WO2022222995A1 - Picolinamide compound - Google Patents

Picolinamide compound Download PDF

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Publication number
WO2022222995A1
WO2022222995A1 PCT/CN2022/088181 CN2022088181W WO2022222995A1 WO 2022222995 A1 WO2022222995 A1 WO 2022222995A1 CN 2022088181 W CN2022088181 W CN 2022088181W WO 2022222995 A1 WO2022222995 A1 WO 2022222995A1
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Prior art keywords
compound
pharmaceutically acceptable
reaction
acceptable salt
added
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PCT/CN2022/088181
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French (fr)
Chinese (zh)
Inventor
陈正霞
戴美碧
赵立雨
张杨
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202280004848.4A priority Critical patent/CN115702156A/en
Publication of WO2022222995A1 publication Critical patent/WO2022222995A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a series of pyridine amide compounds, in particular to the compounds represented by formula (V) and their pharmaceutically acceptable salts.
  • PARP Poly-ADP-ribose polymerase
  • PARP1 is the most important member of the PARP family, and it undertakes more than 90% of the functions of the PARP family in cells. It is a key factor in DNA damage repair and the main target for anti-tumor activity. PARP2 can also accurately recognize single-strand breaks and play a role in 5%-10%, PARP2 plays an important role in DNA damage repair in hematopoietic stem/precursor cells. Studies have found that loss of PARP2 results in decreased red blood cell lifespan, defective erythroid progenitor differentiation, and chronic anemia, while PARP1 has little effect in this process.
  • PARP3 repairs DNA double-strand breaks through a non-homologous end joining mechanism, and has a protective effect on Hematopoietic Stem and Progenitor Cells (HSPCs). It has been reported that the inhibition of PARP3 by small-molecule compounds can lead to bone marrow toxicity (CancerRes, 2016, 76(20): 6084-6094.). Therefore, selective inhibition of PARP1 will not reduce the efficacy of the drug, but can reduce the hematological side effects caused by the inhibition of PARP2/3. PARP1 selective inhibitors will be better tolerated by patients in long-term clinical treatment and have a larger therapeutic window.
  • the present invention provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from N, NH, CH 2 and CR 1 ;
  • T 2 is selected from CH and N;
  • T 3 is selected from CH and N;
  • R 1 is selected from H, F, Cl, Br and I;
  • R 2 is selected from H, C 1-3 alkyl and C 3-5 cycloalkyl, each of which is independently optionally replaced by 1 , 2 or 3 halogens Substituted; R is selected from H or absent;
  • R 4 and R 5 are each independently selected from H, C 1-3 alkyl, C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl, the C 1-3 alkyl, C 3-5 cycloalkyl Alkyl and 3-5 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 R b ;
  • R 6 is selected from H
  • R is selected from H
  • R 8 and R 9 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 halogens;
  • R 10 is selected from H, F, Cl, Br and I;
  • R 11 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 3-5 cycloalkyl and 5-membered heteroaryl, the C 1-3 alkyl, C 3-5 cycloalkane and 5-membered heteroaryl are each independently optionally substituted with 1, 2 or 3 R c ;
  • R2 and R1 together with the attached carbon atoms form a phenyl group optionally substituted with 1 , 2 or 3 halogens;
  • R2 and R3 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
  • R and R together with the attached carbon atoms form a 5 - membered heterocycloalkyl optionally substituted with 1, 2 or 3 halogens;
  • R4 and R6 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1 , 2 or 3 halogens;
  • R5 and R7 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
  • T 3 and -L 1 -R 11 together with the attached carbon atoms form a 5-membered heterocyclic group optionally substituted with 1 CH 3 ;
  • each R b is independently selected from F, Cl, Br, I, OH and CN;
  • each Rc is independently selected from D, F, Cl, Br, I and CH3 ;
  • T 1 is selected from CH
  • T 3 is selected from N
  • R 2 is selected from C 1-3 alkyl, and when the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, R 4 , R 5 and R 10 are not selected from H at the same time;
  • T 1 is selected from CH
  • T 3 is selected from CH
  • T 2 is selected from N.
  • said R1 is selected from H, and other variables are as defined herein.
  • the R 2 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 3 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl are each independently optionally substituted with 1, 2 or 3 halogens, other variables are as defined herein.
  • said R 2 is selected from the group consisting of H, CH 2 CH 3 and cyclopropyl, and other variables are as defined herein.
  • the R 2 and R 1 together with the attached carbon atoms form a phenyl group substituted with 1 F, and other variables are as defined herein.
  • the R2 and R3 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl and oxa cyclobutyl, the CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , cyclopropyl and oxetanyl, each independently optionally surrounded by 1, 2 or 3 R b is substituted, each R b is independently selected from F, Cl, Br, I, OH and CN, and other variables are as defined in the present invention.
  • the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 OH, CH 2 CN, cyclopropyl, Other variables are as defined in the present invention.
  • the R4 and R5 are formed together with the attached carbon atom
  • Other variables are as defined in the present invention.
  • the R4 and R6 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • said R5 and R7 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • said R 8 and R 9 are independently selected from H and CH 3 , respectively, and other variables are as defined herein.
  • said R 10 is selected from H, F and Cl, and other variables are as defined herein.
  • the R 11 is selected from F, CH 3 , CH 2 CH 3 , cyclopropyl, The CH 3 , CH 2 CH 3 , cyclopropyl, Each independently is optionally substituted with 1, 2 or 3 R c , each R c is independently selected from D, F, Cl, Br, I and CH3 , other variables are as defined herein.
  • the R 11 is selected from F, CH 3 , CD 3 , CH 2 CH 3 , cyclopropyl, Other variables are as defined in the present invention.
  • the T3 and -L1 - R11 together with the attached carbon atoms form a 5-membered heterocyclic group, making the structural unit selected from Other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from N, NH, CH 2 and CR 1 ;
  • T 2 is selected from CH and N;
  • T 3 is selected from CH and N;
  • R 1 is selected from H, F, Cl, Br and I;
  • R 2 is selected from H, C 1-3 alkyl and C 3-5 cycloalkyl optionally substituted with 1 , 2 or 3 halogens;
  • R is selected from H or absent
  • R 4 and R 5 are each independently selected from H, C 1-3 alkyl, C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl, the C 1-3 alkyl, C 3-5 cycloalkyl Alkyl and 3-5 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R b ;
  • R 6 is selected from H
  • R is selected from H
  • R 8 and R 9 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 halogens;
  • R 10 is selected from H, F, Cl, Br and I;
  • R 11 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 3-5 cycloalkyl and 5-membered heteroaryl, the C 1-3 alkyl, C 3-5 cycloalkane radicals and 5-membered heteroaryl groups are optionally substituted with 1, 2 or 3 R c ;
  • R2 and R1 together with the attached carbon atoms form a phenyl group optionally substituted with 1 , 2 or 3 halogens;
  • R2 and R3 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
  • R and R together with the attached carbon atoms form a 5 - membered heterocycloalkyl optionally substituted with 1, 2 or 3 halogens;
  • R4 and R6 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1 , 2 or 3 halogens;
  • R5 and R7 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
  • T 3 and -L 1 -R 11 together with the attached carbon atoms form a 5-membered heterocyclic group optionally substituted with 1 CH 3 ;
  • each R b is independently selected from F, Cl, Br, I, OH and CN;
  • each Rc is independently selected from D, F, Cl, Br, I and CH3 ;
  • T 1 is selected from CH
  • T 3 is selected from N
  • R 2 is selected from C 1-3 alkyl, and when the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, R 4 , R 5 and R 10 are not selected from H at the same time;
  • T 1 is selected from CH
  • T 3 is selected from CH
  • T 2 is selected from N.
  • said R1 is selected from H, and other variables are as defined herein.
  • the R 2 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 3 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl are optionally substituted with 1, 2 or 3 halogens, other variables are as defined herein.
  • said R 2 is selected from the group consisting of H, CH 2 CH 3 and cyclopropyl, and other variables are as defined herein.
  • the R 2 and R 1 together with the attached carbon atoms form a phenyl group substituted with 1 F, and other variables are as defined herein.
  • the R2 and R3 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl and oxa cyclobutyl, said CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , cyclopropyl and oxetanyl optionally substituted with 1 , 2 or 3 Rb , Other variables are as defined in the present invention.
  • the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 OH, CH 2 CN, cyclopropyl, Other variables are as defined in the present invention.
  • the R4 and R5 are formed together with the attached carbon atom
  • Other variables are as defined in the present invention.
  • the R4 and R6 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • said R5 and R7 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • said R 8 and R 9 are independently selected from H and CH 3 , respectively, and other variables are as defined herein.
  • said R 10 is selected from H, F and Cl, and other variables are as defined herein.
  • the R 11 is selected from F, CH 3 , CH 2 CH 3 , cyclopropyl, The CH 3 , CH 2 CH 3 , cyclopropyl, Optionally substituted with 1, 2 or 3 R c , other variables are as defined herein.
  • the R 11 is selected from F, CH 3 , CD 3 , CH 2 CH 3 , cyclopropyl, Other variables are as defined in the present invention.
  • the T3 and -L1 - R11 together with the attached carbon atoms form a 5-membered heterocyclic group, making the structural unit selected from Other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from N, NH, CH 2 and CR 1 ;
  • T 2 is selected from CH and N;
  • T 3 is selected from CH and N;
  • R 1 is selected from H, F, Cl, Br and I;
  • R 2 is selected from H, C 1-3 alkyl and C 3-5 cycloalkyl optionally substituted with 1 , 2 or 3 halogens;
  • R is selected from H
  • R 4 and R 5 are each independently selected from H, C 1-3 alkyl, C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl, the C 1-3 alkyl, C 3-5 cycloalkyl Alkyl and 3-5 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R b ;
  • R 6 is selected from H
  • R is selected from H
  • R 8 and R 9 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 halogens;
  • R 10 is selected from H, F, Cl, Br and I;
  • R 11 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 3-5 cycloalkyl and 5-membered heteroaryl, the C 1-3 alkyl, C 3-5 cycloalkane radicals and 5-membered heteroaryl groups are optionally substituted with 1, 2 or 3 R c ;
  • R2 and R1 together with the attached carbon atoms form a phenyl group optionally substituted with 1 , 2 or 3 halogens;
  • R2 and R3 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
  • R and R together with the attached carbon atoms form a 5 - membered heterocycloalkyl optionally substituted with 1, 2 or 3 halogens;
  • R4 and R6 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1 , 2 or 3 halogens;
  • R5 and R7 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
  • T 2 and -L 1 -R 11 together with the attached carbon atoms form a 5-membered heterocyclic group optionally substituted with 1 CH 3 ;
  • each R b is independently selected from F, Cl, Br, I, OH and CN;
  • each Rc is independently selected from D, F, Cl, Br, I and CH3 ;
  • T 1 is selected from CH
  • R 2 is selected from C 1-3 alkyl, when said C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, R 4 , R 5 and R 10 is not selected from H at the same time.
  • said R1 is selected from H, and other variables are as defined herein.
  • the R 2 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 3 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl are optionally substituted with 1, 2 or 3 halogens, other variables are as defined herein.
  • said R 2 is selected from the group consisting of H, CH 2 CH 3 and cyclopropyl, and other variables are as defined herein.
  • the R 2 and R 1 together with the attached carbon atoms form a phenyl group substituted with 1 F, and other variables are as defined herein.
  • the R2 and R3 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl and oxa cyclobutyl, said CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , cyclopropyl and oxetanyl optionally substituted with 1 , 2 or 3 Rb , Other variables are as defined in the present invention.
  • the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 OH, CH 2 CN, cyclopropyl, Other variables are as defined in the present invention.
  • the R4 and R5 are formed together with the attached carbon atom
  • Other variables are as defined in the present invention.
  • the R4 and R6 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • said R5 and R7 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • said R 8 and R 9 are independently selected from H and CH 3 , respectively, and other variables are as defined herein.
  • said R 10 is selected from H, F and Cl, and other variables are as defined herein.
  • the R 11 is selected from F, CH 3 , CH 2 CH 3 , cyclopropyl, The CH 3 , CH 2 CH 3 , cyclopropyl, Optionally substituted with 1, 2 or 3 R c , other variables are as defined herein.
  • the R 11 is selected from F, CH 3 , CD 3 , CH 2 CH 3 , cyclopropyl, Other variables are as defined in the present invention.
  • the T 2 and -L 1 -R 11 together with the attached carbon atoms form a 5-membered heterocyclic group, making the structural unit selected from Other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from N, NH, CH 2 and CR 1 ;
  • R 1 is selected from H, F, Cl, Br and I;
  • R 2 is selected from H, C 1-3 alkyl and C 3-5 cycloalkyl optionally substituted with 1 , 2 or 3 halogens;
  • R is selected from H
  • R 4 and R 5 are each independently selected from H, C 1-3 alkyl, C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl, the C 1-3 alkyl, C 3-5 cycloalkyl Alkyl and 3-5 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R b ;
  • R 6 is selected from H
  • R is selected from H
  • R 8 and R 9 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 halogens;
  • R 10 is selected from H, F, Cl, Br and I;
  • R 11 is selected from CH 3 and CD 3 ;
  • R2 and R1 together with the attached carbon atoms form a phenyl group optionally substituted with 1 , 2 or 3 halogens;
  • R2 and R3 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
  • R and R together with the attached carbon atoms form a 5 - membered heterocycloalkyl optionally substituted with 1, 2 or 3 halogens;
  • R4 and R6 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1 , 2 or 3 halogens;
  • R5 and R7 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
  • each R b is independently selected from F, Cl, Br, I, OH and CN;
  • T 1 is selected from CH
  • R 2 is selected from C 1-3 alkyl, when said C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, R 4 , R 5 and R 10 is not selected from H at the same time.
  • said R1 is selected from H, and other variables are as defined herein.
  • the R 2 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 3 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl are optionally substituted with 1, 2 or 3 halogens, other variables are as defined herein.
  • said R 2 is selected from the group consisting of H, CH 2 CH 3 and cyclopropyl, and other variables are as defined herein.
  • the R 2 and R 1 together with the attached carbon atoms form a phenyl group substituted with 1 F, and other variables are as defined herein.
  • the R2 and R3 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl and oxa cyclobutyl, said CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , cyclopropyl and oxetanyl optionally substituted with 1 , 2 or 3 Rb , Other variables are as defined in the present invention.
  • the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 OH, CH 2 CN, cyclopropyl, Other variables are as defined in the present invention.
  • the R4 and R5 are formed together with the attached carbon atom
  • Other variables are as defined in the present invention.
  • the R4 and R6 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • said R5 and R7 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • said R 8 and R 9 are independently selected from H and CH 3 , respectively, and other variables are as defined herein.
  • said R 10 is selected from H, F and Cl, and other variables are as defined herein.
  • the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from N, NH, CH 2 and CR 1 ;
  • R 1 is selected from H, F, Cl, Br and I;
  • R 2 is selected from H, C 1-3 alkyl and C 3-5 cycloalkyl, said C 1-3 alkyl and C 3-5 cycloalkyl are optionally substituted with 1, 2 or 3 R a ;
  • R is selected from H
  • R 4 and R 5 are each independently selected from H, C 1-3 alkyl, C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl, the C 1-3 alkyl, C 3-5 cycloalkyl Alkyl and 3-5 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R b ;
  • R 6 is selected from H
  • R is selected from H
  • R 8 and R 9 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R g ;
  • R 10 is selected from H, F, Cl, Br and I;
  • R2 and R1 together with the attached carbon atoms form a phenyl group optionally substituted with 1 , 2 or 3 Rcs;
  • R2 and R3 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 Rd ;
  • R4 and R5 together with the attached carbon atoms form a 5 - membered heterocycloalkyl optionally substituted with 1, 2 or 3 R e ;
  • R4 and R6 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1 , 2 or 3 Rf ;
  • R5 and R7 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 Rf ;
  • each of Ra , Rc , Rd , Re , Rf and Rg is independently selected from F, Cl, Br and I;
  • each R b is independently selected from F, Cl, Br, I, OH and CN;
  • T 1 is selected from CH
  • R 2 is selected from C 1-3 alkyl
  • said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a , R 4 , R 5 and R 10 is not selected from H at the same time.
  • said R1 is selected from H, and other variables are as defined herein.
  • the R 2 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 3 2CH3 , CH2CH2CH3 , CH( CH3 ) 2 and cyclopropyl are optionally substituted with 1, 2 or 3 Ra , other variables are as defined herein.
  • said R 2 is selected from the group consisting of H, CH 2 CH 3 and cyclopropyl, and other variables are as defined herein.
  • the R 2 and R 1 together with the attached carbon atoms form a phenyl group substituted with 1 F, and other variables are as defined herein.
  • the R2 and R3 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl and oxa cyclobutyl, said CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , cyclopropyl and oxetanyl optionally substituted with 1 , 2 or 3 Rb , Other variables are as defined in the present invention.
  • the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 OH, CH 2 CN, cyclopropyl, Other variables are as defined in the present invention.
  • the R4 and R5 are formed together with the attached carbon atom
  • Other variables are as defined in the present invention.
  • the R4 and R6 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • said R5 and R7 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • said R 8 and R 9 are independently selected from H and CH 3 , respectively, and other variables are as defined herein.
  • said R 10 is selected from H, F and Cl, and other variables are as defined herein.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from N, NH, CH 2 and CR 1 ;
  • R 1 is selected from H, F, Cl, Br and I;
  • R 2 is selected from H, C 1-3 alkyl and C 3-5 cycloalkyl, said C 1-3 alkyl and C 3-5 cycloalkyl are optionally substituted with 1, 2 or 3 R a ;
  • R is selected from H
  • R 4 and R 5 are each independently selected from H, C 1-3 alkyl, C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl, the C 1-3 alkyl, C 3-5 cycloalkyl Alkyl and 3-5 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R b ;
  • R 6 is selected from H
  • R is selected from H
  • R 8 and R 9 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R g ;
  • R2 and R1 together with the attached carbon atoms form a phenyl group optionally substituted with 1 , 2 or 3 Rcs;
  • R2 and R3 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 Rd ;
  • R4 and R5 together with the attached carbon atoms form a 5 - membered heterocycloalkyl optionally substituted with 1, 2 or 3 R e ;
  • R4 and R6 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1 , 2 or 3 Rf ;
  • R5 and R7 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 Rf ;
  • each of Ra , Rc , Rd , Re , Rf and Rg is independently selected from F, Cl, Br and I;
  • each R b is independently selected from F, Cl, Br, I, OH and CN;
  • T 1 is selected from CH
  • R 2 is selected from C 1-3 alkyl, when the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a , R 4 and R 5 are not Also selected from H.
  • said R1 is selected from H, and other variables are as defined herein.
  • the R 2 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 3 2CH3 , CH2CH2CH3 , CH( CH3 ) 2 and cyclopropyl are optionally substituted with 1, 2 or 3 Ra , other variables are as defined herein.
  • said R 2 is selected from the group consisting of H, CH 2 CH 3 and cyclopropyl, and other variables are as defined herein.
  • the R 2 and R 1 together with the attached carbon atoms form a phenyl group substituted with 1 F, and other variables are as defined herein.
  • the R2 and R3 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl and oxa cyclobutyl, said CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , cyclopropyl and oxetanyl optionally substituted with 1 , 2 or 3 Rb , Other variables are as defined in the present invention.
  • the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 OH, CH 2 CN, cyclopropyl, Other variables are as defined in the present invention.
  • the R4 and R5 are formed together with the attached carbon atom
  • Other variables are as defined in the present invention.
  • the R4 and R6 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • said R5 and R7 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • said R 8 and R 9 are independently selected from H and CH 3 , respectively, and other variables are as defined herein.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from N, NH, CH 2 and CR 1 ;
  • R 1 is selected from H, F, Cl, Br and I;
  • R 2 is selected from H, C 1-3 alkyl and C 3-5 cycloalkyl, said C 1-3 alkyl and C 3-5 cycloalkyl are optionally substituted with 1, 2 or 3 R a ;
  • R is selected from H
  • R 4 and R 5 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ;
  • R2 and R1 together with the attached carbon atoms form a phenyl group optionally substituted with 1 , 2 or 3 Rcs;
  • R2 and R3 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 Rd ;
  • each of Ra , Rc and Rd is independently selected from F, Cl, Br and I;
  • each R b is independently selected from F, Cl, Br, I, OH and CN;
  • T 1 is selected from CH
  • R 2 is selected from C 1-3 alkyl, when the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a , R 4 and R 5 are not Also selected from H.
  • said R1 is selected from H, and other variables are as defined herein.
  • the R 2 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 3 2CH3 , CH2CH2CH3 , CH( CH3 ) 2 and cyclopropyl are optionally substituted with 1, 2 or 3 Ra , other variables are as defined herein.
  • said R 2 is selected from the group consisting of H, CH 2 CH 3 and cyclopropyl, and other variables are as defined herein.
  • the R 2 and R 1 together with the attached carbon atoms form a phenyl group substituted with 1 F, and other variables are as defined herein.
  • the R2 and R3 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
  • the R 4 and R 5 are independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 3 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are optionally substituted with 1, 2 or 3 R b and other variables are as defined in the present invention.
  • said R 4 and R 5 are independently selected from H, CH 3 , CH 2 OH and CH 2 CN, and other variables are as defined herein.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from
  • L 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as defined in the present invention.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from
  • R 4 , R 5 , R 8 , R 9 , R 10 and R 11 are as defined in the present invention.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from
  • R 5 and R 10 are as defined in the present invention.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from
  • R 5 is selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ;
  • each R b is independently selected from F, Cl, Br, I, OH and CN;
  • R 10 is selected from H, F, Cl, Br and I.
  • said R5 is selected from H, CH3 , CH2OH and CH2CN , and other variables are as defined herein.
  • said R5 is selected from H, and other variables are as defined herein.
  • said R 10 is selected from H, F and Cl, and other variables are as defined herein.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from
  • R 5 is selected from C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ;
  • each R b is independently selected from F, Cl, Br, I, OH and CN;
  • R 10 is selected from H, F, Cl, Br and I.
  • said R5 is selected from CH3 , CH2OH and CH2CN , and other variables are as defined herein.
  • said R5 is selected from CH3 , and other variables are as defined herein.
  • said R 10 is selected from H, F and Cl, and other variables are as defined herein.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof,
  • the compound or a pharmaceutically acceptable salt thereof is selected from,
  • the present invention also provides the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating solid tumors.
  • the solid tumors refer to BRCA-mutated ovarian and breast cancers.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in the present invention or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compound of the present invention has better PARP1 inhibitory effect and cell proliferation inhibitory effect, and has high selectivity of PARP1/PARP2 and PARP1/PARP3, which can effectively avoid hematological side effects caused by the inhibition of PARP2 and PARP3.
  • the compounds of the present invention have excellent metabolic stability in vivo, and show excellent oral absorption drug exposure and oral absorption bioavailability in different species.
  • the compounds of the present invention also have significant anti-tumor activity, small changes in body weight, and good safety.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • an "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to achieve the desired effect.
  • an "effective amount” of one active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or patient.
  • Representative carriers include water, oils, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical field.
  • excipient generally refers to the carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
  • a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
  • the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • the direction of attachment is arbitrary, for example,
  • the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites in the group can be linked to other groups by chemical bonds.
  • connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
  • the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
  • a straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in this group;
  • the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
  • Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, said C 3-5 cycloalkyl including C 3 -4 and C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent.
  • Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • the term "3-5 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated monocyclic group consisting of 3 to 5 ring atoms, 1, 2, 3 or 4 ring atoms, respectively are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 3-5 membered heterocycloalkyl includes 4-5 membered, 4 membered, and 5 membered heterocycloalkyl and the like.
  • Examples of 3-5 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) or tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.) and the like.
  • the term "5-membered heterocyclyl” by itself or in combination with other terms denotes, respectively, a saturated or partially unsaturated monocyclic group consisting of 5 ring atoms, wherein 1, 2, 3 or 4 ring atoms are Heteroatoms independently selected from O, S, and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms are optionally oxidized (i.e., CO, NO, and S(O) p , where p is 1 or 2).
  • a heteroatom may occupy the position of attachment of the heterocyclyl to the rest of the molecule.
  • the 5-membered heterocyclic group includes 5-membered heterocycloalkyl, 5-membered heterocycloalkenyl and the like.
  • Examples of 5-membered heterocyclyl groups include, but are not limited to, 2,5-dihydro-1H-pyrrolyl and the like.
  • the term "5-membered heteroaryl” refers to a monocyclic group consisting of 5 ring atoms with a conjugated ⁇ -electron system, wherein 1, 2, 3 or 4 ring atoms are independently selected from O, Heteroatoms of S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a 5-membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
  • Examples of the 5-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, and the like) ), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl) etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4 -triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl
  • Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membere
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • DIBAL-H stands for diisobutylaluminum hydride
  • Pd(dppf) 2 Cl 2 stands for [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • RuPhos stands for 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl
  • Pd 2 (dba) 3 stands for tris(dibenzylideneacetone)dipalladium
  • TBSCl stands for tert-butyldimethyl methacrylate chlorosilane
  • Pd-Xphos-G3 represents sodium methanesulfonate (2-dicyclohexylphosphino 2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino- 1,1'-biphenyl-2-yl
  • Figure 1 Plot of tumor volume change of compound 6 in the DLD-1 model.
  • the intermediate 1a (2.5 g, 12.44 mmol) was dissolved in xylene (35 mL), and the raw material 2,2,6-trimethyl-4H-1,3-dioxin-4-one (2.65 g, 18.65 g) was added. mmol, 2.46 mL), refluxed at 160° C. for 2 hours, cooled to room temperature, filtered the reaction solution, washed the filter cake with xylene (15 mL), and collected the filter cake to obtain Intermediate 1b. MS m/z: 266.8 [M+H] + ; 268.8 [M+H] + .
  • intermediate 1b (4.6 g, 17.22 mmol) and hydrazine hydrate (11.61 g, 197.21 mmol, 11.28 mL, 85%) were added to methanol (60 mL), and the temperature was raised to 65 °C to react for 3 hours. The reaction solution was concentrated and dried to obtain intermediate 1c, which was directly carried to the next step without purification.
  • intermediate 1f 5 mg, 24.48 ⁇ mol was added to THF (1 mL) and MeOH (2 mL), MnO 2 (14.90 mg, 171.38 ⁇ mol) was added in portions, and the reaction was continued for 12 hours.
  • the intermediate 1k (0.28 g, 0.84 mmol) was added to the reaction flask, and then HCl/EtOAc (4 mol/L, 8 mL) was added, and the reaction was stirred for 3 hours.
  • the reaction solution was directly post-treated, and after the reaction solution was filtered, the filtrate was spin-dried under reduced pressure to obtain the hydrochloride salt of intermediate 11.
  • Methylamine ethanol solution (606.32 mg, 6.44 mmol, 150 mL, 33%) was added to a single-necked flask of compound 2c (3 g, 6.44 mmol), and the mixture was stirred at 25° C. for 16 hours. Concentrate under reduced pressure to obtain intermediate 2d. MS m/z: 465.1 [M+1] + .
  • Triethylamine (7.01 mg, 69.24 ⁇ mol, 9.64 ⁇ L) was added to a solution of compound 2f hydrochloride (39.71 mg, 138.47 ⁇ mol) in DCM (2 mL) at 25°C, and 1 g (14 mg) was added to the above solution.
  • 69.24 ⁇ mol) solution in MeOH (2 mL) adjust the pH to 5-6 with acetic acid, stir for 15 min, continue to add NaBH3CN (8.70 mg, 138.47 ⁇ mol), and stir at 25° C. for 16 hours.
  • 0.5 mL of water was added to the reaction solution, and after quenching, it was concentrated under reduced pressure.
  • intermediate 3k (20 mg, 0.07 mmol) was added to THF (5 mL) at 0°C, LiAlH 4 (5.58 mg, 0.15 mmol) was added, and the reaction was stirred for 1 hour. Add 0.5 mL of methanol to quench, filter with suction, concentrate and evaporate to dryness to obtain intermediate 3l. MS m/z: 245.0 [M+H] + .
  • intermediate 4f hydrochloride (30 mg, 119.86 ⁇ mol) in DCM (1 mL) at 25°C was added triethylamine (12.13 mg, 119.86 ⁇ mol, 16.68 ⁇ L), and to the above solution was added intermediate 1 g (48.47 mg) , 119.86 ⁇ mol) in MeOH (1 mL), adjust pH to 5-6 with acetic acid, stir for 15 min, continue to add NaBH3CN (15.06 mg, 239.72 ⁇ mol), and stir at 25° C. for 16 hours. 0.5 mL of water was added to the reaction solution, and after quenching, it was concentrated under reduced pressure.
  • reaction solution was cooled to room temperature, filtered, and subjected to preparative HPLC (column: Welch Xtimate C18 100*40mm*3 ⁇ m; mobile phase: [H 2 O(0.075% trifluoroacetic acid)-acetonitrile]; % acetonitrile: 11%-41 %, 8 min) to obtain the trifluoroacetic acid salt of compound 5.
  • the trifluoroacetic acid salt (20 mg) of compound 5 was taken and separated by chiral HPLC (chromatographic column: Chiralcel OJ-3 100*4.6 mm ID, 3 ⁇ m; mobile phase: A: CO 2 B: methanol (0.05% diethylamine) ); gradient elution: 4min B increased from 5% to 40%, 40% B kept 2.5min, then 5%B kept 1.5min; flow rate: 2.8mL/min; column temperature: 35°C; pressure: 1500psi) to obtain the compound 5A and Compound 5B.
  • chiral HPLC chromatographic column: Chiralcel OJ-3 100*4.6 mm ID, 3 ⁇ m; mobile phase: A: CO 2 B: methanol (0.05% diethylamine)
  • Step 4 Compound 6 free base synthesis
  • reaction solution was cooled to room temperature, filtered, and subjected to preparative HPLC (column: Welch Xtimate C18 100*40mm*3 ⁇ m; mobile phase: [H 2 O(0.075% trifluoroacetic acid)-acetonitrile]; % acetonitrile: 10%-40 %, 8 min) to obtain the trifluoroacetic acid salt of compound 7.
  • reaction solution was cooled to room temperature, 40 mL of water was added, extracted with 3*10 mL of DCM, the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to preparative HPLC (chromatographic column: Xtimate C18 150*40 mm*5 ⁇ m; mobile phase: [H 2 O] (HCl)-acetonitrile]; acetonitrile %: 5%-35%, 10 min) to isolate the hydrochloride salt of compound 9. m/z: 447.0 [M+Na] + .
  • reaction solution was cooled to room temperature, 40 mL of water was added, extracted with 3*10 mL of DCM, the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40 mm*3 ⁇ m; mobile phase: [H 2 O(trifluoroacetic acid)-acetonitrile]; acetonitrile%: 10%-40%, 8 min) was isolated to obtain the trifluoroacetic acid salt of compound 10. m/z: 441.3 [M+H] + .
  • reaction solution was cooled to room temperature, 40 mL of water was added, extracted with 3*10 mL of DCM, the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40 mm*3 ⁇ m; mobile phase: [H 2 O(trifluoroacetic acid)-acetonitrile]; acetonitrile %: 8%-38%, 8 min) was isolated to obtain the trifluoroacetic acid salt of compound 11. m/z: 437.1 [M+H] + .
  • reaction solution was cooled to room temperature, 40 mL of water was added, extracted with 3*10 mL of DCM, the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40 mm*3 ⁇ m; mobile phase: [H 2 O(trifluoroacetic acid)-acetonitrile]; acetonitrile%: 10%-40%, 8 min) was isolated to obtain the trifluoroacetic acid salt of compound 12. m/z: 475.1[M+Na] + .
  • the trifluoroacetic acid salt (20 mg) of compound 13 was taken and separated by chiral HPLC (chromatographic column: Chiralcel OJ-3 100*4.6 mm ID, 3 ⁇ m; mobile phase: A: CO 2 B: methanol (0.05% diethylamine) ); gradient elution: 4min B increased from 5% to 40%, 40% B kept 2.5min, then 5%B kept 1.5min; flow rate: 2.8mL/min; column temperature: 35°C; pressure: 1500psi) to obtain the compound 13A and compound 13B.
  • chiral HPLC chromatographic column: Chiralcel OJ-3 100*4.6 mm ID, 3 ⁇ m; mobile phase: A: CO 2 B: methanol (0.05% diethylamine)
  • 14b (1.50g, 4.47mmol) was added to the ethanol (33%, 15ml) solution of methylamine at room temperature, and the reaction was stirred for 16 hours at 25°C. , then add 10 mL of dichloromethane to the crude product to dissolve, add 10 mL of water to wash, extract and separate the organic phase to collect the organic phase, dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain 14c, m/z: 335.2 [M+H ] + .
  • reaction solution was cooled to room temperature, 80 mL of water was added, extracted with 3*15 mL of DCM, the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40 mm*3 ⁇ m; mobile phase: [H 2 O(trifluoroacetic acid)-acetonitrile]; acetonitrile%: 7%-37%, 8 min) was purified to obtain the trifluoroacetic acid salt of the target product 1B.
  • MS m/z 443.1 [M+Na] + .
  • reaction solution was filtered under reduced pressure, and the filtrate was subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40mm*3 ⁇ m; mobile phase: [H 2 O (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 5%-35%, 8min ) was purified to give compound 4B as the trifluoroacetate salt.
