O-基团，烷氧基前的数字表示碳原子的个数。例如，“C 1-C 6烷氧基”表示具有1-6个碳原子的烷氧基，即-O-C 1-6烷基；“C 1-C 4烷氧基”表示具有1-4个碳原子的烷氧基，即-O-C 1-4烷基；“C 1-C 3烷氧基”表示具有1-3个碳原子的烷氧基，即-O-C 1-3烷基。烷氧基的代表性示例包括但不限于甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基等。优选地，烷氧基含有约1-6个或者约1-4个碳等。
如本文所用，“环烷基”指饱和或部分饱和的非芳香族碳环，包括单-、双-或三环， 优选具有3-12个环碳原子，更优选3-10个环碳原子，例如3-8个、3-7个、3-6个、4-10个、或4-8个环碳原子。"C 3-C 8环烷基"意欲包括C 3、C 4、C 5、C 6、C 7和C 8环烷基基团；"C 3-C 6环烷基"意欲包括C 3、C 4、C 5和C 6环烷基基团；以此类推。示例性的单环环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基和环己烯基等。示例性的二环环烷基包括冰片基、四氢萘基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、6,6-二甲基二环[3.1.1]庚基、2,6,6-三甲基二环[3.1.1]庚基、二环[2.2.2]辛基等。示例性的三环环烷基包括金刚烷基等。
如本文所用，“卤代烷基”指其中一个或多个氢原子、例如1、2、3、4、5、6或7个氢原子、例如1、2或3个氢原子被卤素替代的如本文所定义的烷基，并且当超过一个氢原子被卤素原子替代时，所述卤素原子可以彼此相同或不同。例如“C 1-C 4卤代烷基”意欲包括C 1、C 2、C 3和C 4卤代烷基基团，“C 1-C 3卤代烷基”意欲包括C 1、C 2和C 3卤代烷基基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、1,1-二氟乙基、1,1,-二氟丙基和1,1,1-三氟丙基。卤代烷基的实例还包括“氟烷基”，后者意欲包括其中一个或多个氢原子被氟原子取代的如本文定义的烷基。本文“卤代烷基”优选为烷基中至多三个氢原子被卤素替代。
如本文所用，“卤代烷氧基”表示通过氧桥连接的具有指定碳原子数的如上定义的卤代烷基，其中一个或多个氢原子、例如1、2、3、4、5、6或7个氢原子、例如1、2或3个氢原子被卤素替代。例如，“C 1-C 6卤代烷氧基”或“C 1至C 6卤代烷氧基”意欲包括C 1、C 2、C 3、C 4、C 5和C 6卤代烷氧基基团。卤代烷氧基的实例包括但不限于氟甲氧基、二氟甲氧基、三氟甲氧基、2-氟乙氧基、2,2,2-三氟乙氧基。卤代烷氧基的实例还包括“氟烷氧基”。
如本文所用，“芳基”是由一个环或多个环稠合构成的具有6-20个、优选6-14个、更优选6-12个、最优选6-10个、例如6-9个环碳原子的单环、双环或三环碳环烃基，其中至少一个环是芳族环，而其它环(如果存在的话)可以是芳族或非芳族的。优选的芳基是具有6-10个环碳原子的芳基，即C 6-C 10芳基，其包括：单环芳基(例如苯基)；或稠合二环系统，其中一个环是芳族环、而另一个环是芳族(例如在萘、联苯基中)或非芳族环(例如在二氢茚、四氢萘中)。芳基的非限制性示例包括苯基、联苯基、萘基、四氢萘基、茚基、二氢茚基或蒽基等。
如本文所用，“杂芳基”指含有1-8个、优选1-4个、还优选1-3个、更优选1或2个选自N、O或S的环杂原子的5-14元、优选5-10元、更优选5-7元或5-6元芳香族环系，包括单环或二环或稠合多环，其余环原子为碳原子。杂芳基优选为5-10元杂芳基，更优选为5-7元杂芳基或5-6元杂芳基，各自含有1、2或3个选自N、O或S的环杂原子。杂芳基的实例包括但不限于：吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、三唑基、噻唑基、异噻唑基、噁唑基、吡啶基、吡喃基、吡嗪基、哒嗪基、嘧啶基、噁嗪基、噁二嗪基、喹啉基、异喹啉基、噌啉基、喹唑啉基、喹喔啉基、苯并噁嗪基、2H-色烯、苯并吡喃基、苯并噻吩基、吲哚基、吲唑基、苯并咪唑基、苯并噁唑基、苯并噻唑基、7-氮杂吲哚基、6-氮杂吲哚基、5-氮杂吲哚基、4-氮杂吲哚基、1H-苯并[d][1,2,3]三唑基等。
如本文所用，“杂环烷基”指如本申请中所定义的环烷基，条件是一个或多个环碳被选自N、O或S的杂原子替换，所述杂原子例如是-O-、-N＝、-NR-、-S-、-S(＝O)-和-S(＝O) 2-，其中R是氢、C 1-4烷基或氮保护基(例如，苄氧羰基、对甲氧基苄基羰基、叔丁氧基羰基、乙酰基、苯甲酰基、苄基、对甲氧基-苄基、对甲氧基-苯基、3,4-二甲氧基苄基等)。优选地，杂环烷基是具有3-20个环原子、例如3-12个环原子、例如3-8个环原子、例如3-6个环原子的单环、二环或三环的饱和和部分不饱和非芳族环。更优选地，杂环烷基优选含有1、2或3个选自N、O或S的杂原子的4-至12-元杂环烷基，优选4-至8-元杂环烷基、更优选是4-至7-元、4-至6元或5-至6-元杂环烷基，其中所述杂原子是取代或未取代的，例如被C 1-C 4烷基取代。例如，杂环烷基的实例包括但不限于：环氧乙烷基、氮丙啶基、氮杂环丁烷基、氧杂环丁烷基、氮杂环戊烷基(吡咯烷基)、四氢呋喃基、四氢噻吩基、四氢噻吩基1,1-二氧化物、吡唑烷基、咪唑烷基、噁唑烷基、噻唑烷基、异噻唑烷基、吡咯烷基-2-酮、咪唑酮基、哌啶基(六氢吡啶)、N-甲基哌啶基、四氢吡喃基、噁嗪烷基、1,3-噁嗪烷基、六氢嘧啶基、哌嗪基、哌啶酮基(piperidinylone)、1,4-二氧杂-8-氮杂-螺[4.5]癸烷-8-基、吗啉代基、硫吗啉代基、硫代吗啉代-S-单氧化物(sulfanomorpholino)、硫代吗啉代-S,S-二氧化物(sulfonomorpholino)、八氢吡咯并[3,2-b]吡咯基等。
如本文所用，“部分或完全饱和的杂环”指部分或完全被氢化的非芳香族环，可以作为单环、双环(包括稠环)或螺环存在。除非另有说明，否则杂环通常是含有1至3个、例如1至3个、优选1或2个独立地选自S、O和/或N的杂原子的3-至12-元环、优选5-至10-元环、更优选9-10元的单环或双环环系，所述杂原子例如是-O-、-N＝、-NR-或-S-，其中R是氢、C 1-4烷基或氮保护基。当使用术语"部分或完全饱和的杂环"时，其意欲包括“杂环烷基”和"部分饱和的杂环"。螺环的实例包括2,6-二氮杂螺[3.3]庚烷基、3-氮杂螺[5.5]十一烷基、3,9-二氮杂螺[5.5]十一烷基等。部分饱和的杂环包括诸如二氢吡咯基、二氢呋喃基、二氢噁唑基、二氢吡啶基、咪唑啉基、1H-二氢咪唑基、2H-吡喃基、2H-色烯基、二氢噁嗪基等的基团。部分饱和的杂环还包括具有稠合的芳基或杂芳基环的杂环，优选具有9-10个环成员(例如二氢苯并呋喃基、二氢异苯并呋喃基、二氢吲哚基(或2,3-二氢吲哚基)、二氢苯并噻吩基、二氢苯并噻唑基、二氢苯并吡喃基、四氢喹啉基、四氢异喹啉基、四氢吡啶并[3,4-b]吡嗪基等)。
如本文所用，术语“-C(＝O)”为羰基，“-S(＝O)”为亚砜基、“-S(＝O) 2”为砜基。“＝O”表示氧代，即氧原子通过双键与其它原子连接。
本文所用的“任选”、“任选的”或“任选地”意指随后描述的事件可以发生或可以不发生，并且该描述包括所述事件发生的情形以及所述事件不发生的情形。例如，“任选被取代的烷基”包括本文定义的“未取代的烷基”和“被取代的烷基”。“任选被卤素取代”包括“被卤素取代”的情形和“未被卤素取代”的情形，例如被0-3个卤素取代。本领域技术人员应当理解的是，对于含有一个或多个取代基的任意基团而言，所述基团不包括任何在空间上不切实际的、化学上不正确的、合成上不可行的和/或内在不稳定的取代模式。
当在环结构中使用虚线环时，这表示环结构可以是饱和的、部分饱和的或不饱和的。
本文所用的术语“取代”、“取代的”或“被……取代”意指给定原子或基团上的一个或多个氢原子被一个或多个选自给定的取代基组的取代基替换，条件是不超过该给定原子的正常化合价。当取代基是氧代(即＝O)时，则单个原子上的两个氢原子被氧替换。在芳香族部分上不存在氧代取代基。当环系(例如碳环或杂环)被羰基基团或双键取代时，意欲羰基基团或双键是环的一部分(即，在环内)。只有当取代基和/或变量的组合导致化学上正确的且稳定的化合物时，这类组合才是允许的。化学上正确的且稳定的化合物意味着化合物足够稳定，以至于能从反应混合物中被分离出来并能确定化合物的化学结构，并且随后能被配制成至少具有实际效用的制剂。例如，在没有明确列出取代基的情况下，本文所用的术语“取代”、“被取代的”或“被……取代”意指给定的原子或基团上的一个或多个氢原子独立地被一个或多个、例如1、2、3或4个取代基取代。当一个原子或基团被多个取代基取代时，所述取代基可以相同或不同。
除非另有指出，否则术语“本发明化合物”或“本发明的化合物”指包括本发明的一种或多种本文定义的式(I)或其亚式、如式(I-1)、(I-2)的化合物，或其可药用盐，以及所有异构体如立体异构体(包括非对映异构体、对映异构体和外消旋物)、几何异构体、构象异构体(包括旋转异构体和阻转异构体)、互变异构体、异构体的内部加成产物、前药以及同位素标记的化合物(包括氘取代)和固有形成的部分(例如多晶型物、溶剂合物和/或水合物)。当存在能够形成盐的部分时，则也包括盐、特别是可药用盐。互变异构体或异构体的内部加成产物的存在可由本领域技术人员使用诸如NMR的工具来鉴别。本发明的式(I)化合物能够容易地形成如本文所描绘的互变异构体和异构体的内部加成产物。
本领域技术人员将认可，本发明的化合物可以含有手性中心，照此可以存在不同的异构形式。如本文所用的“异构体”指具有相同分子式、但是原子的排列和构型有区别的不同化合物。
如本文所用，“对映异构体”是相互为不可重叠的镜像的一对立体异构体。一对对映异构体的1:1混合物是"外消旋”混合物。合适时，该术语用于指外消旋混合物。当指示本发明的化合物的立体化学时，采用常规的RS系统指定了具有两个手性中心的已知的相对和绝对构型的单一立体异构体(例如(1S,2S))；具有已知的相对构型、但是绝对构型未知的单一立体异构体标示了星号(例如(1R*,2R*))；具有两个字母的外消旋物(例如(1RS,2RS)为(1R,2R)和(1S,2S)的外消旋混合物；(1RS,2SR)为(1R,2S)和(1S,2R))的外消旋混合物。"非对映异构体”是具有至少两个不对称原子、但是相互不为镜像的立体异构体。根据Cahn-lngold-Prelog R-S系统指明绝对立体化学。当化合物是纯的对映异构体时，各手性碳处的立体化学可以通过R或S说明。绝对构型未知的被拆分的化合物可以根据它们在钠D线波长处旋转平面偏振光的方向(右旋或左旋)指定为(+)或(-)。或者，被拆分的化合物可以通过相应的对映异构体/非对映异构体经由手性HPLC的各自的保留时间来定义。
本文所述的一些化合物含有一个或多个不对称中心或轴，因此可以产生对映异构体、非对映异构体和可以以绝对立体化学定义为(R)-或(S)-的其它立体异构体。
当化合物含有双键或一些其它的使得分子具有一定量结构刚性的特征时，可以发生几 何异构体。如果化合物含有双键，则取代基可以是E或Z构象。如果化合物含有二取代的环烷基，则环烷基取代基可以具有顺式或反式构型。
构象异构体是通过有关一个或多个价键的旋转而不同的异构体。旋转异构体是通过仅单个价键的旋转而不同的构象异构体。
"阻转异构体"指基于分子中的旋转受限所产生的轴向或平面手性的结构异构体。
除非另有说明，否则本发明的化合物意欲包括所有这类可能的异构体，包括外消旋混合物、具有旋光活性的形式和中间体混合物。具有旋光活性的(R)-和(S)-异构体可以采用手性合成子或手性试剂进行制备，或者采用常规技术进行拆分。
本发明的化合物可以分离为具有旋光活性的形式或外消旋形式。用旋光活性的形式可以通过外消旋形式的拆分或通过由具有旋光活性的原料合成来制备。用于制备本发明的化合物的所有方法和其中制备的中间体被认为是本发明的一部分。当制备对映体或非对映异构体产物时，它们可以通过常规方法如通过色谱法或分步结晶来进行分离。
根据方法条件，本发明的终产物以游离(中性)或盐形式获得。这些终产物的游离形式和盐形式在本发明的范围内。如果期望的话，则化合物的一种形式可以转化为其它形式。游离碱或酸可以转化为盐；盐可以转化为游离化合物或其它盐；本发明的同分异构化合物的混合物可以分离为单独异构体。
如本文所用，“可药用盐”指保持本发明化合物的生物学效应和性能的盐，并且该盐在生物学上或其它方面不是不被期望的。所述盐的非限制性示例包括本发明化合物的无毒的、无机或有机碱或酸的加成盐。在许多情况下，由于氨基和/或羧基或与之相似的基团的存在，本发明化合物能够形成酸盐和/或碱盐。可以用无机酸和有机酸形成药学上可接受的酸加成盐。可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。可以用无机和有机碱形成药学上可接受的碱加成盐。可以由其衍生得到盐的无机碱包括例如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝等；特别优选的是铵、钾、钠、钙和镁盐。可以由其衍生得到盐的有机碱包括例如伯胺、仲胺和叔胺、取代的胺(包括天然存在的取代的胺)、环状的胺、碱性离子交换树脂等，尤其例如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺和乙醇胺。通过常规化学方法，可以从母体化合物(碱性或酸性部分)合成本发明可药用盐。一般来讲，可以如下制备所述的盐：使所述化合物的游离酸形式与化学计算量的适当的碱(例如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应或使所述化合物的游离碱形式与化学计算量的适当的酸反应。这类反应通常在水或有机溶剂或两者的混合溶剂中进行。一般来讲，在可行时，非水介质例如醚、乙酸乙酯、乙醇、异丙醇或乙腈是优选的。其它合适的盐可以见于Remington氏药物科学(Remington's Pharmaceutical Sciences)，第20版，Mack出版公司(Mack Publishing Company)，Easton，Pa.，(1985)，将其引入文中作为参考。
如本文所用，“药学上可接受的赋形剂”包括任何和所有的溶剂、分散介质、包衣、 表面活性剂、抗氧化剂、防腐剂(例如抗菌剂、抗真菌剂)、等渗剂、吸收延迟剂、盐、防腐剂、药物、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、矫味剂、染料、所述类似的物质和其组合，其是本领域普通技术人员所公知的(见，例如，Remington氏药物科学(Remington's Pharmaceutical Sciences)，第18版，Mack出版公司(Mack Printing Company)，1990，pp.1289-1329，引入文中作为参考)。除非任何常规载体是与活性成分不能共存的，可以考虑在治疗或药物组合物中使用它。
本文所给的任意式还意欲代表化合物的未标记的形式以及同位素标记的形式。除了一个或多个原子被具有所选原子质量或质量数的原子所代替外，同位素标记的化合物具有本文所给的式所描述的结构。可以掺入到本发明的化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素，例如分别有 2H(即D)、 3H(即T)、 11C、 13C、 14C、 15N、 18F 31P、 32P、 35S、 36Cl、 125I。本发明包括如本文定义的不同的同位素标记的化合物，例如其中存在放射性同位素如 3H、 13C和 14C的那些。这类同位素标记的化合物可用于代谢研究(用 14C)、反应动力学研究(例如用 2H或 3H)、检测或显像技术、例如正电子发射断层扫描(PET)或单光子发射计算机断层扫描(SPECT)、包括药物或底物组织分布测定，或者可用于患者的放射性治疗。特别地， 18F或标记的化合物可以特别希望用于PET或SPECT研究。通常可以通过进行下文所述的流程中或实施例和制备例中所述的那些方法、用容易获得的同位素标记的试剂代替未同位素标记的试剂来制备同位素标记的本发明的化合物。
而且，被较重同位素、特别是氘(即 2H或D)所取代还可以获得由更大的代谢稳定性引起的某些治疗益处，例如延长体内半衰期或降低剂量要求或改善治疗指数。可以理解，上下文中的氘可被看作是本发明的化合物的取代基。这类较重同位素、特别是氘的浓度可以由同位素富集因子来定义。“同位素富集因子”表示指定同位素的同位素丰度和天然丰度之间的比值。
如本文所用，本发明化合物的“治疗有效量”指可以引起个体生物学或医学反应或改善症状、减慢或延缓疾病恶化或预防疾病等的本发明化合物的量。“治疗有效量”可以由参与医师或兽医执业者来确定，并且将随着化合物、所治疗的疾病状态、所治疗的疾病的严重程度、个体的年龄和相关健康状况、施用途径和形式、主治医师或兽医执业者的判断等因素而变化。
如本文所用，“个体”指动物。优选地，动物是哺乳动物。个体还指例如灵长类(例如人类)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟等。在一优选实施方案中，个体是人。
如本文所用，“抑制”指特定的病患、症状或病症或疾病的减轻或抑制，或者生物学活性或过程基线活性的显著降低。
如本文所用，在一个实施方案中术语"治疗"任何疾病或病症指改善疾病或病症(即阻止或减缓疾病或其至少一种临床症状的发展)。在另一个实施方案中，“治疗”指改善至少一种身体参数，其可能不为患者所察觉。在另一个实施方案中，“治疗"指身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。
如本文所用，“预防”指给具有易患所述疾病的体质的个体施用一种或多种药物物质、特别是本发明的化合物和/或其可药用盐，用以防止个体罹患该疾病。
一般而言，术语“约”在本文中用于将所给出的数值调整至高于或低于该数值20％、例如10％、例如5％。
本文所用的未具体定义的技术和科学术语具有本发明所属领域的技术人员通常理解的含义。
具体实施方式
以下实施例说明上述本发明，然而其不以任何方式限制本发明的范围。本发明的组合的有益效果也可以通过本领域技术人员已知的其他测试模型确定。
本发明中，所用试剂、设备的来源和商品名，均在首次出现时标明，其后所用相同试剂如无特殊说明，均与首次标明的内容相同，常规未标注试剂购自国药集团化学试剂有限公司。
反应通式A
Figure PCTCN2022136109-appb-000024
化合物1-a溶于惰性溶剂中，碱性条件下与氯乙酸甲酯反应，得到中间体2-a；中间体化合物2-a与连有R 1基团的硼酸通过偶联反应，在碱性条件下，得到中间体3-a；中间体化合物3-a与惰性溶剂中，在低温条件下与氯磺酰异氰酸酯反应得到中间体化合物4-a；化合物4-a在极性溶剂中，碱性条件下关环得到化合物5-a。
反应通式B
Figure PCTCN2022136109-appb-000025
化合物5-a在诸如乙腈等极性溶剂中，于有机碱及诸如1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐等缩合试剂的作用下与包含R 2的亲核试剂反应，得到通式化合物I。
反应通式C
Figure PCTCN2022136109-appb-000026
化合物5-a溶于有机溶剂中，在惰性气体的保护下，与三氯氧磷在诸如三乙胺的有机碱作用下，得到氯化中间体6-a；中间体6-a与诸如甲基氨等含有R 2基团的亲核试剂反应得到通式化合物I。
反应通式D
Figure PCTCN2022136109-appb-000027
化合物1-b溶解于诸如二甲亚砜等极性非质子溶剂中，与诸如甘氨酸甲酯等包含W部分的酯在加热条件下反应得到中间体2-a；化合物2-a与卤代R 1试剂在含Pd等金属的催化剂以及含P元素的配体作用下，通过偶联反应得到中间体化合物3-a；化合物3-a在低温条件下与氯磺酰异氰酸酯反应得到中间体化合物4-a；化合物4-a在碱性条件下关环得到化合物5-a。
在如上所述的通式中，W、R 1、R 2、R 3、R 4、R 5、R 6各取代基的定义分别如上所述。
实施例1.化合物1-A的合成
Figure PCTCN2022136109-appb-000028
第一步：中间体化合物2-1的合成
反应在100mL三口瓶中进行。将5-氯-2-羟基苯腈1-1(5.0g，32.47mmol)、氯乙酸甲酯(3.5g，32.47mmol)、碳酸钾(9.0g，64.94mmol)用DMF(15mL)溶解，氮气保护下80℃搅拌6h直至反应完全。将反应液倒入200mL水中，析出大量固体，过滤，滤饼用少量水冲洗，然后用EA溶解，用分液漏斗分出残留的少量的水，有机相用无水硫酸钠干燥，过滤，滤液旋干得到化合物2-1，白色固体(8.5g，收率>100％)，无需纯化，可直接用于下一步。 1H NMR(400MHz,DMSO)δ8.08(d,J＝1.8Hz,1H),7.57–7.47(m,2H),6.42(s,2H),3.82(s,3H).LCMS(ESI)m/z＝226.0[M+H] +.
第二步：中间体化合物3-1的合成
反应在100mL三口瓶中进行。将上一步反应得到的化合物2-1(2.0g，8.87mmol)、间甲基苯硼酸(2.4g，17.74mmol)、醋酸铜(1.9g，8.87mmol)、4A分子筛(0.25g)用DCM(30mL)溶解，再加入2.5mL三乙胺，插上氧气球，置换三次成氧气氛，室温下搅拌12h直至反应完全。将反应液用硅藻土过滤，滤饼用二氯甲烷冲洗几次，合并滤液，加硅胶拌样，旋干，然后用石油醚：乙酸乙酯(50：1)过柱，得到化合物3-1为橘红色油状物(2.12g，收率：76％)。 1H NMR(400MHz,DMSO)δ8.25(s,1H),7.70(d,J＝8.9Hz,1H),7.54(dd,J 1＝8.9Hz,J 2＝2.2Hz,1H),7.20(t,J＝7.8Hz,1H),7.13(d,J＝2.1Hz,1H),6.95(s,1H),6.92–6.87(m,2H),3.85(s,3H),2.27(s,3H).
第三步：中间体化合物4-1的合成
反应在250mL三口瓶中进行。将中间体3-1(2.0g，6.35mmol)加入THF(30ml)中，氮气保护温度降至-15℃，加入化合物氯磺酰异氰酸酯(1.34g,9.52mmol)搅拌1h。加入氯化铵水溶液(20ml)淬灭，加入水(200ml)，用EA(200ml)萃取两次，浓缩有机相得到化合物4-1(2.2g，收率：97.9％)白色固体。LCMS(ESI)m/z＝359.0[M+H] +.
第四步：化合物1-A的合成
反应在100mL三口瓶中进行。将中间体4-1(2.2g，6.13mmol)用甲醇(30ml)溶解，加入氢氧化钠(490mg,12.26mmol)氮气保护下60℃搅拌2h。用1mol/L HCl将pH调至3～4，过滤得到白色固体1-A(1.2g,收率：60.0％)。LCMS(ESI)m/z＝327.0[M+H] +.
化合物1-B:是用4-氯-2-羟基苯甲腈代替实施例1中合成步骤第一步中的起始原料5-氯-2-羟基苯腈1-1，参照实施例1的方法，制备得到。
Figure PCTCN2022136109-appb-000029
1H NMR(400MHz,DMSO)δ11.88(s,1H),8.02(d,J＝1.5Hz,1H),7.53(d,J＝7.6Hz,1H),7.47(d,J＝7.7Hz,1H),7.45–7.38(m,2H),7.27(dd,J 1＝8.7Hz,J 2＝1.6Hz,1H),6.09(d,J＝8.7Hz,1H),2.41(s,3H).
参照实施例1的方法，将合成步骤第一步中的起始原料5-氯-2-羟基苯腈1-1分别替 换为5-氟-2-羟基苯氰、2-氯-6-羟基苯腈，分别制备得到化合物1-C、1-D。
化合物1-C：
Figure PCTCN2022136109-appb-000030
1H NMR(400MHz,DMSO)δ11.90(s,1H),7.86(dd,J 1＝9.2Hz,J 2＝4.0Hz,1H),7.55(t,J＝7.6Hz,1H),7.51–7.39(m,4H),5.68(dd,J 1＝8.4Hz,J 2＝2.4Hz,1H),2.42(s,3H).
化合物1-D：
Figure PCTCN2022136109-appb-000031
LCMS(ESI)m/z＝327.0[M+H] +.
参照实施例1的方法，将合成步骤第二步中的间甲基苯硼酸分别替换为间氯苯硼酸、间氟苯硼酸、邻甲基苯硼酸、对甲基苯硼酸，分别制备得到化合物1-E、 化合物1-F、 化 合物1-G、 化合物1-H。
化合物1-E：
Figure PCTCN2022136109-appb-000032
LCMS(ESI)m/z＝347.10[M+H] +.
化合物1-F：
Figure PCTCN2022136109-appb-000033
LCMS(ESI)m/z＝331.10[M+H] +.
化合物1-G：
Figure PCTCN2022136109-appb-000034
LCMS(ESI)m/z＝327.0[M+H] +.
化合物1-H：
Figure PCTCN2022136109-appb-000035
1H NMR(400MHz,DMSO)δ11.90(s,1H),7.85(d,J＝9.0Hz,1H),7.61(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.53–7.43(m,4H),6.03(d,J＝2.2Hz,1H),2.47(s,3H).LCMS(ESI)m/z＝327.0[M+H] +.
实施例2.化合物17的合成
Figure PCTCN2022136109-appb-000036
反应在10mL微波管中进行。将1-A(150mg，0.46mmol)用乙腈(2ml)溶解，加入PyBOP(358mg,0.69mmol)，DBU(140mg,0.92mmol)，2-氨基乙烷-1-醇(56mg,0.920mmol)。微波50℃反应2h。通过Prep-HPLC(H 2O/ACN,0.1％TFA)纯化得到9mg17，白色固体，收率6％。 1H NMR(400MHz,DMSO)δ8.82(s,1H),7.79(d,J＝9.0Hz,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.53(t,J＝7.7Hz,1H),7.45(d,J＝7.6Hz,1H),7.37–7.26(m,2H),6.09(d,J＝2.2Hz,1H),3.63(t,J＝5.6Hz,2H),3.60–3.55(m,2H),2.41(s,3H).LCMS(ESI)m/z＝370.1[M+H] +.
参照前述的方法，分别用甲胺、环丙胺、四氢吡咯、3-羟基吡咯烷、N-甲基乙胺、异丙胺、DL-氨基丙醇、环丁基胺、顺式-3-氨基环丁醇、反式-3-氨基环丁醇、3-氧杂环丁胺、3-氨基四氢呋喃、4-氨基四氢吡喃、1-甲基-1H-吡唑-5-甲胺、乙胺、2-甲氧基乙胺、3-氨基-1-丙醇、环丙基甲基胺、N,N-二甲基乙二胺、N-乙酰基乙二胺代替其中的2-氨基乙烷-1-醇与1-A反应，分别制备得到化合物1、18、19、20、21、24、25、26、28、29、30、31、33、35、36、37、38、39、40、41。
化合物1:
Figure PCTCN2022136109-appb-000037
1H NMR(400MHz,DMSO)δ8.59(d,J＝4.4Hz,1H),7.77(d,J＝9.2Hz,1H),7.57(dd, J＝9.0,2.2Hz,1H),7.52(t,1H),7.43(d,J＝7.6Hz,1H),7.32–7.25(m,2H),6.10(d,J＝2.4Hz,1H),2.97(d,J＝4.4Hz,3H),2.41(s,3H).LCMS(ESI)m/z＝340.0[M+1] +.
化合物18:
Figure PCTCN2022136109-appb-000038
1H NMR(400MHz,DMSO)δ8.73(s,1H),7.74(d,J＝8.9Hz,1H),7.57(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.52(t,J＝7.7Hz,1H),7.44(d,J＝7.6Hz,1H),7.34–7.27(m,2H),6.09(d,J＝2.1Hz,1H),3.08(dd,J 1＝7.3Hz,J 2＝3.5Hz,1H),2.41(s,3H),0.79(d,J＝7.1Hz,2H),0.72(t,J＝3.9Hz,2H).LCMS(ESI)m/z＝366.1[M+H] +.
化合物19:
Figure PCTCN2022136109-appb-000039
1H NMR(400MHz,DMSO)δ7.80(d,J＝9.0Hz,1H),7.57(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.52(t,J＝7.7Hz,1H),7.44(d,J＝7.6Hz,1H),7.29(s,1H),7.25(d,J＝7.9Hz,1H),6.04(d,J＝2.2Hz,1H),4.06(t,J＝6.7Hz,2H),3.66(t,J＝6.8Hz,2H),2.41(s,3H),2.11–2.02(m,2H),1.98–1.89(m,2H).LCMS(ESI)m/z＝380.1[M+H] +.
化合物20:
Figure PCTCN2022136109-appb-000040
1H NMR(400MHz,DMSO)δ7.81(dd,J 1＝8.9Hz,J 2＝5.2Hz,1H),7.57(dd,J 1＝9.0Hz,J 2＝2.1Hz,1H),7.52(t,J＝7.7Hz,1H),7.44(d,J＝7.6Hz,1H),7.28(d,J＝15.7Hz,2H),6.04(d,J＝2.1Hz,1H),5.15(d,J＝28.3Hz,1H),4.47(d,J＝39.9Hz,1H),4.28–3.95(m,2H),3.85–3.58(m,2H),2.41(s,3H),2.13(m,1H),2.06–1.87(m,1H).LCMS(ESI)m/z＝396.1[M+1] +.
化合物21:
Figure PCTCN2022136109-appb-000041
1H NMR(400MHz,CDCl 3)δ7.53–7.37(m,4H),7.25–7.15(m,2H),6.19(s,1H),4.04(s,2H),3.50(s,3H),2.45(s,3H),1.40(s,3H).LCMS(ESI)m/z＝368.1[M+H] +.
化合物24:
Figure PCTCN2022136109-appb-000042
1H NMR(400MHz,DMSO)δ8.50(d,J＝8.0Hz,1H),7.75(d,J＝8.9Hz,1H),7.57(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.52(t,J＝7.6Hz,1H),7.43(d,J＝7.7Hz,1H),7.32(s,1H),7.29(d,J＝7.8Hz,1H),6.09(d,J＝2.1Hz,1H),4.42(m,1H),2.41(s,3H),1.26(d,J＝6.6Hz,6H).LCMS(ESI)m/z＝368.0[M+1] +.
化合物25:
Figure PCTCN2022136109-appb-000043
1H NMR(400MHz,DMSO)δ8.34(d,J＝8.1Hz,1H),7.76(d,J＝9.0Hz,1H),7.58(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.52(t,J＝7.7Hz,1H),7.43(d,J＝7.6Hz,1H),7.32(s,1H),7.29(d,J＝7.7Hz,1H),6.09(d,J＝2.0Hz,1H),4.84(t,J＝5.7Hz,1H),4.40–4.26(m,1H),3.56(dd,J 1＝11.0Hz,J 2＝5.5Hz,1H),3.44(dd,J 1＝11.1Hz,J 2＝5.6Hz,1H),2.41(s,3H),1.21(d,J＝6.7Hz,3H).LCMS(ESI)m/z＝384.0[M+1] +.
化合物26:
Figure PCTCN2022136109-appb-000044
1H NMR(400MHz,DMSO)δ8.88(d,J＝7.5Hz,1H),7.76(d,J＝8.9Hz,1H),7.58(dd,J 1＝9.0Hz,J 2＝2.1Hz,1H),7.51(t,J＝7.6Hz,1H),7.43(d,J＝7.6Hz,1H),7.33–7.25(m,2H),6.08(d,J＝2.1Hz,1H),4.67(m,1H),2.40(s,3H),2.27–2.29(m,2H),2.22–2.12(m, 2H),1.70–1.76(m,2H).LCMS(ESI)m/z＝380.2[M+1] +.
化合物28:
Figure PCTCN2022136109-appb-000045
1H NMR(400MHz,DMSO)δ8.87(d,J＝7.1Hz,1H),7.77(d,J＝9.0Hz,1H),7.58(dd,J 1＝9.0,J 2＝2.1Hz,1H),7.51(t,J＝7.7Hz,1H),7.43(d,J＝7.7Hz,1H),7.31(s,1H),7.28(d,J＝7.9Hz,1H),6.08(d,J＝2.1Hz,1H),5.17(d,J＝5.6Hz,1H),4.13(d,J＝7.3Hz,1H),3.90(d,J＝6.6Hz,1H),2.64–2.54(m,2H),2.40(s,3H),2.01(d,J＝8.7Hz,2H).LCMS(ESI)m/z＝396.1[M+1] +.
化合物29:
Figure PCTCN2022136109-appb-000046
1H NMR(400MHz,DMSO)δ9.09(d,J＝6.3Hz,1H),7.78(d,J＝9.0Hz,1H),7.61–7.57(m,1H),7.51(t,J＝7.7Hz,1H),7.45(s,1H),7.32(s,1H),7.29(d,J＝7.7Hz,1H),6.08(d,J＝2.1Hz,1H),4.69–4.60(m,1H),4.33–4.38(m,1H),2.54(s,1H),2.41(s,3H),2.37–2.43(m,2H),2.20–2.27(m,2H).LCMS(ESI)m/z＝396.1[M+1] +.
化合物30:
Figure PCTCN2022136109-appb-000047
1H NMR(400MHz,DMSO)δ9.34(d,J＝5.1Hz,1H),7.80(d,J＝9.0Hz,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.51(d,J＝7.6Hz,1H),7.44(d,J＝7.6Hz,1H),7.33–7.26(m,2H),6.09(d,J＝2.1Hz,1H),5.18(dd,J 1＝12.7Hz,J 2＝6.5Hz,1H),4.83(t,J＝6.8Hz,2H),4.69(t,J＝6.5Hz,2H),2.41(s,3H).LCMS(ESI)m/z＝382.0[M+1] +.
化合物31:
Figure PCTCN2022136109-appb-000048
1H NMR(400MHz,DMSO)δ8.82(d,J＝6.5Hz,1H),7.76(d,J＝9.0Hz,1H),7.58(dd,J 1＝8.9Hz,J 2＝2.2Hz,1H),7.52(t,J＝7.7Hz,1H),7.44(d,J＝7.6Hz,1H),7.34–7.27(m,2H),6.09(d,J＝1.9Hz,1H),4.71(d,J＝6.5Hz,1H),3.92(q,J＝8.2Hz,2H),3.73(ddd,J 1＝12.9Hz,J 2＝11.4Hz,J 3＝6.1Hz,2H),2.41(s,3H),2.23(dq,J＝14.8,7.6Hz,1H),2.06(td,J＝12.5,6.0Hz,1H).LCMS(ESI)m/z＝396.0[M+1] +.
化合物33:
Figure PCTCN2022136109-appb-000049
1H NMR(400MHz,DMSO)δ9.09(s,1H),7.80(d,J＝9.0Hz,1H),7.62(dd,J 1＝8.9Hz,J 2＝2.1Hz,1H),7.54(t,J＝7.6Hz,1H),7.47(d,J＝7.8Hz,1H),7.36–7.30(m,2H),6.08(d,J＝2.1Hz,1H),4.35–4.32(m,1H),3.94(d,J＝8.2Hz,2H),3.42(t,J＝11.2Hz,2H),2.42(s,3H),1.85(d,J＝10.3Hz,2H),1.73(dd,J 1＝11.0Hz,J 2＝8.0Hz,2H).LCMS(ESI)m/z＝410.2[M+1] +.
化合物35:
Figure PCTCN2022136109-appb-000050
1H NMR(400MHz,DMSO)δ9.29(t,J＝5.2Hz,1H),7.78(d,J＝9.0Hz,1H),7.59(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.52(t,J＝7.8Hz,1H),7.44(d,J＝7.6Hz,1H),7.33(d,J＝1.6Hz,2H),7.30(d,J＝8.0Hz,1H),6.25(d,J＝1.6Hz,1H),6.08(d,J＝2.2Hz,1H),4.74(d,J＝5.0Hz,2H),3.90(s,3H),2.40(s,3H).LCMS(ESI)m/z＝420.1[M+1] +.
化合物36:
Figure PCTCN2022136109-appb-000051
1H NMR(400MHz,DMSO)δ8.65(s,1H),7.76(d,J＝9.0Hz,1H),7.57(dd,J＝8.9,2.2 Hz,1H),7.51(t,J＝7.7Hz,1H),7.43(d,J＝7.6Hz,1H),7.31(s,1H),7.28(d,J＝7.9Hz,1H),6.09(d,J＝2.1Hz,1H),3.50(dd,J 1＝6.4Hz,J 2＝2.8Hz,2H),2.40(s,3H),1.21(t,J＝7.2Hz,3H).LCMS(ESI)m/z＝353.95[M+1] +.
化合物37:
Figure PCTCN2022136109-appb-000052
1H NMR(400MHz,DMSO)δ8.67(t,J＝5.4Hz,1H),7.78(d,J＝8.9Hz,1H),7.58(dd,J＝9.0,1.9Hz,1H),7.52(t,J＝7.6Hz,1H),7.44(d,J＝7.7Hz,1H),7.32(s,1H),7.29(d,J＝7.7Hz,1H),6.09(d,J＝1.7Hz,1H),3.64(t,J＝5.4Hz,2H),3.58(d,J＝5.3Hz,2H),3.30(s,3H),2.41(s,3H).LCMS(ESI)m/z＝384.0[M+1] +.
化合物38:
Figure PCTCN2022136109-appb-000053
1H NMR(400MHz,DMSO)δ8.61(s,1H),7.77(d,J＝9.0Hz,1H),7.57(m,J＝9.0Hz,1H),7.52(t,J＝7.7Hz,1H),7.43(d,J＝7.6Hz,1H),7.32(s,1H),7.29(d,J＝7.8Hz,1H),6.09(d,J＝2.0Hz,1H),4.60(t,J＝5.1Hz,1H),3.56–3.47(m,4H),2.41(s,3H),1.83–1.74(m,2H).LCMS(ESI)m/z＝384.1[M+1] +.
化合物39:
Figure PCTCN2022136109-appb-000054
1H NMR(400MHz,DMSO)δ9.14–9.05(m,1H),7.79(d,J＝9.0Hz,1H),7.61(dd,J 1＝9.0,J 2＝2.1Hz,1H),7.52(d,J＝7.7Hz,1H),7.46(s,1H),7.34(s,1H),7.31(d,J＝7.8Hz,1H),6.09(d,J＝2.0Hz,1H),3.38(t,J＝6.3Hz,2H),2.41(s,3H),1.25–1.13(m,1H),0.50(d,J＝7.9Hz,2H),0.33(d,J＝4.9Hz,2H).LCMS(ESI)m/z＝380.1[M+1] +.
化合物40:
Figure PCTCN2022136109-appb-000055
1H NMR(400MHz,DMSO)δ8.47(t,J＝5.3Hz,1H),7.77(d,J＝9.0Hz,1H),7.57(dd,J 1＝8.9Hz,J 2＝2.2Hz,,1H),7.51(t,J＝7.7Hz,1H),7.43(d,J＝7.6Hz,1H),7.31(s,1H), 7.28(d,J＝7.9Hz,1H),6.08(d,J＝2.1Hz,1H),3.57(q,J＝6.3Hz,2H),2.52(q,J＝6.3Hz,2H),2.40(s,3H),2.20(s,6H).LCMS(ESI)m/z＝397.0[M+1] +.
化合物41:
Figure PCTCN2022136109-appb-000056
1H NMR(400MHz,DMSO)δ8.64(t,J＝5.4Hz,1H),8.05(t,J＝5.2Hz,1H),7.78(d,J＝9.2Hz,1H),7.58(dd,J 1＝8.8Hz,J 2＝2.0Hz,1H),7.52(t,J＝7.6Hz,1H),7.44(d,J＝7.6Hz,1H),7.32(s,1H),7.28(d,J＝7.6Hz,1H),6.10(d,J＝1.6Hz,1H),3.52(dd,J 1＝12.4Hz,J 2＝6.4Hz,2H),3.32(dd,J 1＝12.4Hz,J 2＝6.4Hz,2H),2.41(s,3H),1.83(s,3H).LCMS(ESI)m/z＝411.0[M+1] +.
参照实施例2.化合物17的合成方法，用甲胺代替实施例2中的2-氨基乙烷-1-醇，分别与1-B、1-C、1-D反应，可分别制备得到化合物6、化合物3、化合物5。
化合物6:
Figure PCTCN2022136109-appb-000057
1H NMR(400MHz,DMSO)δ＝9.15(s,1H),7.96(d,J＝1.6Hz,1H),7.52(t,J＝7.6Hz,1H),7.43(d,J＝7.6Hz,1H),7.34–7.27(m,3H),6.19(d,J＝8.6Hz,1H),3.02(d,J＝3.6Hz,3H),2.40(s,3H).
LCMS(ESI)m/z＝340.1[M+H] +.
化合物3:
Figure PCTCN2022136109-appb-000058
1H NMR(400MHz,DMSO)δ8.57(d,J＝4.8Hz,1H),7.78(dd,J 1＝9.2Hz,J 2＝4.0Hz,1H),7.51(t,J＝7.6Hz,1H),7.45–7.39(m,2H),7.30(s,1H),7.27(d,J＝7.6Hz,1H),5.79(dd,J 1＝8.4Hz,J 2＝2.8Hz,1H),2.97(d,J＝4.8Hz,3H),2.41(s,3H).LCMS(ESI)m/z＝324.1[M+H] +.
化合物5:
Figure PCTCN2022136109-appb-000059
1H NMR(400MHz,DMSO)δ7.76(d,J＝8.4Hz,1H),7.54–7.37(m,5H),7.23(dd,J＝7.8,0.7Hz,1H),6.03(s,1H),2.74(d,J＝4.3Hz,3H),2.39(s,3H).LCMS(ESI)m/z＝339.9[M+H] +.