  • reaction solution was cooled to room temperature, 80 mL of water was added, extracted with 3*15 mL of DCM, the organic layers were combined, and dried over anhydrous sodium sulfate to obtain the crude product, which was subjected to preparative HPLC (chromatographic column: Xtimate C18 150*40 mm*5 ⁇ m; mobile phase: [H 2 O(HCl)-acetonitrile]; acetonitrile %: 5%-35%, 10 min) was purified to obtain the hydrochloride salt of the target product 16B.
  • reaction solution was cooled to room temperature, 40 mL of water was added, extracted with 3*10 mL of DCM, the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40 mm*3 ⁇ m; mobile phase: [H 2 O(trifluoroacetic acid)-acetonitrile]; acetonitrile %: 10%-40%, 8 min) was purified to obtain the trifluoroacetic acid salt of the target product 13B.
  • MS m/z 433.1 [M+H] + .
  • reaction solution was filtered under reduced pressure, and the filtrate was directly sent to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40mm*3 ⁇ m; mobile phase: [H 2 O (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 5%-35%, 8min) separation and purification to obtain the trifluoroacetic acid salt of 23a.
  • reaction solution was cooled to room temperature, filtered, and the filtrate was separated and purified by preparative high-performance liquid chromatography (chromatographic column: Welch Xtimate C18 100*40mm*3 ⁇ m; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile%: 8%-38%, 8 min) to obtain the trifluoroacetic acid salt of compound 30.
  • reaction solution was cooled to room temperature, filtered, and the filtrate was subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40mm*3 ⁇ m; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 0%-30%, 8min) separation and purification to obtain the trifluoroacetic acid salt of compound 31.
  • Test platform Wuhan Heyan Biomedical Technology Co., Ltd.
  • PARP1 chemiluminescence detection kit was purchased from BPS Bioscience; EnVision Multilabel Analyzer (PerkinElmer).
  • PBST buffer preparation 1X PBS contains 0.05% Tween-20, that is, 5 ⁇ L of 100% Tween-20 is added to 10mL of PBS
  • Compound solution preparation The compounds to be tested were diluted 5-fold with 100% DMSO to the 8th concentration, that is, from 1000 ⁇ M to 12.8 nM. Internal control compounds were diluted 5-fold with 100% DMSO to the 8th concentration, ie, from 200 ⁇ M to 2.56 nM. Then use 1X test buffer to dilute each compound to be tested into a working solution with 10% DMSO.
  • the IC50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response- in GraphPad Prism -Variable slope mode derived).
  • SPR Surface plasmon resonance
  • the biotinylated PARP1 protein (sequence: 655-end) was coupled with a streptavidin-coated SA chip (Cytiva, 29699622) at 25°C.
  • the specific steps were: using 1 mM NaCl/50 mM
  • the chip was surface activated with NaOH; the PARP1 protein was diluted with coupling buffer (50mM Tris-HCl pH 8.0, 150mM NaCl, 10mM MgCl2, 0.05% P20) to prepare a 10ug/mL ligand solution, which flowed over the chip surface (into the The sample time was 50 s, and the injection flow rate was 5 ⁇ L/min) to couple the PARP1 protein to the surface of the chip; the excess active sites on the chip were blocked with 50% isopropanol/1M NaCl/50mM NaOH solution.
  • the final coupling level of the experiment is 2000-3000RU (Response Units).
  • the small molecule compounds were serially diluted with buffer (50mM Tris pH 8.0, 150mM NaCl, 10mM MgCl2, 0.05% Tween 20) to obtain compound solutions of different concentrations. 50 ⁇ L/min, the injection time was 60 s, and the dissociation time was 20 min. The instrument detects the binding and dissociation curves of protein-small molecule compounds.
  • the data of the sample channel and reference channel were analyzed by Biacore 8K evaluation software to generate sensorgrams, and data fitting was performed based on the 1:1 binding mode.
  • SPR Surface plasmon resonance
  • the biotinylated PARP2 protein (sequence: 223-end) was coupled with a streptavidin-coated SA chip (Cytiva, 29699622) at 25°C.
  • the specific steps were: 1mM NaCl/50mM
  • the chip was surface activated with NaOH; the PARP2 protein was diluted with coupling buffer (50mM Tris-HCl pH 8.0, 150mM NaCl, 10mM MgCl2, 0.05% P20) to prepare a 10ug/mL ligand solution, which flowed over the chip surface (into the The sample time was 60 s, and the injection flow rate was 10 ⁇ L/min), and the PARP2 protein was coupled to the chip surface; the excess active sites on the chip were blocked with 50% isopropanol/1 M NaCl/50 mM NaOH solution.
  • the final coupling level of the experiment was 3000-4000RU (Response Units).
  • the small molecule compounds were serially diluted with buffer (50mM Tris pH 8.0, 150mM NaCl, 10mM MgCl2, 0.05% Tween 20) to obtain compound solutions of different concentrations. 30 ⁇ L/min, the injection time is 60s, and the dissociation time is 400s.
  • the instrument detects the binding and dissociation curves of protein-small molecule compounds.
  • the data of the sample channel and reference channel were analyzed by Biacore 8K evaluation software to generate sensorgrams, and data fitting was performed based on the 1:1 binding mode.
  • the compound of the present invention has significantly lower binding ability to PARP2 than PARP1, and is a selective inhibitor of PARP1.
  • Test platform Beijing Aisipu Biotechnology Co., Ltd.
  • ELISA method was used to test compounds for inhibition of PARP1/PARP3 enzymatic activity.
  • Fifty microliters of histone (BPS, 52029) diluted in PBS (Solarbio, P1022) were added to a 96 reaction plate (Greiner, 781074) for coating overnight at 4°C. After washing with PBST (1XPBS+0.05% Tween-20), 200 microliters of buffer (BPS, 79743) was added for blocking at room temperature for 90 minutes.
  • PARP1 BPS, 80501
  • PARP3 BPS, 80503
  • 5 microliters of compound, biotin-labeled substrate (BPS, 80601) and DNA (BPS, 80605) mixture were added into the 96 reaction plate, and the mixture was Dilutions were performed in PARP buffer solution (BPS, 80602) and incubated for 1 hour at room temperature. Wash with PBST, add 50 liters of horseradish peroxidase-labeled streptavidin (BPS, 80611), and incubate at room temperature for 30 minutes. The plate was washed with PBST, and 100 microliters of ELISA substrate A and substrate B mixed solution (BPS, 79670) was added. After 10 minutes, the chemiluminescence signal value was read with PHERAstar FSX BMG. IC50 calculations were performed by the inhibition-dose (four-parameter) equation in GraphPad Prism 8.0 software.
  • Compound 6 of the present invention has weaker inhibition on PARP3 than AZD5305, and has higher selectivity for PARP1.
  • mice A clear solution of 0.04 mg/mL 2% DMSO/10% PEG400/88% water test compound was injected into female Balb/c mice (overnight fasted, 7-9 weeks old) via tail vein, and administered The dose is 0.2 mg/kg.
  • Female Balb/c mice (overnight fasted, 7-9 weeks old) were administered 0.10 mg/mL of a clear solution of test compound in 2% DMSO/10% PEG400/88% water by gavage at a dose of 1 mg/kg.
  • Plasma was separated by centrifugation in an anticoagulant tube of EDTA-K2. The plasma concentration was determined by LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated by non-compartmental model linear logarithmic trapezoidal method using WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software.
  • C 0 represents initial concentration
  • C max represents peak concentration
  • T max represents time to peak
  • T 1/2 represents elimination half-life
  • V dss represents steady-state apparent volume of distribution
  • Cl represents total clearance
  • T last represents the time point of the last quantifiable drug concentration
  • AUC 0-last represents the area under the plasma concentration-time curve from time 0 to the last quantifiable time point
  • AUC 0-inf represents Area under the plasma concentration-time curve at time 0 extrapolated to infinity
  • F (%) represents bioavailability, calculated using AUC 0-last .
  • Compounds 6 and 13A of the present invention both showed extremely slow clearance rates after intravenous administration of 0.2 mg/kg, Cl were 0.103 and 0.0293 mL/min/kg, respectively, longer half-lives, T 1/2 were 11.4 and 42.8 hours, respectively; After oral administration of 1 mg/kg, it can quickly reach the peak Tmax in 2.5 hours, the peak drug concentration is 17650 and 20850 nM, and the oral absorption bioavailability is 106% and 97.4%.
  • the compounds of the present invention have excellent in vivo metabolic stability, excellent oral absorption drug exposure and oral absorption bioavailability. Compared to AZD5305, the compounds of the present invention can significantly reduce clearance (Cl) and increase oral absorbed exposure (AUC) in mice.
  • Plasma was separated by centrifugation in an anticoagulant tube of EDTA-K2.
  • the plasma concentration was determined by LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated by non-compartmental model linear logarithmic trapezoidal method using WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software.
  • C 0 represents initial concentration
  • C max represents peak concentration
  • T max represents time to peak
  • T 1/2 represents elimination half-life
  • V dss represents steady-state apparent volume of distribution
  • Cl represents total clearance
  • T last represents the time point of the last quantifiable drug concentration
  • AUC 0-last represents the area under the plasma concentration-time curve from time 0 to the last quantifiable time point
  • AUC 0-inf represents Area under the plasma concentration-time curve at time 0 extrapolated to infinity
  • F (%) represents bioavailability, calculated using AUC 0-last .
  • Compound 6 of the present invention showed a very slow clearance rate after intravenous administration of 0.2 mg/kg, and Cl was 0.731 mL/min/kg; after oral administration of 1 mg/kg, it could quickly reach a peak Tmax of 3 hours, and the peak drug concentration was reached 4920nM, orally absorbed bioavailability of 88.2%.
  • the compounds of the present invention have excellent in vivo metabolic stability, excellent oral absorption drug exposure and oral absorption bioavailability. Compared to AZD5305, the compounds of the present invention significantly reduced clearance and significantly increased oral absorbed exposure in rats.
  • Plasma was separated by centrifugation in an anticoagulant tube of EDTA-K2.
  • the plasma concentration was determined by LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated by non-compartmental model linear logarithmic trapezoidal method using WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software.
  • C 0 represents initial concentration
  • C max represents peak concentration
  • T max represents time to peak
  • T 1/2 represents elimination half-life
  • V dss represents steady-state apparent volume of distribution
  • Cl represents total clearance
  • T last represents the time point of the last quantifiable drug concentration
  • AUC 0-last represents the area under the plasma concentration-time curve from time 0 to the last quantifiable time point
  • AUC 0-inf represents Area under the plasma concentration-time curve at time 0 extrapolated to infinity
  • F (%) represents bioavailability, calculated using AUC 0-last .
  • the compound 6 of the present invention showed a very slow clearance rate after intravenous administration of 0.2 mg/kg, and the Cl was 0.319 mL/min/kg; after oral administration of 1 mg/kg, it could quickly reach a peak Tmax of 2.5 hours, and the peak drug concentration was reached. 11647nM, orally absorbed bioavailability of 126%.
  • the compounds of the present invention have excellent in vivo metabolic stability, excellent oral absorption drug exposure and oral absorption bioavailability. Compared to AZD5305, the compounds of the present invention significantly reduced clearance (Cl) and increased oral absorbed exposure (AUC) in mice.
  • Test platform Wuhan Heyan Biomedical Technology Co., Ltd.
  • DLD1 BRAC2 KO cells were seeded in a white 96-well plate, 80 ⁇ L of cell suspension per well, which contained 1000 DLD1 BRAC2 KO cells. Cell plates were incubated overnight in a carbon dioxide incubator. The compounds to be tested were diluted 5-fold to the 8th concentration with a row gun, that is, from 2 mM to 0.0256 ⁇ M, and a double-well experiment was set up. Add 78 ⁇ L of medium to the middle plate, and then transfer 2 ⁇ L of each well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 ⁇ L of each well to the cell plate. Compound concentrations transferred to cell plates ranged from 10 [mu]M to 0.128 nM.
  • the cell plates were placed in a carbon dioxide incubator for 7 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis.
  • the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
  • the compounds of the present invention have excellent proliferation inhibitory activity on DLD-1 BRAC2 KO cells.
  • MDA-MB-436 cells were seeded in a black (clear bottom) 96-well plate with 135 ⁇ L of cell suspension per well, which contained 3500 MDA-MB-436 cells. Cell plates were incubated overnight in a carbon dioxide incubator. Prepare 400X test compound stock solution, dilute the test compound 5-fold to the ninth concentration with a discharge gun, that is, from 4mM to 104nM, and set up a double-well experiment. Add 78 ⁇ L of medium to the middle plate, and then transfer 2 ⁇ L of the compound diluted in each well to the middle plate according to the corresponding position. Add 2 ⁇ L of DMSO to the vehicle control and blank control, and transfer 15 ⁇ L of each well to the cell plate after mixing.
  • Compound concentrations transferred to the cell plate ranged from 10 [mu]M to 0.26 nM with a final DMSO concentration of 0.25%.
  • the cell plates were placed in a carbon dioxide incubator for 7 days. Take out the cell plate and let it equilibrate to room temperature for 30 minutes, add 75 ⁇ L of cell viability chemiluminescence detection reagent to each well, shake the culture plate on an orbital shaker for 3 minutes to induce cell lysis, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. The luminescent signal is detected on the 2104 En Vision plate reader.
  • IR(%) (1-(RLU compound-RLU blank control)/(RLU vehicle control-RLU blank control)*100%.
  • the inhibition rates of different concentrations of compounds were calculated in Excel, and then the GraphPad Prism software was used to plot the inhibition curves and calculate the relevant parameters.
  • the compounds of the present invention have excellent proliferation inhibitory activity on MDA-MB-436 cells.
  • DLD-1 (BRAC2-/-) cells were routinely cultured in RPMI-1640 medium containing 10% fetal bovine serum under the conditions of 5% CO 2 , 37° C., and saturated humidity. Depending on cell growth, passage or rehydration 1 to 2 times a week at a passage ratio of 1:3 to 1:4
  • the tumor diameter was measured twice a week, the tumor volume was calculated, and the body weight of the animal was weighed and recorded.
  • TGI percent or relative tumor proliferation rate T/C (%).
  • Relative tumor proliferation rate T/C (%) T RTV /C RTV ⁇ 100% (T RTV : the average RTV of the treatment group; C RTV : the average RTV of the negative control group).
  • TGI (%) reflecting tumor growth inhibition rate.
  • TGI(%) [(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group))/(average tumor volume at the end of treatment in the solvent control group-the start of treatment in the solvent control group time average tumor volume)] ⁇ 100%.
  • the compound of the present invention has significant antitumor activity and good safety.

Abstract

Provided is a picolinamide compound, and specifically disclosed is a compound represented by formula (V) and a pharmaceutically acceptable salt thereof.

Description

吡啶酰胺类化合物Pyridinamides
本发明主张如下优先权：The present invention claims the following priority:
CN202110443997.8，申请日：2021年04月23日；CN202110443997.8, application date: April 23, 2021;
CN202110594899.4，申请日：2021年05月28日；CN202110594899.4, application date: May 28, 2021;
CN202110653806.0，申请日：2021年06月11日；CN202110653806.0, application date: June 11, 2021;
CN202110839434.0，申请日：2021年07月23日；CN202110839434.0, application date: July 23, 2021;
CN202111127244.2，申请日：2021年09月18日；CN202111127244.2, application date: September 18, 2021;
CN202210045131.6，申请日：2022年01月14日；CN202210045131.6, application date: January 14, 2022;
CN202210363824.X，申请日：2022年04月07日。CN202210363824.X, application date: April 7, 2022.
技术领域technical field
本发明涉及一系列吡啶酰胺类化合物，具体涉及式(V)所示化合物及其药学上可接受的盐。The present invention relates to a series of pyridine amide compounds, in particular to the compounds represented by formula (V) and their pharmaceutically acceptable salts.
背景技术Background technique
多聚ADP核糖聚合酶(poly-ADP-ribose polymerase，PARP)，是一个超大蛋白酶家族，家族目前由18名成员组成，具有多种生物学功能，在DNA损伤修复、炎症调控、转录调控、信号转导、基因组稳定性、细胞周期以及有丝分裂等一系列广泛的细胞代谢过程中发挥着重要作用，其中参与DNA修复机制的有PARP1，PARP2和PARP3。Poly-ADP-ribose polymerase (PARP) is a super large protease family. The family currently consists of 18 members and has a variety of biological functions. It is involved in DNA damage repair, inflammation regulation, transcription regulation, signaling It plays an important role in a wide range of cellular metabolic processes such as transduction, genome stability, cell cycle and mitosis, among which PARP1, PARP2 and PARP3 are involved in DNA repair mechanisms.
PARP1是PARP家族中最主要的成员，其在细胞中承担着PARP家族90％以上的功能，是DNA损伤修复中的关键作用因子，也是发挥抗肿瘤活性的主要靶标。PARP2也能准确识别单链断裂，发挥5％-10％的作用，PARP2在造血干细胞/前体细胞的DNA损伤修复中发挥重要作用。研究发现，PARP2缺失会造成红细胞寿命降低、红系祖细胞分化缺陷，并发生慢性贫血，而PARP1在此过程中作用不大。PARP3通过非同源末端连接机制修复DNA双链断裂，对造血干/祖细胞(Hematopoietic Stem and Progenitor Cells，HSPCs)有保护作用。有报道发现小分子化合物抑制PARP3会导致骨髓毒性(CancerRes，2016，76(20)：6084-6094.)。因此选择性抑制PARP1不会降低药物疗效，却可降低由于抑制PARP2/3带来的血液学副作用。PARP1选择性抑制剂在临床长期治疗中患者耐受性将会更好，具有更大的治疗窗。PARP1 is the most important member of the PARP family, and it undertakes more than 90% of the functions of the PARP family in cells. It is a key factor in DNA damage repair and the main target for anti-tumor activity. PARP2 can also accurately recognize single-strand breaks and play a role in 5%-10%, PARP2 plays an important role in DNA damage repair in hematopoietic stem/precursor cells. Studies have found that loss of PARP2 results in decreased red blood cell lifespan, defective erythroid progenitor differentiation, and chronic anemia, while PARP1 has little effect in this process. PARP3 repairs DNA double-strand breaks through a non-homologous end joining mechanism, and has a protective effect on Hematopoietic Stem and Progenitor Cells (HSPCs). It has been reported that the inhibition of PARP3 by small-molecule compounds can lead to bone marrow toxicity (CancerRes, 2016, 76(20): 6084-6094.). Therefore, selective inhibition of PARP1 will not reduce the efficacy of the drug, but can reduce the hematological side effects caused by the inhibition of PARP2/3. PARP1 selective inhibitors will be better tolerated by patients in long-term clinical treatment and have a larger therapeutic window.
发明内容SUMMARY OF THE INVENTION
本发明提供了式(V)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022088181-appb-000001
Figure PCTCN2022088181-appb-000001
其中，in,
Figure PCTCN2022088181-appb-000002
选自单键和双键；
Figure PCTCN2022088181-appb-000002
selected from single and double bonds;
T 1选自N、NH、CH 2和CR 1； T 1 is selected from N, NH, CH 2 and CR 1 ;
T 2选自CH和N； T 2 is selected from CH and N;
T 3选自CH和N； T 3 is selected from CH and N;
L 1选自键、-C(＝O)-、-C(＝O)NH-和-CF＝CH-； L 1 is selected from bond, -C(=O)-, -C(=O)NH- and -CF=CH-;
R 1选自H、F、Cl、Br和I； R 1 is selected from H, F, Cl, Br and I;
R 2选自H、C 1-3烷基和C 3-5环烷基，所述C 1-3烷基和C 3-5环烷基分别独立地任选被1、2或3个卤素取代；R 3选自H或不存在； R 2 is selected from H, C 1-3 alkyl and C 3-5 cycloalkyl, each of which is independently optionally replaced by 1 , 2 or 3 halogens Substituted; R is selected from H or absent;
R 4和R 5分别独立地选自H、C 1-3烷基、C 3-5环烷基和3-5元杂环烷基，所述C 1-3烷基、C 3-5环烷基和3-5元杂环烷基分别独立地任选被1、2或3个R b取代； R 4 and R 5 are each independently selected from H, C 1-3 alkyl, C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl, the C 1-3 alkyl, C 3-5 cycloalkyl Alkyl and 3-5 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 R b ;
R 6选自H； R 6 is selected from H;
R 7选自H； R is selected from H;
R 8和R 9分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个卤素取代； R 8 and R 9 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 halogens;
R 10选自H、F、Cl、Br和I； R 10 is selected from H, F, Cl, Br and I;
R 11选自H、F、Cl、Br、I、C 1-3烷基、C 3-5环烷基和5元杂芳基，所述C 1-3烷基、C 3-5环烷基和5元杂芳基分别独立地任选被1、2或3个R c取代； R 11 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 3-5 cycloalkyl and 5-membered heteroaryl, the C 1-3 alkyl, C 3-5 cycloalkane and 5-membered heteroaryl are each independently optionally substituted with 1, 2 or 3 R c ;
或者R 2和R 1与相连的碳原子一起形成苯基，所述苯基任选被1、2或3个卤素取代； or R2 and R1 together with the attached carbon atoms form a phenyl group optionally substituted with 1 , 2 or 3 halogens;
或者R 2和R 3与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个卤素取代； or R2 and R3 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
或者R 4和R 5与相连的碳原子一起形成5元杂环烷基，所述5元杂环烷基任选被1、2或3个卤素取代； or R and R together with the attached carbon atoms form a 5 - membered heterocycloalkyl optionally substituted with 1, 2 or 3 halogens;
或者R 4和R 6与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个卤素取代； or R4 and R6 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1 , 2 or 3 halogens;
或者R 5和R 7与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个卤素取代； or R5 and R7 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
或者T 3和-L 1-R 11与相连的碳原子一起形成5元杂环基，所述5元杂环基任选被1个CH 3取代； Or T 3 and -L 1 -R 11 together with the attached carbon atoms form a 5-membered heterocyclic group optionally substituted with 1 CH 3 ;
各R b分别独立地选自F、Cl、Br、I、OH和CN； each R b is independently selected from F, Cl, Br, I, OH and CN;
各R c分别独立地选自D、F、Cl、Br、I和CH 3； each Rc is independently selected from D, F, Cl, Br, I and CH3 ;
条件是，requirement is,
1)当
Figure PCTCN2022088181-appb-000003
选自双键，T 1选自CH，T 3选自N，R 2选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个卤素取代时，R 4、R 5和R 10不同时选自H； 1) When
Figure PCTCN2022088181-appb-000003
is selected from double bonds, T 1 is selected from CH, T 3 is selected from N, R 2 is selected from C 1-3 alkyl, and when the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, R 4 , R 5 and R 10 are not selected from H at the same time;
2)当
Figure PCTCN2022088181-appb-000004
选自双键，T 1选自CH，T 3选自CH时，T 2选自N。 2) When
Figure PCTCN2022088181-appb-000004
is selected from double bonds, T 1 is selected from CH, T 3 is selected from CH, T 2 is selected from N.
在本发明的一些方案中，所述R 1选自H，其他变量如本发明所定义。 In some embodiments of the present invention, said R1 is selected from H, and other variables are as defined herein.
在本发明的一些方案中，所述R 2选自选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基分别独立地任选被1、2或3个卤素取代，其他变量如本发明所定义。 In some aspects of the invention, the R 2 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 3 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl are each independently optionally substituted with 1, 2 or 3 halogens, other variables are as defined herein.
在本发明的一些方案中，所述R 2选自选自H、CH 2CH 3和环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, said R 2 is selected from the group consisting of H, CH 2 CH 3 and cyclopropyl, and other variables are as defined herein.
在本发明的一些方案中，所述R 2和R 1与相连的碳原子一起形成苯基，所述苯基被1个F取代，其他变量如本发明所定义。 In some embodiments of the invention, the R 2 and R 1 together with the attached carbon atoms form a phenyl group substituted with 1 F, and other variables are as defined herein.
在本发明的一些方案中，所述R 2和R 3与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, the R2 and R3 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述结构单元
Figure PCTCN2022088181-appb-000005
选自
Figure PCTCN2022088181-appb-000006
Figure PCTCN2022088181-appb-000007
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2022088181-appb-000005
selected from
Figure PCTCN2022088181-appb-000006
Figure PCTCN2022088181-appb-000007
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5分别独立地选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基和氧杂环丁基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基和氧杂环丁基分别独立地任选被1、2或3个R b取代，各R b分别独立地选自F、Cl、Br、I、OH和CN，其他变量如本发明所定义。 In some aspects of the invention, the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl and oxa cyclobutyl, the CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , cyclopropyl and oxetanyl, each independently optionally surrounded by 1, 2 or 3 R b is substituted, each R b is independently selected from F, Cl, Br, I, OH and CN, and other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5分别独立地选自H、CH 3、CH 2OH、CH 2CN、环丙基、
Figure PCTCN2022088181-appb-000008
Figure PCTCN2022088181-appb-000009
其他变量如本发明所定义。 In some aspects of the invention, the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 OH, CH 2 CN, cyclopropyl,
Figure PCTCN2022088181-appb-000008
Figure PCTCN2022088181-appb-000009
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5与相连的碳原子一起形成
Figure PCTCN2022088181-appb-000010
其他变量如本发明所定义。 In some aspects of the invention, the R4 and R5 are formed together with the attached carbon atom
Figure PCTCN2022088181-appb-000010
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 6与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, the R4 and R6 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述R 5和R 7与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, said R5 and R7 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述R 8和R 9分别独立地选自H和CH 3，其他变量如本发明所定义。 In some aspects of the present invention, said R 8 and R 9 are independently selected from H and CH 3 , respectively, and other variables are as defined herein.
在本发明的一些方案中，所述R 10选自H、F和Cl，其他变量如本发明所定义。 In some aspects of the present invention, said R 10 is selected from H, F and Cl, and other variables are as defined herein.
在本发明的一些方案中，所述R 11选自F、CH 3、CH 2CH 3、环丙基、
Figure PCTCN2022088181-appb-000011
所述CH 3、CH 2CH 3、环丙基、
Figure PCTCN2022088181-appb-000012
分别独立地任选被1、2或3个R c取代，各R c分别独立地选自D、F、Cl、Br、I和CH 3，其他变量如本发明所定义。 In some aspects of the invention, the R 11 is selected from F, CH 3 , CH 2 CH 3 , cyclopropyl,
Figure PCTCN2022088181-appb-000011
The CH 3 , CH 2 CH 3 , cyclopropyl,
Figure PCTCN2022088181-appb-000012
Each independently is optionally substituted with 1, 2 or 3 R c , each R c is independently selected from D, F, Cl, Br, I and CH3 , other variables are as defined herein.
在本发明的一些方案中，所述R 11选自F、CH 3、CD 3、CH 2CH 3、环丙基、
Figure PCTCN2022088181-appb-000013
其他变量如本发明所定义。 In some embodiments of the invention, the R 11 is selected from F, CH 3 , CD 3 , CH 2 CH 3 , cyclopropyl,
Figure PCTCN2022088181-appb-000013
Other variables are as defined in the present invention.
在本发明的一些方案中，所述T 3和-L 1-R 11与相连的碳原子一起形成5元杂环基，使结构单元
Figure PCTCN2022088181-appb-000014
选自
Figure PCTCN2022088181-appb-000015
其他变量如本发明所定义。 In some aspects of the present invention, the T3 and -L1 - R11 together with the attached carbon atoms form a 5-membered heterocyclic group, making the structural unit
Figure PCTCN2022088181-appb-000014
selected from
Figure PCTCN2022088181-appb-000015
Other variables are as defined in the present invention.
本发明提供了式(V)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022088181-appb-000016
Figure PCTCN2022088181-appb-000016
其中，in,
Figure PCTCN2022088181-appb-000017
选自单键和双键；
Figure PCTCN2022088181-appb-000017
selected from single and double bonds;
T 1选自N、NH、CH 2和CR 1； T 1 is selected from N, NH, CH 2 and CR 1 ;
T 2选自CH和N； T 2 is selected from CH and N;
T 3选自CH和N； T 3 is selected from CH and N;
L 1选自键、-C(＝O)-、-C(＝O)NH-和-CF＝CH-； L 1 is selected from bond, -C(=O)-, -C(=O)NH- and -CF=CH-;
R 1选自H、F、Cl、Br和I； R 1 is selected from H, F, Cl, Br and I;
R 2选自H、C 1-3烷基和C 3-5环烷基，所述C 1-3烷基和C 3-5环烷基任选被1、2或3个卤素取代； R 2 is selected from H, C 1-3 alkyl and C 3-5 cycloalkyl optionally substituted with 1 , 2 or 3 halogens;
R 3选自H或不存在； R is selected from H or absent;
R 4和R 5分别独立地选自H、C 1-3烷基、C 3-5环烷基和3-5元杂环烷基，所述C 1-3烷基、C 3-5环烷基和3-5元杂环烷基任选被1、2或3个R b取代； R 4 and R 5 are each independently selected from H, C 1-3 alkyl, C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl, the C 1-3 alkyl, C 3-5 cycloalkyl Alkyl and 3-5 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R b ;
R 6选自H； R 6 is selected from H;
R 7选自H； R is selected from H;
R 8和R 9分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个卤素取代； R 8 and R 9 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 halogens;
R 10选自H、F、Cl、B r和I； R 10 is selected from H, F, Cl, Br and I;
R 11选自H、F、Cl、Br、I、C 1-3烷基、C 3-5环烷基和5元杂芳基，所述C 1-3烷基、C 3-5环烷基和5元杂芳基任选被1、2或3个R c取代； R 11 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 3-5 cycloalkyl and 5-membered heteroaryl, the C 1-3 alkyl, C 3-5 cycloalkane radicals and 5-membered heteroaryl groups are optionally substituted with 1, 2 or 3 R c ;
或者R 2和R 1与相连的碳原子一起形成苯基，所述苯基任选被1、2或3个卤素取代； or R2 and R1 together with the attached carbon atoms form a phenyl group optionally substituted with 1 , 2 or 3 halogens;
或者R 2和R 3与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个卤素取代； or R2 and R3 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
或者R 4和R 5与相连的碳原子一起形成5元杂环烷基，所述5元杂环烷基任选被1、2或3个卤素取代； or R and R together with the attached carbon atoms form a 5 - membered heterocycloalkyl optionally substituted with 1, 2 or 3 halogens;
或者R 4和R 6与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个卤素取代； or R4 and R6 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1 , 2 or 3 halogens;
或者R 5和R 7与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个卤素取代； or R5 and R7 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
或者T 3和-L 1-R 11与相连的碳原子一起形成5元杂环基，所述5元杂环基任选被1个CH 3取代； Or T 3 and -L 1 -R 11 together with the attached carbon atoms form a 5-membered heterocyclic group optionally substituted with 1 CH 3 ;
各R b分别独立地选自F、Cl、Br、I、OH和CN； each R b is independently selected from F, Cl, Br, I, OH and CN;
各R c分别独立地选自D、F、Cl、Br、I和CH 3； each Rc is independently selected from D, F, Cl, Br, I and CH3 ;
条件是，requirement is,
1)当
Figure PCTCN2022088181-appb-000018
选自双键，T 1选自CH，T 3选自N，R 2选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个卤素取代时，R 4、R 5和R 10不同时选自H； 1) When
Figure PCTCN2022088181-appb-000018
is selected from double bonds, T 1 is selected from CH, T 3 is selected from N, R 2 is selected from C 1-3 alkyl, and when the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, R 4 , R 5 and R 10 are not selected from H at the same time;
2)当
Figure PCTCN2022088181-appb-000019
选自双键，T 1选自CH，T 3选自CH时，T 2选自N。 2) When
Figure PCTCN2022088181-appb-000019
is selected from double bonds, T 1 is selected from CH, T 3 is selected from CH, T 2 is selected from N.
在本发明的一些方案中，所述R 1选自H，其他变量如本发明所定义。 In some embodiments of the present invention, said R1 is selected from H, and other variables are as defined herein.
在本发明的一些方案中，所述R 2选自选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基任选被1、2或3个卤素取代，其他变量如本发明所定义。 In some aspects of the invention, the R 2 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 3 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl are optionally substituted with 1, 2 or 3 halogens, other variables are as defined herein.
在本发明的一些方案中，所述R 2选自选自H、CH 2CH 3和环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, said R 2 is selected from the group consisting of H, CH 2 CH 3 and cyclopropyl, and other variables are as defined herein.
在本发明的一些方案中，所述R 2和R 1与相连的碳原子一起形成苯基，所述苯基被1个F取代，其他变量如本发明所定义。 In some embodiments of the invention, the R 2 and R 1 together with the attached carbon atoms form a phenyl group substituted with 1 F, and other variables are as defined herein.