参照实施例2.化合物17的合成方法，用环丙胺代替实施例2中的2-氨基乙烷-1-醇，分别与化合物1-E、化合物1-F、化合物1-G、化合物1-H反应，可分别制备得到化合物42、化合物43、化合物45、化合物46。
化合物42:
Figure PCTCN2022136109-appb-000060
1H NMR(400MHz,DMSO)δ8.79(d,J＝4.3Hz,1H),7.77(d,J＝9.0Hz,1H),7.74–7.69(m,2H),7.69–7.64(m,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.1Hz,1H),7.53(dd,J 1＝7.4Hz,J 2＝1.6Hz,1H),6.17(d,J＝2.0Hz,1H),3.08(d,J＝3.9Hz,1H),0.79(dd,J 1＝6.8Hz,J 2＝4.7Hz,2H),0.72(t,J＝3.8Hz,2H).LCMS(ESI)m/z＝386.04[M+1] +.
化合物43:
Figure PCTCN2022136109-appb-000061
1H NMR(400MHz,DMSO)δ8.79(d,J＝4.2Hz,1H),7.77(d,J＝8.9Hz,1H),7.69(dd,J 1＝15.1Hz,J 2＝7.8Hz,1H),7.60(dd,J 1＝8.9Hz,J 2＝2.1Hz,1H),7.50(t,J＝8.1Hz,2H),7.40(d,J＝8.1Hz,1H),6.16(d,J＝2.0Hz,1H),3.08(d,J＝3.8Hz,1H),0.80(d,J＝7.2Hz,2H),0.72(t,J＝3.9Hz,2H).LCMS(ESI)m/z＝369.9[M+1] +.
化合物45:
Figure PCTCN2022136109-appb-000062
1H NMR(400MHz,DMSO)δ8.75(s,1H),7.75(d,J＝8.9Hz,1H),7.59–7.49(m,3H),7.43(dd,J 1＝17.1,J 2＝5.1Hz,2H),5.90(s,1H),3.10(s,1H),2.07(d,J＝3.5Hz,3H),0.80(d,J＝7.2Hz,2H),0.73(s,2H).LCMS(ESI)m/z＝366.0[M+1] +.
化合物46:
Figure PCTCN2022136109-appb-000063
1H NMR(400MHz,DMSO)δ9.34(s,1H),7.79(d,J＝9.0Hz,1H),7.65–7.58(m,1H),7.47(d,J＝8.2Hz,2H),7.40(d,J＝8.2Hz,2H),6.13(d,J＝2.0Hz,1H),3.02(td,J 1＝6.6Hz,J 2＝4.0Hz,1H),2.48(s,3H),0.90–0.81(m,2H),0.81–0.72(m,2H).LCMS(ESI)m/z＝366.1[M+1] +.
参照实施例2化合物17的合成方法，用甲胺代替实施例2中的2-氨基乙烷-1-醇，与1-G反应，可制备得到化合物64。
化合物64：
Figure PCTCN2022136109-appb-000064
1H NMR(400MHz,DMSO)δ8.63(d,J＝4.6Hz,1H),7.78(d,J＝9.0Hz,1H),7.57(dd,J 1＝8.9Hz,J 2＝2.2Hz,1H),7.55–7.51(m,2H),7.48–7.42(m,1H),7.40(d,J＝7.5Hz,1H),5.91(d,J＝2.1Hz,1H),2.98(d,J＝4.6Hz,3H),2.06(s,3H).LCMS(ESI)m/z＝340.0[M+1] +.
实施例3.化合物2的合成
Figure PCTCN2022136109-appb-000065
第一步：中间体化合物1-A-1的合成
反应在25ml单口烧瓶中进行。将化合物1-A(100mg，0.3mmol)、Pd/C(10mg)、甲醇(5ml)投入单口烧瓶中，用氢气置换三次，室温搅拌反应过夜，取样检测原料反应完全。后处理：将反应液过滤，滤液减压浓缩至干，得到化合物1-A-1(80.0mg，收率：89.5％)，白色固体，无需纯化直接进行下一步反应。
LCMS(ESI)m/z＝293.1[M+H] +.
第二步：化合物2的合成
反应在微波管中进行。将化合物1-A-1(80mg，0.27mmol)、PyBOP(213.3mg，0.41mmol)溶解于乙腈(6ml)中，室温滴加DBU(83.7mg，0.55mmol)，滴加完毕后室温搅拌0.5小时，然后滴加1M甲胺四氢呋喃(1.1ml，1.1mmol)溶液，微波50℃反应1小时，送样检测。后处理：将反应液旋干，用二氯甲烷(50ml)萃取二遍，有机层用纯化水、饱和食盐水各洗涤二遍，用无水硫酸钠干燥，过滤减压浓缩至干，Prep-HPLC(0.1％三氟乙酸体系)纯化、冻干得4-(甲基氨基)1-(间-苯甲基)苯并呋喃[3,2-d]嘧啶2(1H)-酮(化合物2)为白色固体(5.7mg，收率：6.8％)。 1H NMR(400MHz,MeOD)δ7.71(d,J＝8.8Hz,1H),7.64–7.56(m,2H),7.53(d,J＝7.6Hz,1H),7.40(s,1H),7.36(d,J＝7.6Hz,1H),7.18(t,J＝7.8Hz,1H),6.37(d,J＝8.0Hz,1H),3.23(s,3H),2.50(s,3H).LCMS(ESI)m/z＝306.0[M+H] +.
实施例4.化合物4的合成
Figure PCTCN2022136109-appb-000066
第一步：中间体化合物2-4的合成
反应在100mL茄型烧瓶中进行。将2-羟基-5-三氟甲基苯腈1-4(500mg，2.673mmol)溶于DMF(8mL)中，再分别加入氯乙酸甲酯(318mg，2.941mmol)，碳酸钾(553mg，4.010mmol)，60℃下搅拌12h直至反应完全。冷却反应混合物至室温，加入水(20ml)过滤，滤饼干燥得到化合物2-4(400mg，收率：57.7％)为黄色固体。LCMS(ESI)m/z＝260.0[M+H] +.
第二步：中间体化合物3-4的合成
反应在100mL三口瓶中进行。将上一步反应得到的中间体2-4(400mg，1.538mmol)溶于6mL THF溶液，加入叔丁醇钾(190mg,1.698mmol)，冰浴搅拌2h。向体系中加入饱和氯化铵水溶液20mL，用20mL乙酸乙酯萃取三次，将有机相用无水硫酸钠干燥后在真空中浓缩反应混合物得到化合物3-4(240mg,收率：60.0％)黄色固体。 1H NMR(400MHz,DMSO)δ8.50(s,1H),7.82(dd,J 1＝8.8Hz,J 2＝1.8Hz,1H),7.72(d,J＝8.8Hz,1H),6.56(s,2H),3.84(s,3H).
第三步：中间体化合物4-4的合成
反应在100mL三口瓶中进行。将中间体化合物3-4(240mg，0.926mmol)，3-甲基苯硼酸(250mg，1.853mmol)，醋酸铜(84mg，0.463mmol)，三乙胺(94mg,0.926mmol)用5mL DCM溶解，用氧气球置换三次,常温搅拌12h。将反应液过滤，滤液浓 缩得粗品，粗品通过硅胶快速色谱柱(PE:EA＝10:1)纯化得到化合物4-4(200mg，收率：61.8％)为黄色固体。LCMS(ESI)m/z＝350.0[M+H] +.
第四步：中间体化合物5-4的合成
反应在100mL三口瓶中进行。将中间体4-4(200mg，0.573mmol)加入THF(5ml)中，氮气保护温度降至-15℃，加入化合物氯磺酰异氰酸酯(122mg,0.865mmol)搅拌1小时。加入氯化铵水溶液(5ml)淬灭,加入水(20ml),用EA(20ml)萃取两次，浓缩有机相得到化合物5-4(220mg，收率：97.9％)白色固体。LCMS(ESI)m/z＝393.0[M+H] +.
第五步：中间体化合物6-4的合成
反应在100mL三口瓶中进行。将中间体5-4(220mg，0.559mmol)用甲醇(3ml)溶解，加入氢氧化钠(45mg,1.125mmol)氮气保护下60℃搅拌2h。用1mol/L HCl将PH调至3～4，过滤得到化合物6-4(50mg,收率：24.8％)。LCMS(ESI)m/z＝361.0[M+H] +.
第六步：化合物4的合成
反应在10mL微波管中进行。将中间体6-4(50mg，0.138mmol)用乙腈(1ml)溶解，加入PyBOP(108mg,0.207mmol)，加入DBU(42mg,0.276mmol)常温搅拌30min，加入2M的甲胺四氢呋喃溶液0.3ml，微波50℃反应1小时。Prep-TLC纯化得到80mg粗品，粗品经过Prep-HPLC(H 2O/ACN,0.1％TFA)纯化得到6mg白色固体4。 1H NMR(400MHz,DMSO)δ8.84(s,1H),7.97(d,J＝8.8Hz,1H),7.92–7.86(m,1H),7.53(t,J＝7.6Hz,1H),7.46(d,J＝7.7Hz,1H),7.36–7.30(m,2H),6.45(s,1H),3.01(d,J＝4.6Hz,3H),2.40(s,3H).LCMS(ESI)m/z＝374.2[M+H] +.
参照实施例4(化合物4)的合成方法，将合成步骤第一步当中的2-羟基-5-三氟甲基苯腈替换为2-氰基-3-羟基吡啶，可相应制备得到化合物7。
化合物7:
Figure PCTCN2022136109-appb-000067
1H NMR(400MHz,DMSO)δ9.19(s,1H),8.45(dd,J 1＝4.6Hz,J 2＝1.1Hz,1H),8.21(dd,J 1＝8.6Hz,J 2＝1.1Hz,1H),7.56(dd,J 1＝8.6Hz,J 2＝4.6Hz,1H),7.39(t,J＝7.7Hz,1H),7.29(d,J＝7.6Hz,1H),7.25–7.20(m,2H),3.04(d,J＝3.6Hz,3H),2.37(s,3H).LCMS(ESI)m/z＝307.1[M+1] +.
实施例5.化合物10的合成
Figure PCTCN2022136109-appb-000068
第一步：中间体化合物2-10的合成
反应在250mL三口瓶中进行，将3-氰基-2氟吡啶1-10(2.0g，16.4mmol)溶于四氢呋喃(20mL)，氮气保护下将羟乙酸甲酯(1.62g，18.0mmol)用10mL THF溶解然后加入到反应液中，反应液冷至0℃，向反应体系里缓慢加入叔丁醇钾(5.5g,49.0mmol)，加完冰浴搅拌60min，反应液由无色变为黄色。待反应完全，向反应液中加入100mL饱和氯化铵并用100mL乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥后旋干拌样，通过硅胶快速色谱柱纯化(流动相：石油醚/乙酸乙酯＝3：1)，旋干后得到化合物2-10(0.7g，收率：23％)为黄色固体。 1H NMR(400MHz,DMSO)δ8.47(dd,J 1＝4.8Hz,J 2＝1.7Hz,1H),8.42(dd,J 1＝7.8Hz,J 2＝1.8Hz,1H),7.37(dd,J 1＝7.8Hz,J 2＝4.8Hz,1H),6.56(s,2H),3.83(s,3H).
第二步：中间体化合物3-10的合成
反应在100mL茄型烧瓶中进行。将上一步得到的中间体2-10(700mg，3.6mmol)溶于7mL二氯甲烷，加入醋酸铜(326mg，1.8mmol)，间甲基苯硼酸(493mg，3.6mmol)和三乙胺(367mg，3.6mmol)。反应在氧气(14psi)环境中搅拌24h。反应液过滤，母液旋干，粗品通过硅胶快速色谱柱(20％乙酸乙酯/石油醚)纯化得到化合物3-10(600mg，收率：58％)为黄色固体。LCMS(ESI)m/z＝283.1[M+H] +.
第三步：中间体化合物4-10的合成
反应在100mL三口瓶中进行。将中间体3-10(600mg,2.1mmol)加入四氢呋喃5ml溶液中，用氮气置换三次，然后降温至-15℃，滴加氯磺酰异氰酸酯(448mg，3.1mmol)溶液，滴加完毕后在-15℃保温反应1小时，向反应液中滴入2ml纯化水，用氢氧化钠调节pH值为13，升温至室温搅拌2小时。后处理：将反应液倒入冰水(15ml)中，搅拌0.5小时，过滤得产品，用纯化水洗涤一遍后直接冻干，得500mg化合物4-10为白色固体(纯度85％，收率75％)。LCMS(ESI)m/z＝312.1[M+H] +.
第四步：中间体化合物5-10的合成
反应在100mL茄型烧瓶中进行，称取中间体4-10(400mg，1.3mmol)，加入乙酸钠(2.19g,15.0mmol)，加入4mL醋酸酐，80℃搅拌至反应完全。后处理：直接将反应液旋干，向反应液中加入20mL二氯甲烷稀释并过滤，滤液用硅胶拌样，Flash柱纯化 (流动相：0-53％乙酸乙酯/石油醚)，得化合物5-10(150mg，收率：39％)为白色固体。LCMS(ESI)m/z＝294.1[M+H] +.
第五步：化合物10的合成
反应在10mL微波管中进行。将化合物5-10(150mg，0.5mmol)、甲胺(1ml，2.0mmol，2mol/L四氢呋喃溶液)、PyBOP(397mg，0.76mmol)溶解于乙腈3ml中，室温缓慢滴加DBU(190mg，0.96mmol)，用氮气吹扫三次，封管，将反应温度升至50℃反应2小时。后处理：将反应液旋干，用乙酸乙酯(50ml×3)萃取三次，有机层用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤浓缩至干，prep-HPLC(H 2O:CAN,0.1％NH 3.H 2O)制备得到20.17mg 10，为黄色固体(纯度99.0％，收率6.5％)。 1H NMR(400MHz,DMSO)δ8.67(s,1H),8.50(dd,J 1＝4.8Hz,J 2＝1.6Hz,1H),7.50(t,J＝7.7Hz,1H),7.40(d,J＝7.7Hz,1H),7.31(dt,J 1＝11.2Hz,J 2＝6.6Hz,3H),6.70(dd,J 1＝7.9Hz,J 2＝1.6Hz,1H),2.98(s,3H),2.40(s,3H).LCMS(ESI)m/z＝307.1[M+H] +.
参照实施例5(化合物10)的合成方法，将合成步骤第一步当中的3-氰基-2氟吡啶分别替换为4-氟烟腈、3-氟-4-氰基吡啶，可相应制备得到 化合物8、 化合物9。
化合物8:
Figure PCTCN2022136109-appb-000069
1H NMR(400MHz,DMSO)δ8.65(d,J＝4.6Hz,1H),8.61(d,J＝5.9Hz,1H),7.81(d,J＝5.9Hz,1H),7.53(t,J＝7.7Hz,1H),7.44(d,J＝10.3Hz,2H),7.35(s,1H),7.32(d,J＝8.2Hz,1H),2.98(d,J＝4.6Hz,3H),2.41(s,3H).LCMS(ESI)m/z＝307.0[M+1] +.
化合物9:
Figure PCTCN2022136109-appb-000070
1H NMR(400MHz,DMSO)δ9.17(s,1H),9.13(s,1H),8.36(d,J＝5.4Hz,1H),7.52(t,J＝7.6Hz,1H),7.44(d,J＝7.6Hz,1H),7.35–7.26(m,2H),6.24(d,J＝5.4Hz,1H),3.03(d,J＝3.4Hz,3H),2.41(s,3H).LCMS(ESI)m/z＝307.1[M+H] +.
实施例6.化合物14的合成
Figure PCTCN2022136109-appb-000071
第一步：中间体化合物2-14的合成
将化合物2-1(2.98g，13.2mmol)，3-溴吡啶(2.09g,13.2mmol)，Pd 2(dba) 3(1.21mg,1.32mmol)，Xantphos(1.53mg,2.6mmol)，Cs 2CO 3(5.65mg,18.5mmol)用30mL 1,4-二氧六环(dioxane)溶解，氮气保护下110℃搅拌过夜。将反应液冷至室温过滤，滤液浓缩得粗品，经Flash柱纯化(流动相：98％DCM+2％MeOH)得到化合物2-14(1.98g，收率：66％)为白色固体。 1H NMR(400MHz,DMSO)δ8.60(s,1H),8.37(d,J＝2.6Hz,1H),8.20(dd,J 1＝4.6Hz,J 2＝1.2Hz,1H),7.73(d,J＝8.9Hz,1H),7.57(dd,J 1＝8.9Hz,J 2＝2.2Hz,1H),7.38(m,1H),7.32–7.26(m,2H),3.82(s,3H).LCMS(ESI)m/z＝303.1[M+H] +.
第二步：中间体化合物3-14的合成
将中间体2-14(1.98g,6.53mmol)加入THF(20mL)中，氮气保护温度降至-15℃，加入氯磺酰异氰酸酯(1.38g,9.80mmol)搅拌1小时。加入饱和NH 4Cl水溶液淬灭反应，用DCM:MeOH＝10:1(30mL×2)萃取，有机相用饱和NaCl洗涤，浓缩有机相得到化合物3-14粗品(3.94g)黄色固体。LCMS(ESI)m/z＝346.0[M+H] +.
第三步：中间体化合物4-14的合成
将中间体3-14粗品(3.94g，12.54mmol)用甲醇(30mL)溶解，加入氢氧化钠(1.0g,25.10mmol)，氮气保护下60℃搅拌2h。旋蒸除去甲醇，加水，用稀盐酸将pH调至3～4，过滤得到粗产品，经Flash柱纯化(流动相：98％DCM+2％MeOH)得到化合物4-14(280mg，两步收率：14％)，白色固体。 1H NMR(400MHz,DMSO)δ12.08(s,1H),8.92–8.82(m,2H),8.18–8.12(m,1H),7.89(d,J＝9.0Hz,1H),7.76(dd,J 1＝8.1Hz,J 2＝4.8Hz,1H),7.64(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),6.02(d,J＝2.1Hz,1H).LCMS(ESI)m/z＝314.0[M+H] +.
第四步：化合物14的合成
反应在10mL微波管中进行。将化合物4-14(30mg,0.096mmol)用乙腈(5mL)溶解，加入DBU(29mg,0.191mmol)，PyBOP(75mg,0.144mmol)，甲胺四氢呋喃溶液0.25mL(2M)，微波50℃反应1h。通过Prep-HPLC(H 2O:ACN,0.1％FA)纯化，得到4.5mg 白色固体14，收率：14.3％。 1H NMR(400MHz,MeOD)δ8.82(d,J＝4.8Hz,1H),8.77(d,J＝2.2Hz,1H),8.12–8.04(m,1H),7.76(dd,J 1＝8.1Hz,J 2＝4.9Hz,1H),7.68(d,J＝9.0Hz,1H),7.54(dd,J 1＝9.0,J 2＝2.1Hz,1H),6.31(d,J＝2.1Hz,1H),3.14(s,3H).LCMS(ESI)m/z＝326.9[M+H] +.
参照实施例6化合物14的方法，将合成步骤第四步当中的甲胺四氢呋喃溶液分别替换为二甲胺四氢呋喃溶液、甲基乙胺、环丙胺、2,2-二氟乙胺、2,2,2-三氟乙胺、(1S,2R)-2-氟代环丙胺，可相应制备得到15、16、23、52、53、68。
化合物15:
Figure PCTCN2022136109-appb-000072
1H NMR(400MHz,DMSO)δ8.82(dd,J 1＝4.8Hz,J 2＝1.2Hz,1H),8.73(d,J＝2.4Hz,1H),8.04–8.00(m,1H),7.85(d,J＝9.2Hz,1H),7.71(dd,J 1＝8.2Hz,J 2＝4.8Hz,1H),7.62(dd,J 1＝9.0Hz,J 2＝2.4Hz,1H),6.05(d,J＝2.0Hz,1H),3.61(s,3H),3.24(s,3H).LCMS(ESI)m/z＝341.0[M+H] +.
化合物16:
Figure PCTCN2022136109-appb-000073
1H NMR(400MHz,DMSO)δ8.83(d,J＝3.6Hz,1H),8.76(d,J＝1.6Hz,1H),8.05(dd,J 1＝6.0Hz,J 2＝2.0Hz,1H),7.86(d,J＝9.2Hz,1H),7.73(dd,J 1＝8.0Hz,J 2＝4.8Hz,1H),7.62(dd,J 1＝8.8Hz,J 2＝2.4Hz,1H),6.07(d,J＝2.0Hz,1H),4.03(s,1H),3.77(s,1H),3.59(s,1H),3.24(s,2H),1.28(d,J＝36.8Hz,3H).LCMS(ESI)m/z＝355.1[M+H] +.
化合物23:
Figure PCTCN2022136109-appb-000074
1H NMR(400MHz,MeOD)δ8.93(d,J＝4.7Hz,1H),8.89(s,1H),8.21(d,J＝8.3Hz,1H),7.87(dd,J 1＝8.1Hz,J 2＝5.0Hz,1H),7.77(d,J＝9.0Hz,1H),7.67(dd,J 1＝9.1Hz,J 2＝2.0Hz,1H),6.35(d,J＝1.9Hz,1H),3.07(m,1H),1.11-1.14(m,2H),1.01–0.92(m,2H). LCMS(ESI)m/z＝353.0[M+H] +.
化合物52:
Figure PCTCN2022136109-appb-000075
1H NMR(400MHz,DMSO)δ9.14(s,1H),8.85–8.80(m,1H),8.79(d,J＝2.3Hz,1H),8.10–8.04(m,1H),7.85(d,J＝9.0Hz,1H),7.73(dd,J 1＝8.1Hz,J 2＝4.8Hz,1H),7.65(dd,J 1＝9.0,J 2＝2.2Hz,1H),6.26(tt,J 1＝55.6Hz,J 2＝3.9Hz,1H),6.16(d,J＝2.0Hz,1H),3.92(t,J＝15.1Hz,2H).LCMS(ESI)m/z＝377.0[M+1] +.
化合物53:
Figure PCTCN2022136109-appb-000076
1H NMR(400MHz,DMSO)δ9.37(t,J＝6.4Hz,1H),8.82(d,J＝4.4Hz,1H),8.79(s,1H),8.07(d,J＝8.0Hz,1H),7.85(d,J＝9.0Hz,1H),7.72(dd,J 1＝7.6Hz,J 2＝5.2Hz,1H),7.66(d,J＝9.2Hz,1H),6.15(s,1H),4.42–4.31(m,2H).LCMS(ESI)m/z＝395.0[M+1] +.
化合物68：
Figure PCTCN2022136109-appb-000077
1H NMR(400MHz,DMSO)δ9.00(s,1H),8.81(m,J＝4.8Hz,1H),8.78(s,1H),8.05(s,1H),7.81(d,J＝9.0Hz,1H),7.71(m,J＝8.0Hz,1H),7.63(m,J＝9.0Hz,1H),6.15(d,J＝2.0Hz,1H),4.85(d,J＝65.2Hz,1H),3.06(d,J＝4.5Hz,1H),1.47(d,J＝24.5Hz,1H),1.22(dd,J 1＝15.2,J 2＝7.0Hz,1H).LCMS(ESI)m/z＝471.0[M+1] +.
参照实施例6化合物14的方法，将合成步骤第一步当中的3-溴吡啶分别替换为2-甲基-3-溴吡啶、5-溴-3-甲基吡啶、5-溴-2-甲基吡啶，第四步当中的甲胺四氢呋喃溶液替换为环丙胺，可相应制备得到化合物47、49、50。
化合物47：
Figure PCTCN2022136109-appb-000078
1H NMR(400MHz,DMSO)δ8.86(s,1H),8.71(dd,J 1＝4.8Hz,J 2＝1.3Hz,1H),7.92(dd,J 1＝7.9Hz,J 2＝1.3Hz,1H),7.78(d,J 1＝9.0Hz,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.1Hz,1H),7.53(dd,J 1＝7.8Hz,J 2＝4.8Hz,1H),6.00(d,J＝2.0Hz,1H),3.23–3.01(m,1H),2.29(s,3H),0.81(d,J＝7.6Hz,2H),0.74(dd,J 1＝7.6Hz,J 2＝3.7Hz,2H).LCMS(ESI)m/z＝367.10[M+1] +.
化合物49：
Figure PCTCN2022136109-appb-000079
1H NMR(400MHz,DMSO)δ8.81(d,J＝4.4Hz,1H),8.58(d,J＝2.4Hz,1H),7.88(dd,J 1＝8.4Hz,J 2＝2.4Hz,1H),7.78(d,J＝8.8Hz,1H),7.61(dd,J 1＝9.2Hz,J 2＝2.0Hz,1H),7.54(d,J＝8.0Hz,1H),6.23(d,J＝1.6Hz,1H),3.08(m,1H),2.64(s,3H),0.86–0.77(m,2H),0.74–0.64(m,2H).LCMS(ESI)m/z＝367.0[M+1] +.
化合物50：
Figure PCTCN2022136109-appb-000080
1H NMR(400MHz,DMSO)δ8.83(d,J＝4.4Hz,1H),8.65(s,1H),8.54(s,1H),7.86(s,1H),7.78(d,J＝9.2Hz,1H),7.60(d,J＝9.2Hz,1H),6.17(s,1H),3.09(d,J＝4.4Hz,1H),2.43(s,3H),0.80(m,2H),0.75–0.68(m,2H).LCMS(ESI)m/z＝367.2[M+1] +.
实施例7.化合物11的合成
Figure PCTCN2022136109-appb-000081
第一步：中间体化合物2-11的合成
反应在250mL茄型烧瓶中进行。将5-氯-2-氟苯腈1-11(10g，65.7mmol)溶于DMSO(100mL)中，再加入甘氨酸甲酯盐酸盐(16g，98mmol)，碳酸钾(27.2g，196mmol)，100℃下搅拌12h直至反应完全。加入水(90ml)过滤，滤饼干燥得到产品化合物2-11(4.3g，收率：43％)为白色固体。 1H NMR(400MHz,DMSO)δ10.63(s,1H),7.87(d,J＝1.7Hz,1H),7.25–7.15(m,2H),5.74(s,2H),3.82(s,3H).
第二步：中间体化合物3-11的合成
反应在250mL单口瓶中进行。化合物2-11(4.3g，19.1mmol)，间碘甲苯(4.97g,22.9mmol)，醋酸钯(0.42g,1.87mmol)，BINAP(1.18g,1.89mmol)，碳酸铯(8.7g，26.7mmol)溶于50mL甲苯，氮气置换三次，110℃反应16个小时。待反应结束浓缩反应液得粗品，经Flash柱(PE/EA＝2：1)纯化得到产品化合物3-11(0.9g,收率：20.9％)黄色固体。 1H NMR(400MHz,DMSO)δ11.64(s,1H),7.67(s,1H),7.42(d,J＝8.8Hz,1H),7.29–7.24(m,1H),7.23(d,J＝2.0Hz,1H),7.04(s,1H),6.68(s,1H),6.61(d,J＝7.8Hz,2H),3.83(s,3H),2.20(s,3H).
第三步：化合物4-11的合成
反应在100mL三口瓶中进行。将中间体3-11(300mg，0.952mmol)加入THF(5ml)中，氮气保护温度降至-15℃，加入化合物氯磺酰异氰酸酯(268mg,1.90mmol)搅拌1小时。加入氯化铵水溶液(5ml)淬灭，加入水(20ml)，用EA(20ml)萃取两次，无水硫酸钠干燥后浓缩有机相得到化合物4-11(200mg，收率：66.6％)白色固体。LCMS(ESI)m/z＝358.0[M+H] +.
第四步：化合物5-11的合成
反应在100mL单口瓶中进行。将中间体4-11(200mg，0.559mmol)用甲醇(3ml)溶解，加入氢氧化钠(45mg,1.125mmol)氮气保护下60℃搅拌2h。加入氯化铵水溶液(5ml)淬灭，加入水(20ml)，用EA(20ml)萃取两次，有机相用无水硫酸钠干燥，浓缩后得到白色固体化合物5-11(150mg,收率：68％)。LCMS(ESI)m/z＝326.1[M+H] +.
第五步：化合物11的合成
反应在50mL单口瓶中进行。将化合物5-11(150mg，0.460mmol)用乙腈(3ml)溶解，加入PyBOP(358mg,0.688mmol)，DBU(140mg,0.915mmol)，甲胺四氢呋 喃溶液0.5ml(2M)，室温反应2h。通过Prep-HPLC(H 2O:ACN,0.1％TFA)纯化得到14.51mg白色固体11，收率：9.6％。 1H NMR(400MHz,DMSO)δ11.42(s,1H),8.82–8.47(m,1H),7.66(d,J＝8.9Hz,1H),7.54(t,J＝7.7Hz,1H),7.46(d,J＝7.8Hz,1H),7.35(m,J＝8.9,1H),7.30(s,1H),7.27(d,J＝7.7Hz,1H),5.94(d,J＝1.8Hz,1H),3.12(d,J＝4.1Hz,3H),2.42(s,3H).LCMS(ESI)m/z＝339.0[M+H] +.
参照实施例7化合物11的方法，将合成步骤第二步当中的间碘甲苯替换为2-甲基-3-溴吡啶，可相应制备得到化合物57。
化合物57:
Figure PCTCN2022136109-appb-000082
1H NMR(400MHz,DMSO)δ11.20(s,1H),8.70–8.65(m,1H),7.92(s,1H),7.81(d,J＝6.8Hz,1H),7.62(d,J＝8.9Hz,1H),7.51(dd,J 1＝7.8,J 2＝4.8Hz,1H),7.27(m,J＝8.8Hz,1H),5.85(d,J＝1.9Hz,1H),3.04(s,3H),2.20(s,3H).LCMS(ESI)m/z＝340.0[M+1] +.
实施例8.化合物27的合成
Figure PCTCN2022136109-appb-000083
第一步：中间体化合物2-27的合成
反应在10mL微波管中进行。将化合物1-A(327mg,1mmol)用乙腈(10mL)溶解，加入DBU(304mg,2mmol)，PyBOP(780mg,1.5mmol)搅拌15min，然后向反应液中加入1-叔丁氧羰基-3-氨基环丁胺(344mg，2mmol)，微波50℃反应1h。后处理：将反应液缓慢倒入水(25ml)中，用乙酸乙酯萃取二遍，合并有机相，有机层再次用水、饱和食盐水各洗涤一遍，无水硫酸钠干燥，过滤后拌硅胶，过Flash柱，洗脱剂(DCM:MeOH＝20:1)得到化合物2-27(125mg，收率：26.0％)白色固体。LCMS(ESI)m/z＝481.1[M+H] +.
第二步：化合物27的合成
反应在25mL单口瓶中进行。将化合物2-27(60mg,0.12mmol)投入到盐酸1,4-二氧六环溶液(8mL)中，室温搅拌过夜。后处理：将反应液减压浓缩至干。Prep-HPLC(H 2O:ACN,0.1％NH 4OH)纯化，得到27(11.46mg，收率：24.1％)白色固体。 1H NMR(400MHz,DMSO)δ9.14(s,1H),7.78(d,J＝8.8Hz,1H),7.59(dd,J 1＝8.8Hz,J 2＝2.0Hz,1H),7.52(t,J＝7.6Hz,1H),7.44(d,J＝8.0Hz,1H),7.33-7.25(m,2H),6.08(d,J＝2.0Hz,1H),4.99– 4.88(m,1H),3.74(d,J＝7.2Hz,4H),2.41(s,3H).LCMS(ESI)m/z＝381.0[M+H] +.
参照实施例8化合物27的合成方法，将合成步骤第一步当中的1-叔丁氧羰基-3-氨基环丁胺替换为1-叔丁氧羰基-3-氨基环戊胺，可相应制备得到化合物32。
化合物32:
Figure PCTCN2022136109-appb-000084
1H NMR(400MHz,DMSO)δ8.79(s,1H),7.79(d,J＝8.8Hz,1H),7.61(dd,J 1＝8.8Hz,J 2＝2.0Hz,1H),7.54(t,J＝7.6Hz,1H),7.46(d,J＝7.6Hz,1H),7.34–7.27(m,2H),6.10(d,J＝1.6Hz,1H),4.75(s,1H),3.52–3.40(m,2H),3.27–3.12(m,3H),2.42(s,3H),2.25(dd,J 1＝12.8Hz,J 2＝6.8Hz,1H),2.07(d,J＝6.8Hz,1H).LCMS(ESI)m/z＝395.0[M+H] +.
实施例9.化合物12的合成
Figure PCTCN2022136109-appb-000085
第一步：化合物2-11的合成
反应在250mL茄型烧瓶中进行。将5-氯-2-氟苯腈1-11(7.0g，46.0mmol)溶于DMSO(70mL)中，再加入甘氨酸甲酯盐酸盐(11.2g，68.7mmol)，碳酸钾(19.0g，137mmol)，100℃下搅拌12h直至反应完全。加入水(90ml)过滤，滤饼干燥得到产品化合物2-11(2.6g，收率：37％)为黑色固体。 1H NMR(400MHz,DMSO)δ10.63(s,1H),7.87(d,J＝1.7Hz,1H),7.25–7.15(m,2H),5.74(s,2H),3.82(s,3H).
第二步：化合物3-11的合成
反应在250mL单口瓶中进行。化合物2-11(2.6g，11.5mmol)，间碘甲苯(3.7g,16.9mmol)，醋酸钯(0.25g,1.15mmol),1,1’-联萘-2,2’-双二苯膦BINAP(1.43g,2.3mmol)，碳酸铯(5.2g，16.1mmol)溶于50mL甲苯，氮气置换三次，110℃反应16个小时。待反应结束浓缩反应液加入二氯甲烷硅胶拌样，过Flash柱(PE/EA＝2：1)得到产品化合物3-11(0.4g,收率：15.3％)，黄色固体。 1H NMR(400MHz,DMSO)δ11.64(s,1H),7.67(s,1H),7.42(d,J＝8.8Hz,1H),7.29–7.24(m,1H),7.23(d,J＝2.0Hz,1H),7.04 (s,1H),6.68(s,1H),6.61(d,J＝7.8Hz,2H),3.83(s,3H),2.20(s,3H).
第三步：化合物4-12的合成
反应在50mL单口瓶中进行。化合物3-11(400mg，1.26mmol)，碳酸钾(526mg,3.8mmol),碘甲烷(268mg,1.9mmol)溶于5mL DMF中，室温反应2个小时。待反应结束浓缩反应液加入水(20ml),用乙酸乙酯(60ml)萃取三次，用饱和食盐水(60ml)洗有机相浓缩有机相，无水硫酸钠干燥浓缩加入二氯甲烷硅胶拌样，过Flash柱(PE/EA＝2：1)得到化合物4-12(0.26g,收率：65％)黄色固体。 1H NMR(400MHz,DMSO)δ7.71(s,1H),7.64(d,J＝9.0Hz,1H),7.35(dd,J＝9.0,2.0Hz,1H),7.23(d,J＝1.9Hz,1H),7.04(t,J＝7.7Hz,1H),6.67(s,1H),6.60(t,J＝7.8Hz,2H),3.95(s,3H),3.80(s,3H),2.19(s,3H).
第四步：化合物5-12的合成
反应在50mL三口瓶中进行。将中间体4-12(260mg，0.79mmol)加入THF(5ml)中，氮气保护温度降至-15℃，加入氯磺酰异氰酸酯CSI(222mg,1.57mmol)搅拌1小时。加入氯化铵水溶液(5ml)淬灭,加入水(20ml),用EA(20ml)萃取三次，浓缩有机相得到化合物5-12(228mg，收率：66.6％)白色固体。LCMS(ESI)m/z＝372.1[M+H] +.
第五步：化合物6-12的合成
反应在100mL单口瓶中进行。将中间体5-12(200mg，0.559mmol)用甲醇(3ml)溶解，加入氢氧化钠(43mg,1.07mmol)氮气保护下60℃搅拌2h。加入氯化铵水溶液(5ml)淬灭,加入水(20ml),用EA(20ml)萃取两次，浓缩有机相得到化合物6-12(150mg,收率：75％)，白色固体。LCMS(ESI)m/z＝340.0[M+H] +.
第六步：化合物12合成
反应在50mL单口瓶中进行。将化合物6-12(100mg，0.29mmol)用乙腈(3ml)溶解，加入PyBOP(229mg,0.44mmol),DBU(90mg,0.58mmol)，甲胺四氢呋喃溶液0.58ml(2M)，室温反应2h。通过Prep-HPLC(H 2O:ACN,0.1％TFA)纯化得到14.51mg白色固体12，收率：14.5％。 1H NMR(400MHz,DMSO)δ7.67(d,J＝9.1Hz,1H),7.51(t,J＝7.7Hz,1H),7.42(d,J＝6.5Hz,2H),7.35(dd,J 1＝9.0,J 2＝2.0Hz,1H),7.22(s,1H),7.18(d,J＝7.7Hz,1H),5.88(d,J＝1.9Hz,1H),4.04(s,3H),3.02(s,3H),2.40(s,3H).LCMS(ESI)m/z＝353.0[M+H] +.
参照实施例9化合物12的合成方法，将合成步骤第二步当中的间碘甲苯替换为2-甲基-3-溴吡啶，可相应制备得到化合物71。
化合物71:
Figure PCTCN2022136109-appb-000086
1H NMR(400MHz,DMSO)δ8.78–8.72(m,1H),7.99(s,1H),7.93–7.87(m,1H), 7.76(d,J＝9.1Hz,1H),7.59(m,J＝7.8Hz,1H),7.43(dd,J 1＝9.1,J 2＝2.0Hz,1H),5.80(d,J＝1.8Hz,1H),4.09(s,3H),3.10(s,3H),2.25(s,3H).LCMS(ESI)m/z＝354.1[M+1] +.
参照实施例9化合物12的合成方法，将合成步骤第二步当中的间碘甲苯替换为2-甲基-3-溴吡啶，第六步中的甲胺四氢呋喃溶液替换为环丙胺，可相应制备得到化合物87。
化合物87:
Figure PCTCN2022136109-appb-000087
1H NMR(400MHz,DMSO)δ8.78(d,J＝3.4Hz,1H),8.33(brs,1H),7.96(d,J＝6.7Hz,1H),7.74(d,J＝7.7Hz,1H),7.60(m,J＝7.8,1H),7.45(s,1H),5.78(s,1H),4.05(s,3H),3.10(s,1H),2.29(s,3H),0.94(d,J＝6.6Hz,2H),0.82(s,2H).LCMS(ESI)m/z＝380.1[M+1] +.
实施例10.化合物44的合成
Figure PCTCN2022136109-appb-000088
第一步：化合物2-44的合成
反应在250mL单口瓶中进行。将化合物2-1(2.25g，10mmol)，间溴苯硼酸(3g,15mmol)，醋酸铜(0.9g,5mmol)，三乙胺(1.01g,10mmol)，溶于30mL二氯甲烷，氧气置换三次，室温反应16个小时。待反应结束浓缩反应液加入二氯甲烷硅胶拌样，过Flash柱(PE/EA＝5：1)得到产品化合物2-44(1.8g,收率：80％)，黄色固体。 1H NMR(400MHz,CDCl 3)δ7.42(dt,J＝8.9,5.4Hz,2H),7.30–7.27(m,2H),7.26(s,1H),7.21(t,J＝7.9Hz,1H),7.04(d,J＝7.8Hz,1H),4.00(s,3H).
第二步：化合物3-44的合成
反应在100mL三口瓶中进行。将中间体2-44(1.8g，4.76mmol)加入THF(20ml)中，氮气保护温度降至-15℃，加入CSI(1.34g,9.5mmol)搅拌1小时。加入氯化铵水溶液(20ml)淬灭,加入水(20ml)，用EA(20ml)萃取三次，浓缩有机相得到化合物3-44(2g，收率：95％)，白色固体。 1H NMR(400MHz,DMSO)δ7.83(d,J＝8.9Hz,1H),7.63–7.55(m,2H),7.49(d,J＝1.8Hz,1H),7.34(d,J＝3.5Hz,1H),7.24(d,J＝5.8Hz, 2H),6.54(s,2H),3.85(s,3H).LCMS(ESI)m/z＝424.9[M+H] +.
第三步：化合物4-44的合成
反应在100mL单口瓶中进行。将中间体3-44(2g，4.75mmol)用甲醇(3ml)溶解，加入氢氧化钠(0.38g,9.5mmol)氮气保护下60℃搅拌2h。加入氯化铵水溶液(5ml)淬灭,加入水(20ml),用EA(20ml)萃取两次，浓缩有机相得到白色固体化合物4-44(1.6g,收率：80％)。LCMS(ESI)m/z＝392.9[M+H] +.
第四步：化合物5-44的合成
反应在50mL单口瓶中进行。将化合物4-44(500mg，1.27mmol)无水亚铁氰化钾(110mg,0.298mmol)，醋酸钯(30mg,0.137mmol)，dppf(140mg，0.252mmol)，碳酸钠(134mg,0.123mmol)，溶于5mL N-甲基吡咯烷酮，120℃反应16个小时。待反应结束加入水(20ml)，用EA(20ml)萃取三次，浓缩有机相浓缩反应液加入二氯甲烷硅胶拌样，过Flash柱(PE/EA＝1：5)得到产品化合物5-44(0.2g,收率：40％)黑色固体。LCMS(ESI)m/z＝337.9[M+H] +.
第五步：化合物44的合成
反应在50mL单口瓶中进行。将化合物5-44(100mg，0.295mmol)用DMF(1ml)溶解，加入PyBOP(230mg,0.442mmol)，DBU(90mg,0.588mmol)，环丙胺(33mg,0.578mmol)，室温反应4h。通过Prep-HPLC(H 2O:ACN,0.1％FA)纯化得到6.37mg白色固体44，收率：6.3％。 1H NMR(400MHz,DMSO)δ8.85(s,1H),8.14(s,1H),8.11(d,J＝7.6Hz,1H),7.93(d,J＝8.1Hz,1H),7.86(t,J＝7.8Hz,1H),7.78(d,J＝8.9Hz,1H),7.61(m,J＝9.0Hz,1H),6.15(d,J＝1.8Hz,1H),3.09(s,1H),0.84–0.77(m,2H),0.73(t,J＝3.7Hz,2H).LCMS(ESI)m/z＝377.0[M+H] +.
实施例11.化合物22的合成
Figure PCTCN2022136109-appb-000089
第一步：化合物2-22的合成
Figure PCTCN2022136109-appb-000090
反应在100mL三口瓶中进行。将2-氰基-3-羟基吡啶1-22(5g，41.63mmol)溶于50mL ACN:H 2O(5:1)，0℃下，将NBS(8.15g,45.79mmol)溶于50mL ACN:H 2O(5:1)溶液，并缓慢滴加进反应液，低温下反应6h。反应结束后，反应液中加H 2O(50mL×3)， 再加EA(100mL×3)萃取，有机相用饱和NaCl溶液干燥并浓缩，再经Flash柱纯化(流动相：99％DCE+1％MeOH)得到化合物粗品2-22(3.5g，收率：43％)为白色固体。LCMS(ESI)m/z＝199.0[M+H] +.