在本发明的一些方案中，所述R 2和R 3与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, the R2 and R3 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述结构单元
Figure PCTCN2022088181-appb-000020
选自
Figure PCTCN2022088181-appb-000021
Figure PCTCN2022088181-appb-000022
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2022088181-appb-000020
selected from
Figure PCTCN2022088181-appb-000021
Figure PCTCN2022088181-appb-000022
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5分别独立地选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基和氧杂环丁基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基和氧杂环丁基任选被1、2或3个R b取代，其他变量如本发明所定义。 In some aspects of the invention, the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl and oxa cyclobutyl, said CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , cyclopropyl and oxetanyl optionally substituted with 1 , 2 or 3 Rb , Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5分别独立地选自H、CH 3、CH 2OH、CH 2CN、环丙基、
Figure PCTCN2022088181-appb-000023
Figure PCTCN2022088181-appb-000024
其他变量如本发明所定义。 In some aspects of the invention, the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 OH, CH 2 CN, cyclopropyl,
Figure PCTCN2022088181-appb-000023
Figure PCTCN2022088181-appb-000024
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5与相连的碳原子一起形成
Figure PCTCN2022088181-appb-000025
其他变量如本发明所定义。 In some aspects of the invention, the R4 and R5 are formed together with the attached carbon atom
Figure PCTCN2022088181-appb-000025
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 6与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, the R4 and R6 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述R 5和R 7与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, said R5 and R7 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述R 8和R 9分别独立地选自H和CH 3，其他变量如本发明所定义。 In some aspects of the present invention, said R 8 and R 9 are independently selected from H and CH 3 , respectively, and other variables are as defined herein.
在本发明的一些方案中，所述R 10选自H、F和Cl，其他变量如本发明所定义。 In some aspects of the present invention, said R 10 is selected from H, F and Cl, and other variables are as defined herein.
在本发明的一些方案中，所述R 11选自F、CH 3、CH 2CH 3、环丙基、
Figure PCTCN2022088181-appb-000026
所述CH 3、CH 2CH 3、环丙基、
Figure PCTCN2022088181-appb-000027
任选被1、2或3个R c取代，其他变量如本发明所定义。 In some aspects of the invention, the R 11 is selected from F, CH 3 , CH 2 CH 3 , cyclopropyl,
Figure PCTCN2022088181-appb-000026
The CH 3 , CH 2 CH 3 , cyclopropyl,
Figure PCTCN2022088181-appb-000027
Optionally substituted with 1, 2 or 3 R c , other variables are as defined herein.
在本发明的一些方案中，所述R 11选自F、CH 3、CD 3、CH 2CH 3、环丙基、
Figure PCTCN2022088181-appb-000028
其他变量如本发明所定义。 In some embodiments of the invention, the R 11 is selected from F, CH 3 , CD 3 , CH 2 CH 3 , cyclopropyl,
Figure PCTCN2022088181-appb-000028
Other variables are as defined in the present invention.
在本发明的一些方案中，所述T 3和-L 1-R 11与相连的碳原子一起形成5元杂环基，使结构单元
Figure PCTCN2022088181-appb-000029
选自
Figure PCTCN2022088181-appb-000030
其他变量如本发明所定义。 In some aspects of the present invention, the T3 and -L1 - R11 together with the attached carbon atoms form a 5-membered heterocyclic group, making the structural unit
Figure PCTCN2022088181-appb-000029
selected from
Figure PCTCN2022088181-appb-000030
Other variables are as defined in the present invention.
本发明提供了式(V)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022088181-appb-000031
Figure PCTCN2022088181-appb-000031
其中，in,
Figure PCTCN2022088181-appb-000032
选自单键和双键；
Figure PCTCN2022088181-appb-000032
selected from single and double bonds;
T 1选自N、NH、CH 2和CR 1； T 1 is selected from N, NH, CH 2 and CR 1 ;
T 2选自CH和N； T 2 is selected from CH and N;
T 3选自CH和N； T 3 is selected from CH and N;
L 1选自键、-C(＝O)-、-C(＝O)NH-和-CF＝CH-； L 1 is selected from bond, -C(=O)-, -C(=O)NH- and -CF=CH-;
R 1选自H、F、Cl、Br和I； R 1 is selected from H, F, Cl, Br and I;
R 2选自H、C 1-3烷基和C 3-5环烷基，所述C 1-3烷基和C 3-5环烷基任选被1、2或3个卤素取代； R 2 is selected from H, C 1-3 alkyl and C 3-5 cycloalkyl optionally substituted with 1 , 2 or 3 halogens;
R 3选自H； R is selected from H;
R 4和R 5分别独立地选自H、C 1-3烷基、C 3-5环烷基和3-5元杂环烷基，所述C 1-3烷基、C 3-5环烷基和3-5元杂环烷基任选被1、2或3个R b取代； R 4 and R 5 are each independently selected from H, C 1-3 alkyl, C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl, the C 1-3 alkyl, C 3-5 cycloalkyl Alkyl and 3-5 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R b ;
R 6选自H； R 6 is selected from H;
R 7选自H； R is selected from H;
R 8和R 9分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个卤素取代； R 8 and R 9 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 halogens;
R 10选自H、F、Cl、Br和I； R 10 is selected from H, F, Cl, Br and I;
R 11选自H、F、Cl、Br、I、C 1-3烷基、C 3-5环烷基和5元杂芳基，所述C 1-3烷基、C 3-5环烷基和5元杂芳基任选被1、2或3个R c取代； R 11 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 3-5 cycloalkyl and 5-membered heteroaryl, the C 1-3 alkyl, C 3-5 cycloalkane radicals and 5-membered heteroaryl groups are optionally substituted with 1, 2 or 3 R c ;
或者R 2和R 1与相连的碳原子一起形成苯基，所述苯基任选被1、2或3个卤素取代； or R2 and R1 together with the attached carbon atoms form a phenyl group optionally substituted with 1 , 2 or 3 halogens;
或者R 2和R 3与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个卤素取代； or R2 and R3 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
或者R 4和R 5与相连的碳原子一起形成5元杂环烷基，所述5元杂环烷基任选被1、2或3个卤素取代； or R and R together with the attached carbon atoms form a 5 - membered heterocycloalkyl optionally substituted with 1, 2 or 3 halogens;
或者R 4和R 6与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个卤素取代； or R4 and R6 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1 , 2 or 3 halogens;
或者R 5和R 7与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个卤素取代； or R5 and R7 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
或者T 2和-L 1-R 11与相连的碳原子一起形成5元杂环基，所述5元杂环基任选被1个CH 3取代； Or T 2 and -L 1 -R 11 together with the attached carbon atoms form a 5-membered heterocyclic group optionally substituted with 1 CH 3 ;
各R b分别独立地选自F、Cl、Br、I、OH和CN； each R b is independently selected from F, Cl, Br, I, OH and CN;
各R c分别独立地选自D、F、Cl、Br、I和CH 3； each Rc is independently selected from D, F, Cl, Br, I and CH3 ;
条件是，当
Figure PCTCN2022088181-appb-000033
选自双键，T 1选自CH，R 2选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个卤素取代时，R 4、R 5和R 10不同时选自H。 The condition is that when
Figure PCTCN2022088181-appb-000033
is selected from double bonds, T 1 is selected from CH, R 2 is selected from C 1-3 alkyl, when said C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, R 4 , R 5 and R 10 is not selected from H at the same time.
在本发明的一些方案中，所述R 1选自H，其他变量如本发明所定义。 In some embodiments of the present invention, said R1 is selected from H, and other variables are as defined herein.
在本发明的一些方案中，所述R 2选自选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基任选被1、2或3个卤素取代，其他变量如本发明所定义。 In some aspects of the invention, the R 2 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 3 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl are optionally substituted with 1, 2 or 3 halogens, other variables are as defined herein.
在本发明的一些方案中，所述R 2选自选自H、CH 2CH 3和环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, said R 2 is selected from the group consisting of H, CH 2 CH 3 and cyclopropyl, and other variables are as defined herein.
在本发明的一些方案中，所述R 2和R 1与相连的碳原子一起形成苯基，所述苯基被1个F取代，其他变量如本发明所定义。 In some embodiments of the invention, the R 2 and R 1 together with the attached carbon atoms form a phenyl group substituted with 1 F, and other variables are as defined herein.
在本发明的一些方案中，所述R 2和R 3与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, the R2 and R3 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述结构单元
Figure PCTCN2022088181-appb-000034
选自
Figure PCTCN2022088181-appb-000035
Figure PCTCN2022088181-appb-000036
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2022088181-appb-000034
selected from
Figure PCTCN2022088181-appb-000035
Figure PCTCN2022088181-appb-000036
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5分别独立地选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基和氧杂环丁基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基和氧杂环丁基任选被1、2或3个R b取代，其他变量如本发明所定义。 In some aspects of the invention, the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl and oxa cyclobutyl, said CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , cyclopropyl and oxetanyl optionally substituted with 1 , 2 or 3 Rb , Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5分别独立地选自H、CH 3、CH 2OH、CH 2CN、环丙基、
Figure PCTCN2022088181-appb-000037
Figure PCTCN2022088181-appb-000038
其他变量如本发明所定义。 In some aspects of the invention, the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 OH, CH 2 CN, cyclopropyl,
Figure PCTCN2022088181-appb-000037
Figure PCTCN2022088181-appb-000038
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5与相连的碳原子一起形成
Figure PCTCN2022088181-appb-000039
其他变量如本发明所定义。 In some aspects of the invention, the R4 and R5 are formed together with the attached carbon atom
Figure PCTCN2022088181-appb-000039
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 6与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, the R4 and R6 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述R 5和R 7与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, said R5 and R7 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述R 8和R 9分别独立地选自H和CH 3，其他变量如本发明所定义。 In some aspects of the present invention, said R 8 and R 9 are independently selected from H and CH 3 , respectively, and other variables are as defined herein.
在本发明的一些方案中，所述R 10选自H、F和Cl，其他变量如本发明所定义。 In some aspects of the present invention, said R 10 is selected from H, F and Cl, and other variables are as defined herein.
在本发明的一些方案中，所述R 11选自F、CH 3、CH 2CH 3、环丙基、
Figure PCTCN2022088181-appb-000040
所述CH 3、CH 2CH 3、环丙基、
Figure PCTCN2022088181-appb-000041
任选被1、2或3个R c取代，其他变量如本发明所定义。 In some aspects of the invention, the R 11 is selected from F, CH 3 , CH 2 CH 3 , cyclopropyl,
Figure PCTCN2022088181-appb-000040
The CH 3 , CH 2 CH 3 , cyclopropyl,
Figure PCTCN2022088181-appb-000041
Optionally substituted with 1, 2 or 3 R c , other variables are as defined herein.
在本发明的一些方案中，所述R 11选自F、CH 3、CD 3、CH 2CH 3、环丙基、
Figure PCTCN2022088181-appb-000042
其他变量如本发明所定义。 In some embodiments of the invention, the R 11 is selected from F, CH 3 , CD 3 , CH 2 CH 3 , cyclopropyl,
Figure PCTCN2022088181-appb-000042
Other variables are as defined in the present invention.
在本发明的一些方案中，所述T 2和-L 1-R 11与相连的碳原子一起形成5元杂环基，使结构单元
Figure PCTCN2022088181-appb-000043
选自
Figure PCTCN2022088181-appb-000044
其他变量如本发明所定义。 In some aspects of the present invention, the T 2 and -L 1 -R 11 together with the attached carbon atoms form a 5-membered heterocyclic group, making the structural unit
Figure PCTCN2022088181-appb-000043
selected from
Figure PCTCN2022088181-appb-000044
Other variables are as defined in the present invention.
本发明提供了式(IV)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022088181-appb-000045
Figure PCTCN2022088181-appb-000045
其中，in,
Figure PCTCN2022088181-appb-000046
选自单键和双键；
Figure PCTCN2022088181-appb-000046
selected from single and double bonds;
T 1选自N、NH、CH 2和CR 1； T 1 is selected from N, NH, CH 2 and CR 1 ;
R 1选自H、F、Cl、Br和I； R 1 is selected from H, F, Cl, Br and I;
R 2选自H、C 1-3烷基和C 3-5环烷基，所述C 1-3烷基和C 3-5环烷基任选被1、2或3个卤素取代； R 2 is selected from H, C 1-3 alkyl and C 3-5 cycloalkyl optionally substituted with 1 , 2 or 3 halogens;
R 3选自H； R is selected from H;
R 4和R 5分别独立地选自H、C 1-3烷基、C 3-5环烷基和3-5元杂环烷基，所述C 1-3烷基、C 3-5环烷基和3-5元杂环烷基任选被1、2或3个R b取代； R 4 and R 5 are each independently selected from H, C 1-3 alkyl, C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl, the C 1-3 alkyl, C 3-5 cycloalkyl Alkyl and 3-5 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R b ;
R 6选自H； R 6 is selected from H;
R 7选自H； R is selected from H;
R 8和R 9分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个卤素取代； R 8 and R 9 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 halogens;
R 10选自H、F、Cl、B r和I； R 10 is selected from H, F, Cl, Br and I;
R 11选自CH 3和CD 3； R 11 is selected from CH 3 and CD 3 ;
或者R 2和R 1与相连的碳原子一起形成苯基，所述苯基任选被1、2或3个卤素取代； or R2 and R1 together with the attached carbon atoms form a phenyl group optionally substituted with 1 , 2 or 3 halogens;
或者R 2和R 3与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个卤素取代； or R2 and R3 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
或者R 4和R 5与相连的碳原子一起形成5元杂环烷基，所述5元杂环烷基任选被1、2或3个卤素取代； or R and R together with the attached carbon atoms form a 5 - membered heterocycloalkyl optionally substituted with 1, 2 or 3 halogens;
或者R 4和R 6与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个卤素取代； or R4 and R6 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1 , 2 or 3 halogens;
或者R 5和R 7与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个卤素取代； or R5 and R7 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
各R b分别独立地选自F、Cl、Br、I、OH和CN； each R b is independently selected from F, Cl, Br, I, OH and CN;
条件是，当
Figure PCTCN2022088181-appb-000047
选自双键，T 1选自CH，R 2选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个卤素取代时，R 4、R 5和R 10不同时选自H。 The condition is that when
Figure PCTCN2022088181-appb-000047
is selected from double bonds, T 1 is selected from CH, R 2 is selected from C 1-3 alkyl, when said C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, R 4 , R 5 and R 10 is not selected from H at the same time.
在本发明的一些方案中，所述R 1选自H，其他变量如本发明所定义。 In some embodiments of the present invention, said R1 is selected from H, and other variables are as defined herein.
在本发明的一些方案中，所述R 2选自选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基任选被1、2或3个卤素取代，其他变量如本发明所定义。 In some aspects of the invention, the R 2 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 3 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl are optionally substituted with 1, 2 or 3 halogens, other variables are as defined herein.
在本发明的一些方案中，所述R 2选自选自H、CH 2CH 3和环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, said R 2 is selected from the group consisting of H, CH 2 CH 3 and cyclopropyl, and other variables are as defined herein.
在本发明的一些方案中，所述R 2和R 1与相连的碳原子一起形成苯基，所述苯基被1个F取代，其他变量如本发明所定义。 In some embodiments of the invention, the R 2 and R 1 together with the attached carbon atoms form a phenyl group substituted with 1 F, and other variables are as defined herein.
在本发明的一些方案中，所述R 2和R 3与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, the R2 and R3 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述结构单元
Figure PCTCN2022088181-appb-000048
选自
Figure PCTCN2022088181-appb-000049
Figure PCTCN2022088181-appb-000050
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2022088181-appb-000048
selected from
Figure PCTCN2022088181-appb-000049
Figure PCTCN2022088181-appb-000050
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5分别独立地选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基和氧杂环丁基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基和氧杂环丁基任选被1、2或3个R b取代，其他变量如本发明所定义。 In some aspects of the invention, the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl and oxa cyclobutyl, said CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , cyclopropyl and oxetanyl optionally substituted with 1 , 2 or 3 Rb , Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5分别独立地选自H、CH 3、CH 2OH、CH 2CN、环丙基、
Figure PCTCN2022088181-appb-000051
Figure PCTCN2022088181-appb-000052
其他变量如本发明所定义。 In some aspects of the invention, the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 OH, CH 2 CN, cyclopropyl,
Figure PCTCN2022088181-appb-000051
Figure PCTCN2022088181-appb-000052
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5与相连的碳原子一起形成
Figure PCTCN2022088181-appb-000053
其他变量如本发明所定义。 In some aspects of the invention, the R4 and R5 are formed together with the attached carbon atom
Figure PCTCN2022088181-appb-000053
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 6与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, the R4 and R6 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述R 5和R 7与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, said R5 and R7 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述R 8和R 9分别独立地选自H和CH 3，其他变量如本发明所定义。 In some aspects of the present invention, said R 8 and R 9 are independently selected from H and CH 3 , respectively, and other variables are as defined herein.
在本发明的一些方案中，所述R 10选自H、F和Cl，其他变量如本发明所定义。 In some aspects of the present invention, said R 10 is selected from H, F and Cl, and other variables are as defined herein.
本发明提供了式(III)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022088181-appb-000054
Figure PCTCN2022088181-appb-000054
其中，in,
Figure PCTCN2022088181-appb-000055
选自单键和双键；
Figure PCTCN2022088181-appb-000055
selected from single and double bonds;
T 1选自N、NH、CH 2和CR 1； T 1 is selected from N, NH, CH 2 and CR 1 ;
R 1选自H、F、Cl、B r和I； R 1 is selected from H, F, Cl, Br and I;
R 2选自H、C 1-3烷基和C 3-5环烷基，所述C 1-3烷基和C 3-5环烷基任选被1、2或3个R a取代； R 2 is selected from H, C 1-3 alkyl and C 3-5 cycloalkyl, said C 1-3 alkyl and C 3-5 cycloalkyl are optionally substituted with 1, 2 or 3 R a ;
R 3选自H； R is selected from H;
R 4和R 5分别独立地选自H、C 1-3烷基、C 3-5环烷基和3-5元杂环烷基，所述C 1-3烷基、C 3-5环烷基和3-5元杂环烷基任选被1、2或3个R b取代； R 4 and R 5 are each independently selected from H, C 1-3 alkyl, C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl, the C 1-3 alkyl, C 3-5 cycloalkyl Alkyl and 3-5 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R b ;
R 6选自H； R 6 is selected from H;
R 7选自H； R is selected from H;
R 8和R 9分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R g取代； R 8 and R 9 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R g ;
R 10选自H、F、Cl、B r和I； R 10 is selected from H, F, Cl, Br and I;
或者R 2和R 1与相连的碳原子一起形成苯基，所述苯基任选被1、2或3个R c取代； or R2 and R1 together with the attached carbon atoms form a phenyl group optionally substituted with 1 , 2 or 3 Rcs;
或者R 2和R 3与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R d取代； or R2 and R3 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 Rd ;
或者R 4和R 5与相连的碳原子一起形成5元杂环烷基，所述5元杂环烷基任选被1、2或3个R e取代； or R4 and R5 together with the attached carbon atoms form a 5 - membered heterocycloalkyl optionally substituted with 1, 2 or 3 R e ;
或者R 4和R 6与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R f取代； Alternatively R4 and R6 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1 , 2 or 3 Rf ;
或者R 5和R 7与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R f取代； Alternatively R5 and R7 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 Rf ;
各R a、R c、R d、R e、R f和R g分别独立地选自F、Cl、Br和I； each of Ra , Rc , Rd , Re , Rf and Rg is independently selected from F, Cl, Br and I;
各R b分别独立地选自F、Cl、Br、I、OH和CN； each R b is independently selected from F, Cl, Br, I, OH and CN;
条件是，当
Figure PCTCN2022088181-appb-000056
选自双键，T 1选自CH，R 2选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代时，R 4、R 5和R 10不同时选自H。 The condition is that when
Figure PCTCN2022088181-appb-000056
is selected from double bonds, T 1 is selected from CH, R 2 is selected from C 1-3 alkyl, and when said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a , R 4 , R 5 and R 10 is not selected from H at the same time.
在本发明的一些方案中，所述R 1选自H，其他变量如本发明所定义。 In some embodiments of the present invention, said R1 is selected from H, and other variables are as defined herein.
在本发明的一些方案中，所述R 2选自选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基任选被1、2或3个R a取代，其他变量如本发明所定义。 In some aspects of the invention, the R 2 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 3 2CH3 , CH2CH2CH3 , CH( CH3 ) 2 and cyclopropyl are optionally substituted with 1, 2 or 3 Ra , other variables are as defined herein.
在本发明的一些方案中，所述R 2选自选自H、CH 2CH 3和环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, said R 2 is selected from the group consisting of H, CH 2 CH 3 and cyclopropyl, and other variables are as defined herein.
在本发明的一些方案中，所述R 2和R 1与相连的碳原子一起形成苯基，所述苯基被1个F取代，其他变量如本发明所定义。 In some embodiments of the invention, the R 2 and R 1 together with the attached carbon atoms form a phenyl group substituted with 1 F, and other variables are as defined herein.
在本发明的一些方案中，所述R 2和R 3与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, the R2 and R3 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述结构单元
Figure PCTCN2022088181-appb-000057
选自
Figure PCTCN2022088181-appb-000058
Figure PCTCN2022088181-appb-000059
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2022088181-appb-000057
selected from
Figure PCTCN2022088181-appb-000058
Figure PCTCN2022088181-appb-000059
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5分别独立地选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基和氧杂环丁基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基和氧杂环丁基任选被1、2或3个R b取代，其他变量如本发明所定义。 In some aspects of the invention, the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl and oxa cyclobutyl, said CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , cyclopropyl and oxetanyl optionally substituted with 1 , 2 or 3 Rb , Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5分别独立地选自H、CH 3、CH 2OH、CH 2CN、环丙基、
Figure PCTCN2022088181-appb-000060
Figure PCTCN2022088181-appb-000061
其他变量如本发明所定义。 In some aspects of the invention, the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 OH, CH 2 CN, cyclopropyl,
Figure PCTCN2022088181-appb-000060
Figure PCTCN2022088181-appb-000061
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5与相连的碳原子一起形成
Figure PCTCN2022088181-appb-000062
其他变量如本发明所定义。 In some aspects of the invention, the R4 and R5 are formed together with the attached carbon atom
Figure PCTCN2022088181-appb-000062
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 6与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, the R4 and R6 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述R 5和R 7与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, said R5 and R7 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述R 8和R 9分别独立地选自H和CH 3，其他变量如本发明所定义。 In some aspects of the present invention, said R 8 and R 9 are independently selected from H and CH 3 , respectively, and other variables are as defined herein.
在本发明的一些方案中，所述R 10选自H、F和Cl，其他变量如本发明所定义。 In some aspects of the present invention, said R 10 is selected from H, F and Cl, and other variables are as defined herein.
本发明提供了式(II)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022088181-appb-000063
Figure PCTCN2022088181-appb-000063
其中，in,
Figure PCTCN2022088181-appb-000064
选自单键和双键；
Figure PCTCN2022088181-appb-000064
selected from single and double bonds;
T 1选自N、NH、CH 2和CR 1； T 1 is selected from N, NH, CH 2 and CR 1 ;
R 1选自H、F、Cl、Br和I； R 1 is selected from H, F, Cl, Br and I;
R 2选自H、C 1-3烷基和C 3-5环烷基，所述C 1-3烷基和C 3-5环烷基任选被1、2或3个R a取代； R 2 is selected from H, C 1-3 alkyl and C 3-5 cycloalkyl, said C 1-3 alkyl and C 3-5 cycloalkyl are optionally substituted with 1, 2 or 3 R a ;
R 3选自H； R is selected from H;
R 4和R 5分别独立地选自H、C 1-3烷基、C 3-5环烷基和3-5元杂环烷基，所述C 1-3烷基、C 3-5环烷基和3-5元杂环烷基任选被1、2或3个R b取代； R 4 and R 5 are each independently selected from H, C 1-3 alkyl, C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl, the C 1-3 alkyl, C 3-5 cycloalkyl Alkyl and 3-5 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R b ;
R 6选自H； R 6 is selected from H;
R 7选自H； R is selected from H;
R 8和R 9分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R g取代； R 8 and R 9 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R g ;
或者R 2和R 1与相连的碳原子一起形成苯基，所述苯基任选被1、2或3个R c取代； or R2 and R1 together with the attached carbon atoms form a phenyl group optionally substituted with 1 , 2 or 3 Rcs;
或者R 2和R 3与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R d取代； or R2 and R3 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 Rd ;
或者R 4和R 5与相连的碳原子一起形成5元杂环烷基，所述5元杂环烷基任选被1、2或3个R e取代； or R4 and R5 together with the attached carbon atoms form a 5 - membered heterocycloalkyl optionally substituted with 1, 2 or 3 R e ;
或者R 4和R 6与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R f取代； Alternatively R4 and R6 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1 , 2 or 3 Rf ;
或者R 5和R 7与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R f取代； Alternatively R5 and R7 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 Rf ;
各R a、R c、R d、R e、R f和R g分别独立地选自F、Cl、Br和I； each of Ra , Rc , Rd , Re , Rf and Rg is independently selected from F, Cl, Br and I;
各R b分别独立地选自F、Cl、Br、I、OH和CN； each R b is independently selected from F, Cl, Br, I, OH and CN;
条件是，当
Figure PCTCN2022088181-appb-000065
选自双键，T 1选自CH，R 2选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代时，R 4和R 5不同时选自H。 The condition is that when
Figure PCTCN2022088181-appb-000065
is selected from double bonds, T 1 is selected from CH, R 2 is selected from C 1-3 alkyl, when the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a , R 4 and R 5 are not Also selected from H.
在本发明的一些方案中，所述R 1选自H，其他变量如本发明所定义。 In some embodiments of the present invention, said R1 is selected from H, and other variables are as defined herein.
在本发明的一些方案中，所述R 2选自选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基任选被1、2或3个R a取代，其他变量如本发明所定义。 In some aspects of the invention, the R 2 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 3 2CH3 , CH2CH2CH3 , CH( CH3 ) 2 and cyclopropyl are optionally substituted with 1, 2 or 3 Ra , other variables are as defined herein.
在本发明的一些方案中，所述R 2选自选自H、CH 2CH 3和环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, said R 2 is selected from the group consisting of H, CH 2 CH 3 and cyclopropyl, and other variables are as defined herein.
在本发明的一些方案中，所述R 2和R 1与相连的碳原子一起形成苯基，所述苯基被1个F取代，其他变量如本发明所定义。 In some embodiments of the invention, the R 2 and R 1 together with the attached carbon atoms form a phenyl group substituted with 1 F, and other variables are as defined herein.
在本发明的一些方案中，所述R 2和R 3与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, the R2 and R3 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述结构单元
Figure PCTCN2022088181-appb-000066
选自
Figure PCTCN2022088181-appb-000067
Figure PCTCN2022088181-appb-000068
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2022088181-appb-000066
selected from
Figure PCTCN2022088181-appb-000067
Figure PCTCN2022088181-appb-000068
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5分别独立地选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基和氧杂环丁基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基和氧杂环丁基任选被1、2或3个R b取代，其他变量如本发明所定义。 In some aspects of the invention, the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl and oxa cyclobutyl, said CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , cyclopropyl and oxetanyl optionally substituted with 1 , 2 or 3 Rb , Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5分别独立地选自H、CH 3、CH 2OH、CH 2CN、环丙基、
Figure PCTCN2022088181-appb-000069
Figure PCTCN2022088181-appb-000070
其他变量如本发明所定义。 In some aspects of the invention, the R 4 and R 5 are each independently selected from H, CH 3 , CH 2 OH, CH 2 CN, cyclopropyl,
Figure PCTCN2022088181-appb-000069
Figure PCTCN2022088181-appb-000070
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5与相连的碳原子一起形成
Figure PCTCN2022088181-appb-000071
其他变量如本发明所定义。 In some aspects of the invention, the R4 and R5 are formed together with the attached carbon atom
Figure PCTCN2022088181-appb-000071
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 6与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, the R4 and R6 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述R 5和R 7与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, said R5 and R7 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述R 8和R 9分别独立地选自H和CH 3，其他变量如本发明所定义。 In some aspects of the present invention, said R 8 and R 9 are independently selected from H and CH 3 , respectively, and other variables are as defined herein.
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022088181-appb-000072
Figure PCTCN2022088181-appb-000072
其中，in,
Figure PCTCN2022088181-appb-000073
选自单键和双键；
Figure PCTCN2022088181-appb-000073
selected from single and double bonds;
T 1选自N、NH、CH 2和CR 1； T 1 is selected from N, NH, CH 2 and CR 1 ;
R 1选自H、F、Cl、Br和I； R 1 is selected from H, F, Cl, Br and I;
R 2选自H、C 1-3烷基和C 3-5环烷基，所述C 1-3烷基和C 3-5环烷基任选被1、2或3个R a取代； R 2 is selected from H, C 1-3 alkyl and C 3-5 cycloalkyl, said C 1-3 alkyl and C 3-5 cycloalkyl are optionally substituted with 1, 2 or 3 R a ;
R 3选自H； R is selected from H;
R 4和R 5分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代； R 4 and R 5 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ;
或者R 2和R 1与相连的碳原子一起形成苯基，所述苯基任选被1、2或3个R c取代； or R2 and R1 together with the attached carbon atoms form a phenyl group optionally substituted with 1 , 2 or 3 Rcs;
或者R 2和R 3与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R d取代； or R2 and R3 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 Rd ;
各R a、R c和R d分别独立地选自F、Cl、Br和I； each of Ra , Rc and Rd is independently selected from F, Cl, Br and I;
各R b分别独立地选自F、Cl、Br、I、OH和CN； each R b is independently selected from F, Cl, Br, I, OH and CN;
条件是，当
Figure PCTCN2022088181-appb-000074
选自双键，T 1选自CH，R 2选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代时，R 4和R 5不同时选自H。 The condition is that when
Figure PCTCN2022088181-appb-000074
is selected from double bonds, T 1 is selected from CH, R 2 is selected from C 1-3 alkyl, when the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a , R 4 and R 5 are not Also selected from H.
在本发明的一些方案中，所述R 1选自H，其他变量如本发明所定义。 In some embodiments of the present invention, said R1 is selected from H, and other variables are as defined herein.
在本发明的一些方案中，所述R 2选自选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基任选被1、2或3个R a取代，其他变量如本发明所定义。 In some aspects of the invention, the R 2 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 3 2CH3 , CH2CH2CH3 , CH( CH3 ) 2 and cyclopropyl are optionally substituted with 1, 2 or 3 Ra , other variables are as defined herein.
在本发明的一些方案中，所述R 2选自选自H、CH 2CH 3和环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, said R 2 is selected from the group consisting of H, CH 2 CH 3 and cyclopropyl, and other variables are as defined herein.
在本发明的一些方案中，所述R 2和R 1与相连的碳原子一起形成苯基，所述苯基被1个F取代，其他变量如本发明所定义。 In some embodiments of the invention, the R 2 and R 1 together with the attached carbon atoms form a phenyl group substituted with 1 F, and other variables are as defined herein.
在本发明的一些方案中，所述R 2和R 3与相连的碳原子一起形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, the R2 and R3 together with the attached carbon atom form a cyclopropyl group, other variables are as defined herein.
在本发明的一些方案中，所述结构单元
Figure PCTCN2022088181-appb-000075
选自
Figure PCTCN2022088181-appb-000076
Figure PCTCN2022088181-appb-000077
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2022088181-appb-000075
selected from
Figure PCTCN2022088181-appb-000076
Figure PCTCN2022088181-appb-000077
Other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5分别独立地选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2，所述CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2任选被1、2或3个R b取代，其他变量如本发明所定义。 In some aspects of the present invention, the R 4 and R 5 are independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 3 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are optionally substituted with 1, 2 or 3 R b and other variables are as defined in the present invention.
在本发明的一些方案中，所述R 4和R 5分别独立地选自H、CH 3、CH 2OH和CH 2CN，其他变量如本发明所定义。 In some aspects of the present invention, said R 4 and R 5 are independently selected from H, CH 3 , CH 2 OH and CH 2 CN, and other variables are as defined herein.
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自In some embodiments of the invention, the compound, or a pharmaceutically acceptable salt thereof, is selected from
Figure PCTCN2022088181-appb-000078
Figure PCTCN2022088181-appb-000078
其中，L 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11如本发明所定义。 Wherein, L 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as defined in the present invention.
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自In some embodiments of the invention, the compound, or a pharmaceutically acceptable salt thereof, is selected from
Figure PCTCN2022088181-appb-000079
Figure PCTCN2022088181-appb-000079
其中，R 4、R 5、R 8、R 9、R 10和R 11如本发明所定义。 Wherein, R 4 , R 5 , R 8 , R 9 , R 10 and R 11 are as defined in the present invention.
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自In some embodiments of the invention, the compound, or a pharmaceutically acceptable salt thereof, is selected from
Figure PCTCN2022088181-appb-000080
Figure PCTCN2022088181-appb-000080
其中，R 5和R 10如本发明所定义。 wherein, R 5 and R 10 are as defined in the present invention.
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自In some embodiments of the invention, the compound, or a pharmaceutically acceptable salt thereof, is selected from
Figure PCTCN2022088181-appb-000081
Figure PCTCN2022088181-appb-000081
其中，in,
R 5选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代； R 5 is selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ;
各R b分别独立地选自F、Cl、Br、I、OH和CN； each R b is independently selected from F, Cl, Br, I, OH and CN;
R 10选自H、F、Cl、Br和I。 R 10 is selected from H, F, Cl, Br and I.
在本发明的一些方案中，所述R 5选自H、CH 3、CH 2OH和CH 2CN，其他变量如本发明所定义。 In some embodiments of the present invention, said R5 is selected from H, CH3 , CH2OH and CH2CN , and other variables are as defined herein.
在本发明的一些方案中，所述R 5选自H，其他变量如本发明所定义。 In some embodiments of the present invention, said R5 is selected from H, and other variables are as defined herein.