第二步：化合物3-22的合成
Figure PCTCN2022136109-appb-000091
反应在100mL单口瓶中进行。将化合物2-22(3.5g,17.59mmol)，氯乙酸甲酯(2.1g,19.35mmol)，碳酸钾(4.86g,35.17mmol)，溶于DMF(30mL)，氮气保护80℃下反应6h，反应结束后加水(100mL)析出固体，将固体抽滤，得到化合物3-22(2.3g,收率：49％)白色固体。 1H NMR(400MHz,DMSO)δ8.01(d,J＝8.8Hz,1H),7.73(d,J＝8.8Hz,1H),6.36(s,2H),3.83(s,3H).LCMS(ESI)m/z＝271.0[M+H] +.
第三步：化合物4-22的合成
Figure PCTCN2022136109-appb-000092
反应在100mL三口瓶中进行。将化合物3-22(2.28g，8.4mmol)，3-甲基苯硼酸(2.28g,16.8mmol)，醋酸铜(840mg，4.21mmol)，三乙胺(1.9g,16.8mmol)，分子筛(0.2g)，用50mL DCM溶解，用氧气球置换氧气，常温搅拌12h。将反应液过滤，滤液浓缩得粗品，经Flash柱纯化(流动相：80％DCM+20％PE)得到化合物4-22(1.14g，收率：35％)为黄色固体。 1H NMR(400MHz,DMSO)δ8.27(s,1H),8.13(d,J＝8.8Hz,1H),7.74(d,J＝8.8Hz,1H),7.10(t,J＝7.8Hz,1H),6.96(s,1H),6.89(d,J＝8.0Hz,1H),6.76(d,J＝7.5Hz,1H),3.85(s,3H),2.24(s,3H).LCMS(ESI)m/z＝361.0[M+H] +.
第四步：化合物5-22的合成
Figure PCTCN2022136109-appb-000093
反应在100mL三口瓶中进行。将化合物4-22(1.14g，3.17mmol)加入THF(10mL)中，氮气保护温度降至-15℃，加入CSI(673mg,4.75mmol)搅拌1小时。反应结束，加入饱和NH 4Cl溶液淬灭反应，用EA(50mL×3)萃取，有机相用饱和NaCl洗涤，浓 缩有机相得到粗品5-22(1.48g)黄色油状物。LCMS(ESI)m/z＝406.1[M+H] +.
第五步：化合物6-22的合成
Figure PCTCN2022136109-appb-000094
反应在100mL三口瓶中进行。将粗品5-22(1.48g，3.66mmol)用甲醇(30mL)溶解，加入氢氧化钠(293mg,7.33mmol)，氮气保护下60℃搅拌2h。旋蒸除去甲醇，加水，用稀盐酸将pH调至3～4，过滤得到粗产品，打浆得到化合物6-22(850mg，收率：63％)为白色固体。 1H NMR(400MHz,DMSO)δ12.03(s,1H),8.24(d,J＝8.8Hz,1H),7.75(d,J＝8.8Hz,1H),7.40(t,J＝7.4Hz,1H),7.32(dd,J 1＝14.4Hz,J 2＝7.8Hz,3H),2.38(s,3H).LCMS(ESI)m/z＝373.9[M+H] +.
第六步：化合物7-22的合成
Figure PCTCN2022136109-appb-000095
反应在100mL单口瓶中进行。将化合物6-22(430mg,1.16mmol)，CuI(0.66g，3.47mmol)，MFSDA(0.67g，1.08mmol)，三乙胺(0.35g，3.46mmol)溶于DMF(5mL)，氮气保护80℃下反应16h，反应液冷至室温倒入水中(50mL)，用乙酸乙酯萃取三次(50mL/次)，合并有机相，用水洗三次(50mL/次)，用饱和食盐水洗一次(50mL)，无水硫酸钠干燥后柱层析纯化(DCM:MeOH＝20:1)，得260mg化合物7-22粗品。LCMS(ESI)m/z＝361.9[M+H] +.
第七步：化合物22的合成
Figure PCTCN2022136109-appb-000096
将化合物7-22粗品(220mg,0.588mmol)用乙腈(5mL)溶解，加入DBU(179mg,1.18mmol)，PyBOP(459mg,0.88mmol),甲胺四氢呋喃溶液1.25mL(2M)，50℃微波条件下反应1h。通过Prep-HPLC(H 2O:ACN,0.1％TFA)纯化，得到11.55mg白色固 体22。 1H NMR(400MHz,DMSO)δ8.82–8.73(m,1H),8.44(d,J＝8.8Hz,1H),8.01(d,J＝8.8Hz,1H),7.35(t,J＝7.6Hz,1H),7.29–7.23(m,2H),7.22(d,J＝8.0Hz,1H),3.00(d,J＝4.6Hz,3H),2.34(s,3H).LCMS(ESI)m/z＝375.1[M+H] +.
实施例12.化合物13的合成
Figure PCTCN2022136109-appb-000097
第一步：化合物4-13的合成
反应在100mL三口瓶中进行。将化合物2-1(2.00g，8.89mmol)，化合物3-13(3.20g，9.78mmol)，Pd 2(dba) 3(0.81g,0.89mmol)，Xantphos(1.03g，1.78mmol)，Cs 2CO 3(4.33g，13.33mmol)加入到45mL 1,4-二氧六环(dioxane)中，氮气保护，100℃反应12小时至反应完成。反应液中加入500ml水，用300ml EA萃取三次，浓缩有机相，粗品通过硅胶快速色谱柱(PE:EA＝10:1)纯化得到中间体4-13(1.50g，收率：35.7％)为黄色固体。LCMS(ESI)m/z＝472.0[M+H] +.
第二步：化合物5-13的合成
反应在100mL三口瓶中进行。将中间体4-13(400mg，0.847mmol)加入THF(8ml)中，氮气保护温度降至-15℃，加入CSI(179mg,1.270mmol)搅拌1小时。加氯化铵水溶液(8ml)淬灭，加入水(30ml)，用EA(30ml)萃取两次，浓缩有机相得到化合物5-13(400mg，收率：91.7％)白色固体。LCMS(ESI)m/z＝515.2[M+H] +.
第三步：化合物6-13的合成
反应在100mL三口瓶中进行。将中间体5-13(400mg，0.776mmol)用甲醇(8ml)溶解，加入氢氧化钠(62.1mg,1.552mmol)氮气保护下60℃搅拌2h。用1mol/L HCl将pH调至3～4，过滤得到粗品，粗品通过硅胶快速色谱柱(DCM:MeOH＝20:1)纯化得到化合物6-13(260mg,收率：69.5％)。LCMS(ESI)m/z＝483.2[M+H] +.
第四步：化合物7-13的合成
反应在10mL封管中进行。将中间体6-13(260mg，0.538mmol)用乙腈(3ml)溶解，加入PyBOP(420mg,0.807mmol)，加入DBU(164mg,1.076mmol)，加入甲胺四氢呋喃溶液1.6ml(2M)，常温反应1小时。减压浓缩后Prep-TLC(DCM：MeOH＝5： 1)纯化得到300mg白色固体粗品7-13(含PyBOP副产物)。LCMS(ESI)m/z＝496.1[M+H] +.
第五步：化合物13的合成
反应在100mL单口瓶中进行。将中间体7-13(300mg，0.604mmol)用四正丁基氟化铵TBAF(8ml)溶解，60℃反应8小时直至完成。反应液中加入30ml水，用30ml DCM萃取2次。浓缩有机相，通过Prep-TLC(DCM：MeOH＝10：1)纯化得到50mg白色固体粗品，再通过Prep-HPLC(0.1％TFA)纯化得到2mg白色固体13(收率：1.0％)。 1HNMR(400MHz,DMSO)δ13.54(s,1H),8.31(s,1H),8.19(d,J＝1.6Hz,1H),7.88(d,J＝8.7Hz,1H),7.79(d,J＝9.0Hz,1H),7.57(dd,J 1＝8.7Hz,J 2＝1.9Hz,1H),7.50(dd,J 1＝8.9Hz,J 2＝2.2Hz,1H),6.55(d,J＝4.5Hz,1H),5.74(d,J＝2.2Hz,1H),2.74(d,J＝4.4Hz,3H).LCMS(ESI)m/z＝366.1[M+H] +.
实施例13.化合物34的合成
Figure PCTCN2022136109-appb-000098
第一步：中间体2-34的合成
反应在50mL单口瓶中进行。将化合物1-A(2.00g，6.12mmol)投入单口瓶中，再加入三氯氧磷(20ml)和两滴催化量的DMF，氮气保护下回流搅拌12h，中控检测反应完全。减压浓缩除去三氯氧磷，往反应瓶中加入25mL冰水混合物，用二氯甲烷萃取三次(20mL/次)，合并有机相用无水硫酸钠干燥，室温下不加热减压旋干，得2.60g中间体2-34，灰白色固体(收率>100％，LCMS纯度16％，大部分为异构体)。LCMS(ESI)m/z＝345.1[M+H] +.
第二步:化合物34的合成
反应在50mL单口瓶中进行。将化合物2-34(400mg，1.15mmol)用四氢呋喃(4ml)溶解，加入4-氨基吡啶(218mg,2.31mmol)，DIEA(299.5mg,2.3mmol)，60℃反应16h。反应结束浓缩反应液通过Prep-TLC分离纯化得到9.68mg化合物34，白色固体,收率2.4％。 1H NMR(400MHz,DMSO)δ10.80(s,1H),8.52(d,J＝5.5Hz,2H),8.08(d,J＝5.1Hz,2H),7.85(d,J＝8.9Hz,1H),7.66(d,J＝9.1Hz,1H),7.57(t,J＝7.7Hz,1H),7.49(d,J＝7.6Hz,1H),7.40(s,1H),7.37(d,J＝7.8Hz,1H),6.12(s,1H),2.43(s,3H).LCMS(ESI)m/z＝403.0[M+H] +.
实施例14.化合物51的合成
Figure PCTCN2022136109-appb-000099
第一步：化合物2-51的合成
反应在250mL茄型烧瓶中进行。将5-氯-2-氟苯腈1-11(5.00g，32.26mmol)溶于DMF(80mL)中，加入巯基乙酸甲酯(3.76g，35.48mmol)，碳酸钾(8.90g，64.52mmol)，在80℃下搅拌12h直至反应完全。冷却反应混合物至室温，加入水(3L)析出固体，过滤，滤饼干燥得到产品化合物2-51(6.00g，收率：77.2％)为黄色固体。 1H NMR(400MHz,DMSO)δ8.31(d,J＝2.0Hz,1H),7.89(d,J＝8.6Hz,1H),7.54(dd,J 1＝8.6,J 2＝2.1Hz,1H),7.19(s,2H),3.79(s,3H).
第二步：化合物3-51的合成
反应在100mL三口瓶中进行。将化合物2-51(2.00g，8.30mmol)，3-溴吡啶(1.42g，9.13mmol)，Pd 2(dba) 3(0.76g，0.83mmol)，Xantphos(0.96g,1.66mmol)，Cs 2CO 3(5.39g,16.60mmol)用30mL 1,4-dioxane溶解，氮气保护，100℃反应12h。反应液冷至室温，倒入300ml水中，用300ml二氯甲烷萃取三次(100ml/次)，合并有机相，无水硫酸钠干燥过滤，减压浓缩得粗品，通过硅胶快速色谱柱(DCM:MeOH＝20:1)纯化得到中间体3-51(2.00g，收率：75.8％)为黄色固体。LCMS(ESI)m/z＝318.8[M+H] +.
第三步：中间体4-51的合成
反应在100mL三口瓶中进行。将中间体3-51(600mg，1.89mmol)加入THF(10ml)中，氮气保护温度降至-15℃，加入CSI(400mg，2.83mmol)搅拌1小时至反应完成。加入氯化铵水溶液(10ml)淬灭，加入水(20ml)，用DCM(20ml)萃取三次，浓缩有机相得到中间体4-51的粗品(800mg，收率>100％)白色固体。LCMS(ESI)m/z＝361.9[M+H] +.
第四步：中间体5-51的合成
反应在100mL三口瓶中进行。将中间体4-51(800mg，2.22mmol)用甲醇(10ml)溶解，加入氢氧化钠(177mg,4.43mmol)，氮气保护下60℃搅拌1h。LCMS检测反应完成，粗品通过硅胶快速色谱柱(DCM:MeOH＝20:1)纯化得到中间体5-51(240mg,收率：32.9％)，白色固体。 1H NMR(400MHz,DMSO)δ12.18(s,1H),8.90(d,J＝4.8Hz,1H),8.84(d,J＝2.3Hz,1H),8.20(d,J＝8.8Hz,1H),8.14(d,J＝8.0Hz,1H),7.76(dd,J 1＝8.1 Hz,J 2＝4.8Hz,1H),7.58(dd,J 1＝8.8Hz,J 2＝2.0Hz,1H),5.85(d,J＝1.8Hz,1H).
第五步：化合物51的合成
反应在10mL封管中进行。将中间体5-51(240mg，0.73mmol)用DMF(3ml)溶解，加入PyBOP(568mg,1.09mmol)，加入DBU(221mg,1.46mmol)常温搅拌1min,加入2M的甲胺四氢呋喃溶液1.5ml，常温反应1小时。Prep-HPLC(0.1％NH 3H 2O)纯化得到30mg粗品，粗品经过Prep-HPLC(0.1％FA)纯化得到5.15mg 51，白色固体，收率：2.0％。 1H NMR(400MHz,DMSO)δ8.92(s,2H),8.52(s,1H),8.16(d,J＝8.7Hz,1H),8.02(d,J＝7.9Hz,1H),7.80(s,1H),7.58(dd,J 1＝8.8,J 2＝1.7Hz,1H),5.89(s,1H),3.02(s,3H).LCMS(ESI)m/z＝343.0[M+1] +.
参照实施例6化合物14的方法，将合成步骤第一步当中的3-溴吡啶分别替换为3-溴-4-甲基吡啶、1-甲基-4-溴吡唑，第四步当中的甲胺四氢呋喃溶液替换为环丙胺，可相应制备得到化合物48、55。
化合物48：
Figure PCTCN2022136109-appb-000100
1H NMR(400MHz,DMSO)δ9.16(s,1H),8.74(t,J＝4.6Hz,1H),8.68(d,J＝6.8Hz,1H),7.80(d,J＝9.0Hz,1H),7.68(t,J＝5.8Hz,1H),7.63(d,J＝8.8Hz,1H),6.03(s,1H),3.11(dt,J 1＝9.6Hz,J 2＝4.2Hz,1H),2.18(s,3H),0.89–0.80(m,2H),0.80–0.69(m,2H).LCMS(ESI)m/z＝367.0[M+1] +.
化合物55：
Figure PCTCN2022136109-appb-000101
1H NMR(400MHz,DMSO)δ8.73(d,J＝3.6Hz,1H),8.06(s,1H),7.75(d,J＝8.9Hz,1H),7.64(s,1H),7.61(d,J＝9.1Hz,1H),6.61(s,1H),3.98(s,3H),3.05(d,J＝4.0Hz,1H),0.79(d,J＝5.5Hz,2H),0.70(d,J＝3.0Hz,2H).LCMS(ESI)m/z＝356.05[M+1] +.
参照实施例6化合物14的方法，将合成步骤第一步当中的3-溴吡啶分别替换为2-甲基-3-溴吡啶、3-溴-2-三氟甲基吡啶、2-溴-3-甲基吡嗪、1-氯-2-碘苯，可相应制备得到化合物59、61、62、65：
化合物59：
Figure PCTCN2022136109-appb-000102
1H NMR(400MHz,DMSO)δ9.08(s,1H),8.77(d,J＝4.9Hz,1H),8.05(d,J＝7.8Hz,1H),7.84(d,J＝9.0Hz,1H),7.63(dd,J 1＝9.0Hz,J 2＝2.4Hz,2H),6.10(s,1H),3.02(d,J＝4.6Hz,3H),2.34(s,3H).LCMS(ESI)m/z＝341.0[M+1] +.
化合物61：
Figure PCTCN2022136109-appb-000103
1H NMR(400MHz,DMSO)δ9.04(d,J＝4.4Hz,1H),8.88(d,J＝4.2Hz,1H),8.35(d,J＝8.1Hz,1H),8.08(dd,J 1＝8.0Hz,J 2＝4.7Hz,1H),7.84(d,J＝9.0Hz,1H),7.62(dd,J 1＝8.9Hz,J 2＝2.0Hz,1H),6.01(d,J＝1.9Hz,1H),3.00(d,J＝4.3Hz,3H).LCMS(ESI)m/z＝395.05[M+1] +.
化合物62：
Figure PCTCN2022136109-appb-000104
1H NMR(400MHz,DMSO)δ8.90(d,J＝4.7Hz,1H),8.83(d,J＝2.5Hz,1H),8.67(d,J＝2.5Hz,1H),7.82(d,J＝9.0Hz,1H),7.62(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),6.10(d,J＝2.1Hz,1H),3.01(d,J＝4.7Hz,3H),2.46(s,3H).LCMS(ESI)m/z＝341.95[M+1] +.
化合物65：
Figure PCTCN2022136109-appb-000105
1H NMR(400MHz,DMSO)δ8.76(d,J＝4.6Hz,1H),7.81(dd,J 1＝8.1Hz,J 2＝3.9Hz,2H),7.69(dd,J 1＝9.6Hz,J 2＝7.5Hz,2H),7.64(d,J＝7.4Hz,1H),7.61(dd,J 1＝8.9Hz,J 2＝2.0Hz,1H),6.01(d,J＝2.0Hz,1H),2.99(d,J＝4.6Hz,3H).LCMS(ESI)m/z＝359.90[M+1] +.
参照实施例6化合物14的方法，将合成步骤第四步当中的甲胺四氢呋喃溶液替换为氨的二氧六环溶液，可相应制备得到化合物66。
化合物66：
Figure PCTCN2022136109-appb-000106
1H NMR(400MHz,DMSO)δ9.04(s,1H),8.85(dd,J 1＝4.8Hz,J 2＝1.2Hz,1H),8.80(d,J＝2.0Hz,1H),8.67(s,1H),8.09(ddd,J 1＝8.2Hz,J 2＝2.3Hz,J 3＝1.4Hz,1H),7.86(d,J＝9.0Hz,1H),7.75(dd,J 1＝8.2Hz,J 2＝4.8Hz,1H),7.68(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),6.15(d,J＝2.0Hz,1H).LCMS(ESI)m/z＝313.0[M+1] +.
参照实施例7化合物11的方法，将合成步骤第二步当中的间碘甲苯替换为2-碘甲苯，可相应制备得到化合物69。
化合物69：
Figure PCTCN2022136109-appb-000107
1H NMR(400MHz,DMSO)δ11.24(s,1H),7.82(d,J＝4.8Hz,1H),7.61(d,J＝8.8Hz,1H),7.51(d,J＝3.9Hz,2H),7.43(d,J＝3.9Hz,1H),7.34–7.26(m,2H),5.80(s,1H),3.04(d,J＝4.1Hz,3H),2.01(d,J＝15.8Hz,3H).LCMS(ESI)m/z＝339.0[M+1] +.
参照实施例9化合物12的合成方法，将合成步骤第二步当中的间碘甲苯分别替换为2-碘甲苯、3-溴吡啶、2-溴吡啶、3-溴苄腈，可相应制备得到化合物70、88、111、113。
化合物70：
Figure PCTCN2022136109-appb-000108
1H NMR(400MHz,DMSO)δ7.68(d,J＝9.1Hz,1H),7.52(s,2H),7.43(d,J＝3.5Hz,2H),7.32(m,J＝20.4Hz,2H),5.73(s,1H),4.06(s,3H),3.03(d,J＝4.2Hz,3H),1.98(s,3H).LCMS(ESI)m/z＝352.8[M+1] +. 化合物88：
Figure PCTCN2022136109-appb-000109
1H NMR(400MHz,DMSO)δ8.80(m,J＝4.8Hz,1H),8.66(d,J＝2.2Hz,1H),7.97–7.89(m,1H),7.74–7.66(m,2H),7.54(d,J＝4.5Hz,1H),7.39(d,J＝9.1Hz,1H),5.88(d,J＝2.0Hz,1H),4.06(s,3H),3.03(d,J＝4.4Hz,3H).LCMS(ESI)m/z＝340.0[M+1] +.
化合物111：
Figure PCTCN2022136109-appb-000110
1H NMR(400MHz,DMSO)δ8.71(d,J＝3.9Hz,1H),8.13(td,J＝7.8,1.8Hz,1H),7.72–7.64(m,2H),7.61(d,J＝7.9Hz,1H),7.53(d,J＝4.5Hz,1H),7.47(dd,J＝9.0,2.0Hz,1H),5.67(d,J＝1.7Hz,1H),4.06(s,3H),3.03(d,J＝4.4Hz,3H).LCMS(ESI)m/z＝340.0[M+1] +.
化合物113：
Figure PCTCN2022136109-appb-000111
1H NMR(400MHz,DMSO)δ8.13–8.08(m,1H),8.06(t,J＝1.7Hz,1H),7.86–7.80(m,2H),7.72(d,J＝9.1Hz,1H),7.59–7.50(m,1H),7.39(dd,J＝9.1,2.1Hz,1H),5.88(d,J＝2.0Hz,1H),4.06(s,3H),3.03(d,J＝4.4Hz,3H).
参照实施例9化合物12的合成方法，将合成步骤第二步当中的间碘甲苯分别替换为3-溴吡啶、2-碘甲苯、1-氯-2-碘苯、2-甲基-3-溴吡啶，将合成步骤第六步中的甲胺四氢呋喃溶液替换为环丙胺，可分别相应制备得到化合物89、91、92、87。
化合物89：
Figure PCTCN2022136109-appb-000112
1H NMR(400MHz,DMSO+D 2O)δ8.83(d,J＝4.2Hz,1H),8.65(s,1H),7.98(d,J＝8.0 Hz,1H),7.77(dd,J＝8.1,4.9Hz,1H),7.67(d,J＝9.1Hz,1H),7.43(dd,J＝9.1,1.9Hz,1H),5.89(d,J＝1.8Hz,1H),3.99(s,3H),3.06-3.03(m,J＝7.4,3.9Hz,1H),0.89(d,J＝5.2Hz,2H),0.77(d,J＝2.9Hz,2H).LCMS(ESI)m/z＝366.0[M+1] +.
化合物91：
Figure PCTCN2022136109-appb-000113
1H NMR(400MHz,DMSO+D 2O)δ7.36–7.27(m,4H),7.13(d,J＝7.6Hz,1H),6.98(d,J＝9.2Hz,1H),5.66(s,1H),4.13(s,3H),3.70–0.67(m,1H),2.00(s,3H),0.58–0.53(m,2H),0.36–0.35(m,2H).LCMS(ESI)m/z＝479.1[M+1] +.
化合物92：
Figure PCTCN2022136109-appb-000114
1H NMR(400MHz,DMSO+D 2O)δ7.82(d,J＝7.9Hz,1H),7.73–7.70(m,1H),7.68–7.64(m,2H),7.59(d,J＝7.6Hz,1H),7.42(d,J＝9.1Hz,1H),5.84(s,1H),3.99(s,3H),3.07–3.05(m,1H),0.91–0.86(m,2H),0.80–0.74(m,2H).LCMS(ESI)m/z＝399.0[M+1] +.
化合物87：
Figure PCTCN2022136109-appb-000115
1H NMR(400MHz,DMSO)δ8.78(d,J＝3.4Hz,1H),8.33(brs,1H),7.96(d,J＝6.7Hz,1H),7.74(d,J＝7.7Hz,1H),7.60(m,J＝7.8,1H),7.45(s,1H),5.78(s,1H),4.05(s,3H),3.10(s,1H),2.29(s,3H),0.94(d,J＝6.6Hz,2H),0.82(s,2H).LCMS(ESI)m/z＝380.1[M+1] +.
参照实施例9化合物12的合成方法，将合成步骤第二步当中的间碘甲苯替换为2-甲基-3-溴吡啶，将合成第三步中的碘甲烷替换为碘乙烷，可相应制备得到化合物72。
化合物72：
Figure PCTCN2022136109-appb-000116
1H NMR(400MHz,DMSO)δ8.70(d,J＝4.7Hz,1H),7.82(d,J＝7.8Hz,1H),7.75(d,J＝9.1Hz,1H),7.52(m,J＝7.8Hz,1H),7.45–7.35(m,2H),5.78(d,J＝1.9Hz,1H),4.61(t,J＝7.1Hz,2H),3.06(d,J＝4.3Hz,3H),2.19(s,3H),1.21(t,J＝7.0Hz,3H).LCMS(ESI)m/z＝367.9[M+1] +.
参照实施例9化合物12的合成方法，将合成步骤第二步当中的间碘甲苯替换为3-溴吡啶，将合成步骤第六步中的甲胺四氢呋喃溶液替换为乙胺四氢呋喃溶液，可相应制备得到化合物90。
化合物90：
Figure PCTCN2022136109-appb-000117
1H NMR(400MHz,DMSO)δ8.80(m,J＝4.8Hz,1H),8.67(d,J＝2.4Hz,1H),8.00–7.92(m,1H),7.74–7.67(m,2H),7.54(s,1H),7.39(m,J＝9.1Hz,1H),5.87(d,J＝2.0Hz,1H),4.06(s,3H),3.65–3.56(m,2H),1.26(t,J＝7.1Hz,3H).LCMS(ESI)m/z＝354.0[M+1] +.
参照实施例9化合物12的合成方法，将合成步骤第二步当中的间碘甲苯替换为3-溴吡啶，将合成步骤第六步中的甲胺四氢呋喃溶液替换为氨的二氧六环溶液，可相应制备得到化合物98。
化合物98：
Figure PCTCN2022136109-appb-000118
1H NMR(400MHz,DMSO)δ8.80(d,J＝4.5Hz,1H),8.66(d,J＝2.1Hz,1H),7.95(d,J＝8.0Hz,1H),7.81–7.47(m,4H),7.45–7.33(m,1H),5.90(s,1H),4.04(s,3H).LCMS(ESI)m/z＝326.1[M+1] +.
参照实施例9化合物12的合成方法，将合成步骤第二步当中的间碘甲苯替换为1-氯-2-碘苯，可相应制备得到化合物95。
化合物95：
Figure PCTCN2022136109-appb-000119
1H NMR(400MHz,DMSO)δ7.82–7.78(m,1H),7.70(d,J＝9.1Hz,1H),7.68–7.63(m,1H),7.63–7.58(m,2H),7.51(d,J＝4.5Hz,1H),7.47(m,J＝9.1Hz,1H),5.81(d,J＝1.9Hz,1H),4.07(s,3H),3.03(d,J＝4.5Hz,3H).LCMS(ESI)m/z＝473.0[M+1] +.
参照实施例9化合物12的合成方法，将合成步骤第二步当中的间碘甲苯分别替换为2-溴氯苯、2-甲基-3-溴吡啶，第六步中的甲胺四氢呋喃溶液分别替换为环丙胺、乙胺四氢呋喃溶液，可相应制备得到化合物92、109。
化合物92：
Figure PCTCN2022136109-appb-000120
1H NMR(400MHz,DMSO+D 2O)δ7.82(d,J＝7.9Hz,1H),7.73–7.70(m,1H),7.68–7.64(m,2H),7.59(d,J＝7.6Hz,1H),7.42(d,J＝9.1Hz,1H),5.84(s,1H),3.99(s,3H),3.07–3.05(m,1H),0.91–0.86(m,2H),0.80–0.74(m,2H).LCMS(ESI)m/z＝399.0[M+1] +.
化合物109：
Figure PCTCN2022136109-appb-000121
1H NMR(400MHz,DMSO)δ8.70(d,J＝3.7Hz,1H),7.82(d,J＝7.3Hz,1H),7.72(d,J＝9.1Hz,1H),7.52(m,J＝7.8Hz,2H),7.38(dd,J 1＝9.0,J 2＝1.7Hz,1H),5.78(d,J＝1.5Hz,1H),4.07(s,3H),3.60(dt,J＝22.7,6.9Hz,2H),2.19(s,3H),1.27(t,J＝7.1Hz,3H).LCMS(ESI)m/z＝368.1[M+1] +.
参照实施例9化合物12的合成方法，将合成步骤第二步当中的间碘甲苯替换为2-溴-6-甲基吡啶，并将第六步反应得到的游离碱产物进一步用盐酸-二氧六环溶液处理，最终得到化合物112的盐酸盐。
化合物112盐酸盐：
Figure PCTCN2022136109-appb-000122
1H NMR(400MHz,DMSO)δ8.48(s,1H),8.08(t,J＝7.7Hz,1H),7.77(d,J＝9.1Hz,1H),7.61(d,J＝7.6Hz,1H),7.51(d,J＝7.7Hz,1H),7.46(dd,J＝9.1,2.0Hz,1H),5.70(d,J＝1.9Hz,1H),4.09(s,3H),3.15(s,3H),2.53(s,3H).LCMS(ESI)m/z＝354.1[M+1] +.
参照实施例9化合物12的合成方法，将合成步骤第二步当中的间碘甲苯替换为3-溴吡啶，合成步骤第六步中甲胺四氢呋喃溶液替换为乙胺四氢呋喃溶液，并将第六步反应得到的游离碱产物进一步用盐酸-二氧六环溶液处理，最终得到化合物110的盐酸盐。
化合物110盐酸盐：
Figure PCTCN2022136109-appb-000123
1H NMR(400MHz,DMSO)δ8.91(m,J＝4.9Hz,1H),8.81(t,J＝9.4Hz,2H),8.17–8.09(m,1H),7.82(m,J＝6.2Hz,2H),7.50(d,J＝9.1Hz,1H),5.88(d,J＝1.9Hz,1H),4.13(s,3H),3.73(d,J＝6.0Hz,2H),1.30(t,J＝7.1Hz,3H).LCMS(ESI)m/z＝354.0[M+1] +.
实施例15.化合物47的合成
Figure PCTCN2022136109-appb-000124
第一步：中间体 2-1的合成
反应在100mL三口瓶中进行。将5-氯-2-羟基苯腈1-1(4.0g，26.14mmol)、氯乙酸甲酯(3.1g，28.76mmol)、碳酸钾(7.2g，52.29mmol)用DMF(50mL)溶解，氮气保护下80℃搅拌12h直至反应完全。将反应液倒入500mL水中，析出大量固体，过滤，滤饼用少量水冲洗，然后用EA溶解，用分液漏斗分出残留的少量水，有机相用无水硫酸钠干燥，过滤，滤液旋干得化合物2-1(5.0g，收率:85.0％)，白色固体，无需纯化，可直接用于下一步。LCMS(ESI)m/z＝225.9[M+H] +.
第二步：中间体3-47的合成
反应在250mL三口瓶中进行。将化合物2-1(4.0g，17.7mmol)，2-甲基-3-溴吡啶(3.6g，21.24mmol)，Cs 2CO 3(8.6g，26.55mmol),Pd 2(dba) 3(1.6g，1.77mmol)，Xantphos(2.0g，3.54mmol)用100mL二氧六环溶解，氮气保护下100℃反应12h。反应结束，浓缩反应液，粗品通过硅胶快速色谱柱(PE:EA＝5:1)纯化得到中间体3-47(3.8g，收率：67.4％)为黄色固体。 1H NMR(400MHz,DMSO)δ8.34–8.24(m,1H),7.91(s,1H),7.70(d,J＝8.9Hz,1H),7.54(dd,J＝8.9,2.2Hz,1H),7.44(d,J＝7.9Hz,1H),7.22(dd,J＝7.9,4.7Hz,1H),6.87(d,J＝2.1Hz,1H),3.83(s,3H),2.48(s,3H).LCMS(ESI)m/z＝317.05[M+H] +.
第三步：中间体4-47的合成
反应在250mL单口瓶中进行。将化合物3-47(3.8g，11.0mmol)用100mL氨甲醇溶液(7M)溶解，室温反应12h。反应结束，过滤，用100mL甲醇洗涤滤饼得到中间体4-47(3.5g，收率：96.6％)为白色固体。LCMS(ESI)m/z＝302.05[M+H] +.
第四步：中间体5-47的合成
反应在250mL三口瓶中进行。将化合物4-47(3.5g，11.58mmol)投入三口瓶，氮气置换三次，加入100ml DMF溶解，冰浴降至0℃，加入氢化钠(含量60％)(1.39g，34.74mmol)，冰浴搅拌30min，加入CDI(2.8g，17.47mmol)，冰浴搅拌2h。待反应结束，冰浴下加入饱和氯化铵水溶液(200ml)淬灭反应，再加入200mL水，室温搅拌30min，过滤得粗品，经硅胶柱层析纯化(DCM:MeOH＝8:1)得中间体5-47(2.4g，收率：63.1％)为白色固体。 1H NMR(400MHz,DMSO)δ12.09(s,1H),8.81–8.71(m,1H),8.05(d,J＝7.9Hz,1H),7.90(d,J＝9.0Hz,1H),7.64(dd,J＝9.0,2.1Hz,1H),7.58(dd,J＝7.9,4.8Hz,1H),5.92(d,J＝2.0Hz,1H),2.36(s,3H).LCMS(ESI)m/z＝328.0[M+H] +.
第五步：中间体6-47的合成
反应在250mL单口瓶中进行。将化合物5-47(2.4g，7.31mmol)用100mL乙腈溶解，加入DIPEA(4.72g，36.55mmol)，三氯氧磷(5.60g，36.55mmol)，80℃搅拌2h。反应结束，减压浓缩至干得粗品中间体6-47，直接进行下一步。LCMS(ESI)m/z＝345.9[M+H] +.
第六步：化合物47的合成
反应在250mL单口瓶中进行。将中间体6-47(2.4g，6.93mmol)用THF(30mL) 溶解，加入DIEA(3.6g，27.72mmol)，室温搅拌1min，加入环丙胺(0.8g，13.86mmol)，室温搅拌0.5h。反应结束，浓缩反应液，粗品通过硅胶柱(DCM/MeOH＝10:1)纯化得1.8g粗品，将粗品移至1L单口瓶，用乙醇(160mL)加热至80℃溶解，缓慢滴加800mL水，滴完自然冷却至室温，析出固体，过滤得到47(1.35g，收率：53.1％)，白色固体。 1H NMR(400MHz,DMSO)δ8.85(s,1H),8.71(dd,J 1＝4.8Hz,J 2＝1.3Hz,1H),7.92(dd,J 1＝7.9Hz,J 2＝1.3Hz,1H),7.78(d,J 1＝9.0Hz,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.1Hz,1H),7.53(dd,J 1＝7.8Hz,J 2＝4.8Hz,1H),6.00(d,J＝2.0Hz,1H),3.23–3.01(m,1H),2.29(s,3H),0.80(d,J＝7.6Hz,2H),0.73(dd,J 1＝7.6Hz,J 2＝3.7Hz,2H).LCMS(ESI)m/z＝367.0[M+H] +.
Figure PCTCN2022136109-appb-000125
化合物47(200mg)经制备超临界流体色谱法(柱子：DAICEL AD-H(4.6mm*250mm,5μm)；流动相：A:二氧化碳B:甲醇(0.1％氨水))分离得到一对对映体化合物47-P1(75mg,RT:2.88min)和化合物47-P2(78mg,RT:8.22min)。两者互为阻转异构体。
化合物47-P1: 1H NMR(400MHz,DMSO)δ8.85(s,1H),8.71(dd,J 1＝4.8Hz,J 2＝1.3Hz,1H),7.92(dd,J 1＝7.9Hz,J 2＝1.3Hz,1H),7.78(d,J 1＝9.0Hz,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.1Hz,1H),7.53(dd,J 1＝7.8Hz,J 2＝4.8Hz,1H),6.00(d,J＝2.0Hz,1H),3.23–3.01(m,1H),2.29(s,3H),0.80(d,J＝7.6Hz,2H),0.73(dd,J 1＝7.6Hz,J 2＝3.7Hz,2H).LCMS(ESI)m/z＝367.0[M+H] +.
化合物47-P2: 1H NMR(400MHz,DMSO)δ8.85(s,1H),8.71(dd,J 1＝4.8Hz,J 2＝1.3Hz,1H),7.92(dd,J 1＝7.9Hz,J 2＝1.3Hz,1H),7.78(d,J 1＝9.0Hz,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.1Hz,1H),7.53(dd,J 1＝7.8Hz,J 2＝4.8Hz,1H),6.00(d,J＝2.0Hz,1H),3.23–3.01(m,1H),2.29(s,3H),0.80(d,J＝7.6Hz,2H),0.73(dd,J 1＝7.6Hz,J 2＝3.7Hz,2H).LCMS(ESI)m/z＝367.0[M+H] +.
参照实施例15化合物47的合成方法，将合成步骤第六步中的环丙胺替换为甲胺四氢呋喃溶液，可制备得到化合物59。
化合物59：
Figure PCTCN2022136109-appb-000126
1H NMR(400MHz,DMSO)δ8.76–8.68(m,2H),7.91(m,J＝1.5Hz,1H),7.81(d,J＝9.0Hz,1H),7.61(m,J＝9.0Hz,1H),7.53(m,J＝7.8Hz,1H),6.01(d,J＝2.1Hz,1H),2.99 (d,J＝4.3Hz,3H),2.28(s,3H).LCMS(ESI)m/z＝341.0[M+1] +.
化合物59采用化合物47相似的制备方法，用超临界流体色谱法制备分离得到一对对映体化合物59-P1(RT＝11.73min)和59-P2(RT＝15.63min)。两者互为阻转异构体。
59-P1和59-P2的结构式：
Figure PCTCN2022136109-appb-000127
化合物59-P1: 1H NMR(400MHz,DMSO)δ8.76–8.68(m,2H),7.91(m,J＝1.5Hz,1H),7.81(d,J＝9.0Hz,1H),7.61(m,J＝9.0Hz,1H),7.53(m,J＝7.8Hz,1H),6.01(d,J＝2.1Hz,1H),2.99(d,J＝4.3Hz,3H),2.28(s,3H).LCMS(ESI)m/z＝341.0[M+1] +.
化合物59-P2: 1H NMR(400MHz,DMSO)δ8.76–8.68(m,2H),7.91(m,J＝1.5Hz,1H),7.81(d,J＝9.0Hz,1H),7.61(m,J＝9.0Hz,1H),7.53(m,J＝7.8Hz,1H),6.01(d,J＝2.1Hz,1H),2.99(d,J＝4.3Hz,3H),2.28(s,3H).LCMS(ESI)m/z＝341.0[M+1] +.
参照实施例15化合物47的合成方法，将合成步骤第二步当中的2-甲基-3-溴吡啶分别替换为2-溴甲苯、4-溴-3-甲基吡啶、2-氟碘苯、2,4-二氟碘苯、3-溴-1-甲基-2-吡啶酮、4-溴-2-甲基吡啶、2-溴吡啶、2-溴-3-甲基吡啶、2-溴-4-甲基吡啶、2-溴-6-甲基吡啶、3-溴-2-环丙基吡啶，将合成步骤第六步中的环丙胺替换为甲胺四氢呋喃溶液，可分别相应制备得到化合物64、99、100、101、102、104、105、106、107甲酸盐(该化合物用含甲酸的制备液相体系分离得到的是甲酸盐产物)、108、116。
化合物64：
Figure PCTCN2022136109-appb-000128
1H NMR(400MHz,DMSO)δ8.63(d,J＝4.6Hz,1H),7.78(d,J＝9.0Hz,1H),7.57(dd,J 1＝8.9Hz,J 2＝2.2Hz,1H),7.55–7.51(m,2H),7.48–7.42(m,1H),7.40(d,J＝7.5Hz,1H),5.91(d,J＝2.1Hz,1H),2.98(d,J＝4.6Hz,3H),2.06(s,3H).LCMS(ESI)m/z＝340.0[M+1] +.
化合物99：
Figure PCTCN2022136109-appb-000129
1H NMR(400MHz,DMSO)δ8.78(s,2H),8.68(d,J＝5.2Hz,1H),7.81(d,J＝8.8Hz,1H),7.61(dd,J＝8.8,2.0Hz,1H),7.53(d,J＝5.2Hz,1H),6.10(d,J＝2.0Hz,1H),2.99(d,J＝4.4Hz,3H),2.11(s,3H).LCMS(ESI)m/z＝340.95[M+1] +.
化合物100：
Figure PCTCN2022136109-appb-000130
1H NMR(400MHz,DMSO)δ8.76(d,J＝4.6Hz,1H),7.81(d,J＝9.0Hz,1H),7.74–7.69(m,1H),7.68–7.64(m,1H),7.61(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.60–7.54(m,1H),7.51–7.45(m,1H),6.19(d,J＝2.1Hz,1H),2.99(d,J＝4.7Hz,3H).LCMS(ESI)m/z＝344.05[M+1] +.
化合物101：
Figure PCTCN2022136109-appb-000131
1H NMR(400MHz,DMSO)δ8.95(d,J＝4.7Hz,1H),7.85(d,J＝9.0Hz,1H),7.82–7.74(m,1H),7.66(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.50(t,J＝8.2Hz,2H),6.38(d,J＝2.0Hz,1H),2.99(d,J＝4.6Hz,3H).LCMS(ESI)m/z＝362.00[M+1] +.
化合物102：
Figure PCTCN2022136109-appb-000132
1H NMR(400MHz,DMSO)δ8.63(d,J＝4.7Hz,1H),8.01(dd,J 1＝6.8Hz,J 2＝2.0Hz,1H),7.85–7.72(m,2H),7.62(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),6.73(d,J＝2.1Hz,1H),6.47(t,J＝7.0Hz,1H),3.55(s,3H),2.96(d,J＝4.6Hz,3H).LCMS(ESI)m/z＝357.00[M+1] +.
化合物104：
Figure PCTCN2022136109-appb-000133
1H NMR(400MHz,DMSO)δ8.75(dd,J＝9.2,4.4Hz,1H),8.71(d,J＝5.2Hz,1H),7.81(d,J＝9.0Hz,1H),7.62(dd,J＝9.0,2.2Hz,1H),7.48(d,J＝1.6Hz,1H),7.40(dd,J＝5.2,1.7Hz,1H),6.34(d,J＝2.1Hz,1H),2.98(d,J＝4.6Hz,3H),2.59(s,3H).LCMS(ESI)m/z＝341.0[M+1] +.