在本发明的一些方案中，所述R 10选自H、F和Cl，其他变量如本发明所定义。 In some aspects of the present invention, said R 10 is selected from H, F and Cl, and other variables are as defined herein.
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自In some embodiments of the invention, the compound, or a pharmaceutically acceptable salt thereof, is selected from
Figure PCTCN2022088181-appb-000082
Figure PCTCN2022088181-appb-000082
其中，in,
R 5选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代； R 5 is selected from C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ;
各R b分别独立地选自F、Cl、Br、I、OH和CN； each R b is independently selected from F, Cl, Br, I, OH and CN;
R 10选自H、F、Cl、Br和I。 R 10 is selected from H, F, Cl, Br and I.
在本发明的一些方案中，所述R 5选自CH 3、CH 2OH和CH 2CN，其他变量如本发明所定义。 In some embodiments of the present invention, said R5 is selected from CH3 , CH2OH and CH2CN , and other variables are as defined herein.
在本发明的一些方案中，所述R 5选自CH 3，其他变量如本发明所定义。 In some embodiments of the present invention, said R5 is selected from CH3 , and other variables are as defined herein.
在本发明的一些方案中，所述R 10选自H、F和Cl，其他变量如本发明所定义。 In some aspects of the present invention, said R 10 is selected from H, F and Cl, and other variables are as defined herein.
本发明还有一些方案是由上述变量任意组合而来。There are also some solutions of the present invention that are formed by any combination of the above variables.
本发明还提供了下列化合物或其药学上可接受的盐，The present invention also provides the following compounds or pharmaceutically acceptable salts thereof,
Figure PCTCN2022088181-appb-000083
Figure PCTCN2022088181-appb-000083
Figure PCTCN2022088181-appb-000084
Figure PCTCN2022088181-appb-000084
Figure PCTCN2022088181-appb-000085
Figure PCTCN2022088181-appb-000085
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，In some aspects of the invention, the compound or a pharmaceutically acceptable salt thereof, the compound is selected from,
Figure PCTCN2022088181-appb-000086
Figure PCTCN2022088181-appb-000086
Figure PCTCN2022088181-appb-000087
Figure PCTCN2022088181-appb-000087
Figure PCTCN2022088181-appb-000088
Figure PCTCN2022088181-appb-000088
Figure PCTCN2022088181-appb-000089
Figure PCTCN2022088181-appb-000089
本发明还提供了所述化合物或其药学上可接受的盐在制备治疗实体瘤药物中的应用。The present invention also provides the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating solid tumors.
在本发明的一些方案中，所述实体瘤指BRCA突变的卵巢癌和乳腺癌。In some embodiments of the invention, the solid tumors refer to BRCA-mutated ovarian and breast cancers.
本发明还提供了一种药物组合物，包括治疗有效量的如本发明所定义的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体、稀释剂或赋形剂。The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in the present invention or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier, diluent or excipient.
技术效果technical effect
本发明化合物具有较好的PARP1抑制作用、细胞增殖抑制作用，且PARP1/PARP2、PARP1/PARP3具有高选择性，可有效避免由于抑制PARP2、PARP3带来的血液学副作用。并且，本发明化合物有优异的体内代谢稳定性，在不同的种属中均体现出优异的口服吸收药物暴露量和口服吸收生物利用度。此外，本发明化合物也具有显著的抗肿瘤活性，体重变化小，安全性佳。The compound of the present invention has better PARP1 inhibitory effect and cell proliferation inhibitory effect, and has high selectivity of PARP1/PARP2 and PARP1/PARP3, which can effectively avoid hematological side effects caused by the inhibition of PARP2 and PARP3. In addition, the compounds of the present invention have excellent metabolic stability in vivo, and show excellent oral absorption drug exposure and oral absorption bioavailability in different species. In addition, the compounds of the present invention also have significant anti-tumor activity, small changes in body weight, and good safety.
相关定义Related Definitions
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without specific definitions, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计 量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of one active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or patient. Representative carriers include water, oils, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical field.
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。The term "excipient" generally refers to the carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise indicated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.
除非另有说明，用楔形实线键
Figure PCTCN2022088181-appb-000090
和楔形虚线键
Figure PCTCN2022088181-appb-000091
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022088181-appb-000092
和直形虚线键
Figure PCTCN2022088181-appb-000093
表示立体中心的相对构型，用波浪线
Figure PCTCN2022088181-appb-000094
表示楔形实线键
Figure PCTCN2022088181-appb-000095
或楔形虚线键
Figure PCTCN2022088181-appb-000096
或用波浪线
Figure PCTCN2022088181-appb-000097
表示直形实线键
Figure PCTCN2022088181-appb-000098
和直形虚线键
Figure PCTCN2022088181-appb-000099
Use solid wedge keys unless otherwise specified
Figure PCTCN2022088181-appb-000090
and wedge-dotted keys
Figure PCTCN2022088181-appb-000091
Indicate the absolute configuration of a stereocenter, using a straight solid key
Figure PCTCN2022088181-appb-000092
and straight dashed keys
Figure PCTCN2022088181-appb-000093
Indicate the relative configuration of the stereocenter, with a wavy line
Figure PCTCN2022088181-appb-000094
Represents a solid wedge key
Figure PCTCN2022088181-appb-000095
or wedge-dotted key
Figure PCTCN2022088181-appb-000096
or with wavy lines
Figure PCTCN2022088181-appb-000097
Represents a straight solid key
Figure PCTCN2022088181-appb-000098
and straight dashed keys
Figure PCTCN2022088181-appb-000099
除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2，4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature. A chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise indicated, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in one enantiomer" refer to one of the isomers or pairs The enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise indicated, the terms "isomeric excess" or "enantiomeric excess" refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). For another example, deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. .
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable. When the substituent is oxygen (ie =O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups connected to it are directly connected, for example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2022088181-appb-000100
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2022088181-appb-000101
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2022088181-appb-000102
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 When the listed linking group does not indicate its direction of attachment, the direction of attachment is arbitrary, for example,
Figure PCTCN2022088181-appb-000100
The linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right.
Figure PCTCN2022088181-appb-000101
It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
Figure PCTCN2022088181-appb-000102
Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连 接的化学键可以用直形实线键
Figure PCTCN2022088181-appb-000103
直形虚线键
Figure PCTCN2022088181-appb-000104
或波浪线
Figure PCTCN2022088181-appb-000105
表示。例如-OCH3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2022088181-appb-000106
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2022088181-appb-000107
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2022088181-appb-000108
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2022088181-appb-000109
Figure PCTCN2022088181-appb-000110
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022088181-appb-000111
仍包括
Figure PCTCN2022088181-appb-000112
这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价哌啶基；
Figure PCTCN2022088181-appb-000113
表示R可以任意连接在双键的两端，即表示
Figure PCTCN2022088181-appb-000114
Unless otherwise specified, when a group has one or more attachable sites, any one or more sites in the group can be linked to other groups by chemical bonds. When the connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group. The chemical bond connecting the site to other groups can be represented by straight solid line bonds
Figure PCTCN2022088181-appb-000103
straight dotted key
Figure PCTCN2022088181-appb-000104
or wavy lines
Figure PCTCN2022088181-appb-000105
express. For example, a straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in this group;
Figure PCTCN2022088181-appb-000106
The straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
Figure PCTCN2022088181-appb-000107
The wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
Figure PCTCN2022088181-appb-000108
Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least
Figure PCTCN2022088181-appb-000109
Figure PCTCN2022088181-appb-000110
These 4 connection methods, even if the H atom is drawn on -N-, but
Figure PCTCN2022088181-appb-000111
still includes
Figure PCTCN2022088181-appb-000112
For the group in this connection method, when one chemical bond is connected, the H at the site will be correspondingly reduced by one to become the corresponding monovalent piperidinyl group;
Figure PCTCN2022088181-appb-000113
Indicates that R can be arbitrarily attached to both ends of the double bond, that is,
Figure PCTCN2022088181-appb-000114
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。 Unless otherwise specified, the term "C 1-3 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) . Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
除非另有规定，“C 3-5环烷基”表示由3至5个碳原子组成的饱和环状碳氢基团，其为单环体系，所述C 3-5环烷基包括C 3-4和C 4-5环烷基等；其可以是一价、二价或者多价。C 3-5环烷基的实例包括，但不限于，环丙基、环丁基、环戊基等。 Unless otherwise specified, "C 3-5 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, said C 3-5 cycloalkyl including C 3 -4 and C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
除非另有规定，术语“3-5元杂环烷基”本身或者与其他术语联合分别表示由3至5个环原子组成的饱和单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。此外，就该“3-5元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-5元杂环烷基包括4-5元、4元、和5元杂环烷基等。3-5元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)或四氢呋喃基(包括四氢呋喃-2-基等)等。 Unless otherwise specified, the term "3-5 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated monocyclic group consisting of 3 to 5 ring atoms, 1, 2, 3 or 4 ring atoms, respectively are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (ie, NO and S(O) p , p is 1 or 2). Furthermore, with respect to the "3-5 membered heterocycloalkyl", a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule. The 3-5 membered heterocycloalkyl includes 4-5 membered, 4 membered, and 5 membered heterocycloalkyl and the like. Examples of 3-5 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) or tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.) and the like.
除非另有规定，术语“5元杂环基”本身或者与其他术语联合分别表示由5个环原子组成的饱和或部分不饱和单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即CO、NO和S(O) p，p是1或2)。此外，就该“5元杂环基”而言，杂原子可以占据杂环基与分子其余部分的连接位置。所述5元杂环基包括5元杂环烷基、5元杂环烯基等。5元杂环基的实例包括但不限于2，5-二氢-1H-吡咯基等。 Unless otherwise specified, the term "5-membered heterocyclyl" by itself or in combination with other terms denotes, respectively, a saturated or partially unsaturated monocyclic group consisting of 5 ring atoms, wherein 1, 2, 3 or 4 ring atoms are Heteroatoms independently selected from O, S, and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms are optionally oxidized (i.e., CO, NO, and S(O) p , where p is 1 or 2). Furthermore, with respect to the "5-membered heterocyclyl", a heteroatom may occupy the position of attachment of the heterocyclyl to the rest of the molecule. The 5-membered heterocyclic group includes 5-membered heterocycloalkyl, 5-membered heterocycloalkenyl and the like. Examples of 5-membered heterocyclyl groups include, but are not limited to, 2,5-dihydro-1H-pyrrolyl and the like.
除非另有规定，术语“5元杂芳基”表示由5个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫 杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5元杂芳基实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1，2，3-三唑基、2H-1，2，3-三唑基、1H-1，2，4-三唑基和4H-1，2，4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)。 Unless otherwise specified, the term "5-membered heteroaryl" refers to a monocyclic group consisting of 5 ring atoms with a conjugated π-electron system, wherein 1, 2, 3 or 4 ring atoms are independently selected from O, Heteroatoms of S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2). A 5-membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom. Examples of the 5-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, and the like) ), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl) etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4 -triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-isoxazolyl, etc.) thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.).
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。 Unless otherwise specified, Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring , 10-membered ring, 11-membered ring, and 12-membered ring, also including any one range from n to n+m, for example, 3-12-membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2022088181-appb-000115
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。 The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is:
Figure PCTCN2022088181-appb-000115
After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：DIBAL-H代表二异丁基氢化铝；Pd(dppf) 2Cl 2代表[1，1′-双(二苯基膦)二茂铁]二氯化钯；RuPhos代表2-双环己基膦-2，6-二异丙氧基-1，1-联苯；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯；TBSCl代表叔丁基二甲基氯硅烷；Pd-Xphos-G3代表甲磺酸钠(2-二环己基膦基2′，4′，6′-三异丙基-1，1′-联苯)(2′-氨基-1，1′-联苯-2-基)钯；TBAF代表四丁基氟化氨；Cs 2CO 3代表碳酸铯；NaBH 4代表硼氢化钠；TBSCl代表叔丁基二甲基氯硅烷；RuPhos Pd G3代表(2-二环己基膦基-2，6-二异丙氧基-1，1-联苯基)[2-(2-氨基-1，1-联苯基)]钯(II)；Et 3N代表三乙胺；MsCl代表甲基磺酰氯；Pd(PPh 3) 4代表四(三苯基膦)钯；MeB(OH) 2代表甲基硼酸；LiAlH 4代表四氢锂铝；NaBH 3CN代表氰基硼氢化钠；LiHMDS代表二(三甲基硅基)氨基锂；n-BuLi代表正丁基锂；TEA代表三乙胺；Psi代表Pounds per square inch，压强计量单位；HPLC代表高效液相色谱。 The solvent used in the present invention is commercially available. The present invention adopts the following abbreviations: DIBAL-H stands for diisobutylaluminum hydride; Pd(dppf) 2 Cl 2 stands for [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; RuPhos stands for 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl; Pd 2 (dba) 3 stands for tris(dibenzylideneacetone)dipalladium; TBSCl stands for tert-butyldimethyl methacrylate chlorosilane; Pd-Xphos-G3 represents sodium methanesulfonate (2-dicyclohexylphosphino 2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino- 1,1'-biphenyl-2-yl)palladium; TBAF for tetrabutylammonium fluoride ; Cs2CO3 for cesium carbonate; NaBH4 for sodium borohydride; TBSCl for tert - butyldimethylsilyl chloride; RuPhos Pd G3 stands for (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II ); Et 3 N represents triethylamine; MsCl represents methylsulfonyl chloride; Pd(PPh 3 ) 4 represents tetrakis(triphenylphosphine)palladium; MeB(OH) 2 represents methylboronic acid; LiAlH 4 represents lithium aluminum tetrahydride ; NaBH 3 CN stands for sodium cyanoborohydride; LiHMDS stands for lithium bis(trimethylsilyl) amide; n-BuLi stands for n-butyl lithium; TEA stands for triethylamine; Psi stands for Pounds per square inch, the unit of pressure measurement; HPLC stands for High Performance Liquid Chromatography.
附图说明Description of drawings
图1.化合物6在DLD-1模型中的肿瘤体积变化图。Figure 1. Plot of tumor volume change of compound 6 in the DLD-1 model.
图2.化合物6在DLD-1模型中的体重变化率图。Figure 2. Body weight change rate graph for compound 6 in the DLD-1 model.
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情 况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. For those skilled in the art, various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention. will be obvious.
实施例1Example 1
Figure PCTCN2022088181-appb-000116
Figure PCTCN2022088181-appb-000116
步骤1：中间体1a的合成Step 1: Synthesis of Intermediate 1a
将原料3-氨基-5-溴吡啶-2-甲酸(2.96g，13.64mmol)加入二氯甲烷(25mL)中，降温-78℃，滴加DIBAL-H(1M，27.28mL)，继续反应2小时，缓慢滴加水(13.6mL)，然后缓慢滴加15％NaOH(13.6mL)，最后加入水(40mL)淬灭，滴加结束后有大量固体析出使用硅藻土过滤掉固体，二氯甲烷(20mL*3)萃取，收集有机相，合并有机相，无水硫酸钠干燥后浓缩减压得1a。MS m/z：200.7[M+H] +；202.7[M+H] +。 The raw material 3-amino-5-bromopyridine-2-carboxylic acid (2.96 g, 13.64 mmol) was added to dichloromethane (25 mL), the temperature was lowered to -78 °C, DIBAL-H (1 M, 27.28 mL) was added dropwise, and the reaction was continued for 2 hour, slowly add water (13.6mL) dropwise, then slowly add 15% NaOH (13.6mL) dropwise, and finally add water (40mL) to quench, after the dropwise addition, a large amount of solid is precipitated Use diatomaceous earth to filter out the solid, dichloromethane (20mL*3) extraction, collect the organic phases, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain 1a. MS m/z: 200.7 [M+H] + ; 202.7 [M+H] + .
步骤2：中间体1b的合成Step 2: Synthesis of Intermediate 1b
取中间体1a(2.5g，12.44mmol)溶于二甲苯(35mL)中，加入原料2，2，6-三甲基-4H-1，3-二恶英-4-酮(2.65g，18.65mmol，2.46mL)，160℃回流反应2小时，冷却至室温，将反应液过滤，使用二甲苯(15mL)洗滤饼，收集滤饼，得到中间体1b。MS m/z：266.8[M+H] +；268.8[M+H] +。 1H NMR(400MHz，DMSO-d 6)δppm12.32(br s，1H)8.64(d，J＝1.51Hz，1H)8.23(s，1H)7.91(s，1H)2.62(s，3H)。 The intermediate 1a (2.5 g, 12.44 mmol) was dissolved in xylene (35 mL), and the raw material 2,2,6-trimethyl-4H-1,3-dioxin-4-one (2.65 g, 18.65 g) was added. mmol, 2.46 mL), refluxed at 160° C. for 2 hours, cooled to room temperature, filtered the reaction solution, washed the filter cake with xylene (15 mL), and collected the filter cake to obtain Intermediate 1b. MS m/z: 266.8 [M+H] + ; 268.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.32 (br s, 1H) 8.64 (d, J=1.51 Hz, 1H) 8.23 (s, 1H) 7.91 (s, 1H) 2.62 (s, 3H).
步骤3：中间体1c的合成Step 3: Synthesis of Intermediate 1c
25℃条件下，将中间体1b(4.6g，17.22mmol)和水合肼(11.61g，197.21mmol，11.28mL，85％)加入甲醇(60mL)中，升温至65℃反应3小时。将反应液浓缩干燥得中间体1c，不经纯化，直接进行下一步。At 25 °C, intermediate 1b (4.6 g, 17.22 mmol) and hydrazine hydrate (11.61 g, 197.21 mmol, 11.28 mL, 85%) were added to methanol (60 mL), and the temperature was raised to 65 °C to react for 3 hours. The reaction solution was concentrated and dried to obtain intermediate 1c, which was directly carried to the next step without purification.
步骤4：中间体1d的合成Step 4: Synthesis of Intermediate 1d
将中间体1c(4.84g，17.22mmol)加入一缩二乙二醇(50mL)中，加入KOH(3.86g，68.88mmol)，升温至190℃反应1.5小时。反应结束后，用1mol/L的盐酸调节反应液为中性，抽滤滤饼，得到中间体1d。Intermediate 1c (4.84 g, 17.22 mmol) was added to diethylene glycol (50 mL), KOH (3.86 g, 68.88 mmol) was added, and the temperature was raised to 190° C. to react for 1.5 hours. After the reaction, the reaction solution was adjusted to be neutral with 1 mol/L hydrochloric acid, and the filter cake was suction filtered to obtain the intermediate 1d.
步骤5：中间体1e的合成Step 5: Synthesis of Intermediate 1e
将中间体1d(1.0g，3.95mmol)，Pd(dppf) 2Cl 2(322.66mg，0.40mmol)和三乙胺(2.00g，19.76mmol，2.75mL)加入甲醇(20mL)和DMF(20mL)中，用N 2置换反应瓶中气体3次，用CO置换气体三次，调压50Psi，升温50℃，反应18小时。漏斗滤除固体，收集有机溶剂，蒸出甲醇，然后倾入80mL水中，析出固体，抽滤得得目标产物粗品，浓缩后加入8mL甲醇打浆，抽滤得中间体1e。MS m/z：232.9[M+H] +。 1H NMR(400MHz，DMSO-d 6)δppm 12.09(s，1H)8.89(d，J＝1.51Hz，1H)8.15(d，J＝1.51Hz，1H)7.82(s，1H)3.92(s，3H)2.58(q，J＝7.53Hz，2H)1.20(t，J＝7.28Hz，3H)。 Intermediate 1d (1.0 g, 3.95 mmol), Pd(dppf)2Cl2 ( 322.66 mg , 0.40 mmol) and triethylamine (2.00 g, 19.76 mmol, 2.75 mL) were added to methanol (20 mL) and DMF (20 mL) In the reaction flask, the gas in the reaction flask was replaced by N 2 three times, and the gas was replaced by CO three times. The solid was filtered off with a funnel, the organic solvent was collected, methanol was evaporated, and then poured into 80 mL of water to separate out the solid, and the crude product was obtained by suction filtration. MS m/z: 232.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δppm 12.09 (s, 1H) 8.89 (d, J=1.51 Hz, 1H) 8.15 (d, J=1.51 Hz, 1H) 7.82 (s, 1H) 3.92 (s, 3H) 2.58 (q, J=7.53 Hz, 2H) 1.20 (t, J=7.28 Hz, 3H).
步骤6：中间体1f的合成Step 6: Synthesis of Intermediate 1f
0℃条件下，将中间体1e(40mg，172.24μmol)加入THF(5mL)中，再加入LiAlH 4(6.54mg，172.24μmol)，N 2保护，剧烈搅拌，继续反应2小时。缓慢滴加水(0.17mL)，然后缓慢滴加15％NaOH(0.17mL)，最后加入水(0.51mL)淬灭，滴加结束，使用硅藻土过滤掉固体，浓缩滤液得中间体1f。MS m/z：204.9[M+H] +。 1H NMR(400MHz，DMSO-d 6)δppm 11.90(s，1H)8.38(d，J＝1.51Hz，1H)7.74(s，1H)7.62(s，1H)5.46(t，J＝5.52Hz，1H)4.62(d，J＝5.52Hz，2H)2.53-2.58(m，2H)1.19(t，J＝7.28Hz，3H)。 At 0°C, intermediate 1e (40 mg, 172.24 μmol) was added to THF (5 mL), then LiAlH 4 (6.54 mg, 172.24 μmol) was added, protected by N 2 , and the reaction was continued for 2 h with vigorous stirring. Water (0.17 mL) was slowly added dropwise, then 15% NaOH (0.17 mL) was slowly added dropwise, and finally water (0.51 mL) was added to quench. After the dropwise addition was completed, the solid was filtered off using celite, and the filtrate was concentrated to obtain Intermediate 1f. MS m/z: 204.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δppm 11.90 (s, 1H) 8.38 (d, J=1.51 Hz, 1H) 7.74 (s, 1H) 7.62 (s, 1H) 5.46 (t, J=5.52 Hz, 1H) 4.62 (d, J=5.52 Hz, 2H) 2.53-2.58 (m, 2H) 1.19 (t, J=7.28 Hz, 3H).
步骤7：中间体1g的合成Step 7: Synthesis of Intermediate 1g
25℃条件下，将中间体1f(5mg，24.48μmol)加入THF(1mL)和MeOH(2mL)中，分批加入MnO 2(14.90mg，171.38μmol)，继续反应12小时。反应液用漏斗过滤，浓缩滤液得粗品，用DCM∶MeOH＝30∶1进行柱层析得中间体1g。MS m/z：202.7[M+H] +。 1H NMR(400MHz，DMSO-d 6)δppm 12.19(br s，1H)10.16(s，1H)8.93(s，1H)8.05(s，1H)7.87(s，1H)2.57-2.69(m，2H)1.18-1.22(m，3H)。 At 25°C, intermediate 1f (5 mg, 24.48 μmol) was added to THF (1 mL) and MeOH (2 mL), MnO 2 (14.90 mg, 171.38 μmol) was added in portions, and the reaction was continued for 12 hours. The reaction solution was filtered with a funnel, and the filtrate was concentrated to obtain a crude product, which was subjected to column chromatography with DCM:MeOH=30:1 to obtain 1 g of the intermediate. MS m/z: 202.7 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δppm 12.19(br s, 1H) 10.16(s, 1H) 8.93(s, 1H) 8.05(s, 1H) 7.87(s, 1H) 2.57-2.69(m, 2H) ) 1.18-1.22 (m, 3H).
步骤8：中间体1j的合成Step 8: Synthesis of Intermediate 1j
将原料1h(1.08g，4.99mmol)，原料1i(1.0g，4.99mmol)，RuPhos(232.99mg，499.31μmol)，Pd 2(dba) 3(457.22mg，499.31μmol)，Cs 2CO 3(3.25g，9.99mmol)加入甲苯(30mL)中，N 2保护，升温100℃反应5小时。将反应液冷却至室温，用硅藻土过滤，用DCM洗涤，减压蒸干有机相得粗品，经柱层析分离得到目标产物1j。MS m/z：336.0[M+H] +。 1H NMR(400MHz，DMSO-d 6)δppm 8.33(d，J＝2.88Hz，1H)7.89(d，J＝8.88Hz，1H)7.30(dd，J＝9.01，3.00Hz，1H)4.26(br d，J＝6.38Hz，1H)3.90-4.02(m，1H)3.75-3.85(m，4H)3.61-3.71(m，1H)3.22(br d，J＝4.00Hz，1H)3.08(br d，J＝11.51Hz，2H)1.43(s，9H)1.03(d，J＝6.50Hz，3H)。 Starting material 1h (1.08 g, 4.99 mmol), starting material 1i (1.0 g, 4.99 mmol), RuPhos (232.99 mg, 499.31 μmol), Pd2(dba) 3 (457.22 mg, 499.31 μmol), Cs2CO3 ( 3.25 g, 9.99 mmol) was added to toluene (30 mL), protected by N 2 , and the temperature was increased to 100 °C for 5 hours. The reaction solution was cooled to room temperature, filtered through celite, washed with DCM, and the organic phase was evaporated to dryness under reduced pressure to obtain a crude product, which was separated by column chromatography to obtain the target product 1j. MS m/z: 336.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δppm 8.33 (d, J=2.88 Hz, 1H) 7.89 (d, J=8.88 Hz, 1H) 7.30 (dd, J=9.01, 3.00 Hz, 1H) 4.26 (br d, J=6.38Hz, 1H) 3.90-4.02 (m, 1H) 3.75-3.85 (m, 4H) 3.61-3.71 (m, 1H) 3.22 (br d, J=4.00Hz, 1H) 3.08 (br d, J=11.51 Hz, 2H) 1.43 (s, 9H) 1.03 (d, J=6.50 Hz, 3H).
步骤9：中间体1k的合成Step 9: Synthesis of Intermediate 1k
取中间体1j(1g，3.11mmol)室温下加入甲胺乙醇溶液(322.13mg，3.11mmol，30％～34％)，25℃搅拌反应1小时，反应液直接减压旋蒸得粗品，然后在粗品中加入10mL二氯甲烷溶解，加10mL水洗涤，萃取分液收集有机相，有机相使用无水硫酸钠干燥，减压旋蒸，得到中间体1k。MS m/z：335.0[M+H] +。 Take the intermediate 1j (1 g, 3.11 mmol) and add methylamine ethanol solution (322.13 mg, 3.11 mmol, 30%～34%) at room temperature, stir and react at 25°C for 1 hour, the reaction solution is directly decompressed and rotary evaporated to obtain the crude product, and then in The crude product was dissolved in 10 mL of dichloromethane, washed with 10 mL of water, extracted and separated to collect the organic phase, dried over anhydrous sodium sulfate, and rotary-evaporated under reduced pressure to obtain intermediate 1k. MS m/z: 335.0 [M+H] + .
步骤10：中间体1l盐酸盐的合成Step 10: Synthesis of intermediate 1l hydrochloride
25℃条件下，向反应瓶中加入中间体1k(0.28g，0.84mmol)后，再加入HCl/EtOAc(4mol/L，8mL)中，搅拌反应3小时。将反应液直接后处理，反应液经过滤后，将滤液减压旋干，获得中间体1l的盐酸盐。At 25°C, the intermediate 1k (0.28 g, 0.84 mmol) was added to the reaction flask, and then HCl/EtOAc (4 mol/L, 8 mL) was added, and the reaction was stirred for 3 hours. The reaction solution was directly post-treated, and after the reaction solution was filtered, the filtrate was spin-dried under reduced pressure to obtain the hydrochloride salt of intermediate 11.
步骤11：化合物1的三氟乙酸盐的合成Step 11: Synthesis of the trifluoroacetate salt of compound 1
25℃条件下，将中间体1l的盐酸盐(66.95mg，247.27μmol)加入DCM(3mL)中，滴加三乙胺(50.04mg， 494.54μmol，68.83μL)，将上述溶液加入中间体1g(50mg，247.27μmol)的MeOH(3mL)溶液中，滴加少许醋酸调节反应液pH＝5～6，搅拌10min，加入NaBH 3CN(31.08mg，494.54μmol)，继续反应2小时。向反应液滴加0.5mL水，搅拌1小时，蒸除溶剂减压得目标产物粗品，经过制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(0.075％三氟乙酸)-乙腈]；乙腈％：8％-38％，8min)分离得化合物1的三氟乙酸盐。MS m/z：421.0[M+H] +。 1H NMR(400MHz，CD 3OD-d 4)δppm 8.65(d，J＝2.01Hz，1H)8.35(d，J＝2.76Hz，1H)8.01(d，J＝8.78Hz，1H)7.95(d，J＝1.76Hz，1H)7.91(s，1H)7.55(br d，J＝8.28Hz，1H)4.96(br s，2H)4.57(s，2H)3.79(br s，1H)3.58(br d，J＝11.54Hz，1H)3.39-3.51(m，3H)2.96(s，3H)2.67-2.76(m，2H)1.31(t，J＝7.40Hz，3H)1.24(br d，J＝6.78Hz，3H)。 At 25°C, the hydrochloride of intermediate 1l (66.95 mg, 247.27 μmol) was added to DCM (3 mL), triethylamine (50.04 mg, 494.54 μmol, 68.83 μL) was added dropwise, and the above solution was added to intermediate 1 g (50 mg, 247.27 μmol) in MeOH (3 mL) solution, a little acetic acid was added dropwise to adjust the pH of the reaction solution to 5-6, stirred for 10 min, NaBH 3 CN (31.08 mg, 494.54 μmol) was added, and the reaction continued for 2 hours. 0.5 mL of water was added dropwise to the reaction, stirred for 1 hour, and the solvent was evaporated under reduced pressure to obtain the crude product of the target product, which was subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40mm*3 μm; mobile phase: [H 2 O (0.075% triplicate) Fluoroacetic acid)-acetonitrile]; acetonitrile%: 8%-38%, 8min) was isolated to obtain the trifluoroacetic acid salt of compound 1. MS m/z: 421.0 [M+H] + . 1 H NMR (400 MHz, CD 3 OD-d 4 ) δppm 8.65 (d, J=2.01 Hz, 1H) 8.35 (d, J=2.76 Hz, 1H) 8.01 (d, J=8.78 Hz, 1H) 7.95 (d , J=1.76Hz, 1H)7.91(s,1H)7.55(br d,J=8.28Hz,1H)4.96(br s,2H)4.57(s,2H)3.79(br s,1H)3.58(br d , J=11.54Hz, 1H) 3.39-3.51(m, 3H) 2.96(s, 3H) 2.67-2.76(m, 2H) 1.31(t, J=7.40Hz, 3H) 1.24(br d, J=6.78Hz , 3H).
实施例2Example 2
Figure PCTCN2022088181-appb-000117
Figure PCTCN2022088181-appb-000117
步骤1：中间体2b的合成Step 1: Synthesis of Intermediate 2b
0℃条件下，向化合物2a(1g，4.62mmol)的DCM(20mL)溶液中加入咪唑(700.00mg，10.28mmol)，再滴加TBSCl(1.39g，9.25mmol，1.13mL)，升至20℃搅拌16小时。向反应液中加入水(50mL)，再加入二氯甲烷(20mL)萃取两次，合并有机相并用无水硫酸钠干燥后，抽滤减压浓缩得粗品。粗品经柱层析纯化即得中间体2b。MS m/z：331.1[M+1] +。 1H NMR(400MHz，CDCl 3)δppm 3.7-4.01(m，3H)，3.60(br d，J＝4.52Hz，1H)，3.17(d，J＝12.55Hz，1H)，2.82-2.99(m，2H)，2.60-2.79(m，2H)，1.48-1.55(m，1H)，1.42-1.48(m，9H)，0.84-0.92(m，9H)，0.01-0.12(m，6H)。 At 0 °C, imidazole (700.00 mg, 10.28 mmol) was added to a solution of compound 2a (1 g, 4.62 mmol) in DCM (20 mL), followed by dropwise addition of TBSCl (1.39 g, 9.25 mmol, 1.13 mL), and the temperature was increased to 20 °C Stir for 16 hours. Water (50 mL) was added to the reaction solution, and dichloromethane (20 mL) was added for extraction twice. The organic phases were combined and dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain intermediate 2b. MS m/z: 331.1 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δppm 3.7-4.01 (m, 3H), 3.60 (br d, J=4.52 Hz, 1H), 3.17 (d, J=12.55 Hz, 1H), 2.82-2.99 (m, 2H), 2.60-2.79 (m, 2H), 1.48-1.55 (m, 1H), 1.42-1.48 (m, 9H), 0.84-0.92 (m, 9H), 0.01-0.12 (m, 6H).
步骤2：中间体2c的合成Step 2: Synthesis of Intermediate 2c
向化合物2b(3g，9.08mmol)，5-溴-2-甲酯吡啶(1.96g，9.08mmol)的1，4-二氧六环(50mL)溶液中加 入Pd-Xphos-G3(759.10mg，907.61μmol)，Cs 2CO 3(8.87g，27.23mmol)。氮气保护下100℃搅拌16小时。将反应液过滤，滤液经减压浓缩得粗品。粗品经柱层析分离(PE∶EA＝1∶1)得中间体2c。MS m/z：466.1[M+1] +。 To a solution of compound 2b (3 g, 9.08 mmol), 5-bromo-2-methylpyridine (1.96 g, 9.08 mmol) in 1,4-dioxane (50 mL) was added Pd-Xphos-G3 (759.10 mg, 907.61 μmol), Cs2CO3 (8.87 g, 27.23 mmol). Stir at 100°C for 16 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (PE:EA=1:1) to obtain intermediate 2c. MS m/z: 466.1 [M+1] + .