化合物105：
Figure PCTCN2022136109-appb-000134
1H NMR(400MHz,DMSO)δ8.76(d,J＝4.7Hz,1H),8.71(dd,J 1＝4.8Hz,J 2＝1.1Hz,1H),8.13(td,J 1＝7.7Hz,J 2＝1.9Hz,1H),7.80(d,J＝9.0Hz,1H),7.70–7.64(m,2H),7.60(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),6.13(d,J＝2.2Hz,1H),2.99(d,J＝4.6Hz,3H).LCMS(ESI)m/z＝327.05[M+1] +.
化合物106：
Figure PCTCN2022136109-appb-000135
1H NMR(400MHz,DMSO)δ8.38(s,1H),8.09(dd,J＝4.8,1.4Hz,1H),7.96(d,J＝2.1Hz,1H),7.82(d,J＝8.9Hz,1H),7.78(d,J＝7.3Hz,1H),7.68(dd,J＝8.9,2.3Hz,1H),7.19(dd,J＝7.3,4.9Hz,1H),2.85(s,3H),2.23(s,3H).LCMS(ESI)m/z＝LCMS(ESI)m/z＝341.0[M+1] +.
化合物107甲酸盐：
Figure PCTCN2022136109-appb-000136
1H NMR(400MHz,DMSO)δ8.74(d,J＝4.6Hz,1H),8.55(d,J＝5.0Hz,1H),7.79(d,J＝9.0Hz,1H),7.59(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.53–7.47(m,2H),6.15(d,J＝2.1 Hz,1H),2.98(d,J＝4.6Hz,3H),2.47(s,3H).LCMS(ESI)m/z＝LCMS(ESI)m/z＝340.95[M+1] +.
化合物108：
Figure PCTCN2022136109-appb-000137
1H NMR(400MHz,DMSO)δ8.76(d,J＝4.7Hz,1H),8.01(t,J＝7.7Hz,1H),7.79(d,J＝9.0Hz,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.50(dd,J 1＝14.7Hz,J 2＝7.7Hz,2H),6.19(d,J＝2.1Hz,1H),2.99(d,J＝4.7Hz,3H),2.53(s,3H).LCMS(ESI)m/z＝340.95[M+1] +.
化合物116：
Figure PCTCN2022136109-appb-000138
1H NMR(400MHz,DMSO)δ8.72(m,1H),8.66(dd,J＝4.8,1.6Hz,1H),7.85(dd,J＝8.0,1.6Hz,1H),7.81(d,J＝9.2Hz,1H),7.60(dd,J＝8.8,2.0Hz,1H),7.42(dd,J＝8.0,4.8Hz,1H),6.02(d,J＝2.0Hz,1H),2.99(d,J＝4.8Hz,3H),1.88–1.79(m,1H),1.14–1.05(m,1H),0.83(m,1H),0.72(m,1H),0.66–0.55(m,1H).LCMS(ESI)m/z＝367.1[M+1] +.
化合物116采用化合物47相似的制备方法，用超临界流体色谱法制备分离得到一对对映体化合物116-P1(RT＝11.73min)和116-P2(RT＝15.63min)。两者互为阻转异构体。
116-P1和116-P2的结构式：
Figure PCTCN2022136109-appb-000139
化合物116-P1: 1H NMR(400MHz,DMSO)δ8.72(m,1H),8.66(dd,J＝4.8,1.6Hz,1H),7.85(dd,J＝8.0,1.6Hz,1H),7.81(d,J＝9.2Hz,1H),7.60(dd,J＝8.8,2.0Hz,1H),7.42(dd,J＝8.0,4.8Hz,1H),6.02(d,J＝2.0Hz,1H),2.99(d,J＝4.8Hz,3H),1.88–1.79(m,1H),1.14–1.05(m,1H),0.83(m,1H),0.72(m,1H),0.66–0.55(m,1H).LCMS(ESI)m/z＝367.1[M+1] +.
化合物116-P2: 1H NMR(400MHz,DMSO)δ8.72(m,1H),8.66(dd,J＝4.8,1.6Hz,1H),7.85(dd,J＝8.0,1.6Hz,1H),7.81(d,J＝9.2Hz,1H),7.60(dd,J＝8.8,2.0Hz,1H),7.42(dd,J＝8.0,4.8Hz,1H),6.02(d,J＝2.0Hz,1H),2.99(d,J＝4.8Hz,3H),1.88–1.79(m,1H), 1.14–1.05(m,1H),0.83(m,1H),0.72(m,1H),0.66–0.55(m,1H).LCMS(ESI)m/z＝367.1[M+1] +.
参照实施例15化合物47的合成方法，将合成步骤第二步当中的2-甲基-3-溴吡啶替换为3-溴吡啶，将合成步骤第六步中的环丙胺替换为乙胺四氢呋喃溶液，可相应制备得到化合物115。
化合物115：
Figure PCTCN2022136109-appb-000140
1H NMR(400MHz,DMSO)δ9.44(s,1H),8.88(d,J＝5.2Hz,2H),8.22–8.15(m,1H),7.89–7.80(m,2H),7.67(dd,J＝9.0,2.2Hz,1H),6.23(d,J＝2.0Hz,1H),3.63–3.52(m,2H),1.24(t,J＝7.2Hz,3H).LCMS(ESI)m/z＝341.2[M+1] +.
参照实施例15化合物47的合成方法，将合成步骤第二步当中的2-甲基-3-溴吡啶分别替换为5-溴-4,6-二甲基嘧啶、3-溴-2-环丙基吡啶，可分别相应制备得到化合物96、97。
化合物96：
Figure PCTCN2022136109-appb-000141
1H NMR(400MHz,DMSO)δ9.13(s,1H),9.00(d,J＝4.4Hz,1H),7.81(d,J＝8.8Hz,1H),7.64(dd,J 1＝9.2Hz,J 2＝2.0Hz,1H),6.15(d,J＝2.0Hz,1H),3.16(m,1H),2.26(s,6H),0.85–0.79(m,2H),0.77(m,2H).LCMS(ESI)m/z＝382.10[M+1] +.
化合物97：
Figure PCTCN2022136109-appb-000142
1H NMR(400MHz,DMSO)δ8.84(s,1H),8.69–8.63(m,1H),7.86(m,J＝7.8Hz,1H),7.77(d,J＝8.9Hz,1H),7.59(d,J＝8.8Hz,1H),7.42(m,J＝7.9Hz,1H),6.01(d,J＝2.0Hz,1H),3.14(s,1H),1.92–1.80(m,1H),1.11(d,J＝4.7Hz,1H),0.85(d,J＝8.3Hz,1H),0.81(t,J＝8.1Hz,2H),0.72(d,J＝4.0Hz,3H),0.64(m,J＝11.6Hz,1H).LCMS(ESI)m/z＝393.0[M+1] +.
实施例16.化合物67的合成
Figure PCTCN2022136109-appb-000143
第一步：化合物 2-67的合成
将化合物4-14(300mg，0.96mmol)，环丙基硼酸(124mg，1.43mmol)，K 3PO 4(406mg，1.91mmol)，Ruphos(90mg，0.19mmol)，Pd(OAc) 2(22mg，0.10mmol)用1,4二氧六环(1,4-dioxane)(3mL)溶解，100℃下搅拌过夜。将反应液过滤，滤液浓缩得粗品，经Flash柱纯化(流动相：98％DCM+2％MeOH)得到180mg化合物2-67，白色固体。LCMS(ESI)m/z＝320.0[M+H] +.
第二步：化合物67的合成
将化合物2-67(120mg，0.475mmol)用DMF(3mL)溶解，加入DIPEA(97mg，0.75mmol)，PyBOP(292mg,0.56mmol)，甲胺四氢呋喃溶液0.75mL(2M)，50℃反应16h。通过Prep-HPLC(H 2O:ACN,0.1％TFA)纯化得到26.95mg白色固体67，收率：21.6％。 1H NMR(400MHz,DMSO)δ9.19(s,1H),8.84(d,J＝4.8Hz,1H),8.78(s,1H),8.07(d,J＝8.0Hz,1H),7.75(dd,J 1＝8.0Hz,J 2＝4.8Hz,1H),7.65(d,J＝8.8Hz,1H),7.33(d,J＝8.8Hz,1H),5.84(s,1H),3.03(d,J＝4.2Hz,3H),1.82–1.77(m,1H),0.87(q,J＝5.0Hz,2H),0.34(q,J＝5.0Hz,2H).LCMS(ESI)m/z＝332.9[M+H] +.
实施例17.化合物54盐酸盐的合成
Figure PCTCN2022136109-appb-000144
第一步：中间体2-54的合成
反应在50mL三口瓶中进行。将中间体2-1(2.25g，10.0mmol)、5-溴-嘧啶(1.6g，10.0mmol)、Pd 2(dba) 3(0.92g，1.0mmol)、Xantphos(1.15g，2mmol)、碳酸铯(4.6g，14mmol)、1,4-二氧六环(60mL)投入三口瓶中，用氮气置换三次，升温至110℃ 搅拌12小时。后处理：将反应液倒入水(100mL)中，用二氯甲烷(50mL×2)萃取二次，合并有机层用水、食盐水各洗涤一次，硫酸钠干燥，过滤旋干，粗品经硅胶flash柱纯化(流动相：DCM/MeOH＝98/2)得到中间体2-54(1.5g，收率：49.5％)，淡黄色固体。LCMS(ESI)m/z＝304.2[M+H] +.
第二步：中间体3-54的合成
反应在25mL高压釜中进行。将中间体2-54(500mg，1.65mmol)加入7M氨甲醇溶液45mL溶液中，封管，升温至50℃，保温反应12h。将反应液减压浓缩得480mg中间体3-54，白色固体，收率：100％。LCMS(ESI)m/z＝289.1[M+H] +.
第三步：中间体4-54的合成
反应在25mL三口瓶中进行。将中间体3-54(300mg,1.05mmol)加入DMF(5mL)中，降温至0℃，分批加入60％NaH(75.6mg，3.15mmol)，加完在此温度保温反应0.5h，然后将CDI(255mg，1.6mmol)加入上述反应液中，保温反应0.5h。后处理：将反应液倒入200mL水中，用2M稀盐酸将pH调至7～8，用二氯甲烷(50mL×2)萃取二次，合并有机层用水、食盐水各洗涤一次，硫酸钠干燥，过滤旋干，粗品拌硅胶，flash柱纯化(流动相：DCM:MeOH＝90:10)得到中间体4-54(150mg，收率：45.7％)，白色固体。 1H NMR(400MHz,DMSO)δ12.23(s,1H),9.48(s,1H),9.18(s,2H),7.93(d,J＝9.2Hz,1H),7.68(d,J＝8.8Hz,1H),6.32(s,1H).
第四步：中间体5-54的合成
反应在25mL单口瓶中进行。将中间体4-54(50mg，0.16mmol)、三氯氧磷(74mg，0.48mmol)、DIPEA(62mg，0.48mmol)、乙腈(5mL)投入反应瓶中，升温80℃搅拌2小时，送样检测。后处理：将反应液减压浓缩得得中间体5-54粗品，无需纯化，直接进行下一步。
第五步：化合物54盐酸盐的合成
反应在20mL单口瓶中进行。将中间体5-54粗品用5mL四氢呋喃溶解，加入环丙胺(57mg，1mmol)，室温反应1小时，送样检测。后处理：将反应液倒入25mL水中，用甲醇/二氯甲烷(1/10)萃取二次(50mL×2)，有机层用纯化水、饱和食盐水各洗涤二次(50mL×2)，有机相浓缩，通过硅胶flash柱纯化，洗脱剂为DCM:MeOH＝10:1，得产物54盐酸盐(13.24mg，两步收率:23.5％)，白色固体。 1H NMR(400MHz,DMSO)δ9.40(s,1H),9.10(s,2H),8.97(d,J＝4.5Hz,1H),7.81(d,J＝9.2Hz,1H),7.64(d,J＝8.8Hz,1H),6.42(s,1H),3.11(d,J＝4.0Hz,1H),0.85–0.79(m,2H),0.76–0.70(m,2H).LCMS(ESI)m/z＝354.05[M+H] +.
实施例18.化合物14盐酸盐的合成
Figure PCTCN2022136109-appb-000145
第一步：化合物2-14的合成
反应在500mL三口瓶中进行。将中间体2-1(12g，53.18mmol)、3-溴吡啶(12.6g，79.78mmol)、Pd 2(dba) 3(4.87g，5.32mmol)、Xantphos(6.18g，10.64mmol)、碳酸铯(34.68g，106.47mmol)、1,4-二氧六环(250ml)投入三口瓶中，用氮气置换三次，升温至100℃搅拌15小时。反应液抽滤，滤液蒸馏旋干，粗品过Flash(流动相：DCM:MeOH＝98:2)得到化合物2-14(7.1g，收率：44.1％)，灰色固体。LCMS(ESI)m/z＝303.0[M+H] +.
第二步：化合物3-14-2的合成
反应在250mL反应釜中进行。将中间体2-14(7.1g,23.45mmol)和150mL氨-甲醇溶液(7M)一起加入反应釜中，油锅升温至100℃搅拌18小时，将釜中反应液减压浓缩，用乙酸乙酯打浆，浓缩得6.9g中间体3-14-2，灰色固体，收率100％。LCMS(ESI)m/z＝288.05[M+H] +.
第三步：化合物4-14的合成
反应在500mL三口瓶中进行，瓶内确保干燥。将化合物3-14-2(6.9g,23.98mmol)加入80mL DMF中，用氮气置换三次，降温至0℃后，加入NaH(60％)(2.88g,71.95mmol)。反应液搅拌10分钟后，加入CDI(5.83mg,35.97mmol)继续搅拌10分钟。在反应液中加入饱和氯化铵水溶液淬灭，加入十倍量的水，抽滤，滤饼旋干得到7.2g化合物4-14，收率：95.74％，棕灰色固体。 1H NMR(400MHz,DMSO)δ12.06(s,1H),8.96–8.76(m,2H),8.15(ddd,J＝8.1,2.4,1.6Hz,1H),7.89(d,J＝9.0Hz,1H),7.76(ddd,J＝8.1,4.8,0.4Hz,1H),7.64(dd,J＝9.0,2.2Hz,1H),6.03(d,J＝2.1Hz,1H).
第四步：化合物5-14的合成
反应在500ml单口瓶中进行。将中间体4-14(3.5g,11.16mmol)、DIEA(7.21g,55.79mmol)、POCl 3(8.56g，55.79mmol)和350mL的1,2-二氯乙烷投入单口瓶中，升温至80℃反应2小时。将反应液浓缩至干，得到中间体5-14，直接用于下一步反应。LCMS(ESI)m/z＝331.85[M+H] +.
第五步：化合物14的合成
反应在100ml单口瓶中进行。将中间体5-14(3.71g，11.17mmol)，甲胺四氢呋喃溶液(27.92mL，55.85mmol)和DIPEA(7.22g，55.85mmol)加入到40mL DCE，室 温搅拌10分钟左右，将反应液浓缩干，粗品用Flash进行分离纯化(流动相：DCM:MeOH＝96:4)，杂质再用乙腈打浆除去，加入水和乙腈冻干得到1.1g化合物14，黄色固体，收率：30.14％。 1H NMR(400MHz,DMSO)δ8.80(dd,J＝4.7,1.1Hz,1H),8.74(t,J＝4.0Hz,2H),8.10–7.98(m,1H),7.81(d,J＝9.0Hz,1H),7.70(dd,J＝8.0,4.8Hz,1H),7.61(dd,J＝9.0,2.1Hz,1H),6.15(d,J＝2.0Hz,1H),2.98(d,J＝4.6Hz,3H).
第六步：化合物14盐酸盐的合成
反应在50ml单口瓶中进行。将化合物14(2.12g，6.49mmol)加入到25mL盐酸-二氧六环溶液中，室温搅拌10分钟左右，将反应液过滤，滤饼加入水和乙腈冻干，得到最终产物14盐酸盐2.3g，黄色固体，收率98％。 1H NMR(400MHz,DMSO)δ9.56(s,1H),8.89(dd,J＝7.0,1.8Hz,2H),8.20(d,J＝8.2Hz,1H),8.00–7.76(m,2H),7.67(dd,J＝9.0,2.1Hz,1H),6.25(d,J＝1.8Hz,1H),3.07(d,J＝3.9Hz,3H).LCMS(ESI)m/z＝327.05[M+H] +.
参照实施例18化合物14盐酸盐的合成方法，将合成步骤第一步当中的3-溴吡啶替换为3-溴-2-氯-吡啶，可分别相应制备得到化合物60盐酸盐。
化合物60盐酸盐：
Figure PCTCN2022136109-appb-000146
1H NMR(400MHz,DMSO)δ8.87(s,1H),8.70(d,J＝3.3Hz,1H),8.26(d,J＝6.4Hz,1H),7.84(d,J＝9.0Hz,1H),7.77(dd,J 1＝7.7Hz,J 2＝4.8Hz,1H),7.64(dd,J 1＝9.0Hz,J 2＝2.0Hz,1H),6.14(d,J＝1.9Hz,1H),3.00(s,3H).LCMS(ESI)m/z＝360.85[M+1] +.
实施例19.化合物114的合成
Figure PCTCN2022136109-appb-000147
第一步：化合物2-114的合成
反应在100mL三口瓶中进行。将2,3-二氟-6-甲氧基苯甲腈1-114(2.28g，13.48mmol)和二氯甲烷30mL投入三口瓶中，冷却至-78℃后滴加BBr 3(10.13g，40.44)，滴加完毕，移至室温下反应20h。反应液加入冰水中淬灭，用二氯甲烷萃取两次，浓缩干，得到 化合物2-114(2.05g，收率：44.1％)，棕色固体。
第二步：化合物3-114的合成
反应在100mL单口瓶中进行。将中间体2-114(2.04g,13.15mmol)，氯乙酸甲酯(3.64g,26.31mmol)，K 2CO 3(1.57g,14.47mmol)和25mL DMF加入到单口瓶中，N 2保护，升温至80℃搅拌18小时，反应液进行过滤，然后浓缩拌样过Flash柱(流动相:20％EtOAcin PE)，得到1.8g白色固体3-114，收率为60％。
第三步：化合物4-114的合成
反应在50mL单口瓶中进行，将化合物3-114(1.05g,4.62mmol)，2-甲基-3溴吡啶(1.19g，6.93mmol)、Pd 2(dba) 3(423mg，0.46mmol)、Xantphos(535mg，0.92mmol)、碳酸铯(3.01g，9.24mmol)、1,4-二氧六环(12ml)投入单口瓶中，用氮气置换三次，升温至100℃搅拌15小时。反应液抽滤，滤液蒸馏旋干，粗品过硅胶Flash(流动相：35％EtOAc in PE)得到化合物4-114(800mg，收率：54.42％)，灰色固体。 1H NMR(400MHz,DMSO)δ8.13(dd,J＝4.7,1.2Hz,1H),7.64(s,1H),7.50(ddd,J＝10.2,9.1,3.7Hz,1H),7.23(d,J＝7.9Hz,1H),7.09(dd,J＝8.0,4.7Hz,1H),7.02(td,J＝9.3,3.0Hz,1H),3.88(s,3H),3.33(s,3H).
第四步：化合物5-114的合成
反应在100mL反应釜中进行。将中间体4-114(800mg,2.51mmol)和60mL氨-甲醇溶液一起加入反应釜中，油锅升温至100℃搅拌18小时，釜中反应液直接过滤，得到630mg中间体5-114，灰色固体，收率82.68％。LCMS(ESI)m/z＝304.00[M+H] +.
第五步：化合物6-114的合成
反应在50mL三口瓶中进行，瓶内确保干燥。将化合物5-114(630mg,2.08mmol)加入10mL DMF中，用氮气置换三次，降温至0℃后，加入NaH(60％)(249mg,6.24mmol)。反应液搅拌10分钟后，加入CDI(505mg,3.12mmol)继续搅拌10分钟。在反应液中加入饱和氯化铵水溶液淬灭，加入十倍量的水，抽滤，滤饼旋干得到550mg化合物6-114，收率：80.41％，灰白色固体。 1H NMR(400MHz,DMSO)δ12.24(s,1H),8.61(d,J＝4.0Hz,1H),7.93(d,J＝7.6Hz,1H),7.60(td,J＝9.5,3.0Hz,1H),7.43(dd,J＝7.4,5.0Hz,1H),7.05(dd,J＝13.4,5.8Hz,1H),2.36(s,3H).
第六步：化合物7-114的合成
反应在50ml单口瓶中进行。将中间体6-114(150mg,0.45mmol)、DIEA(294mg,2.27mmol)、POCl 3(348mg，2.27mmol)和8mL二氯乙烷投入单口瓶中，升温至80℃反应2小时。将反应液浓缩至干，得到化合物7-114，直接用于下一步反应。LCMS(ESI)m/z＝348.00[M+H] +.
第七步：化合物114的合成
反应在50ml单口瓶中进行。将上一步得到的中间体7-114(148mg，0.45mmol)，甲胺溶液(1.1mL，2.27mmol)和DIPEA(293mg，2.27mmol)加入到5mL四氢呋喃中，室温搅拌10分钟左右，将反应液浓缩干，粗品用Flash进行分离纯化(流动相：DCM: MeOH＝96:4)，加入水和乙腈冻干得到70mg最终产物化合物114，白色固体，收率：47.95％。 1H NMR(400MHz,DMSO)δ8.83(q,J＝4.0Hz,1H),8.55(dd,J＝4.8,1.5Hz,1H),7.77(dd,J＝7.8,1.3Hz,1H),7.68–7.49(m,1H),7.38(dd,J＝7.9,4.8Hz,1H),7.07–6.94(m,1H),2.99(d,J＝4.6Hz,3H),2.27(s,3H).LCMS(ESI)m/z＝343.05[M+H] +.