步骤3：化合物2d的合成Step 3: Synthesis of Compound 2d
向化合物2c(3g，6.44mmol)的单口瓶中加入甲胺乙醇溶液(606.32mg，6.44mmol，150mL，33％)，25℃搅拌16小时。减压浓缩得中间体2d。MS m/z：465.1[M+1] +。 Methylamine ethanol solution (606.32 mg, 6.44 mmol, 150 mL, 33%) was added to a single-necked flask of compound 2c (3 g, 6.44 mmol), and the mixture was stirred at 25° C. for 16 hours. Concentrate under reduced pressure to obtain intermediate 2d. MS m/z: 465.1 [M+1] + .
步骤4：中间体2e的合成Step 4: Synthesis of Intermediate 2e
向化合物2d(3g，6.46mmol)的THF(30mL)溶液中加入TBAF(1M，12.91mL)，25℃搅拌16小时。向反应液中加入水(50mL)，加入乙酸乙酯(50mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得粗品。粗品经柱层析分离得中间体2e。MS m/z：351.0[M+1] +。 1H NMR(400MHz，DMSO-d 6)δ＝8.40(br d，J＝4.78Hz，1H)，8.23(d，J＝2.76Hz，1H)，7.83(d，J＝8.78Hz，1H)，7.36(dd，J＝2.76，8.78Hz，1H)，4.95(t，J＝5.52Hz，1H)，3.88-4.07(m，2H)，3.78(br t，J＝14.56Hz，2H)，3.45-3.58(m，1H)，3.08-3.24(m，1H)，3.00(dd，J＝3.76，12.80Hz，1H)，2.82-2.94(m，1H)，2.78(d，J＝4.77Hz，3H)，1.42(s，9H)。 To a solution of compound 2d (3 g, 6.46 mmol) in THF (30 mL) was added TBAF (1 M, 12.91 mL), followed by stirring at 25°C for 16 hours. Water (50 mL) was added to the reaction solution, ethyl acetate (50 mL*3) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was isolated by column chromatography to obtain intermediate 2e. MS m/z: 351.0 [M+1] + . 1 H NMR (400MHz, DMSO-d 6 ) δ=8.40 (br d, J=4.78Hz, 1H), 8.23 (d, J=2.76Hz, 1H), 7.83 (d, J=8.78Hz, 1H), 7.36 (dd, J=2.76, 8.78Hz, 1H), 4.95 (t, J=5.52Hz, 1H), 3.88-4.07 (m, 2H), 3.78 (br t, J=14.56Hz, 2H), 3.45- 3.58(m, 1H), 3.08-3.24(m, 1H), 3.00(dd, J=3.76, 12.80Hz, 1H), 2.82-2.94(m, 1H), 2.78(d, J=4.77Hz, 3H) , 1.42 (s, 9H).
步骤5：中间体2f的盐酸盐的合成Step 5: Synthesis of the hydrochloride salt of intermediate 2f
向化合物2e(0.45g，1.28mmol)的EtOAc(5mL)溶液中加入HCl/EtOAc(4M，5.64mL)，25℃搅拌16小时。减压蒸干溶剂得中间体2f的盐酸盐。MS m/z：250.9[M+1] +。 To a solution of compound 2e (0.45 g, 1.28 mmol) in EtOAc (5 mL) was added HCl/EtOAc (4 M, 5.64 mL), followed by stirring at 25°C for 16 hours. The solvent was evaporated to dryness under reduced pressure to obtain the hydrochloride of intermediate 2f. MS m/z: 250.9 [M+1] + .
步骤6：化合物2的三氟乙酸盐的合成Step 6: Synthesis of the trifluoroacetate salt of compound 2
25℃条件下，向化合物2f的盐酸盐(39.71mg，138.47μmol)的DCM(2mL)溶液中加入三乙胺(7.01mg，69.24μmol，9.64μL)，再向上述溶液中加入1g(14mg，69.24μmol)的MeOH(2mL)溶液，用醋酸调pH至5-6，搅拌15min，继续加入NaBH3CN(8.70mg，138.47μmol)，25℃搅拌16小时。反应液中加入0.5mL水，淬灭后，减压浓缩。送制备HPLC(色谱柱：WelchXtimate C18 100*40mm*3μm；流动相：[H 2O(0.075％三氟乙酸)-乙腈]；乙腈％：7％-37％，8min)分离，减压浓缩得化合物2的三氟乙酸盐。MS m/z：437.0[M+H] +； 1H NMR(400MHz，CD 3OD)δ＝8.64(d，J＝1.64Hz，1H)，8.38(br s，1H)，7.98(br d，J＝8.64Hz，1H)，7.94(s，1H)，7.89(s，1H)，7.52(br d，J＝6.50Hz，1H)，5.11-4.95(m，2H)，4.41(br d，J＝13.26Hz，1H)，4.34(br dd，J＝3.94，12.58Hz，1H)，4.11(br d，J＝13.76Hz，1H)，3.91-4.03(m，2H)，3.69(br d，J＝8.26Hz，1H)，3.38-3.50(m，2H)，3.18-3.29(m，1H)，2.94(s，3H)，2.63-2.75(m，2H)，1.29(t，J＝7.44Hz，3H)。 Triethylamine (7.01 mg, 69.24 μmol, 9.64 μL) was added to a solution of compound 2f hydrochloride (39.71 mg, 138.47 μmol) in DCM (2 mL) at 25°C, and 1 g (14 mg) was added to the above solution. , 69.24 μmol) solution in MeOH (2 mL), adjust the pH to 5-6 with acetic acid, stir for 15 min, continue to add NaBH3CN (8.70 mg, 138.47 μmol), and stir at 25° C. for 16 hours. 0.5 mL of water was added to the reaction solution, and after quenching, it was concentrated under reduced pressure. sent to preparative HPLC (chromatographic column: WelchXtimate C18 100*40mm*3μm; mobile phase: [H 2 O (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile %: 7%-37%, 8min) for separation, and concentrated under reduced pressure to obtain The trifluoroacetate salt of compound 2. MS m/z: 437.0 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ=8.64 (d, J=1.64 Hz, 1H), 8.38 (br s, 1H), 7.98 (br d, J=8.64Hz, 1H), 7.94(s, 1H), 7.89(s, 1H), 7.52(br d, J=6.50Hz, 1H), 5.11-4.95(m, 2H), 4.41(br d, J = 13.26Hz, 1H), 4.34 (br dd, J=3.94, 12.58Hz, 1H), 4.11 (br d, J=13.76Hz, 1H), 3.91-4.03 (m, 2H), 3.69 (br d, J =8.26Hz, 1H), 3.38-3.50(m, 2H), 3.18-3.29(m, 1H), 2.94(s, 3H), 2.63-2.75(m, 2H), 1.29(t, J=7.44Hz, 3H).
步骤7：化合物2A和2B的制备Step 7: Preparation of Compounds 2A and 2B
取化合物2的三氟乙酸盐(20mg)，经手性HPLC制备分离(色谱柱：Chiralpak IE-3 50*4.6mm I.D.，3μm，流动相：A：甲醇(0.05％二乙胺)B：乙腈，等度洗脱：A/B＝50/50，流速：1.0mL/min，柱温：35℃)得到化合物2A和化合物2B。The trifluoroacetic acid salt (20 mg) of compound 2 was taken and separated by chiral HPLC (chromatographic column: Chiralpak IE-3 50*4.6 mm I.D., 3 μm, mobile phase: A: methanol (0.05% diethylamine) B: acetonitrile , isocratic elution: A/B=50/50, flow rate: 1.0 mL/min, column temperature: 35°C) to obtain compound 2A and compound 2B.
化合物2A，Rt＝8.278min，MS m/z：437.1[M+H] +， 1H NMR(400MHz，CD 3OD)δppm 8.53(s，1H)8.30(d，J＝2.76Hz，1H)7.92(d，J＝8.78Hz，1H)7.83(d，J＝12.05Hz，2H)7.38(dd，J＝8.78，2.76Hz，1H)4.61(br s，1H)4.30(d，J＝14.30Hz，1H)3.88-3.97(m，1H)3.70-3.84(m，2H)3.65(d，J＝14.31Hz，1H)3.54(br d，J＝12.55Hz，1H)3.12-3.27(m，2H)2.87-2.99(m，4H)2.77(br s，1H)2.68(q，J＝7.53Hz，2H)2.47-2.57(m，1H)1.28-1.31(m，3H)。 Compound 2A, Rt=8.278 min, MS m/z: 437.1 [M+H] + , 1 H NMR (400 MHz, CD 3 OD) δppm 8.53 (s, 1H) 8.30 (d, J=2.76 Hz, 1H) 7.92 (d, J=8.78Hz, 1H) 7.83 (d, J=12.05Hz, 2H) 7.38 (dd, J=8.78, 2.76Hz, 1H) 4.61 (br s, 1H) 4.30 (d, J=14.30Hz, 1H)3.88-3.97(m,1H)3.70-3.84(m,2H)3.65(d,J=14.31Hz,1H)3.54(br d,J=12.55Hz,1H)3.12-3.27(m,2H)2.87 -2.99(m, 4H) 2.77(br s, 1H) 2.68(q, J=7.53Hz, 2H) 2.47-2.57(m, 1H) 1.28-1.31(m, 3H).
化合物2B，Rt＝10.641min，MS m/z：437.2[M+H] +， 1H NMR(400MHz，CD 3OD)δppm 8.53(s，1H)8.30 (d，J＝2.51Hz，1H)7.92(d，J＝8.78Hz，1H)7.83(d，J＝12.30Hz，2H)7.38(dd，J＝8.78，2.76Hz，1H)4.62(s，1H)4.30(d，J＝14.31Hz，1H)3.89-3.95(m，1H)3.70-3.84(m，2H)3.65(d，J＝14.31Hz，1H)3.54(br d，J＝12.30Hz，1H)3.13-3.27(m，2H)2.87-2.98(m，4H)2.77(br d，J＝3.76Hz，1H)2.68(q，J＝7.53Hz，2H)2.47-2.57(m，1H)1.27-1.31(m，3H)。 Compound 2B, Rt=10.641 min, MS m/z: 437.2 [M+H] + , 1 H NMR (400 MHz, CD 3 OD) δppm 8.53 (s, 1H) 8.30 (d, J=2.51 Hz, 1H) 7.92 (d, J=8.78Hz, 1H) 7.83 (d, J=12.30Hz, 2H) 7.38 (dd, J=8.78, 2.76Hz, 1H) 4.62 (s, 1H) 4.30 (d, J=14.31Hz, 1H) )3.89-3.95(m,1H)3.70-3.84(m,2H)3.65(d,J=14.31Hz,1H)3.54(br d,J=12.30Hz,1H)3.13-3.27(m,2H)2.87- 2.98(m, 4H) 2.77(br d, J=3.76Hz, 1H) 2.68(q, J=7.53Hz, 2H) 2.47-2.57(m, 1H) 1.27-1.31(m, 3H).
实施例3Example 3
Figure PCTCN2022088181-appb-000118
Figure PCTCN2022088181-appb-000118
步骤1：中间体3c的合成Step 1: Synthesis of Intermediate 3c
取原料3a(3g，13.89mmol)加甲苯(30mL)溶解，然后加入原料3b(2.59g，13.89mmol)，RuPhos(648.01mg，1.39mmol)，Pd 2(dba) 3(381.49mg，416.61μmol)，Cs 2CO 3(13.57g，41.66mmol)，氮气氛围下100℃搅拌16小时。将反应液使用硅藻土过滤，滤液减压浓缩得到粗品，粗品经柱层析分离，得到中间体3c。MS m/z：321.9[M+1] +。 Take raw material 3a (3g, 13.89mmol) and add toluene (30mL) to dissolve, then add raw material 3b (2.59g, 13.89mmol), RuPhos (648.01mg, 1.39mmol), Pd 2 (dba) 3 (381.49mg, 416.61μmol) , Cs 2 CO 3 (13.57 g, 41.66 mmol), stirred at 100 °C for 16 hours under nitrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography to obtain intermediate 3c. MS m/z: 321.9 [M+1] + .
步骤2：中间体3d的合成Step 2: Synthesis of Intermediate 3d
25℃条件下，取中间体3c(1g，3.11mmol)加入甲胺(322.13mg，3.11mmol)乙醇溶液，25℃搅拌反应1小时，反应结束后反应液直接减压旋蒸得粗品，然后在粗品中加入10mL二氯甲烷溶解，加10mL水洗涤，萃取分液收集有机相，有机相使用无水硫酸钠干燥，减压旋蒸，得到中间体3d。MS m/z：320.9[M+1] +。 1H NMR(400MHz，CDCl 3)δ8.16(d，J＝2.25Hz，1H)，8.08(d，J＝8.76Hz，1H)，7.85(br s，1H)，7.24(dd，J＝2.50，8.75Hz，1H)，3.56-3.69(m，4H)，3.30(br d，J＝4.63Hz，4H)，3.01(d，J＝5.00Hz，3H)，1.49(s，9H)。 Under the condition of 25°C, take the intermediate 3c (1g, 3.11mmol), add methylamine (322.13mg, 3.11mmol) ethanol solution, and stir the reaction at 25°C for 1 hour. The crude product was dissolved in 10 mL of dichloromethane, washed with 10 mL of water, extracted and separated to collect the organic phase, dried over anhydrous sodium sulfate, and rotary-evaporated under reduced pressure to obtain intermediate 3d. MS m/z: 320.9 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (d, J=2.25 Hz, 1H), 8.08 (d, J=8.76 Hz, 1H), 7.85 (br s, 1H), 7.24 (dd, J=2.50 , 8.75Hz, 1H), 3.56-3.69 (m, 4H), 3.30 (br d, J=4.63Hz, 4H), 3.01 (d, J=5.00Hz, 3H), 1.49 (s, 9H).
步骤3：中间体3e盐酸盐的合成Step 3: Synthesis of Intermediate 3e Hydrochloride
取中间体3d(0.3g，936.37μmol)加入HC1/EtOAc(4M，2.34mL)中，25℃搅拌2小时。将反应液过滤，收集滤饼，使用少量乙酸乙酯洗涤滤饼，然后将滤饼减压蒸干得到中间体3e盐酸盐。MS m/z：220.9[M+1] +。 1H NMR(400MHz，DMSO-d 6)δ9.53(br s，2H)，8.67(br s，1H)，8.33(d，J＝3.01Hz，1H)，8.00(d，J＝8.78Hz，1H)，7.50-7.69(m，1H)，3.44-3.79(m，4H)，3.21(br s，4H)，2.80(d，J＝4.27Hz，3H)。 Intermediate 3d (0.3 g, 936.37 μmol) was added to HCl/EtOAc (4 M, 2.34 mL), and stirred at 25° C. for 2 hours. The reaction solution was filtered, the filter cake was collected, the filter cake was washed with a small amount of ethyl acetate, and then the filter cake was evaporated to dryness under reduced pressure to obtain the intermediate 3e hydrochloride. MS m/z: 220.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.53 (br s, 2H), 8.67 (br s, 1H), 8.33 (d, J=3.01 Hz, 1H), 8.00 (d, J=8.78 Hz, 1H), 7.50-7.69 (m, 1H), 3.44-3.79 (m, 4H), 3.21 (br s, 4H), 2.80 (d, J=4.27Hz, 3H).
步骤4：中间体3h的合成Step 4: Synthesis of Intermediate 3h
将原料3f(1.0g，4.29mmol)，原料3g(1.31g，5.15mmol)，Pd(dppf)Cl 2(313.90mg，429.00μmol)和KOAc(842.06mg，8.58mmol)加入到二氧六环(30mL)中，N 2保护，升温100℃反应6小时.将反应液冷却至室温，加入100mL水，用乙酸乙酯(25mL*3)萃取，合并有机相，无水硫酸钠干燥，浓缩，经柱层析得中间体3h。MS m/z：280.9[M+H] +。 1H NMR(400MHz，CDCl 3)δppm 7.64(dd，J＝9.51，2.50Hz，1H)7.51(dd，J＝8.13，5.88Hz，1H)7.24(td，J＝8.32，2.50Hz，1H)3.94(s，3H)1.43(s，12H)。 Starting material 3f (1.0 g, 4.29 mmol), starting material 3g (1.31 g, 5.15 mmol), Pd(dppf)Cl 2 (313.90 mg, 429.00 μmol) and KOAc (842.06 mg, 8.58 mmol) were added to dioxane ( 30mL), protected by N2 , heated to 100°C and reacted for 6 hours. The reaction solution was cooled to room temperature, 100mL of water was added, extracted with ethyl acetate (25mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to Column chromatography gave the intermediate for 3h. MS m/z: 280.9 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δppm 7.64 (dd, J=9.51, 2.50 Hz, 1H) 7.51 (dd, J=8.13, 5.88 Hz, 1H) 7.24 (td, J=8.32, 2.50 Hz, 1H) 3.94 (s, 3H) 1.43 (s, 12H).
步骤5：中间体3j的合成Step 5: Synthesis of Intermediate 3j
将中间体3h(0.1g，357.02μmol)，原料3i(115.98mg，535.53μmol)，K 3PO 4(151.57mg，714.04μmol)，Pd(dppf)Cl 2(26.12mg，35.70μmol)加入水(0.5mL)和THF(5mL)中，N 2保护，70℃反应3小时。冷却至室温，加10mL乙酸乙酯，用水(10mL*2)洗涤，无水硫酸钠干燥，浓缩得粗品，经柱层析分离得中间体3j。MS m/z：334.9[M+H] +。 Intermediate 3h (0.1 g, 357.02 μmol), starting material 3i (115.98 mg, 535.53 μmol), K3PO4 ( 151.57 mg, 714.04 μmol), Pd(dppf)Cl2 (26.12 mg, 35.70 μmol) were added to water ( 0.5 mL) and THF (5 mL), protected by N2 , and reacted at 70°C for 3 hours. Cool to room temperature, add 10 mL of ethyl acetate, wash with water (10 mL*2), dry over anhydrous sodium sulfate, and concentrate to obtain the crude product, which is separated by column chromatography to obtain intermediate 3j. MS m/z: 334.9 [M+H] + .
步骤6：中间体3k的合成Step 6: Synthesis of Intermediate 3k
将中间体3j(0.2g，0.60mmol)和Pd/C(63.68mg，0.06mmol)加入MeOH(30mL)中，通入H 2，50Psi，升温30℃反应8小时。将Pd/C过滤，浓缩得目标产物，加3ml甲醇打浆，抽滤得中间体3k。MS m/z：272.9[M+H] +。 1H NMR(400MHz，DMSO-d 6)δppm 7.67-9.03(m，6H)3.77(s，3H)。 Intermediate 3j (0.2 g, 0.60 mmol) and Pd/C (63.68 mg, 0.06 mmol) were added to MeOH (30 mL), passed through H 2 , 50 Psi, and heated at 30° C. to react for 8 hours. The Pd/C was filtered and concentrated to obtain the target product, 3 ml of methanol was added to make a slurry, and the intermediate 3k was obtained by suction filtration. MS m/z: 272.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.67-9.03 (m, 6H) 3.77 (s, 3H).
步骤7：中间体3l的合成Step 7: Synthesis of Intermediate 3l
N 2气保护，0℃将中间体3k(20mg，0.07mmol)加入THF(5mL)中，加入LiAlH 4(5.58mg，0.15mmol)，搅拌反应1小时。加0.5mL甲醇淬灭，抽滤，浓缩蒸干得中间体3l。MS m/z：245.0[M+H] +。 Under N2 gas, intermediate 3k (20 mg, 0.07 mmol) was added to THF (5 mL) at 0°C, LiAlH 4 (5.58 mg, 0.15 mmol) was added, and the reaction was stirred for 1 hour. Add 0.5 mL of methanol to quench, filter with suction, concentrate and evaporate to dryness to obtain intermediate 3l. MS m/z: 245.0 [M+H] + .
步骤8：中间体3m的合成Step 8: Synthesis of Intermediate 3m
将中间体3l(20mg，81.89μmol)加入THF(10mL)中，加入MnO 2(106.79mg，1.23mmol)，升温60℃搅拌反应24小时。将反应液冷却至室温，抽滤，浓缩得中间体3m，不经纯化，直接用于下一步反应。MS m/z：242.9[M+H] +。 Intermediate 31 (20 mg, 81.89 μmol) was added to THF (10 mL), MnO 2 (106.79 mg, 1.23 mmol) was added, and the temperature was increased to 60° C. and the reaction was stirred for 24 hours. The reaction solution was cooled to room temperature, filtered with suction, and concentrated to obtain the intermediate 3m, which was directly used in the next reaction without purification. MS m/z: 242.9 [M+H] + .
步骤9：化合物3的三氟乙酸盐的合成Step 9: Synthesis of the trifluoroacetate salt of compound 3
25℃条件下，将3e(31.80mg，123.86μmol)加入DCM(3mL)中，滴加三乙胺(6.27mg，61.93μmol)，将上述溶液加入3m(15mg，61.93μmol)的MeOH(3mL)溶液中，滴加少许醋酸调节反应液pH＝5～6，搅拌10min，加入NaBH3CN(7.78mg，123.86μmol)，继续反应2小时。向反应液滴加0.3mL水，搅拌1小时，将反应液过滤，滤液经减压浓缩得目标产物粗品，经过制备HPLC(色谱柱：WelchXtimate C18 100*40mm*3μm；流动相：[H 2O(0.075％三氟乙酸)-乙腈]；乙腈％：14％-44％，8min)分离得目标化合物3的三氟乙酸盐。MS m/z：447.0[M+H] +。 1H NMR(400MHz，CD 3OD-d 4)δppm 8.94(dd，J＝8.78，5.27Hz，1H)8.70(d，J＝2.01Hz，1H)8.37(d，J＝2.26Hz，1H)8.06(dd，J＝9.03，2.76Hz，1H)7.97(d，J＝8.78Hz，1H)7.89(d，J＝1.76Hz，1H)7.74(td，J＝8.53，2.76Hz，1H)7.49(dd，J＝8.66，2.89Hz，1H)4.61(s，2H)3.34(s，8H)2.93(s，3H)。 At 25°C, 3e (31.80 mg, 123.86 μmol) was added to DCM (3 mL), triethylamine (6.27 mg, 61.93 μmol) was added dropwise, and the above solution was added to 3 m (15 mg, 61.93 μmol) of MeOH (3 mL) In the solution, a little acetic acid was added dropwise to adjust the pH of the reaction solution to 5-6, stirred for 10 min, NaBH3CN (7.78 mg, 123.86 μmol) was added, and the reaction was continued for 2 hours. 0.3 mL of water was added dropwise to the reaction, stirred for 1 hour, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the target product, which was subjected to preparative HPLC (chromatographic column: WelchXtimate C18 100*40mm*3 μm; mobile phase: [H 2 O (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile%: 14%-44%, 8 min) to obtain the trifluoroacetic acid salt of the target compound 3. MS m/z: 447.0 [M+H] + . 1 H NMR (400 MHz, CD 3 OD-d 4 ) δppm 8.94 (dd, J=8.78, 5.27 Hz, 1H) 8.70 (d, J=2.01 Hz, 1H) 8.37 (d, J=2.26 Hz, 1H) 8.06 (dd, J=9.03, 2.76Hz, 1H) 7.97 (d, J=8.78Hz, 1H) 7.89 (d, J=1.76Hz, 1H) 7.74 (td, J=8.53, 2.76Hz, 1H) 7.49 (dd , J=8.66, 2.89Hz, 1H) 4.61 (s, 2H) 3.34 (s, 8H) 2.93 (s, 3H).
实施例4Example 4
Figure PCTCN2022088181-appb-000119
Figure PCTCN2022088181-appb-000119
步骤1：中间体4b的合成Step 1: Synthesis of Intermediate 4b
0℃将化合物4a(3.0g，13.87mmol)，咪唑(1.13g，16.65mmol)加入DCM(30mL)，缓慢滴加TBSCl(2.30g，15.26mmol，1.87mL)，滴毕，升至室温，反应12小时。TLC(DCM∶MeOH＝10∶1)检测原料反应完全，停止继续反应。反应液用2*15mL水洗涤，分液，有机相无水硫酸钠干燥，浓缩得中间体4b。Compound 4a (3.0 g, 13.87 mmol), imidazole (1.13 g, 16.65 mmol) was added to DCM (30 mL) at 0°C, TBSCl (2.30 g, 15.26 mmol, 1.87 mL) was slowly added dropwise, the drop was completed, the temperature was raised to room temperature, and the reaction was carried out. 12 hours. TLC (DCM:MeOH=10:1) detected that the reaction of the raw materials was complete, and the reaction was stopped. The reaction solution was washed with 2*15 mL of water, separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain intermediate 4b.
步骤2：中间体4c的合成Step 2: Synthesis of Intermediate 4c
向中间体4b(2.3g，6.96mmol)的1，4-二氧六环(20mL)溶液中加入5-溴-2-甲酯吡啶(1.65g，7.65mmol)，Pd-Xphos-G3(581.97mg，695.84μmol)，Cs 2CO 3(6.80g，20.88mmol)。氮气保护下100℃搅拌18小时。反应液经硅藻土过滤，再用DCM洗涤，滤液浓缩得粗品。粗品经硅胶柱层析(PE∶EA＝1∶1)纯化得中间体4c MS m/z：466.5[M+1] +。 To a solution of intermediate 4b (2.3 g, 6.96 mmol) in 1,4-dioxane (20 mL) was added 5-bromo-2-methylpyridine (1.65 g, 7.65 mmol), Pd-Xphos-G3 (581.97 mg, 695.84 μmol), Cs2CO3 ( 6.80 g, 20.88 mmol). Stir at 100°C for 18 hours under nitrogen protection. The reaction solution was filtered through celite, washed with DCM, and the filtrate was concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (PE:EA=1:1) to obtain Intermediate 4c MS m/z: 466.5 [M+1] + .
步骤3：中间体4d的合成Step 3: Synthesis of Intermediate 4d
向中间体4c(1.5g，3.22mmol)的单口瓶中加入甲胺乙醇溶液(3.03g，32.21mmol，30mL，33％含量)，25℃搅拌16小时。减压浓缩得中间体4d。MS m/z：465.0[M+1] +。 Methylamine ethanol solution (3.03 g, 32.21 mmol, 30 mL, 33% content) was added to a single-necked flask of Intermediate 4c (1.5 g, 3.22 mmol), and stirred at 25° C. for 16 hours. Concentrate under reduced pressure to obtain intermediate 4d. MS m/z: 465.0 [M+1] + .
步骤4：中间体4e的合成Step 4: Synthesis of Intermediate 4e
向中间体4d(1.4g，3.01mmol)的THF(40mL)溶液中加入TBAF(1M，6.03mL)，25℃搅拌16小时。反应液中加水(100mL)，加入乙酸乙酯(100mL*3)萃取，合并有机相再用饱和氯化钠溶液(150mL*3)洗涤，并用无水硫酸钠干燥，减压浓缩得粗品，得中间体4e。MS m/z：350.9[M+1] +。 To a solution of intermediate 4d (1.4 g, 3.01 mmol) in THF (40 mL) was added TBAF (1 M, 6.03 mL) and stirred at 25°C for 16 hours. Water (100mL) was added to the reaction solution, ethyl acetate (100mL*3) was added for extraction, the organic phases were combined and washed with saturated sodium chloride solution (150mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, Intermediate 4e. MS m/z: 350.9 [M+1] + .
步骤5：中间体4f盐酸盐的合成Step 5: Synthesis of Intermediate 4f Hydrochloride
向中间体4e(0.9g，2.57mmol)的EtOAc(10mL)溶液中加入HCl/EtOAc(4M，20mL)，20℃搅拌1小时。过滤，固体减压浓缩得化合物4f的盐酸盐。MS m/z：250.9[M+1] +。 To a solution of intermediate 4e (0.9 g, 2.57 mmol) in EtOAc (10 mL) was added HCl/EtOAc (4M, 20 mL) and stirred at 20°C for 1 hour. After filtration, the solid was concentrated under reduced pressure to obtain the hydrochloride salt of compound 4f. MS m/z: 250.9 [M+1] + .
步骤6：化合物4的三氟乙酸盐的合成Step 6: Synthesis of the trifluoroacetate salt of compound 4
25℃下向中间体4f盐酸盐(30mg，119.86μmol)的DCM(1mL)溶液中加入三乙胺(12.13mg，119.86μmol，16.68μL)，再向上述溶液中加入中间体1g(48.47mg，119.86μmol)的MeOH(1mL)溶液，用醋酸调pH至5-6，搅拌15min，继续加入NaBH3CN(15.06mg，239.72μmol)，25℃搅拌16小时。反应液中加入0.5mL水，淬灭后，减压浓缩。粗品先经制备TLC(DCM∶MeOH＝20∶1)，再送制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(0.075％三氟乙酸)-乙腈]；乙腈％：8％-38％，8min)分离得化合物4的三氟乙酸盐。MS m/z：437.3[M+1] +， 1H NMR(400MHz，CD 3OD)δ8.65＝(d，J＝2.02Hz，1H)，8.33(d，J＝2.76Hz，1H)，7.94-8.02(m，2H)，7.88(s，1H)，7.52(dd，J＝2.90，8.92Hz，1H)，4.64(d，J＝13.56Hz，1H)，4.33-4.50(m，2H)，3.99(br d，J＝13.56Hz，1H)，3.82-3.90(m，1H)，3.62-3.82(m，4H)，3.33-3.49(m，2H)，2.91-2.98(m，3H)，2.63-2.73(m，2H)，1.29(t，J＝7.40Hz，3H)。 To a solution of intermediate 4f hydrochloride (30 mg, 119.86 μmol) in DCM (1 mL) at 25°C was added triethylamine (12.13 mg, 119.86 μmol, 16.68 μL), and to the above solution was added intermediate 1 g (48.47 mg) , 119.86 μmol) in MeOH (1 mL), adjust pH to 5-6 with acetic acid, stir for 15 min, continue to add NaBH3CN (15.06 mg, 239.72 μmol), and stir at 25° C. for 16 hours. 0.5 mL of water was added to the reaction solution, and after quenching, it was concentrated under reduced pressure. The crude product was first subjected to preparative TLC (DCM:MeOH=20:1), and then to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [H 2 O (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile %: 8%-38%, 8 min) to isolate the trifluoroacetic acid salt of compound 4. MS m/z: 437.3 [M+1] + , 1 H NMR (400 MHz, CD 3 OD) δ 8.65=(d, J=2.02 Hz, 1H), 8.33 (d, J=2.76 Hz, 1H), 7.94-8.02 (m, 2H), 7.88 (s, 1H), 7.52 (dd, J=2.90, 8.92Hz, 1H), 4.64 (d, J=13.56Hz, 1H), 4.33-4.50 (m, 2H) , 3.99(br d, J=13.56Hz, 1H), 3.82-3.90(m, 1H), 3.62-3.82(m, 4H), 3.33-3.49(m, 2H), 2.91-2.98(m, 3H), 2.63-2.73 (m, 2H), 1.29 (t, J=7.40Hz, 3H).
步骤7：化合物4A和4B的制备Step 7: Preparation of Compounds 4A and 4B
取化合物4的三氟乙酸盐(20mg)，经手性HPLC制备分离(色谱柱：Chiralcel OD-3 100*4.6mm I.D.，3μm；流动相：A：CO 2 B：MeOH(0.05％二乙胺)；等度洗脱：40％B；流速：2.8mL/min；柱温：35℃；压力：1500psi)得到化合物4A和化合物4B。 The trifluoroacetic acid salt (20 mg) of compound 4 was taken and separated by chiral HPLC preparative separation (chromatographic column: Chiralcel OD-3 100*4.6 mm ID, 3 μm; mobile phase: A: CO 2 B: MeOH (0.05% diethylamine) ); isocratic elution: 40% B; flow rate: 2.8 mL/min; column temperature: 35° C.; pressure: 1500 psi) to obtain compound 4A and compound 4B.
化合物4A，Rt＝1.853min，MS m/z：437.2[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 8.47(d，J＝1.38Hz，1H)8.19(br d，J＝2.25Hz，1H)7.72-7.85(m，3H)7.25-7.33(m，1H)4.05-4.17(m，1H)3.98(br d，J＝12.26Hz，1H)3.82(br dd，J＝10.82，6.44Hz，1H)3.71(br d，J＝12.88Hz，1H)3.61(br dd，J＝10.94，4.69Hz，1H)3.29-3.40(m，2H)3.25(br s，2H)2.83(s，2H)2.81-2.86(m，1H)2.68-2.81(m，2H)2.57(q，J＝7.25Hz，2H)1.19(t，J＝7.44Hz，3H)。 Compound 4A, Rt = 1.853 min, MS m/z: 437.2 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.47 (d, J=1.38 Hz, 1H) 8.19 (br d, J=2.25 Hz, 1H) 7.72-7.85 (m, 3H) 7.25-7.33 (m, 1H) 4.05-4.17(m, 1H) 3.98(br d, J=12.26Hz, 1H) 3.82(br dd, J=10.82, 6.44Hz, 1H) 3.71(br d, J=12.88Hz, 1H) 3.61(br dd, J=10.82, 6.44Hz, 1H) , J=10.94, 4.69Hz, 1H) 3.29-3.40(m, 2H) 3.25(br s, 2H) 2.83(s, 2H) 2.81-2.86(m, 1H) 2.68-2.81(m, 2H) 2.57(q , J=7.25Hz, 2H) 1.19 (t, J=7.44Hz, 3H).