测试例
测试例1、生物化学测试
试验原理简介：MAT2A可以催化L-甲硫氨酸和ATP转化为SAM、无机磷酸盐和无机二磷酸盐。通过向酶促反应体系中加入显色剂，可以定量检测样品中无机磷酸盐的含量，进而表征MAT2A的酶活性。
试验材料：
1.Tris(Life science#0497)
2.BSA(Sigma#)
3.MAT2A his-tag(BPS#71401-1)
4.384孔板(Corning#3765)
5.L-methionine(Admas#1100469)
6.ATP(Sigma#A7699)
7.MgCl2(Sigma#M8266)
8.KCl(Sigma#7447-40-7)
9.Brij35(Sigma#B4184)
10.EDTA(Sigma#E1644)
试验方法：
1.配制1xAssaybuffer。
2.化合物浓度梯度的配制：受试化合物测试浓度为10μM起始，3倍稀释，10个浓度，复孔测试。在384孔板中梯度稀释成100倍终浓度的10个不同浓度的溶液。然后用Echo550转移250nL到384反应板中备用。阴性对照孔和阳性对照孔中分别加入250nL的100％DMSO。
3.用1xAssaybuffer配制1.67倍终浓度的酶溶液。
4.在化合物孔和阳性对照孔中分别加入15μL的1.67倍终浓度的酶溶液；在阴性对照孔中加入15μL的1xAssaybuffer。
5.1000rpm离心60秒，振荡混匀后孵育15分钟。
6.用1xAssaybuffer配制2.5倍终浓度的底物混合溶液。
7.加入10μL的2.5倍终浓度的底物混合溶液，起始反应。
8.将384孔板1000rpm离心60秒，振荡混匀后孵育150分钟。
9.加入50μLBiomol终止反应，1000rpm离心60秒后孵育15分钟。读取OD620，处理 数据。
数据分析：
计算化合物抑制率(％)，拟合得到受试化合物的IC 50
化合物抑制率(％)＝(OD620_max-OD620_sample)/(OD620_max-OD620_min)X100
其中：OD620_sample是样品孔吸光值；OD620_min是阳性对照孔吸光值，表示没有酶活孔的读数；OD620_max是阴性对照孔吸光值，表示没有化合物抑制孔的读数
试验结果：
在本试验条件下，待测化合物对MAT2A酶活的抑制作用可以用对酶促反应过程中磷酸产生水平抑制的IC 50值表示。待测化合物的MAT2A抑制活性具体见表1。其中，0nM＜A＜100nM，100nM≤B＜500nM，C≥500nM。
表1
化合物 MAT2A抑制活性IC 50(nM) 化合物 MAT2A抑制活性IC 50(nM)
1 A 31 B
2 B 32 C
3 A 33 B
4 A 34 A
7 C 35 A
8 C 36 A
9 C 37 A
10 C 38 A
11 A 39 A
12 A 40 C
13 C 41 B
14 A 42 A
15 A 43 A
16 A 44 A
17 A 45 A
18 A 46 A
19 B 47 A
20 B 48 A
21 A 49 A
22 A 50 B
23 A 52 A
24 A 53 A
25 A 57 A
26 A 64 A
27 C 71 A
28 B 87 A
29 A 30 B
47-P1 B 47-P2 A
51 A 54 A
55 A 59 A
59-P1 A 59-P2 B
60 A 61 A
62 A 65 A
66 A 67 B
68 A 69 A
70 A 72 A
88 A 89 A
90 A 91 A
92 A 95 A
96 C 97 A
98 A 99 B
100 A 101 A
104 C 105 B
106 C 107 C
108 C 109 A
110 A 111 A
112 B 113 A
114 B 115 A
116-P1 C 116-P2 A
测试例2、细胞内SAM水平检测
试验原理简介：将待测MAT2A抑制剂与细胞共孵育一段时间后，使用裂解液裂解细胞，淬灭MAT2A酶活性。通过LC-MS/MS的方法检测细胞裂解液中SAM的含量，用以表征细胞内的MAT2A酶活性。
试验材料：
1.HCT116MTAP -/-细胞(Horizon#HD R02-033)
2.RPMI-1640(BI#C3010-0500)
3.胎牛血清(Fetal bovine serum)(EXCELL#FND500)
4.青霉素-链霉素(Penicillin-Streptomycin)(Gibco#15140-122)
5.0.25％Typsin-EDTA(Gibco#25200-072)
6.DMSO(Sigma#D2650)
7.甲醇(Methanol)(Sigma#34860)
8.乙酸(Acetic acid)(GREAGENT#G73562B)
9.96孔板(Corning#3599)
试验方法：
1.HCT116 MTAP -/-细胞用含有10％胎牛血清和1％青霉素-链霉素的RPMI-1640培养基于37℃、5％CO 2条件下置于细胞培养箱中培养，处于对数生长期细胞方可用于后续试验。
2.调整细胞浓度为每孔20000个细胞，接种96孔板，于37℃、5％CO 2条件下置于细胞培养箱中培养过夜。
3.使用DMSO溶解化合物，并用培养基稀释至适当浓度后加入细胞板中。于37℃、5％CO 2条件下继续培养6小时。
4.吸去上清，PBS洗一遍后，加入裂解液裂解细胞。
5.裂解液经过处理后，通过LC-MS/MS分析，测定SAM浓度。
数据分析：
计算化合物抑制率(％)％，拟合得到受试化合物的IC 50
化合物抑制率(％)＝(SAM_max-SAM_sample)/(SAM_max-SAM_min)X100
其中：SAM_sample是样品孔SAM浓度；SAM_min是阳性对照孔SAM浓度，表示没有细胞的读数；SAM_max是阴性对照孔吸光值，表示没有化合物抑制孔的SAM浓度。
试验结果：
在本试验条件下，用待测化合物对HCT116MTAP -/-细胞内SAM生成抑制的IC 50值表征待测化合物对细胞内MAT2A酶活的抑制能力。待测化合物对细胞内SAM生成抑制活性见表2。
表2
化合物 SAM生成抑制活性IC 50(nM)
1 12.9
14 3.6
15 28.7
18 8.5
23 9.6
29 29.3
39 25.2
45 1.7
47 1.5
59 1.0
测试例3、人胰腺癌KP-4细胞活性抑制试验
试验原理简介：将待测MAT2A抑制剂与癌细胞共孵育一段时间后，采用基于ATP含量的细胞活性测量方法来表征待测化合物对细胞活性的影响。
试验材料：
1.KP-4细胞(JCRB#JCRB0182)
2.IMDM(Gibco#12440061)
3.胎牛血清(Fetal bovine serum)(EXCELL#FND500)
4.青霉素-链霉素(Penicillin-Streptomycin)(Gibco#15140-122)
5.0.25％Typsin-EDTA(Gibco#25200-072)
6.DMSO(Sigma#D2650)
7.96孔板(Corning#3610)
8.CellTiter-Glo(Promega#G7571)
试验方法：
1.KP-4细胞用含有10％胎牛血清和1％青霉素-链霉素的IMDM培养基于37℃、5％CO 2条件下置于细胞培养箱中培养，处于对数生长期细胞方可用于后续试验。
2.调整细胞浓度为每孔500个细胞，接种96孔板，于37℃、5％CO 2条件下置于细胞培养箱中培养过夜。
3.使用DMSO溶解化合物，并用培养基稀释至适当浓度后加入细胞板中。于37℃、5％CO 2条件下继续培养5天。
4.加入CellTiter-Glo试剂，使用酶标仪检测细胞活性。
数据分析：
计算化合物抑制率(％)，拟合得到受试化合物的IC 50
化合物抑制率(％)＝(Signal_max-Signal_sample)/(Signal_max-Signal_min)X100
其中：Signal_sample是样品孔读数，表示化合物抑制孔的细胞活性；Signal_min是阳性对照孔读数，表示没有细胞的本底活性；Signal_max是阴性对照孔读数，表示没有化合物抑制孔的细胞活性。
试验结果：
在本试验条件下，待测化合物对KP-4细胞活性抑制的IC 50值见表3。 表3
化合物 KP-4细胞抗增殖活性IC 50(nM)
1 131.2
11 30.0
12 60.7
14 159.2
15 209.1
17 20.4
23 126.9
29 91.6
39 25.2
45 15.5
47 11.3
17 1164.0
44 355.4
57 52.3
59 97.1
60 38.7
61 74.4
62 333.5
64 47.7
66 56.3
69 120.5
71 28.1
88 114.0
89 46.0
90 20.9
92 18.0
87 45.3
97 51.0
98 2.8
109 33.0
110 20.9
113 138.8
115 225.2
116-P2 3.6

Claims (14)

  1. 一种如式(I)所示的化合物、其立体异构体或其可药用盐，
    Figure PCTCN2022136109-appb-100001
    其中，
    X 1为CR 3或N，X 2为CR 4或N，X 3为CR 5或N，X 4为CR 6或N；且X 1、X 2、X 3、X 4至多两个同时为N；
    R 3，R 4，R 5，R 6各自独立的选自H、D、卤素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6烷基磺酰基、C 3-C 7环烷基、氰基、羟基、巯基、C 1-C 6烷基氨基、氨基、硝基、羧基、NHCOR a，所述烷基、烯基、炔基、烷氧基、环烷基为无取代或任选地被一个或多个选自D、卤素的取代基所取代，R a选自C 1-C 10烷基、C 3-C 10环烷基；
    W选自O、NR b、S、CHR b；所述R b选自H、D、C 1-C 4烷基、C 3-C 6环烷基，所述烷基、环烷基无取代或被选自D、卤素、-OH中的一个或多个取代基所取代；
    R 1选自无取代或取代的C 3-C 10环烷基、无取代或取代的C 6-C 10芳基、无取代或取代的5-6元杂环烷基、无取代或取代的5-10元杂芳基，其中，R 1中所述取代是指被一个或多个选自A组的取代基所取代，A组取代基包括：卤素、CN、OH、氧代、SH、NH 2、NO 2、C 1-C 4烷基、C 3-C 7环烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基、COOH、CONHR c、NHCOR c、NHSO 2R c，R c选自H、C 1-C 4烷基、C 3-C 10环烷基、C 1-C 10烷氧基、C 6-C 10芳基，其中R c中的C 1-C 4烷基、C 3-C 10环烷基、C 1-C 10烷氧基、C 6-C 10芳基为无取代的或被选自卤素、羟基、氰基的一个或多个取代；
    R 2选自NR 7R 8、-OR 9、或-SR 9；
    R 7、R 8、R 9各自独立地选自H、D、无取代或取代的C 1-C 6烷基、无取代或取代的C 1-C 6烷氧基、无取代或取代的C 2-C 6烯基、无取代或取代的C 2-C 6炔基、无取代或取代的C 3-C 7环烷基、无取代或取代的C 5-C 10芳基、无取代或取代的3-7元杂环烷基、无取代或取代的5-10元杂芳基、-NHCO-(C 1-C 6烷基)、-NHSO 2-(C 1-C 6烷基)；其中，R 7、R 8、R 9中所述取代是指被一个或多个选自如下的取代基所取代：D、卤素、-NHR d、-N(R d) 2、-OR d、-SR d、无取代或被一个或多个选自B组的取代基所取代的C 1-C 3烷基、无取代或被一个或多个选自B组的取代基所取代的C 3-C 7环烷基、无取代或被一个或多个选自B组的取代基所取代的5-10元杂芳基；R d为H、COOH、Boc、无取代或被一个或多个选自B组的取代基所取代的C 1-C 3烷基、无取代或被一个或多个选自B组的取代基所取代的C 3-C 7环烷基、无取代或被一个或多个选自B组的取代基所取代的5-10元杂芳基；B组取代基包括：C 1-C 6烷基、卤素、OH、氨基；
    或R 7、R 8与它们相连的N原子一起形成无取代或被选自如下的一个或多个取代基所取代的4-6元杂环烷基：OH、卤素、C 1-C 10烷基、C 3-C 10环烷基；
    所述杂芳基和杂环烷基分别含有选自N、O、S中的一个或多个杂原子。
  2. 根据权利要求1所述的如式(I)所示的化合物、其立体异构体或其可药用盐，
    其中，
    R 3，R 4，R 5，R 6各自独立的选自H、卤素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 3-C 7环烷基、氰基、羟基、氨基，所述烷基、烯基、炔基、烷氧基、环烷基为无取代或任选地被一个或多个选自D、卤素的取代基取代；进一步优选地，R 3、R 5、R 6各自独立地选自H和卤素，R 4选自H、卤素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 3-C 7环烷基、氰基、羟基、氨基，所述烷基、烯基、炔基、烷氧基、环烷基为无取代或任选地被一个或多个选自D、卤素的取代基取代；进一步优选地，R 3、R 5、R 6均为H，R 4选自H、卤素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 3-C 7环烷基、氰基、羟基、氨基，所述烷基、烯基、炔基、烷氧基、环烷基为无取代或任选地被一个或多个选自D、卤素的取代基取代；
    所述R b选自H、D、C 1-C 3烷基、C 3-C 6环烷基，所述烷基、环烷基无取代或被选自卤素、-OH中的一个或多个取代基所取代；更优选地，所述R b选自H、D、甲基、乙基、正丙基、异丙基、环丙基、环丁基，其中甲基、乙基、正丙基、异丙基、环丙基、环丁基为无取代或被选自D、卤素、-OH中的一个或多个取代基所取代；
    R 1选自无取代或取代的苯基、无取代或取代的C 3-C 7环烷基、无取代或取代的5-6元杂环烷基、无取代或取代的5-10元杂芳基，其中，R 1中所述取代是指被一个或多个选自A组的取代基所取代，A组取代基包括：卤素、CN、OH、氧代、SH、NH 2、NO 2、C 1-C 4烷基、C 3-C 7环烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基、COOH、CONHR c、NHCOR c、NHSO 2R c，R c选自H、C 1-C 4烷基、C 3-C 10环烷基、C 1-C 10烷氧基或C 6-C 10芳基，其中R c中的C 1-C 4烷基、C 3-C 10环烷基、C 1-C 10烷氧基、C 6-C 10芳基为无取代的或被选自卤素、羟基、氰基的一个或多个取代；
    优选地，R 1选自无取代或取代的苯基、无取代或取代的C 3-C 7环烷基、无取代或取代的5-6元杂环烷基、无取代或取代的5-10元杂芳基，其中，R 1中所述取代是指被一个或多个选自A组的取代基所取代，A组取代基包括：卤素、CN、OH、氧代、SH、NH 2、NO 2、C 1-C 4烷基、C 3-C 7环烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基；
    R 2选自NR 7R 8、-OR 9、或-SR 9；
    R 7、R 8、R 9各自独立地选自H、无取代或取代的C 1-C 3烷基、无取代或取代的C 1-C 3烷氧基、无取代或取代的C 3-C 7环烷基、无取代或取代的苯基、无取代或取代的3-6元杂环烷基、无取代或取代的5-10元杂芳基、-NHCO-(C 1-C 3烷基)、-NHSO 2-(C 1-C 3烷基)；其中，R 7、R 8、R 9中所述取代是指被一个或多个选自如下的取代基所取代：卤素、-NHR d、-N(R d) 2、-OR d、-SR d、无取代或被一个或多个选自B组的取代基所取代的C 1-C 3烷基、无取代或被一个或多个选自B组的取代基所取代的C 3-C 7环烷基、无取代或被一个或多个选自B组的取代基所取代的5-10元杂芳基，R d为H、COOH、Boc、无取代或被一个或多个选自B组的取代 基所取代的C 1-C 3烷基、无取代或被一个或多个选自B组的取代基所取代的C 3-C 7环烷基、无取代或被一个或多个选自B组的取代基所取代的5-10元杂芳基；B组取代基包括：C 1-C 3烷基、卤素、OH、氨基；
    或R 7、R 8与它们相连的N原子一起形成无取代或被选自如下的一个或多个取代基所取代的5-6元杂环烷基：OH、卤素、C 1-C 3烷基、C 3-C 6环烷基；
    其中所述杂芳基和杂环烷基分别含有选自N、O、S中的一个或多个杂原子。
  3. 根据权利要求2所述的如式(I)所示的化合物、其立体异构体或其可药用盐，
    其中，X 1为CH或N，X 2为CR 4或N，X 3为CH或N，X 4为CH或N；且X 1、X 2、X 3、X 4至多两个同时为N；所述R 4选自F、Cl、Br、CH 3、CD 3、CF 3、CF 2H、CF 2D、OH、SH、NH 2、CN、OCH 3、CH 3CH 2、-CH 2CH 2CH 3、环丙基、-CH 2(CH 3)CH 3、NO 2。
  4. 根据权利要求2所述的如式(I)所示的化合物、其立体异构体或其可药用盐，
    其中，W选自O、NH、NCH 3、NC 2H 4OH、NCH(CH 3) 2、NC 2H 5、S、CH 2。
  5. 根据权利要求1-4中任一项所述的如式(I)所示的化合物、其立体异构体或其可药用盐，
    其中，R 1选自无取代或取代的苯基、无取代或取代的C 3-C 7环烷基、无取代或取代的5-6元杂环烷基、无取代或取代的5-10元杂芳基；所述5-10元杂芳基选自如下基团：
    Figure PCTCN2022136109-appb-100002
    其中，R 1中所述取代是指被一个或多个选自A组的取代基所取代；A组取代基包括：卤素、CN、OH、氧代、SH、NH 2、NO 2、C 1-C 4烷基、C 3-C 7环烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基(如CF 3、CF 2H)、COOH、CONHR c、NHCOR c、NHSO 2R c，R c选自H、C 1-C 4烷基、C 3-C 10环烷基、C 1-C 10烷氧基、C 6-C 10芳基，其中R c中的C 1-C 4烷基、C 3-C 10环烷基、C 1-C 10烷氧基、C 6-C 10芳基为无取代或被选自卤素、羟基、氰基的一个或多个取代。
  6. 根据权利要求1-4中任一项所述的如式(I)所示的化合物、其立体异构体或其可药用盐，
    其中，所述R 1选自
    Figure PCTCN2022136109-appb-100003
    Figure PCTCN2022136109-appb-100004
    Figure PCTCN2022136109-appb-100005
    其中，R 10和R 11各自独立地选自卤素、CN、OH、SH、NH 2、C 1-C 4烷基、C 3-C 7环烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基、COOH、CONH 2、CONHR c、NHCOR c，R c选自无取代或被选自卤素、羟基、氰基的一个或多个取代的C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4烷氧基或苯基。
  7. 根据权利要求1-4中任一项所述的如式(I)所示的化合物、其立体异构体或其可药用盐，其中，所述R 1选自
    Figure PCTCN2022136109-appb-100006
  8. 根据权利要求1-4中任一项所述的如式(I)所示的化合物、其立体异构体或其可药 用盐，其中，R 2选自NH 2、
    Figure PCTCN2022136109-appb-100007
    Figure PCTCN2022136109-appb-100008
  9. 如权利要求1-8任一项所述的化合物、其立体异构体或其可药用盐，其中，式(I)所示的化合物如下式I-A所示，
    Figure PCTCN2022136109-appb-100009
    其中，W、R 1、R 2、R 3、R 4、R 5、R 6分别如相应权利要求所述。
  10. 如权利要求1所述的化合物、其立体异构体或其可药用盐，其中，式(I)所示的化合物选自如下结构：
    Figure PCTCN2022136109-appb-100010
    Figure PCTCN2022136109-appb-100011
    Figure PCTCN2022136109-appb-100012
    Figure PCTCN2022136109-appb-100013
    Figure PCTCN2022136109-appb-100014
    Figure PCTCN2022136109-appb-100015
    Figure PCTCN2022136109-appb-100016
    Figure PCTCN2022136109-appb-100017
    Figure PCTCN2022136109-appb-100018
    Figure PCTCN2022136109-appb-100019
    Figure PCTCN2022136109-appb-100020
  11. 一种组合物，包含至少一种根据权利要求1-10中任一项所述的式(I)所示的化合物、其立体异构体或其可药用盐。
  12. 一种药物制剂，包含治疗有效量的根据权利要求1-10中任一项所述的式(I)所示的化合物、其立体异构体或其可药用盐，以及一种或多种可药用的载体、稀释剂或赋形剂。
  13. 一种药物组合，其包含至少一种治疗有效量的根据权利要求1-10中任一项所述的式(I)所示的化合物、其立体异构体或其可药用盐，及一种或多种其它治疗剂。
  14. 权利要求1-10中任一项所述的式(I)所示的化合物、其立体异构体或其可药用盐在制备治疗和/或预防肿瘤的药物中的用途，
    优选地，所述肿瘤包括：MTAP缺失的肿瘤；MTAP低表达的肿瘤；MAT2A异常表达的肿瘤；其他MAT2A依赖的肿瘤，
    优选地，所述肿瘤包括：乳腺癌、肺癌、胶质母细胞瘤、脑癌和脊椎癌、头颈癌、皮肤癌、生殖系统癌症、胃肠系统癌症、食道癌、鼻咽癌、胰腺癌、直肠癌、肝细胞癌、胆管癌、胆囊癌、结肠癌、多发性骨髓瘤、肾脏和膀胱癌、骨癌、恶性间皮瘤、肉瘤、淋巴瘤、腺癌、甲状腺癌、心脏肿瘤、生殖细胞肿瘤、恶性神经内分泌肿瘤、恶性横纹肌样瘤、软组织肉瘤、中线束癌和未知原发癌。
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