化合物4B，Rt＝2.532min，MS m/z：437.0[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 8.40(d，J＝1.25Hz，1H)8.16(br d，J＝2.25Hz，1H)7.66-7.82(m，3H)7.19-7.28(m，1H)3.98(br s，1H)3.84-3.91(m，1H)3.61-3.69(m，2H)3.54-3.60(m，2H)3.05-3.18(m，2H)2.91(br d，J＝10.13Hz，1H)2.83(s，3H)2.56(q，J＝7.30Hz，2H)2.29(br d，J＝14.01Hz，2H)1.18(t，J＝7.38Hz，3H)。 Compound 4B, Rt = 2.532 min, MS m/z: 437.0 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.40 (d, J=1.25 Hz, 1H) 8.16 (br d, J=2.25 Hz, 1H) 7.66-7.82 (m, 3H) 7.19-7.28 (m, 1H) 3.98(br s, 1H) 3.84-3.91(m, 1H) 3.61-3.69(m, 2H) 3.54-3.60(m, 2H) 3.05-3.18(m, 2H) 2.91(br d, J=10.13Hz, 1H ) 2.83(s, 3H) 2.56(q, J=7.30Hz, 2H) 2.29(br d, J=14.01Hz, 2H) 1.18(t, J=7.38Hz, 3H).
实施例5Example 5
Figure PCTCN2022088181-appb-000120
Figure PCTCN2022088181-appb-000120
步骤1：中间体5d盐酸盐的合成Step 1: Synthesis of Intermediate 5d Hydrochloride
0℃将1f(0.15g，734.49μmol)加入DCM(5mL)，滴加SOCl 2(436.91mg，3.67mmol，266.41μL)，1滴DMF，升温25℃反应2小时。LCMS检测原料反应完全，停止继续反应。减压除有机溶剂，得目标产物5d盐酸盐。MS m/z：222.8[M+1] +。 1f (0.15 g, 734.49 μmol) was added to DCM (5 mL) at 0° C., SOCl 2 (436.91 mg, 3.67 mmol, 266.41 μL) and 1 drop of DMF were added dropwise, and the temperature was increased to 25° C. to react for 2 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The organic solvent was removed under reduced pressure to obtain the target product 5d hydrochloride. MS m/z: 222.8 [M+1] + .
步骤2：中间体5a的合成Step 2: Synthesis of Intermediate 5a
0℃将中间体4e(0.3g，856.14μmol)加入DCM(10mL)中，加入三乙胺(216.58mg，2.14mmol，297.91μL)，甲烷磺酰氯(147.11mg，1.28mmol，99.40μL)，反应1小时。TLC(DCM∶MeOH＝20∶1)检测原料反应完全，停止继续反应。用3*10mL水洗有机层，合并有机相浓缩得到中间体5a。Intermediate 4e (0.3 g, 856.14 μmol) was added to DCM (10 mL) at 0°C, triethylamine (216.58 mg, 2.14 mmol, 297.91 μL), methanesulfonyl chloride (147.11 mg, 1.28 mmol, 99.40 μL) were added to react 1 hour. TLC (DCM:MeOH=20:1) detected that the reaction of the raw materials was complete, and the reaction was stopped and continued. The organic layer was washed with 3*10 mL of water, and the combined organic phases were concentrated to obtain intermediate 5a.
MS m/z：429.0[M+1] +。 MS m/z: 429.0 [M+1] + .
步骤3：中间体5b的合成Step 3: Synthesis of Intermediate 5b
将中间体5a(368.51mg，0.86mmol)，NaCN(210.73mg，4.30mmol)加入DMF(10mL)中，100℃反应10小时.向反应液加入50mL水，用3*15mL乙酸乙酯进行萃取，合并有机相，无水硫酸钠干燥，浓缩，柱层析得中间体5b。MS m/z：360.0[M+1] +。 Intermediate 5a (368.51 mg, 0.86 mmol), NaCN (210.73 mg, 4.30 mmol) were added to DMF (10 mL), and reacted at 100°C for 10 hours. 50 mL of water was added to the reaction solution, and extracted with 3*15 mL of ethyl acetate, The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain intermediate 5b. MS m/z: 360.0 [M+1] + .
步骤4：中间体5c的盐酸盐的合成Step 4: Synthesis of the hydrochloride salt of intermediate 5c
25℃，将中间体5b(0.15g，417.34μmol)加入HCl/EtOAc(5mL)中，搅拌反应1小时。减压蒸出溶剂得中 间体5c的盐酸盐。MS m/z：259.9[M+1] +。 1H NMR(400MHz，DMSO-d 6)δppm 9.56-9.76(m，2H)8.55(br d，J＝4.77Hz，1H)8.37(d，J＝2.76Hz，1H)7.93(d，J＝8.78Hz，1H)7.58(dd，J＝8.78，3.01Hz，1H)4.84(br s，1H)3.88(br d，J＝14.31Hz，1H)3.02-3.38(m，6H)2.80(d，J＝4.52Hz，3H)。 Intermediate 5b (0.15 g, 417.34 μmol) was added to HCl/EtOAc (5 mL) at 25° C. and the reaction was stirred for 1 hour. The solvent was evaporated under reduced pressure to obtain the hydrochloride of intermediate 5c. MS m/z: 259.9 [M+1] + . 1 H NMR (400MHz, DMSO-d 6 ) δppm 9.56-9.76 (m, 2H) 8.55 (br d, J=4.77Hz, 1H) 8.37 (d, J=2.76Hz, 1H) 7.93 (d, J=8.78 Hz, 1H) 7.58(dd, J=8.78, 3.01Hz, 1H) 4.84(br s, 1H) 3.88(br d, J=14.31Hz, 1H) 3.02-3.38(m, 6H) 2.80(d, J= 4.52Hz, 3H).
步骤5：化合物5的三氟乙酸盐的合成Step 5: Synthesis of the trifluoroacetate salt of compound 5
25℃将中间体5c盐酸盐(26.57mg，89.82μmol)，KI(2.98mg，17.96μmol)和K 2CO 3(37.24mg，269.46μmol)加入DMF(5mL)中，加入中间体5d(20mg，89.82μmol)，升温80℃，继续搅拌2小时。将反应液冷却至室温，过滤，经过制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(0.075％三氟乙酸)-乙腈]；乙腈％：11％-41％，8min)分离得化合物5的三氟乙酸盐。MS m/z：446.0[M+1] +。 1H-NMR(400MHz，CD 3OD)δppm 8.62(d，J＝1.76Hz，1H)8.37(d，J＝3.01Hz，1H)8.00(d，J＝8.78Hz，1H)7.98(s，1H)7.88(s，1H)7.56(dd，J＝8.91，2.89Hz，1H)4.62(br s，1H)3.87-4.05(m，2H)3.74(br d，J＝13.05Hz，1H)3.37(s，2H)3.18(br d，J＝11.54Hz，2H)3.01-3.12(m，1H)2.96(s，3H)2.84(dd，J＝16.81，6.02Hz，1H)2.68-2.78(m，3H)1.31(t，J＝7.53Hz，3H)。 Intermediate 5c hydrochloride (26.57 mg, 89.82 μmol), KI (2.98 mg, 17.96 μmol) and K2CO3 (37.24 mg , 269.46 μmol) were added to DMF (5 mL) at 25°C, intermediate 5d (20 mg) was added , 89.82 μmol), the temperature was increased to 80 °C, and the stirring was continued for 2 hours. The reaction solution was cooled to room temperature, filtered, and subjected to preparative HPLC (column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [H 2 O(0.075% trifluoroacetic acid)-acetonitrile]; % acetonitrile: 11%-41 %, 8 min) to obtain the trifluoroacetic acid salt of compound 5. MS m/z: 446.0 [M+1] + . 1 H-NMR (400 MHz, CD 3 OD) δppm 8.62 (d, J=1.76 Hz, 1H) 8.37 (d, J=3.01 Hz, 1H) 8.00 (d, J=8.78 Hz, 1H) 7.98 (s, 1H) ) 7.88(s, 1H) 7.56(dd, J=8.91, 2.89Hz, 1H) 4.62(br s, 1H) 3.87-4.05(m, 2H) 3.74(br d, J=13.05Hz, 1H) 3.37(s , 2H) 3.18(br d, J=11.54Hz, 2H) 3.01-3.12(m, 1H) 2.96(s, 3H) 2.84(dd, J=16.81, 6.02Hz, 1H) 2.68-2.78(m, 3H) 1.31 (t, J=7.53 Hz, 3H).
步骤6：化合物5A和5B的制备Step 6: Preparation of Compounds 5A and 5B
取化合物5的三氟乙酸盐(20mg)，经手性HPLC制备分离(色谱柱：Chiralcel OJ-3 100*4.6mm I.D.，3μm；流动相：A：CO 2 B：甲醇(0.05％二乙胺)；梯度洗脱：4min B从5％升到40％，40％B保持2.5min，然后5％B保持1.5min；流速：2.8mL/min；柱温：35℃；压力：1500psi)得到化合物5A和化合物5B。 The trifluoroacetic acid salt (20 mg) of compound 5 was taken and separated by chiral HPLC (chromatographic column: Chiralcel OJ-3 100*4.6 mm ID, 3 μm; mobile phase: A: CO 2 B: methanol (0.05% diethylamine) ); gradient elution: 4min B increased from 5% to 40%, 40% B kept 2.5min, then 5%B kept 1.5min; flow rate: 2.8mL/min; column temperature: 35°C; pressure: 1500psi) to obtain the compound 5A and Compound 5B.
化合物5A，Rt＝5.072min，MS m/z：445.9[M+H] +， 1H NMR(400MHz，CD 3OD)δppm 8.52(d，J＝1.38Hz，1H)8.33(d，J＝2.75Hz，1H)7.94(d，J＝8.88Hz，1H)7.84(d，J＝8.63Hz，2H)7.43(dd，J＝8.88，2.75Hz，1H)4.57(br s，1H)3.67-3.85(m，3H)3.24-3.31(m，1H)3.02-3.13(m，3H)2.95(s，3H)2.77(dd，J＝16.70，5.57Hz，1H)2.68(q，J＝7.46Hz，2H)2.52(br dd，J＝11.76，2.75Hz，1H)2.36-2.47(m，1H)1.30(t，J＝7.44Hz，3H)。 Compound 5A, Rt=5.072 min, MS m/z: 445.9 [M+H] + , 1 H NMR (400 MHz, CD 3 OD) δppm 8.52 (d, J=1.38 Hz, 1 H) 8.33 (d, J=2.75 Hz, 1H) 7.94(d, J=8.88Hz, 1H) 7.84(d, J=8.63Hz, 2H) 7.43(dd, J=8.88, 2.75Hz, 1H) 4.57(br s, 1H) 3.67-3.85( m, 3H) 3.24-3.31 (m, 1H) 3.02-3.13 (m, 3H) 2.95 (s, 3H) 2.77 (dd, J=16.70, 5.57Hz, 1H) 2.68 (q, J=7.46Hz, 2H) 2.52 (br dd, J=11.76, 2.75Hz, 1H) 2.36-2.47 (m, 1H) 1.30 (t, J=7.44Hz, 3H).
化合物5B，Rt＝4.428min，MS m/z：446.0[M+H] +， 1H NMR(400MHz，CD 3OD)δppm 8.53(d，J＝1.63Hz，1H)8.33(d，J＝2.75Hz，1H)7.95(d，J＝8.75Hz，1H)7.84(d，J＝9.01Hz，2H)7.44(dd，J＝8.88，2.88Hz，1H)4.54-4.64(m，2H)3.80-3.86(m，1H)3.70(br d，J＝13.88Hz，2H)3.02-3.13(m，3H)2.95(s，3H)2.78(dd，J＝16.63，5.63Hz，1H)2.69(q，J＝7.38Hz，2H)2.53(br dd，J＝11.94，2.94Hz，1H)2.38-2.47(m，1H)1.30(t，J＝7.44Hz，3H). Compound 5B, Rt=4.428 min, MS m/z: 446.0 [M+H] + , 1 H NMR (400 MHz, CD 3 OD) δppm 8.53 (d, J=1.63 Hz, 1H) 8.33 (d, J=2.75 Hz, 1H) 7.95 (d, J=8.75Hz, 1H) 7.84 (d, J=9.01Hz, 2H) 7.44 (dd, J=8.88, 2.88Hz, 1H) 4.54-4.64 (m, 2H) 3.80-3.86 (m, 1H) 3.70 (br d, J=13.88Hz, 2H) 3.02-3.13 (m, 3H) 2.95 (s, 3H) 2.78 (dd, J=16.63, 5.63Hz, 1H) 2.69 (q, J= 7.38Hz, 2H) 2.53(br dd, J=11.94, 2.94Hz, 1H) 2.38-2.47(m, 1H) 1.30(t, J=7.44Hz, 3H).
实施例6Example 6
Figure PCTCN2022088181-appb-000121
Figure PCTCN2022088181-appb-000121
步骤1：中间体6b的合成Step 1: Synthesis of Intermediate 6b
取化合物6a1(286.46mg，2.24mmol)溶于无水THF(3mL)中，-78℃加入LiHMDS(1M，5.22mL)，搅拌20min，然后加入化合物6a(0.3g，1.49mmol)的THF(2mL)溶液搅拌一会后升温至25℃，继续搅拌16小时。LCMS显示反应原料基本反应完全，剩余较少的中间态加少量甲醇继续搅拌6h，反应停止，反应液直接减压旋蒸得到粗品，粗品使用硅胶柱层析分离纯化(梯度洗脱：DCM∶MeOH＝50∶1～20∶1)分离得到中间体6b。MS m/z：266.7[M+1] +。 1H NMR(400MHz，DMSO-d 6)：δ11.96(br s，1H)，8.49(d，J＝1.76Hz，1H)，7.79(d，J＝1.76Hz，1H)，7.40(s，1H)，2.13(br t，J＝5.27Hz，1H)，0.98(br dd，J＝2.26，8.28Hz，2H)，0.81-0.89(m，2H)。 Dissolve compound 6a1 (286.46 mg, 2.24 mmol) in anhydrous THF (3 mL), add LiHMDS (1 M, 5.22 mL) at -78°C, stir for 20 min, and then add compound 6a (0.3 g, 1.49 mmol) in THF (2 mL) ) solution was stirred for a while, then the temperature was raised to 25°C, and stirring was continued for 16 hours. LCMS showed that the reaction of the raw materials was basically complete, and a small amount of methanol was added to the remaining intermediate state to continue stirring for 6 h, the reaction was stopped, and the reaction solution was directly evaporated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (gradient elution: DCM:MeOH =50:1～20:1) to isolate intermediate 6b. MS m/z: 266.7[M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.96 (br s, 1H), 8.49 (d, J=1.76 Hz, 1H), 7.79 (d, J=1.76 Hz, 1H), 7.40 (s, 1H), 2.13 (br t, J=5.27Hz, 1H), 0.98 (br dd, J=2.26, 8.28Hz, 2H), 0.81-0.89 (m, 2H).
步骤2：中间体6c的合成Step 2: Synthesis of Intermediate 6c
-78℃氮气保护下，将n-BuLi(2.5M，301.77μL)缓慢加入6b(0.04g，150.88μmol)的THF(3mL)中，搅拌0.5h，加入N，N-二甲基甲酰胺(44.11mg，603.53μmol，46.44μL)搅拌反应1.5小时，LCMS显示原料基本反应完全，停止反应，加1mL NH 4Cl水淬灭反应，然后用3mol/L盐酸调节为中性，用乙酸乙酯(3*5mL)萃取，干燥浓缩得到粗品。粗品经薄层色谱分离(DCM∶MeOH＝20∶1)纯化得到中间体6c。MS m/z：214.9[M+1] +。 1H NMR(400MHz，CD 3OD)δ10.13(s，1H)，8.90(s，1H)，8.09(s，1H)，7.71(s，1H)，2.22-2.30(m，1H)，1.13(br dd，J＝2.13，8.41Hz，2H)，0.90(br d，J＝4.77Hz，2H)。 Under nitrogen protection at -78°C, n-BuLi (2.5M, 301.77 μL) was slowly added to 6b (0.04 g, 150.88 μmol) in THF (3 mL), stirred for 0.5 h, and N,N-dimethylformamide ( 44.11 mg, 603.53 μmol, 46.44 μL) stirred and reacted for 1.5 hours, LCMS showed that the reaction of the raw materials was basically complete, the reaction was stopped, and 1 mL of NH 4 Cl water was added to quench the reaction, then adjusted to neutral with 3 mol/L hydrochloric acid, and ethyl acetate ( 3*5mL) extraction, drying and concentration to obtain crude product. The crude product was purified by thin layer chromatography (DCM:MeOH=20:1) to give intermediate 6c. MS m/z: 214.9 [M+1] + . 1 H NMR (400 MHz, CD 3 OD) δ 10.13 (s, 1H), 8.90 (s, 1H), 8.09 (s, 1H), 7.71 (s, 1H), 2.22-2.30 (m, 1H), 1.13 (br dd, J=2.13, 8.41 Hz, 2H), 0.90 (br d, J=4.77 Hz, 2H).
步骤3：化合物6的三氟乙酸盐的合成Step 3: Synthesis of the trifluoroacetate salt of compound 6
25℃下取6c(30.85mg，140.04μmol)加入DCM(1mL)溶解，滴加TEA(14.17mg，140.04μmol，19.49μL)调节反应为碱性将上述溶液加入到3e(30mg，140.04μmol)的MeOH(1mL)溶液中，然后滴加少许醋酸调节反应液pH＝5-6，搅拌10min，加入NaBH 3CN(17.60mg，280.09μmol)，继续反应16小时。LCMS检测原料反应完全，停止反应，向反应液滴加1mL水，搅拌1小时，抽滤得到滤液，滤液蒸干得目标产物粗品。粗品经薄层色谱(DCM∶MeOH＝20∶1)分离纯化得到粗产物，粗品使用制备HPLC(方法为色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(0.075％三氟乙酸)-乙腈]；乙腈％：8％-38％，8min)分离得到化合物6的三氟乙酸盐。MS m/z：419.0[M+1] +。 1H NMR(400MHz，CDCl 3)δ8.61(d，J＝1.76Hz，1H)，8.36(d，J＝2.51Hz，1H)，7.99(d，J＝8.78Hz，1H)，7.94(d，J＝1.51Hz，1H)，7.55(dd，J＝2.76，9.03Hz，1H)，7.52(s，1H)，4.60(s，2H)，3.69(br s，3H)，3.53(br d，J＝4.52Hz，4H)，3.31-3.32(m，1H)，2.94(s，3H)，2.23(s，1H)，1.05-1.16(m，2H)，0.76-0.95(m，2H)。 6c (30.85 mg, 140.04 μmol) was added to DCM (1 mL) to dissolve at 25°C, TEA (14.17 mg, 140.04 μmol, 19.49 μL) was added dropwise to adjust the reaction to be basic, and the above solution was added to 3e (30 mg, 140.04 μmol). In MeOH (1 mL) solution, a little acetic acid was added dropwise to adjust the pH of the reaction solution to 5-6, stirred for 10 min, NaBH 3 CN (17.60 mg, 280.09 μmol) was added, and the reaction was continued for 16 hours. LCMS detected that the reaction of the raw materials was complete, the reaction was stopped, 1 mL of water was added dropwise to the reaction, stirred for 1 hour, suction filtered to obtain a filtrate, and the filtrate was evaporated to dryness to obtain the crude product of the target product. The crude product was separated and purified by thin layer chromatography (DCM:MeOH=20:1) to obtain the crude product. The crude product was subjected to preparative HPLC (method: chromatographic column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [H 2 O (0.075% triplicate) Fluoroacetic acid)-acetonitrile]; acetonitrile %: 8%-38%, 8 min) was isolated to give compound 6 as a trifluoroacetic acid salt. MS m/z: 419.0 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.61 (d, J=1.76 Hz, 1H), 8.36 (d, J=2.51 Hz, 1H), 7.99 (d, J=8.78 Hz, 1H), 7.94 (d , J=1.51Hz, 1H), 7.55(dd, J=2.76, 9.03Hz, 1H), 7.52(s, 1H), 4.60(s, 2H), 3.69(br s, 3H), 3.53(br d, J=4.52Hz, 4H), 3.31-3.32 (m, 1H), 2.94 (s, 3H), 2.23 (s, 1H), 1.05-1.16 (m, 2H), 0.76-0.95 (m, 2H).
步骤4：化合物6游离碱合成Step 4: Compound 6 free base synthesis
将化合物6c(0.5g，2.33mmol)、化合物3e(752.76mg，2.57mmol)、三乙胺(519.60mg，5.13mmol，714.72uL)加入到DCM(10mL)中，用冰乙酸调节反应液pH＝5，25℃搅拌反应1小时，降温至0℃，分批加入NaBH(OAc) 3(1.48g，7.00mmol)，25℃反应1小时。向反应液中加入20mL水，用2*20mL二氯甲烷萃取，合并有机相，20mL饱和食盐水洗涤，干燥、过滤、浓缩得粗品，用柱层析(DCM∶MeOH＝50∶1)纯化得到化合物6。MS m/z：419.0[M+1] +。 1H NMR(400MHz，DMSO-d 6)δppm 11.88(s，1H)，8.38-8.40(m，2H)，8.27(d，J＝1.6Hz，1H)，7.83(d，J＝2.4Hz，1H)，7.61(s，1H)，7.42(s，1H)，7.40(dd，J＝2.76，9.03Hz，1H)，3.65(s，2H)，3.28(br s，4H)，2.78(d，J＝4.52Hz，3H)，2.54(br s，4H)，2.14-2.18(m，1H)，0.95-0.99(m，2H)，0.82-0.84(m，2H)。 Compound 6c (0.5 g, 2.33 mmol), compound 3e (752.76 mg, 2.57 mmol), triethylamine (519.60 mg, 5.13 mmol, 714.72 uL) were added to DCM (10 mL), and the pH of the reaction solution was adjusted with glacial acetic acid= 5. The reaction was stirred at 25 °C for 1 hour, cooled to 0 °C, NaBH(OAc) 3 (1.48 g, 7.00 mmol) was added in batches, and the reaction was carried out at 25 °C for 1 hour. 20 mL of water was added to the reaction solution, extracted with 2*20 mL of dichloromethane, the organic phases were combined, washed with 20 mL of saturated brine, dried, filtered and concentrated to obtain the crude product, which was purified by column chromatography (DCM:MeOH=50:1) to obtain Compound 6. MS m/z: 419.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) δppm 11.88 (s, 1H), 8.38-8.40 (m, 2H), 8.27 (d, J=1.6 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H) ), 7.61(s, 1H), 7.42(s, 1H), 7.40(dd, J=2.76, 9.03Hz, 1H), 3.65(s, 2H), 3.28(br s, 4H), 2.78(d, J = 4.52 Hz, 3H), 2.54 (br s, 4H), 2.14-2.18 (m, 1H), 0.95-0.99 (m, 2H), 0.82-0.84 (m, 2H).
实施例7Example 7
Figure PCTCN2022088181-appb-000122
Figure PCTCN2022088181-appb-000122
步骤1：中间体7b的合成Step 1: Synthesis of Intermediate 7b
氮气保护下，将中间体1h(100mg，462.89μmol)，中间体7a(81.89mg，385.75μmol)，RuPhos(18.00mg，38.57μmol)，Pd 2(dba) 3(35.32mg，38.57μmol)，Cs 2CO 3(377.05mg，1.16mmol)，加入甲苯(30mL)中，升温100℃反应5小时。TLC(DCM∶MEOH＝20∶1)检测原料反应完全，有新点生成。将反应液冷却至室温，用硅藻土抽滤，用二氯甲烷洗涤，将有机相合并减压旋干得到中间体7b。MS m/z：348.1[M+H] +。 Under nitrogen protection, intermediate 1h (100 mg, 462.89 μmol), intermediate 7a (81.89 mg, 385.75 μmol), RuPhos (18.00 mg, 38.57 μmol), Pd 2 (dba) 3 (35.32 mg, 38.57 μmol), Cs 2 CO 3 (377.05 mg, 1.16 mmol) was added to toluene (30 mL), and the temperature was increased to 100° C. to react for 5 hours. TLC (DCM:MEOH=20:1) detected that the reaction of the raw materials was complete, and new spots were formed. The reaction solution was cooled to room temperature, suction filtered through celite, washed with dichloromethane, and the organic phases were combined and spin-dried under reduced pressure to obtain intermediate 7b. MS m/z: 348.1 [M+H] + .
步骤2：中间体7c的合成Step 2: Synthesis of Intermediate 7c
向反应瓶中加入中间体7b(600mg，1.73mmol)后，继续加入甲胺(1g，32.20mmol，5mL)和EtOH(5mL)后，至于25℃搅拌3小时。LCMS显示原料完全进行反应，将反应液直接减压旋干，获得到中间体7c。MS m/z 347.1[M+H] +。 Intermediate 7b (600 mg, 1.73 mmol) was added to the reaction flask, methylamine (1 g, 32.20 mmol, 5 mL) and EtOH (5 mL) were further added, and the mixture was stirred at 25°C for 3 hours. LCMS showed that the raw materials were completely reacted, and the reaction solution was directly spin-dried under reduced pressure to obtain intermediate 7c. MS m/z 347.1 [M+H] + .
步骤3：中间体7d盐酸盐的合成Step 3: Synthesis of Intermediate 7d Hydrochloride
向反应瓶中加入中间体7c(0.150g，433.00μmol)后，继续加入HCl/EtOAc(4M，5mL)，在25℃下搅拌3小时。LCMS显示原料完全反应，有目标产物生成。将反应液直接后处理，反应液经过滤后，将滤液减压旋干，获得中间体7d的盐酸盐。After intermediate 7c (0.150 g, 433.00 μmol) was added to the reaction flask, HCl/EtOAc (4 M, 5 mL) was further added, and the mixture was stirred at 25° C. for 3 hours. LCMS showed complete reaction of starting material with formation of target product. The reaction solution was directly post-treated. After the reaction solution was filtered, the filtrate was spin-dried under reduced pressure to obtain the hydrochloride of intermediate 7d.
步骤4：化合物7的三氟乙酸盐的合成Step 4: Synthesis of the trifluoroacetate salt of compound 7
25℃将中间体7d(14mg，49.45μmol)加入DCM(3mL)中，滴加TEA(10.01mg，98.91μmol，13.77μL)，将上述溶液加入中间体1g(10mg，49.45μmol)的MeOH(3mL)溶液中，滴加少许醋酸调节反应液pH＝5-6，搅拌10min，加入NaBH 3CN(6.22mg，98.91μmol)，继续反应2小时。LCMS检测原料反应完全，停止继续反应。将反应液冷却至室温，过滤，经过制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(0.075％三氟乙酸)-乙腈]；乙腈％：10％-40％，8min)分离得化合物7的三氟乙酸盐。MS m/z：433.1[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 8.55(s，1H)8.35(br s，1H)7.98(d，J＝9.03Hz，1H)7.86(d，J＝8.28Hz，2H)7.49(br d，J＝8.78Hz，1H)4.47(br s，2H)3.65(br s，2H)3.50(s，2H)2.97(s，3H)2.66-2.74(m，2H)2.06(br s，1H)1.62(br s，1H)1.35(br s，3H)1.03(br s，2H)0.94(br s，2H)。 Intermediate 7d (14 mg, 49.45 μmol) was added to DCM (3 mL) at 25°C, TEA (10.01 mg, 98.91 μmol, 13.77 μL) was added dropwise, and the above solution was added to intermediate 1 g (10 mg, 49.45 μmol) in MeOH (3 mL). ) solution, a little acetic acid was added dropwise to adjust the pH of the reaction solution to 5-6, stirred for 10 min, NaBH 3 CN (6.22 mg, 98.91 μmol) was added, and the reaction was continued for 2 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was cooled to room temperature, filtered, and subjected to preparative HPLC (column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [H 2 O(0.075% trifluoroacetic acid)-acetonitrile]; % acetonitrile: 10%-40 %, 8 min) to obtain the trifluoroacetic acid salt of compound 7. MS m/z: 433.1 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δppm 8.55(s, 1H) 8.35(br s, 1H) 7.98(d, J=9.03Hz, 1H) 7.86(d, J=8.28Hz, 2H) 7.49(br d , J=8.78Hz, 1H) 4.47(br s, 2H) 3.65(br s, 2H) 3.50(s, 2H) 2.97(s, 3H) 2.66-2.74(m, 2H) 2.06(br s, 1H) 1.62 (br s, 1H) 1.35 (br s, 3H) 1.03 (br s, 2H) 0.94 (br s, 2H).
实施例8Example 8
Figure PCTCN2022088181-appb-000123
Figure PCTCN2022088181-appb-000123
步骤1：化合物8的三氟乙酸盐的合成Step 1: Synthesis of the trifluoroacetate salt of compound 8
25℃下取6c(11.68mg，46.68μmol)加入DCM(1mL)溶解，滴加TEA(4.72mg，46.68μmol，6.50μL)调节反应为碱性将上述溶液加入到2f(10mg，46.68μmol)的MeOH(1mL)溶液中，然后滴加少许醋酸调节反应液pH＝5-6，搅拌10min，加入NaBH 3CN(5.87mg，93.36μmol)，继续反应16小时。LCMS检测原料反应完全，停止反应，向反应液滴加1mL水，搅拌1小时，抽滤得到滤液，滤液蒸干得目标产物粗品。粗品经薄层色谱(DCM∶MeOH＝20∶1)分离纯化得到粗品，粗品使用制备HPLC分离(色谱柱：Welch Xtimate C18100*40mm*3μm；流动相：[H 2O(0.075％三氟乙酸)-乙腈]；乙腈％：8％-38％，8min)分离，得到化合物8的三氟乙酸盐。MS m/z：449.1[M+H] +。 1H NMR(400MHz，CDCl 3)δ8.61(s，1H)，8.37(br s，1H)，7.93-8.03(m，1H)，7.90(s，1H)，7.53(s，1H)，7.50(br s，1H)，4.22-4.44(m，2H)，4.09(br d，J＝13.55Hz，1H)，3.85-4.01(m，2H)，3.65(br d，J＝7.28Hz，1H)，3.40-3.53(m，2H)，3.39(br s，2H)，3.23(br s，1H)，2.94(br s，3H)，2.23(br s，1H)，1.02-1.19(m，2H)，0.87(br d，J＝3.76Hz，2H)。 6c (11.68 mg, 46.68 μmol) was added to DCM (1 mL) at 25°C to dissolve, TEA (4.72 mg, 46.68 μmol, 6.50 μL) was added dropwise to adjust the reaction to be alkaline, and the above solution was added to 2f (10 mg, 46.68 μmol). In MeOH (1 mL) solution, a little acetic acid was added dropwise to adjust the pH of the reaction solution to 5-6, stirred for 10 min, NaBH 3 CN (5.87 mg, 93.36 μmol) was added, and the reaction was continued for 16 hours. LCMS detected that the reaction of the raw materials was complete, the reaction was stopped, 1 mL of water was added dropwise to the reaction, stirred for 1 hour, suction filtered to obtain a filtrate, and the filtrate was evaporated to dryness to obtain the crude product of the target product. The crude product was separated and purified by thin layer chromatography (DCM:MeOH=20:1) to obtain the crude product, which was separated by preparative HPLC (chromatographic column: Welch Xtimate C18100*40mm*3μm; mobile phase: [H 2 O (0.075% trifluoroacetic acid)] -acetonitrile]; acetonitrile %: 8%-38%, 8 min) was isolated to give compound 8 as a trifluoroacetate salt. MS m/z: 449.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.61 (s, 1H), 8.37 (br s, 1H), 7.93-8.03 (m, 1H), 7.90 (s, 1H), 7.53 (s, 1H), 7.50 (br s, 1H), 4.22-4.44 (m, 2H), 4.09 (br d, J=13.55Hz, 1H), 3.85-4.01 (m, 2H), 3.65 (br d, J=7.28Hz, 1H) , 3.40-3.53(m, 2H), 3.39(br s, 2H), 3.23(br s, 1H), 2.94(br s, 3H), 2.23(br s, 1H), 1.02-1.19(m, 2H) , 0.87 (br d, J=3.76Hz, 2H).
步骤2：化合物8A和8B的制备Step 2: Preparation of Compounds 8A and 8B
取化合物8的三氟乙酸盐(20mg)，经手性HPLC制备分离(色谱柱：Chiralpak IE-3 50*4.6mmI.D.，3μm；流动相：MeOH(0.05％二乙胺)；流速：1.0mL/min；柱温：35℃)得到化合物8A和化合物8B。The trifluoroacetic acid salt (20 mg) of compound 8 was taken and separated by chiral HPLC (chromatographic column: Chiralpak IE-3 50*4.6 mmI.D., 3 μm; mobile phase: MeOH (0.05% diethylamine); flow rate: 1.0 mL/min; column temperature: 35° C.) to obtain compound 8A and compound 8B.
化合物8A，Rt＝8.019min，MS m/z：449.1[M+H] +， 1H NMR(400MHz，CD 3OD)δppm 8.50(d，J＝1.76Hz，1H)8.30(d，J＝2.76Hz，1H)7.92(d，J＝8.78Hz，1H)7.80(s，1H)7.51(s，1H)7.38(dd，J＝8.78，3.01Hz，1H)4.60(s，1H)4.29(d，J＝14.31Hz，1H)3.88-3.95(m，1H)3.79(dd，J＝11.29，6.53Hz，1H)3.73(dd，J＝12.30，2.76Hz，1H)3.64(d，J＝14.31Hz，1H)3.50-3.58(m，1H)3.13-3.28(m，2H)2.95(s，3H)2.86-2.94(m，1H)2.77(td，J＝7.09，3.64Hz，1H)2.51(ddd，J＝11.86，8.85，3.14Hz，1H)1.05-1.13(m，2H)0.81-0.87(m，2H)。 Compound 8A, Rt=8.019 min, MS m/z: 449.1 [M+H] + , 1 H NMR (400 MHz, CD 3 OD) δppm 8.50 (d, J=1.76 Hz, 1 H) 8.30 (d, J=2.76 Hz, 1H) 7.92(d, J=8.78Hz, 1H) 7.80(s, 1H) 7.51(s, 1H) 7.38(dd, J=8.78, 3.01Hz, 1H) 4.60(s, 1H) 4.29(d, J=14.31Hz, 1H) 3.88-3.95 (m, 1H) 3.79 (dd, J=11.29, 6.53Hz, 1H) 3.73 (dd, J=12.30, 2.76Hz, 1H) 3.64 (d, J=14.31Hz, 1H) 3.50-3.58 (m, 1H) 3.13-3.28 (m, 2H) 2.95 (s, 3H) 2.86-2.94 (m, 1H) 2.77 (td, J=7.09, 3.64Hz, 1H) 2.51 (ddd, J = 11.86, 8.85, 3.14 Hz, 1H) 1.05-1.13 (m, 2H) 0.81-0.87 (m, 2H).
化合物8B，Rt＝9.138min，MS m/z：449.1[M+H] +， 1H NMR(400MHz，CD 3OD)δppm 8.38(d，J＝1.51Hz，1H)8.19(d，J＝2.76Hz，1H)7.80(d，J＝9.03Hz，1H)7.68(s，1H)7.39(s，1H)7.27(dd，J＝8.78，2.76Hz，1H)4.49(br s，1H)4.17(d，J＝14.31Hz，1H)3.77-3.83(m，1H)3.67(dd，J＝11.29，6.53Hz，1H)3.57-3.64(m，1H)3.52(d，J＝14.31Hz，1H)3.38-3.47(m，1H)3.01-3.16(m，2H)2.83(s，3H)2.74-2.82(m，1H)2.65(td，J＝7.03，3.76Hz，1H)2.39(ddd，J＝11.92，8.91，3.26Hz，1H)0.94-1.00(m，2H)0.69-0.74(m，2H)。 Compound 8B, Rt=9.138 min, MS m/z: 449.1 [M+H] + , 1 H NMR (400 MHz, CD 3 OD) δppm 8.38 (d, J=1.51 Hz, 1H) 8.19 (d, J=2.76 Hz, 1H) 7.80(d, J=9.03Hz, 1H) 7.68(s, 1H) 7.39(s, 1H) 7.27(dd, J=8.78, 2.76Hz, 1H) 4.49(br s, 1H) 4.17(d , J=14.31Hz, 1H) 3.77-3.83 (m, 1H) 3.67 (dd, J=11.29, 6.53Hz, 1H) 3.57-3.64 (m, 1H) 3.52 (d, J=14.31Hz, 1H) 3.38- 3.47 (m, 1H) 3.01-3.16 (m, 2H) 2.83 (s, 3H) 2.74-2.82 (m, 1H) 2.65 (td, J=7.03, 3.76Hz, 1H) 2.39 (ddd, J=11.92, 8.91 , 3.26Hz, 1H) 0.94-1.00 (m, 2H) 0.69-0.74 (m, 2H).
实施例9Example 9
Figure PCTCN2022088181-appb-000124
Figure PCTCN2022088181-appb-000124
步骤1：化合物9b的合成Step 1: Synthesis of Compound 9b
取化合物9a(3g，13.64mmol)溶于MeOH(30mL)中，缓慢滴加SOCl 2(8.11g，68.18mmol，4.95mL)，然后升温至70℃搅拌反应3小时，LCMS显示原料转化完全，反应停止，反应结束后，反应液直接减压旋蒸得到产物9b。MS m/z：236.0[M+H] +。 1H NMR(400MHz，CD 3OD)δ8.61(d，J＝1.00Hz，1H)，8.09-8.18(m，1H)，3.97(s，3H)。 Compound 9a (3 g, 13.64 mmol) was dissolved in MeOH (30 mL), SOCl 2 (8.11 g, 68.18 mmol, 4.95 mL) was slowly added dropwise, then the temperature was raised to 70° C. and stirred for 3 hours. LCMS showed that the conversion of the raw materials was complete, and the reaction After the reaction was completed, the reaction solution was directly rotary-evaporated under reduced pressure to obtain the product 9b. MS m/z: 236.0 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δ 8.61 (d, J=1.00 Hz, 1H), 8.09-8.18 (m, 1H), 3.97 (s, 3H).
步骤2：化合物9c的合成Step 2: Synthesis of Compound 9c
将9b(3g，12.82mmol)溶于甲苯(80mL)中，然后加入3b(2.87g，15.38mmol)，RuPhos(598.20mg，1.28mmol)，Pd 2(dba) 3(586.94mg，640.96μmol)，Cs 2CO 3(12.53g，38.46mmol)氮气氛围下100℃搅拌16小时，LCMS显示原料转化完全，将反应液使用硅藻土过滤，滤液减压浓缩得到粗品，粗品使用硅胶柱层析分离纯化(梯度洗脱：PE∶EA＝10∶1～1∶1)分离得到产物9c。MS m/z：340.0[M+H] +。 1H NMR(400MHz，CDCl 3)δ8.01-8.30(m，1H)，6.81(dd，J＝2.26，13.55Hz，1H)，3.97(s，3H)，3.62(br s，4H)，3.38(br d，J＝5.52Hz，4H)，1.49(s，9H)。 9b (3 g, 12.82 mmol) was dissolved in toluene (80 mL), then 3b (2.87 g, 15.38 mmol), RuPhos (598.20 mg, 1.28 mmol), Pd2(dba )3 ( 586.94 mg, 640.96 μmol) were added, Cs 2 CO 3 (12.53 g, 38.46 mmol) was stirred at 100° C. for 16 hours under nitrogen atmosphere. LCMS showed that the conversion of the raw materials was complete. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography. (Gradient elution: PE:EA=10:1-1:1) The product 9c was isolated. MS m/z: 340.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.01-8.30 (m, 1H), 6.81 (dd, J=2.26, 13.55 Hz, 1H), 3.97 (s, 3H), 3.62 (br s, 4H), 3.38 (br d, J=5.52 Hz, 4H), 1.49 (s, 9H).
步骤3：化合物9d的合成Step 3: Synthesis of Compound 9d
取9c(2.2g，6.48mmol)室温下溶于EtOH(20mL)中，加入甲胺的乙醇溶液(6.71g，64.83mmol，317.19μL，30％含量)，25℃搅拌反应16小时，LCMS显示原料反应完全，反应结束后，减压蒸除有机溶剂得粗品，然后向粗品中加入30mL二氯甲烷溶解，加20mL水洗涤，萃取分液收集有机相，有机相使用无水硫酸钠干燥，减压旋蒸得到9d。MS m/z：338.9[M+H] +。 1H NMR(400MHz，CDCl 3)δppm 7.99(d，J＝1.51Hz，1H)，7.51-7.67(m，1H)，6.83(dd，J＝2.38，13.68Hz，1H)，3.52-3.64(m，4H)，3.29-3.38(m，4H)，2.98(d，J＝5.02Hz，3H)，1.48(s，9H)。 Dissolve 9c (2.2 g, 6.48 mmol) in EtOH (20 mL) at room temperature, add methylamine ethanol solution (6.71 g, 64.83 mmol, 317.19 μL, 30% content), and stir the reaction at 25°C for 16 hours, LCMS shows the raw material The reaction was complete, after the reaction was completed, the organic solvent was evaporated under reduced pressure to obtain the crude product, then 30 mL of dichloromethane was added to the crude product to dissolve, 20 mL of water was added to wash, the organic phase was collected by extraction and separation, and the organic phase was dried with anhydrous sodium sulfate and reduced under reduced pressure. 9d was obtained by rotary evaporation. MS m/z: 338.9 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δppm 7.99 (d, J=1.51 Hz, 1H), 7.51-7.67 (m, 1H), 6.83 (dd, J=2.38, 13.68 Hz, 1H), 3.52-3.64 (m , 4H), 3.29-3.38 (m, 4H), 2.98 (d, J=5.02Hz, 3H), 1.48 (s, 9H).
步骤4：化合物9e盐酸盐的合成Step 4: Synthesis of Compound 9e Hydrochloride
将HCl/EtOAc(4M，8.77mL)加入9d(2.0g，5.91mmol)的EtOAc(10mL)中，25℃搅拌反应。LCMS检测原料反应完全，停止继续反应。将反应液过滤得目标产物9e的盐酸盐。MS m/z：238.9[M+H] +。 1H NMR(400MHz，DMSO-d 6)δppm 8.33(br s，1H)8.19(s，1H)7.34(dd，J＝14.56，2.26Hz，1H)3.61-3.68(m，4H)3.20(br s，4H)2.75(br d，J＝3.51Hz，3H)。 HCl/EtOAc (4M, 8.77 mL) was added to 9d (2.0 g, 5.91 mmol) in EtOAc (10 mL) and the reaction was stirred at 25°C. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was filtered to obtain the hydrochloride of the target product 9e. MS m/z: 238.9 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δppm 8.33 (br s, 1H) 8.19 (s, 1H) 7.34 (dd, J=14.56, 2.26 Hz, 1H) 3.61-3.68 (m, 4H) 3.20 (br s) , 4H) 2.75 (br d, J=3.51 Hz, 3H).
步骤5：化合物9的盐酸盐的合成Step 5: Synthesis of the hydrochloride salt of compound 9
25℃将9e盐酸盐(34.99mg，127.35μmol)，KI(3.84mg，23.15μmol)和K 2CO 3(48.00mg，347.31μmol)加入DMF(4mL)中，加入5d(30mg，115.77μmol)，升温50℃，继续搅拌2小时。LCMS检测原料反应完全，停止继续反应。将反应液冷却至室温，加40mL水，用3*10mL DCM萃取，合并有机层，无水硫酸钠干燥，经制备HPLC(色谱柱：Xtimate C18 150*40mm*5μm；流动相：[H 2O(HCl)-乙腈]；乙腈％：5％-35％，10min)分离得化合物9的盐酸盐。m/z：447.0[M+Na] +。 1H NMR(400MHz，CD 3OD)δppm 9.02(d，J＝1.25Hz，1H)8.65(s，1H)8.37(s，1H)7.98(s，1H)7.73(dd，J＝13.55，2.01Hz，1H)4.99-5.13(m，2H)4.82(s，2H)3.80-4.11(m，2H)3.65(br s，4H)2.99(s，3H)2.74-2.84(m，2H)1.34(t，J＝7.40Hz，3H)。 9e hydrochloride (34.99 mg, 127.35 μmol), KI (3.84 mg, 23.15 μmol) and K2CO3 (48.00 mg , 347.31 μmol) were added to DMF (4 mL) at 25°C, 5d (30 mg, 115.77 μmol) was added , the temperature was increased to 50 °C, and the stirring was continued for 2 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was cooled to room temperature, 40 mL of water was added, extracted with 3*10 mL of DCM, the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to preparative HPLC (chromatographic column: Xtimate C18 150*40 mm*5 μm; mobile phase: [H 2 O] (HCl)-acetonitrile]; acetonitrile %: 5%-35%, 10 min) to isolate the hydrochloride salt of compound 9. m/z: 447.0 [M+Na] + . 1 H NMR (400 MHz, CD 3 OD) δppm 9.02 (d, J=1.25 Hz, 1H) 8.65 (s, 1H) 8.37 (s, 1H) 7.98 (s, 1H) 7.73 (dd, J=13.55, 2.01 Hz , 1H)4.99-5.13(m,2H)4.82(s,2H)3.80-4.11(m,2H)3.65(br s,4H)2.99(s,3H)2.74-2.84(m,2H)1.34(t, J=7.40Hz, 3H).
实施例10Example 10
Figure PCTCN2022088181-appb-000125
Figure PCTCN2022088181-appb-000125
步骤1：化合物10b的合成Step 1: Synthesis of Compound 10b
0℃将SOCl 2(7.55g，63.44mmol，4.60mL)滴加至10a(5.0g，21.15mmol)的MeOH(50mL)中，65℃反应1小时。LCMS检测原料反应完全，停止进行反应。蒸除有机溶剂得目标产物10b。MS m/z：251.7[M+H] +。 SOCl 2 (7.55 g, 63.44 mmol, 4.60 mL) was added dropwise to 10a (5.0 g, 21.15 mmol) in MeOH (50 mL) at 0°C, and reacted at 65°C for 1 hour. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The organic solvent was evaporated to obtain the target product 10b. MS m/z: 251.7 [M+H] + .
步骤2：化合物10c的合成Step 2: Synthesis of Compound 10c
将3b(1g，5.37mmol)，10b(1.34g，5.37mmol)，RuPhos(250.54mg，536.91μmol)，Pd 2(dba) 3(491.66mg，536.91μmol)和Cs 2CO 3(3.50g，10.74mmol)加入甲苯(30mL)中，N 2保护，升温100℃反应12小时。LCMS检测原料反应完全，停止继续反应。将反应液冷却至室温，过滤反应液，旋干滤液，经柱层析(EA∶PE＝1∶1)得到10c。MS m/z：356.0[M+H] +。 3b (1 g, 5.37 mmol), 10b (1.34 g, 5.37 mmol), RuPhos (250.54 mg, 536.91 μmol), Pd2(dba) 3 (491.66 mg, 536.91 μmol) and Cs2CO3 ( 3.50 g , 10.74 mmol) was added to toluene (30 mL), protected by N 2 , and the temperature was increased to 100 °C to react for 12 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was cooled to room temperature, the reaction solution was filtered, the filtrate was spin-dried, and 10c was obtained by column chromatography (EA:PE=1:1). MS m/z: 356.0 [M+H] + .
步骤3：化合物10d的合成Step 3: Synthesis of Compound 10d
25℃将10c(0.4g，1.12mmol)加入甲胺的乙醇溶液中(173.92mg，5.60mmol)溶液中，搅拌反应12小时。LCMS检测原料反应完全，停止继续反应。蒸除有机溶剂得目标产物10d。MS m/z：354.9[M+H] +。 10c (0.4 g, 1.12 mmol) was added to a solution of methylamine in ethanol (173.92 mg, 5.60 mmol) at 25°C and the reaction was stirred for 12 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The organic solvent was evaporated to obtain the target product 10d. MS m/z: 354.9 [M+H] + .
步骤4：化合物10e盐酸盐的合成Step 4: Synthesis of Compound 10e Hydrochloride
25℃将10d(387.63mg，1.09mmol)，HCl/EtOAc(4M，1.09mL)加入EtOAc(5mL)中，升温40℃反应12小时。LCMS检测原料反应完全，停止继续反应。将反应液抽滤、收集滤饼、干燥得目标产物10e的盐酸盐。MS m/z：254.9[M+H] +。 10d (387.63 mg, 1.09 mmol), HCl/EtOAc (4M, 1.09 mL) were added to EtOAc (5 mL) at 25°C, and the temperature was increased to 40°C to react for 12 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was suction filtered, the filter cake was collected, and dried to obtain the hydrochloride of the target product 10e. MS m/z: 254.9 [M+H] + .
步骤5：化合物10的三氟乙酸盐的合成Step 5: Synthesis of the trifluoroacetate salt of compound 10
25℃将10e的盐酸盐(37.08mg，127.35μmol)，KI(3.84mg，23.15μmol)和K 2CO 3(48.00mg，347.31μmol)加入DMF(4mL)中，加入5d(30mg，115.77μmol)，升温50℃，继续搅拌2小时。LCMS检测原料反应完全，停止继续反应。将反应液冷却至室温，加40mL水，用3*10mL DCM萃取，合并有机层，无水硫酸钠干燥，经制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(三氟乙酸)-乙腈]；乙腈％：10％-40％，8min)分离得化合物10的三氟乙酸盐。m/z：441.3[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 8.64(d，J＝1.76Hz，1H)8.29(d，J＝2.26Hz，1H)7.87-7.96(m，2H)7.51(d，J＝2.51Hz，1H)4.61(s，2H)3.49-3.77(m，8H)2.92(s，3H)2.71(q，J＝7.19Hz，2H)1.31(t，J＝7.53Hz，3H)。 10e hydrochloride (37.08 mg, 127.35 μmol), KI (3.84 mg, 23.15 μmol) and K 2 CO 3 (48.00 mg, 347.31 μmol) were added to DMF (4 mL) at 25°C, 5d (30 mg, 115.77 μmol) was added ), the temperature was increased to 50°C, and the stirring was continued for 2 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was cooled to room temperature, 40 mL of water was added, extracted with 3*10 mL of DCM, the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [H 2 O(trifluoroacetic acid)-acetonitrile]; acetonitrile%: 10%-40%, 8 min) was isolated to obtain the trifluoroacetic acid salt of compound 10. m/z: 441.3 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.64 (d, J=1.76 Hz, 1H) 8.29 (d, J=2.26 Hz, 1H) 7.87-7.96 (m, 2H) 7.51 (d, J=2.51 Hz, 1H) 4.61 (s, 2H) 3.49-3.77 (m, 8H) 2.92 (s, 3H) 2.71 (q, J=7.19 Hz, 2H) 1.31 (t, J=7.53 Hz, 3H).
实施例11Example 11
Figure PCTCN2022088181-appb-000126
Figure PCTCN2022088181-appb-000126
步骤1：化合物11a的合成Step 1: Synthesis of Compound 11a
取6c(847.52mg，3.96mmol)溶于MeOH(10mL)中，加入NaBH 4(374.19mg，9.89mmol)，室温25℃搅拌2h，LCMS显示原料反应完全，反应停止，反应液加2mL水淬灭，然后反应液减压旋蒸得到粗品，粗品使用硅胶柱层析(DCM∶MeOH＝20∶1)纯化得到产物，得到11a。MSm/z：217.2M+H] +。 1H NMR(400MHz，DMSO-d 6)δ8.35(d，J＝1.76Hz，1H)，7.59(s，1H)，7.40(s，1H)，5.45(t，J＝5.65Hz，1H)，4.60(d，J＝5.52Hz，2H)，2.13(s，1H)，0.96(dd，J＝2.38，8.41Hz，2H)，0.75-0.86(m，2H)。 Dissolve 6c (847.52 mg, 3.96 mmol) in MeOH (10 mL), add NaBH 4 (374.19 mg, 9.89 mmol), stir at room temperature 25 ° C for 2 h, LCMS shows that the reaction of the raw materials is complete, the reaction stops, the reaction solution is quenched by adding 2 mL of water , and then the reaction solution was rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain the product to obtain 11a. MS m/z: 217.2M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.35 (d, J=1.76 Hz, 1H), 7.59 (s, 1H), 7.40 (s, 1H), 5.45 (t, J=5.65 Hz, 1H) , 4.60 (d, J=5.52 Hz, 2H), 2.13 (s, 1H), 0.96 (dd, J=2.38, 8.41 Hz, 2H), 0.75-0.86 (m, 2H).
步骤2：化合物11b的合成Step 2: Synthesis of Compound 11b
0℃将11a(0.5g，2.31mmol)加入DCM(10mL)，滴加SOCl 2(1.65g，13.87mmol，1.01mL)，滴加1滴DMF，升温25℃反应2小时，LCMS检测目标产物反应生成，停止反应，减压浓缩得目标产物11b。MS m/z：234.8[M+H] +。 11a (0.5 g, 2.31 mmol) was added to DCM (10 mL) at 0 °C, SOCl 2 (1.65 g, 13.87 mmol, 1.01 mL) was added dropwise, 1 drop of DMF was added dropwise, the temperature was increased to 25 °C and the reaction was performed for 2 hours. LCMS detected the reaction of the target product formed, the reaction was stopped, and the target product 11b was obtained by concentrating under reduced pressure. MS m/z: 234.8 [M+H] + .
步骤3：化合物11的三氟乙酸盐的合成Step 3: Synthesis of the trifluoroacetate salt of compound 11
25℃将9e(33.44mg，121.71μmol)，KI(3.67mg，22.13μmol)和K 2CO 3(45.88mg，331.93μmol)加入DMF(4mL)中，加入11b(30mg，110.64μmol)，升温50℃，继续搅拌2小时。LCMS检测原料反应完全，停止继续反应。将反应液冷却至室温，加40mL水，用3*10mL DCM萃取，合并有机层，无水硫酸钠干燥，经制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(三氟乙酸)-乙腈]；乙腈％：8％-38％，8min)分离得化合物11的三氟乙酸盐。m/z：437.1[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 8.60(d， J＝2.01Hz，1H)8.23(s，1H)7.89(d，J＝1.51Hz，1H)7.55(s，1H)7.26(dd，J＝13.93，2.13Hz，1H)4.56(s，2H)3.71(br s，2H)3.48(br s，4H)3.37(s，2H)2.93(s，3H)2.21-2.30(m，1H)1.10-1.17(m，2H)0.87-0.93(m，2H)。 9e (33.44 mg, 121.71 μmol), KI (3.67 mg, 22.13 μmol) and K 2 CO 3 (45.88 mg, 331.93 μmol) were added to DMF (4 mL) at 25°C, 11b (30 mg, 110.64 μmol) was added, and the temperature was increased to 50 °C, stirring was continued for 2 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was cooled to room temperature, 40 mL of water was added, extracted with 3*10 mL of DCM, the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [H 2 O(trifluoroacetic acid)-acetonitrile]; acetonitrile %: 8%-38%, 8 min) was isolated to obtain the trifluoroacetic acid salt of compound 11. m/z: 437.1 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.60 (d, J=2.01 Hz, 1H) 8.23 (s, 1H) 7.89 (d, J=1.51 Hz, 1H) 7.55 (s, 1H) 7.26 (dd, J = 13.93, 2.13Hz, 1H) 4.56(s, 2H) 3.71(br s, 2H) 3.48(br s, 4H) 3.37(s, 2H) 2.93(s, 3H) 2.21-2.30(m, 1H) 1.10- 1.17 (m, 2H) 0.87-0.93 (m, 2H).
实施例12Example 12
Figure PCTCN2022088181-appb-000127
Figure PCTCN2022088181-appb-000127
步骤1：化合物12的三氟乙酸盐的合成Step 1: Synthesis of the trifluoroacetate salt of compound 12
25℃将10e(35.44mg，121.70μmol)，KI(3.67mg，22.13μmol)和K 2CO 3(45.88mg，331.92μmol)加入DMF(4mL)中，加入11b(30mg，110.64μmol)，升温50℃，继续搅拌2小时。LCMS检测原料反应完全，停止继续反应。将反应液冷却至室温，加40mL水，用3*10mL DCM萃取，合并有机层，无水硫酸钠干燥，经制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(三氟乙酸)-乙腈]；乙腈％：10％-40％，8min)分离得化合物12的三氟乙酸盐。m/z：475.1[M+Na] +。 1H NMR(400MHz，CD 3OD)δppm 8.61(s，1H)8.29(d，J＝2.01Hz，1H)7.91(s，1H)7.48-7.58(m，2H)4.60(s，2H)3.69-3.52(m，8H)2.92(s，3H)2.19-2.30(m，1H)1.09-1.18(m，2H)0.86-0.94(m，2H)。 10e (35.44 mg, 121.70 μmol), KI (3.67 mg, 22.13 μmol) and K 2 CO 3 (45.88 mg, 331.92 μmol) were added to DMF (4 mL) at 25°C, 11b (30 mg, 110.64 μmol) was added, and the temperature was increased to 50 °C, stirring was continued for 2 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was cooled to room temperature, 40 mL of water was added, extracted with 3*10 mL of DCM, the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [H 2 O(trifluoroacetic acid)-acetonitrile]; acetonitrile%: 10%-40%, 8 min) was isolated to obtain the trifluoroacetic acid salt of compound 12. m/z: 475.1[M+Na] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.61 (s, 1H) 8.29 (d, J=2.01 Hz, 1H) 7.91 (s, 1H) 7.48-7.58 (m, 2H) 4.60 (s, 2H) 3.69- 3.52 (m, 8H) 2.92 (s, 3H) 2.19-2.30 (m, 1H) 1.09-1.18 (m, 2H) 0.86-0.94 (m, 2H).
实施例13Example 13
Figure PCTCN2022088181-appb-000128
Figure PCTCN2022088181-appb-000128
步骤1：化合物13的三氟乙酸盐的合成Step 1: Synthesis of the trifluoroacetate salt of compound 13
25℃下取1l(87.50mg，373.45μmol)加入DCM(5mL)溶解，滴加TEA(37.79mg，373.45μmol，51.98μL)调节反应为碱性将上述溶液加入到6c(0.2g，373.45μmol)的MeOH(5mL)溶液中，然后滴加少许醋酸调节反应液pH＝5-6，搅拌10min，加入NaBH 3CN(46.94mg，746.90μmol)，继续反应16小时。LCMS检测原料反应完全，停止继续反应。向反应液滴加1mL水，搅拌1小时，抽滤得到滤液，滤液蒸干得目标产物粗品。经柱层析(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(三氟乙酸)-乙腈]；乙腈％：10％-40％，8min)分离得化合物13的三氟乙酸盐。MS m/z：433.1[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 8.61(d，J＝2.01Hz，1H)8.32(br s，1H)7.96-8.01(m，1H)7.94(d，J＝1.51Hz，1H)7.51(s，1H)7.46-7.51(m，1H)4.55(s，2H)4.36(br s，1H)3.78(br d，J＝12.30Hz，1H)3.58(br d，J＝11.80Hz，1H)3.46(br d，J＝2.01Hz，2H)3.38-3.44 (m，1H)3.35-3.38(m，1H)2.94(s，3H)2.14-2.27(m，1H)1.22(br d，J＝6.78Hz，3H)1.11(dd，J＝8.41，2.13Hz，2H)0.87(dd，J＝5.14，1.88Hz，2H)。 1l (87.50mg, 373.45μmol) was added to DCM (5mL) to dissolve at 25°C, TEA (37.79mg, 373.45μmol, 51.98μL) was added dropwise to adjust the reaction to alkaline, the above solution was added to 6c (0.2g, 373.45μmol) In the solution of MeOH (5 mL), a little acetic acid was added dropwise to adjust the pH of the reaction solution to 5-6, stirred for 10 min, NaBH 3 CN (46.94 mg, 746.90 μmol) was added, and the reaction was continued for 16 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. 1 mL of water was added dropwise to the reaction, stirred for 1 hour, suction filtered to obtain a filtrate, and the filtrate was evaporated to dryness to obtain the crude product of the target product. Through column chromatography (chromatographic column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [H 2 O (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 10%-40%, 8min), the triplicate of compound 13 was obtained. Fluoroacetate. MS m/z: 433.1 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.61 (d, J=2.01 Hz, 1H) 8.32 (br s, 1H) 7.96-8.01 (m, 1H) 7.94 (d, J=1.51 Hz, 1H) 7.51 ( s,1H)7.46-7.51(m,1H)4.55(s,2H)4.36(br s,1H)3.78(br d,J=12.30Hz,1H)3.58(br d,J=11.80Hz,1H)3.46 (br d, J=2.01Hz, 2H) 3.38-3.44 (m, 1H) 3.35-3.38 (m, 1H) 2.94 (s, 3H) 2.14-2.27 (m, 1H) 1.22 (br d, J=6.78Hz , 3H) 1.11 (dd, J=8.41, 2.13 Hz, 2H) 0.87 (dd, J=5.14, 1.88 Hz, 2H).
步骤2：化合物13A和13B的制备Step 2: Preparation of Compounds 13A and 13B
取化合物13的三氟乙酸盐(20mg)，经手性HPLC制备分离(色谱柱：Chiralcel OJ-3 100*4.6mm I.D.，3μm；流动相：A：CO 2 B：甲醇(0.05％二乙胺)；梯度洗脱：4min B从5％升到40％，40％B保持2.5min，然后5％B保持1.5min；流速：2.8mL/min；柱温：35℃；压力：1500psi)得到化合物13A和化合物13B。 The trifluoroacetic acid salt (20 mg) of compound 13 was taken and separated by chiral HPLC (chromatographic column: Chiralcel OJ-3 100*4.6 mm ID, 3 μm; mobile phase: A: CO 2 B: methanol (0.05% diethylamine) ); gradient elution: 4min B increased from 5% to 40%, 40% B kept 2.5min, then 5%B kept 1.5min; flow rate: 2.8mL/min; column temperature: 35°C; pressure: 1500psi) to obtain the compound 13A and compound 13B.
化合物13A，Rt＝4.494min，MS m/z：433.1[M+H] +， 1H NMR(400MHz，CD 3OD)δppm 8.47(d，J＝1.51Hz，1H)8.22(d，J＝2.76Hz，1H)7.89(d，J＝8.78Hz，1H)7.78(s，1H)7.49(s，1H)7.30(dd，J＝8.78，2.76Hz，1H)4.59(s，2H)4.15-4.27(m，1H)3.69-3.77(m，1H)3.16-3.27(m，1H)2.99(br d，J＝11.29Hz，1H)2.93(s，3H)2.79(br d，J＝11.04Hz，1H)2.46(dd，J＝11.17，3.39Hz，1H)2.28-2.38(m，1H)2.13-2.23(m，1H)1.22(d，J＝6.53Hz，3H)1.03-1.10(m，2H)0.79-0.86(m，2H)。 Compound 13A, Rt=4.494 min, MS m/z: 433.1 [M+H] + , 1 H NMR (400 MHz, CD 3 OD) δppm 8.47 (d, J=1.51 Hz, 1 H) 8.22 (d, J=2.76 Hz, 1H) 7.89(d, J=8.78Hz, 1H) 7.78(s, 1H) 7.49(s, 1H) 7.30(dd, J=8.78, 2.76Hz, 1H) 4.59(s, 2H) 4.15-4.27( m, 1H) 3.69-3.77 (m, 1H) 3.16-3.27 (m, 1H) 2.99 (br d, J=11.29Hz, 1H) 2.93 (s, 3H) 2.79 (br d, J=11.04Hz, 1H) 2.46(dd, J=11.17, 3.39Hz, 1H) 2.28-2.38(m, 1H) 2.13-2.23(m, 1H) 1.22(d, J=6.53Hz, 3H) 1.03-1.10(m, 2H) 0.79- 0.86 (m, 2H).
化合物13B，Rt＝5.196min，MS m/z：433.1[M+H] +， 1H NMR(400MHz，CD 3OD)δppm 8.47(d，J＝1.51Hz，1H)8.18-8.26(m，1H)7.89(d，J＝9.03Hz，1H)7.78(s，1H)7.49(s，1H)7.27-7.33(m，1H)4.59(s，2H)4.14-4.24(m，1H)3.71(s，1H)3.22(td，J＝11.98，3.39Hz，1H)2.98(br d，J＝11.54Hz，1H)2.93(s，3H)2.79(br d，J＝11.29Hz，1H)2.45(dd，J＝11.17，3.39Hz，1H)2.26-2.38(m，1H)2.14-2.24(m，1H)1.22(d，J＝6.53Hz，3H)1.07(br d，J＝8.53Hz，2H)0.82(br d，J＝5.27Hz，2H)。 Compound 13B, Rt=5.196 min, MS m/z: 433.1 [M+H] + , 1 H NMR (400 MHz, CD 3 OD) δppm 8.47 (d, J=1.51 Hz, 1 H) 8.18-8.26 (m, 1 H ) 7.89(d, J=9.03Hz, 1H) 7.78(s, 1H) 7.49(s, 1H) 7.27-7.33(m, 1H) 4.59(s, 2H) 4.14-4.24(m, 1H) 3.71(s, 1H) 3.22(td, J=11.98, 3.39Hz, 1H) 2.98(br d, J=11.54Hz, 1H) 2.93(s, 3H) 2.79(br d, J=11.29Hz, 1H) 2.45(dd, J =11.17,3.39Hz,1H)2.26-2.38(m,1H)2.14-2.24(m,1H)1.22(d,J=6.53Hz,3H)1.07(br d,J=8.53Hz,2H)0.82(br d, J=5.27 Hz, 2H).
实施例14Example 14
Figure PCTCN2022088181-appb-000129
Figure PCTCN2022088181-appb-000129
步骤1：化合物14b的合成Step 1: Synthesis of Compound 14b
将1h(5g，23.14mmol)溶于甲苯(50mL)中，然后加入14a(5.56g，27.77mmol)，RuPhos(1.08g，2.31mmol)，Pd 2(dba) 3(635.82mg，694.20μmol)，Cs 2CO 3(22.62g，69.42mmol)氮气氛围下100℃搅拌16小时，LCMS显示原料转化完全，将反应液使用硅藻土过滤，滤液减压浓缩得到粗品，粗品使用硅胶柱层析分离得到目标产物14b。MS m/z：336.1[M+H] +。 Ih (5 g, 23.14 mmol) was dissolved in toluene (50 mL), then 14a (5.56 g, 27.77 mmol), RuPhos (1.08 g, 2.31 mmol), Pd2(dba )3 ( 635.82 mg, 694.20 μmol) were added, Cs 2 CO 3 (22.62 g, 69.42 mmol) was stirred at 100° C. for 16 hours under nitrogen atmosphere. LCMS showed that the conversion of the raw materials was complete. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography. Target product 14b. MS m/z: 336.1 [M+H] + .
步骤2：化合物14c的合成Step 2: Synthesis of Compound 14c
取14b(1.50g，4.47mmol)室温下加入到甲胺的乙醇(33％，15ml)溶液，25℃搅拌反应16小时，LCMS显示原料反应完全，反应结束后，减压蒸除反应液得粗品，然后向粗品中加入10mL二氯甲烷溶解，加10 mL水洗涤，萃取分液收集有机相，有机相使用无水硫酸钠干燥，抽滤、浓缩得到14c，m/z：335.2[M+H] +。 1H NMR(400MHz，DMSO-d 6)δ8.39(q，J＝4.52Hz，1H)，8.21(d，J＝2.76Hz，1H)，7.83(d，J＝8.78Hz，1H)，7.33(dd，J＝2.89，8.91Hz，1H)，4.19(br s，1H)，3.96(br s，1H)，3.79(br d，J＝13.05Hz，1H)，3.48-3.58(m，1H)，3.15-3.28(m，1H)，3.03(br s，2H)，2.78(d，J＝4.77Hz，3H)，1.42(s，9H)，0.98(d，J＝6.53Hz，2H)。 14b (1.50g, 4.47mmol) was added to the ethanol (33%, 15ml) solution of methylamine at room temperature, and the reaction was stirred for 16 hours at 25°C. , then add 10 mL of dichloromethane to the crude product to dissolve, add 10 mL of water to wash, extract and separate the organic phase to collect the organic phase, dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain 14c, m/z: 335.2 [M+H ] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.39 (q, J=4.52 Hz, 1H), 8.21 (d, J=2.76 Hz, 1H), 7.83 (d, J=8.78 Hz, 1H), 7.33 (dd, J=2.89, 8.91Hz, 1H), 4.19 (br s, 1H), 3.96 (br s, 1H), 3.79 (br d, J=13.05Hz, 1H), 3.48-3.58 (m, 1H) , 3.15-3.28 (m, 1H), 3.03 (br s, 2H), 2.78 (d, J=4.77Hz, 3H), 1.42 (s, 9H), 0.98 (d, J=6.53Hz, 2H).
步骤3：化合物14d的盐酸盐的合成Step 3: Synthesis of the hydrochloride salt of compound 14d
取14c(1.45g，4.34mmol)加入HCl/EtOAc(4mol/L，10.84mL)中，25℃搅拌2小时，LCMS显示化合物原料反应完全，反应液直接过滤，滤饼使用乙酸乙酯洗涤，然后再减压旋蒸得到产物，得到化合物14d的盐酸盐。MS m/z：235.2[M+H] +。 14c (1.45 g, 4.34 mmol) was added to HCl/EtOAc (4 mol/L, 10.84 mL), and stirred at 25° C. for 2 hours. LCMS showed that the reaction of the compound raw materials was complete, the reaction solution was directly filtered, and the filter cake was washed with ethyl acetate, then The product was obtained by rotary evaporation under reduced pressure to obtain the hydrochloride salt of compound 14d. MS m/z: 235.2 [M+H] + .
步骤4：化合物1B的三氟乙酸盐的合成Step 4: Synthesis of the trifluoroacetate salt of compound 1B
25℃将14d盐酸盐(22.99mg，84.90μmol)，KI(2.56mg，15.44μmol)和K 2CO 3(32.00mg，231.54μmol)加入DMF(8mL)中，加入5d(20mg，77.18μmol)，升温50℃，继续搅拌2小时。LCMS检测原料反应完全，停止反应。将反应液冷却至室温，加80mL水，用3*15mL DCM萃取，合并有机层，无水硫酸钠干燥，经制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(三氟乙酸)-乙腈]；乙腈％：7％-37％，8min)纯化得到目标产物1B的三氟乙酸盐。MSm/z：443.1[M+Na] +。 1H NMR(400MHz，CD 3OD)δppm8.64(d，J＝1.51Hz，1H)8.35(d，J＝2.51Hz，1H)8.01(d，J＝8.78Hz，1H)7.92(d，J＝8.78Hz，2H)7.54(br s，1H)4.80-4.86(m，2H)4.54(s，2H)3.55(br d，J＝11.54Hz，1H)3.38-3.48(m，3H)3.37(s，1H)2.96(s，3H)2.71(q，J＝7.45Hz，2H)1.31(t，J＝7.40Hz，3H)1.24(br d，J＝6.53Hz，3H)。 14d hydrochloride (22.99 mg, 84.90 μmol), KI (2.56 mg, 15.44 μmol) and K 2 CO 3 (32.00 mg, 231.54 μmol) were added to DMF (8 mL) at 25°C, 5d (20 mg, 77.18 μmol) was added , the temperature was increased to 50 °C, and the stirring was continued for 2 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was cooled to room temperature, 80 mL of water was added, extracted with 3*15 mL of DCM, the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [H 2 O(trifluoroacetic acid)-acetonitrile]; acetonitrile%: 7%-37%, 8 min) was purified to obtain the trifluoroacetic acid salt of the target product 1B. MS m/z: 443.1 [M+Na] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.64 (d, J=1.51 Hz, 1H) 8.35 (d, J=2.51 Hz, 1H) 8.01 (d, J=8.78 Hz, 1H) 7.92 (d, J = 8.78Hz, 2H) 7.54(br s, 1H) 4.80-4.86(m, 2H) 4.54(s, 2H) 3.55(br d, J=11.54Hz, 1H) 3.38-3.48(m, 3H) 3.37(s , 1H) 2.96(s, 3H) 2.71(q, J=7.45Hz, 2H) 1.31(t, J=7.40Hz, 3H) 1.24(br d, J=6.53Hz, 3H).
实施例15Example 15
Figure PCTCN2022088181-appb-000130
Figure PCTCN2022088181-appb-000130
步骤1：化合物15b的合成Step 1: Synthesis of Compound 15b
0℃将15a(3.00g，13.87mmol)，咪唑(1.13g，16.65mmol)加入DCM(50mL)中，缓慢滴加TBSCl(2.30g，15.26mmol，1.87mL)，滴毕，升至室温，反应12小时。TLC检测原料反应完全，停止继续反应。反应液用2*15mL水洗涤，无水硫酸钠干燥，浓缩得目标产物15b。15a (3.00 g, 13.87 mmol), imidazole (1.13 g, 16.65 mmol) were added to DCM (50 mL) at 0°C, TBSCl (2.30 g, 15.26 mmol, 1.87 mL) was slowly added dropwise, the dropping was completed, the temperature was raised to room temperature, and the reaction was carried out. 12 hours. TLC detected that the reaction of the raw materials was complete, and the reaction was stopped. The reaction solution was washed with 2*15 mL of water, dried over anhydrous sodium sulfate, and concentrated to obtain the target product 15b.
步骤2：化合物15c的合成Step 2: Synthesis of Compound 15c
将Pd-RuPhos-G3(126.52mg，151.27μmol)，Cs 2CO 3(1.48g，4.54mmol)，化合物15b(0.5g，1.51mmol)和1h(326.79mg，1.51mmol)加入到二氧六环(10mL)溶液中，反应100℃搅拌24小时。TLC(PE/EA＝2/1)和LCMS检测原料反应完全。向反应液加20mL甲醇，0.4mL 2M的氯化氢溶液，调节溶液pH＝8，然后用二氯甲烷2*10mL萃取，合并有机相，有机相中加入无水硫酸钠干燥，减压抽滤，滤液减压浓缩得到化合物15c。MS m/z：466.1[M+H] +。 Pd-RuPhos-G3 (126.52 mg, 151.27 μmol), Cs 2 CO 3 (1.48 g, 4.54 mmol), compound 15b (0.5 g, 1.51 mmol) and 1 h (326.79 mg, 1.51 mmol) were added to dioxane (10 mL) solution, the reaction was stirred at 100°C for 24 hours. TLC (PE/EA=2/1) and LCMS detected the complete reaction of the starting materials. Add 20 mL of methanol and 0.4 mL of 2M hydrogen chloride solution to the reaction solution, adjust the pH of the solution to 8, then extract with dichloromethane 2*10 mL, combine the organic phases, add anhydrous sodium sulfate to the organic phase to dry, filter under reduced pressure, and the filtrate Concentration under reduced pressure gave compound 15c. MS m/z: 466.1 [M+H] + .
步骤3：化合物15d的合成Step 3: Synthesis of Compound 15d
将化合物15c(450mg，966.38μmol)和甲胺的乙醇溶液(454.74mg，4.83mmol，33％含量)加入到EtOH(10mL)溶液中，反应20℃搅拌24小时。LCMS检测原料反应完全。反应液浓缩得到化合物15d。MS m/z：465.1[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 8.14(d，J＝2.51Hz，1H)8.05(d，J＝8.78Hz，1H)7.77(d，J＝4.02Hz，1H)7.18(dd，J＝8.78，2.76Hz，1H)4.24(d，J＝13.55Hz，1H)3.70-3.79(m，2H)3.62(s，1H)3.49-3.55(m，1H)3.16-3.26(m，3H)3.03(d，J＝5.02Hz，3H)2.77-2.85(m，1H)1.51(s，9H)0.84(s，9H)0.01-0.12(m，6H)。 Compound 15c (450 mg, 966.38 μmol) and methylamine in ethanol (454.74 mg, 4.83 mmol, 33% content) were added to EtOH (10 mL) solution, and the reaction was stirred at 20° C. for 24 hours. The reaction of the raw materials was detected by LCMS. The reaction solution was concentrated to obtain compound 15d. MS m/z: 465.1 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.14 (d, J=2.51 Hz, 1H) 8.05 (d, J=8.78 Hz, 1H) 7.77 (d, J=4.02 Hz, 1H) 7.18 (dd, J= 8.78, 2.76Hz, 1H) 4.24(d, J=13.55Hz, 1H) 3.70-3.79(m, 2H) 3.62(s, 1H) 3.49-3.55(m, 1H) 3.16-3.26(m, 3H) 3.03( d, J=5.02Hz, 3H) 2.77-2.85 (m, 1H) 1.51 (s, 9H) 0.84 (s, 9H) 0.01-0.12 (m, 6H).
步骤4：化合物15e的合成Step 4: Synthesis of Compound 15e
将化合物15d(0.4g，860.82μmol)加入到THF(10mL)溶液中，将TBAF(1M，1.72mL)加入到反应液中，反应25℃搅拌24小时。TLC(PE/EA＝2/1)，检测原料反应完全。向反应液中加入30mL乙酸乙酯，用2*15mL水洗涤，无水硫酸钠干燥，抽滤得滤液、减压蒸除有机溶剂得化合物15e。MS m/z：351.0[M+H] +。 1H NMR(400MHz，DMSO-d 6)δppm 8.42(d，J＝4.88Hz，1H)8.26(d，J＝2.75Hz，1H)7.85(d，J＝8.76Hz，1H)7.38(dd，J＝8.82，2.81Hz，1H)4.03-4.09(m，2H)3.66(dd，J＝8.82，3.81Hz，1H)3.30-3.34(m，2H)3.22(br s，1H)3.18(s，2H)2.82(d，J＝4.75Hz，3H)2.31-2.41(m，1H)1.46(s，9H)。 Compound 15d (0.4 g, 860.82 μmol) was added to THF (10 mL) solution, TBAF (1 M, 1.72 mL) was added to the reaction solution, and the reaction was stirred at 25° C. for 24 hours. TLC (PE/EA=2/1) showed that the reaction of the raw materials was complete. 30 mL of ethyl acetate was added to the reaction solution, washed with 2*15 mL of water, dried over anhydrous sodium sulfate, suction filtered to obtain the filtrate, and the organic solvent was evaporated under reduced pressure to obtain compound 15e. MS m/z: 351.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δppm 8.42 (d, J=4.88 Hz, 1H) 8.26 (d, J=2.75 Hz, 1H) 7.85 (d, J=8.76 Hz, 1H) 7.38 (dd, J =8.82,2.81Hz,1H)4.03-4.09(m,2H)3.66(dd,J=8.82,3.81Hz,1H)3.30-3.34(m,2H)3.22(br s,1H)3.18(s,2H) 2.82 (d, J=4.75 Hz, 3H) 2.31-2.41 (m, 1H) 1.46 (s, 9H).
步骤5：化合物15f的合成Step 5: Synthesis of Compound 15f
将化合物15e(301.64mg，860.82μmol)加入到EtOAc(5mL)溶液中，将HCl/EtOAc(4M，215.21μL)加入到反应液中，反应25℃搅拌24小时。LCMS检测原料反应完全。反应液减压抽滤，干燥滤饼得到产物15f的盐酸盐。MS m/z：251.1[M+H] +。 Compound 15e (301.64 mg, 860.82 μmol) was added to EtOAc (5 mL) solution, HCl/EtOAc (4 M, 215.21 μL) was added to the reaction solution, and the reaction was stirred at 25° C. for 24 hours. The reaction of the raw materials was detected by LCMS. The reaction solution was filtered under reduced pressure, and the filter cake was dried to obtain the hydrochloride salt of the product 15f. MS m/z: 251.1 [M+H] + .
步骤6：化合物4B的三氟乙酸盐的合成Step 6: Synthesis of Trifluoroacetate Salt of Compound 4B
将化合物5d(35mg，135.07μmol)和化合物15f(38.73mg，135.07μmol)加入到DMF(3mL)溶液中，将K 2CO 3(93.34mg，675.33μmol)和KI(2.24mg，13.51μmol)加入到反应液中，反应50℃搅拌2小时。LCMS检测原料反应完全。反应液减压抽滤，滤液经制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(三氟乙酸)-乙腈]；乙腈％：5％-35％，8min)纯化得到化合物4B的三氟乙酸盐。MS m/z：437.0[M+1] +； 1H NMR(400MHz，CD 3OD)δppm 8.67(d，J＝1.51Hz，1H)8.34(d，J＝2.26Hz，1H)7.96-8.04(m，2H)7.90(s，1H)7.45-7.54(m，1H)4.65(br d，J＝13.55Hz，1H)4.37-4.51(m，2H)3.88-4.01(m，1H)3.64-3.82(m，4H)3.33(dt，J＝3.26，1.63Hz，3H)2.96(s，3H)2.65-2.76(m，2H)1.30-1.36(m，3H)。化合物4B的三氟乙酸盐经手性HPLC分析(色谱柱：Chiralcel OD-3 100*4.6mm I.D.，3μm；流动相：A：CO 2B：MeOH(0.05％二乙胺)；等度洗脱：40％B；流速：2.8mL/min；柱温：35℃；压力：1500psi)，确定其保留时间Rt＝2.489min，ee％＝99.58％。 Compound 5d (35 mg, 135.07 μmol) and compound 15f (38.73 mg, 135.07 μmol) were added to DMF (3 mL) solution, K 2 CO 3 (93.34 mg, 675.33 μmol) and KI (2.24 mg, 13.51 μmol) were added Into the reaction solution, the reaction was stirred at 50°C for 2 hours. The reaction of the raw materials was detected by LCMS. The reaction solution was filtered under reduced pressure, and the filtrate was subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [H 2 O (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 5%-35%, 8min ) was purified to give compound 4B as the trifluoroacetate salt. MS m/z: 437.0 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.67 (d, J=1.51 Hz, 1H) 8.34 (d, J=2.26 Hz, 1H) 7.96-8.04 ( m, 2H) 7.90(s, 1H) 7.45-7.54(m, 1H) 4.65(br d, J=13.55Hz, 1H) 4.37-4.51(m, 2H) 3.88-4.01(m, 1H) 3.64-3.82( m, 4H) 3.33 (dt, J=3.26, 1.63 Hz, 3H) 2.96 (s, 3H) 2.65-2.76 (m, 2H) 1.30-1.36 (m, 3H). The trifluoroacetate salt of compound 4B was analyzed by chiral HPLC (column: Chiralcel OD-3 100*4.6 mm ID, 3 μm; mobile phase: A: CO 2 B: MeOH (0.05% diethylamine); isocratic elution : 40%B; flow rate: 2.8mL/min; column temperature: 35°C; pressure: 1500psi), determine its retention time Rt=2.489min, ee%=99.58%.
实施例16Example 16
Figure PCTCN2022088181-appb-000131
Figure PCTCN2022088181-appb-000131
步骤1：化合物16b的合成Step 1: Synthesis of Compound 16b
将1h(5g，23.14mmol)溶于甲苯(80mL)中，然后加入16a(5.10g，25.45mmol)，RuPhos(1.08g，2.31mmol)，Pd 2(dba) 3(635.82mg，694.20μmol)，Cs 2CO 3(22.62g，69.42mmol)氮气氛围下100℃搅拌16小时，LCMS显示原料转化完全，将反应液使用硅藻土过滤，滤液减压浓缩得到粗品，粗品使用硅胶柱层析分离纯化(梯度洗脱：PE∶EA＝10∶1～1∶1)分离得到产物16b。MS m/z：336.2[M+H] +。 1H NMR(400MHz，CDCl 3)δ8.31(d，J＝2.76Hz，1H)，8.02(br d，J＝8.78Hz，1H)，7.13(dd，J＝3.01，8.78Hz，1H)，4.39(br s，1H)，3.97(s，3H)，3.72(br d，J＝12.05Hz，1H)，3.52-3.65(m，1H)，3.29-3.42(m，1H)，3.22-3.30(m，1H)，2.94-3.16(m，1H)，1.95-2.21(m，1H)，1.50(s，9H)，1.26(br d，J＝6.78Hz，3H)。 1 h (5 g, 23.14 mmol) was dissolved in toluene (80 mL), then 16a (5.10 g, 25.45 mmol), RuPhos (1.08 g, 2.31 mmol), Pd2(dba )3 ( 635.82 mg, 694.20 μmol) were added, Cs 2 CO 3 (22.62 g, 69.42 mmol) was stirred at 100° C. for 16 hours under nitrogen atmosphere. LCMS showed that the conversion of the starting material was complete. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography. (Gradient elution: PE:EA=10:1-1:1) The product 16b was isolated. MS m/z: 336.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.31 (d, J=2.76 Hz, 1H), 8.02 (br d, J=8.78 Hz, 1H), 7.13 (dd, J=3.01, 8.78 Hz, 1H), 4.39(br s, 1H), 3.97(s, 3H), 3.72(br d, J=12.05Hz, 1H), 3.52-3.65(m, 1H), 3.29-3.42(m, 1H), 3.22-3.30( m, 1H), 2.94-3.16 (m, 1H), 1.95-2.21 (m, 1H), 1.50 (s, 9H), 1.26 (br d, J=6.78Hz, 3H).
步骤2：化合物16c的合成Step 2: Synthesis of Compound 16c
取16b(2.92g，8.71mmol)室温下加入甲胺的乙醇溶液(9.03g，80.1mmol，10.25mL，33％含量)，25℃搅拌反应16小时，LCMS显示原料反应完全，反应结束后反应液直接减压浓缩，蒸除有机溶剂得粗品，然后在粗品中加入10mL二氯甲烷溶解，加10mL水洗涤，萃取分液收集有机相，有机相使用无水硫酸钠干燥，减压旋蒸得到16c。MS m/z：335.2[M+H] +。 1H NMR(400MHz，DMSO-d 6)δ8.38(br d，J＝4.77Hz，1H)，8.23(d，J＝2.76Hz，1H)，7.82(d，J＝8.53Hz，1H)，7.36(dd，J＝2.89，8.91Hz，1H)，4.11-4.27(m，1H)，3.74-3.85(m，2H)，3.70(brd，J＝12.55Hz，1H)，3.16-3.27(m，1H)，3.04-3.14(m，1H)，2.87(dt，J＝3.89，11.86Hz，1H)，2.78(d，J＝4.77Hz，3H)，1.41(s，9H)，1.15(d，J＝6.53Hz，3H)。 Take 16b (2.92g, 8.71mmol) at room temperature and add the ethanol solution of methylamine (9.03g, 80.1mmol, 10.25mL, 33% content), 25 ℃ of stirring reaction 16 hours, LCMS shows that the reaction of the raw materials is complete, and the reaction solution after the reaction finishes Directly concentrate under reduced pressure, evaporate the organic solvent to obtain the crude product, then add 10 mL of dichloromethane to the crude product to dissolve, add 10 mL of water to wash, extract and separate to collect the organic phase, dry the organic phase with anhydrous sodium sulfate, and rotate under reduced pressure to obtain 16c . MS m/z: 335.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.38 (br d, J=4.77Hz, 1H), 8.23 (d, J=2.76Hz, 1H), 7.82 (d, J=8.53Hz, 1H), 7.36 (dd, J=2.89, 8.91Hz, 1H), 4.11-4.27 (m, 1H), 3.74-3.85 (m, 2H), 3.70 (brd, J=12.55Hz, 1H), 3.16-3.27 (m, 1H), 3.04-3.14(m, 1H), 2.87(dt, J=3.89, 11.86Hz, 1H), 2.78(d, J=4.77Hz, 3H), 1.41(s, 9H), 1.15(d, J =6.53Hz, 3H).
步骤3：化合物16d的合成Step 3: Synthesis of Compound 16d
取16c(2.9g，8.67mmol)加入HCl/EtOAc(4M，10.84mL)25℃搅拌2小时，LCMS显示化合物原料反应完全，反应液直接过滤，滤饼使用乙酸乙酯洗涤，然后再减压旋蒸得到产物16d的盐酸盐。MS m/z：235.15[M+H] +。 1H NMR(400MHz，CD 3OD)δ8.49(d，J＝2.76Hz，1H)，8.30(d，J＝9.04Hz，1H)，8.15(br d，J＝3.01Hz，1H)，4.17-4.30(m，2H)，3.52-3.61(m，2H)，3.41-3.50(m，1H)，3.35(brdd，J＝3.14，12.42Hz，1H)，3.22(dd，J＝10.92，13.93Hz，1H)，3.00(s，3H)，1.45(d，J＝6.78Hz，3H)。 Take 16c (2.9 g, 8.67 mmol), add HCl/EtOAc (4 M, 10.84 mL) and stir at 25°C for 2 hours. LCMS showed that the reaction of the compound raw materials was complete. The reaction solution was directly filtered, and the filter cake was washed with ethyl acetate, and then spun under reduced pressure. Evaporation gave the product 16d as the hydrochloride salt. MS m/z: 235.15 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δ 8.49 (d, J=2.76 Hz, 1H), 8.30 (d, J=9.04 Hz, 1H), 8.15 (br d, J=3.01 Hz, 1H), 4.17 -4.30 (m, 2H), 3.52-3.61 (m, 2H), 3.41-3.50 (m, 1H), 3.35 (brdd, J=3.14, 12.42Hz, 1H), 3.22 (dd, J=10.92, 13.93Hz) , 1H), 3.00 (s, 3H), 1.45 (d, J=6.78 Hz, 3H).
步骤4：化合物16B的盐酸盐的合成Step 4: Synthesis of the hydrochloride salt of compound 16B
25℃将16d(34.48mg，127.35μmol)，KI(3.84mg，23.15μmol)和K 2CO 3(48.00mg，347.31μmol)加入DMF(4mL，95.41％含量)中，加入5d(30mg，115.77μmol)，升温50℃，继续搅拌2小时。LCMS检测原 料反应完全，停止反应。将反应液冷却至室温，加80mL水，用3*15mL DCM萃取，合并有机层，无水硫酸钠干燥得粗品，经制备HPLC(色谱柱：Xtimate C18 150*40mm*5μm；流动相：[H 2O(HCl)-乙腈]；乙腈％：5％-35％，10min)纯化得到目标产物16B的盐酸盐。MS m/z：443.0[M+Na] +。 1H NMR(400MHz，CD 3OD)δppm 9.01(s，1H)8.62(s，1H)8.53(d，J＝2.26Hz，1H)8.33(d，J＝9.04Hz，1H)8.16(dd，J＝9.29，2.51Hz，1H)7.98(s，1H)5.17-5.21(m，1H)4.62(br d，J＝13.05Hz，1H)4.30(br s，1H)4.14(br s，1H)3.91(br s，1H)3.73(br s，2H)3.45-3.61(m，2H)3.01(s，3H)2.77(q，J＝7.19Hz，2H)1.77(br d，J＝6.27Hz，3H)1.33(t，J＝7.40Hz，3H)。 16d (34.48 mg, 127.35 μmol), KI (3.84 mg, 23.15 μmol) and K2CO3 (48.00 mg , 347.31 μmol) were added to DMF (4 mL, 95.41% content) at 25°C, 5d (30 mg, 115.77 μmol) was added ), the temperature was increased to 50°C, and the stirring was continued for 2 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was cooled to room temperature, 80 mL of water was added, extracted with 3*15 mL of DCM, the organic layers were combined, and dried over anhydrous sodium sulfate to obtain the crude product, which was subjected to preparative HPLC (chromatographic column: Xtimate C18 150*40 mm*5 μm; mobile phase: [H 2 O(HCl)-acetonitrile]; acetonitrile %: 5%-35%, 10 min) was purified to obtain the hydrochloride salt of the target product 16B. MS m/z: 443.0 [M+Na] + . 1 H NMR (400 MHz, CD 3 OD) δppm 9.01 (s, 1H) 8.62 (s, 1H) 8.53 (d, J=2.26 Hz, 1H) 8.33 (d, J=9.04 Hz, 1H) 8.16 (dd, J) =9.29,2.51Hz,1H)7.98(s,1H)5.17-5.21(m,1H)4.62(br d,J=13.05Hz,1H)4.30(br s,1H)4.14(br s,1H)3.91( br s,1H)3.73(br s,2H)3.45-3.61(m,2H)3.01(s,3H)2.77(q,J=7.19Hz,2H)1.77(br d,J=6.27Hz,3H)1.33 (t, J=7.40 Hz, 3H).
实施例17Example 17
Figure PCTCN2022088181-appb-000132
Figure PCTCN2022088181-appb-000132
步骤1：化合物17b的合成Step 1: Synthesis of Compound 17b
向17a(3g，14.98mmol)和1h(3.24g，14.98mmol)的甲苯(50mL)溶液中加入Pd 2(dba) 3(1.37g，1.50mmol)，RuPhos(1.40g，3.00mmol)，Cs 2CO 3(14.64g，44.94mmol)，氮气保护下100℃搅拌16小时。LCMS检测原料反应完全，停止反应。反应液过滤，滤液减压浓缩得粗品，粗品经硅胶柱层析纯化(PE∶EA＝3∶1)得产物17b。MS m/z：336.0[M+H] +。 To a solution of 17a (3 g, 14.98 mmol) and 1 h (3.24 g, 14.98 mmol) in toluene (50 mL) was added Pd 2 (dba) 3 (1.37 g, 1.50 mmol), RuPhos (1.40 g, 3.00 mmol), Cs 2 CO 3 (14.64 g, 44.94 mmol) was stirred at 100° C. for 16 hours under nitrogen protection. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA=3:1) to obtain the product 17b. MS m/z: 336.0 [M+H] + .
步骤2：化合物17c的合成Step 2: Synthesis of Compound 17c
向含有17b(1.5g，4.47mmol)的单口瓶中加入甲胺的乙醇溶液(420.90mg，4.47mmol，25mL，33％含量)，25℃搅拌16小时。LCMS检测原料反应完全，停止反应。减压整除溶剂得目标产物17c。MS m/z：335.0[M+H] +。 To a single-necked flask containing 17b (1.5 g, 4.47 mmol), methylamine ethanol solution (420.90 mg, 4.47 mmol, 25 mL, 33% content) was added, and the mixture was stirred at 25° C. for 16 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The solvent was removed under reduced pressure to obtain the target product 17c. MS m/z: 335.0 [M+H] + .
步骤3：化合物17d盐酸盐的合成Step 3: Synthesis of Compound 17d Hydrochloride
向含EtOAc(15mL)的单口瓶中加入17c(1.5g，4.49mmol)，再加入HCl/EtOAc(4M，15mL)，25℃搅拌16小时。LCMS检测原料反应完全，停止反应。将反应液过滤、干燥得目标产物17d。MS m/z：235.0[M+H] +。 17c (1.5 g, 4.49 mmol) was added to a single-neck flask containing EtOAc (15 mL), followed by HCl/EtOAc (4 M, 15 mL), and the mixture was stirred at 25° C. for 16 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was filtered and dried to obtain the target product 17d. MS m/z: 235.0 [M+H] + .
步骤4：化合物16A的三氟乙酸盐的合成Step 4: Synthesis of the trifluoroacetate salt of compound 16A
向17d(78.37mg，289.43μmol)，5d(50mg，192.95μmol)的DMF(3mL)溶液中加入KI(6.41mg，38.59μmol)，K 2CO 3(106.67mg，771.81μmol)。50℃搅拌16小时。LCMS检测原料反应完全，停止反应。将反应液冷却至室温，加30mL水，用3*8mL DCM萃取，合并有机层，无水硫酸钠干燥得粗品，经制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(三氟乙酸)-乙腈]；乙腈％：7％-37％，8min)纯化得 到目标产物16A的三氟乙酸盐。MS m/z：421.3[M+H] +。 1H NMR(400MHz，CD 3OD)δ8.62(d，J＝1.76Hz，1H)，8.35(d，J＝2.76Hz，1H)，7.96(d，J＝8.78Hz，1H)，7.90(d，J＝1.51Hz，1H)，7.88(s，1H)，7.49(dd，J＝2.76，8.78Hz，1H)，4.93-5.04(m，1H)，4.80(s，1H)，4.40(br d，J＝13.55Hz，1H)，3.97(s，1H)，3.84(br s，1H)，3.72(br s，1H)，3.40-3.54(m，1H)，3.34(br s，2H)，2.93(s，3H)，2.61-2.76(m，2H)，1.68(d，J＝6.53Hz，3H)，1.28(t，J＝7.40Hz，3H)。 To a solution of 17d (78.37 mg, 289.43 μmol), 5d (50 mg, 192.95 μmol) in DMF ( 3 mL) was added KI (6.41 mg, 38.59 μmol), K2CO3 ( 106.67 mg, 771.81 μmol). Stir at 50°C for 16 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was cooled to room temperature, 30 mL of water was added, extracted with 3*8 mL of DCM, the organic layers were combined, and dried over anhydrous sodium sulfate to obtain the crude product, which was subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [ H 2 O (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 7%-37%, 8 min) was purified to give the target product 16A as the trifluoroacetic acid salt. MS m/z: 421.3 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δ 8.62 (d, J=1.76 Hz, 1H), 8.35 (d, J=2.76 Hz, 1H), 7.96 (d, J=8.78 Hz, 1H), 7.90 ( d, J=1.51Hz, 1H), 7.88 (s, 1H), 7.49 (dd, J=2.76, 8.78Hz, 1H), 4.93-5.04 (m, 1H), 4.80 (s, 1H), 4.40 (br d, J=13.55Hz, 1H), 3.97(s, 1H), 3.84(br s, 1H), 3.72(br s, 1H), 3.40-3.54(m, 1H), 3.34(br s, 2H), 2.93 (s, 3H), 2.61-2.76 (m, 2H), 1.68 (d, J=6.53 Hz, 3H), 1.28 (t, J=7.40 Hz, 3H).
实施例18Example 18
Figure PCTCN2022088181-appb-000133
Figure PCTCN2022088181-appb-000133
步骤1：化合物18b的合成Step 1: Synthesis of Compound 18b
向1h(5g，23.14mmol)，18a(4.64g，23.14mmol)的反应瓶中加入甲苯(50mL)，再依次加入RuPhos(1.08g，2.31mmol)，Cs 2CO 3(15.08g，46.29mmol)，Pd 2(dba) 3(2.12g，2.31mmol)，氮气保护下100℃搅拌16小时。LCMS检测原料反应完全，停止继续反应。反应液直接过滤，滤液减压浓缩得粗品。粗品经制备硅胶柱层析(PE∶EA＝5∶1)纯化得产物18b。MS m/z：336.0[M+H] +。 To the reaction flask of 1h (5g, 23.14mmol), 18a (4.64g, 23.14mmol) was added toluene (50mL), followed by RuPhos (1.08g, 2.31mmol), Cs2CO3 ( 15.08g , 46.29mmol) , Pd 2 (dba) 3 (2.12 g, 2.31 mmol), stirred at 100 °C for 16 hours under nitrogen protection. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative silica gel column chromatography (PE:EA=5:1) to obtain product 18b. MS m/z: 336.0 [M+H] + .
步骤2：化合物18c的合成Step 2: Synthesis of Compound 18c
向18b(2.7g，8.05mmol)的单口瓶中加入甲胺的乙醇溶液(757.62mg，8.05mmol，80mL，33％含量)，25℃搅拌16小时。LCMS检测原料反应完全，停止继续反应。反应液直接减压浓缩得产物18c。MS m/z：335.0[M+H] +。 An ethanol solution of methylamine (757.62 mg, 8.05 mmol, 80 mL, 33% content) was added to a single-necked flask of 18b (2.7 g, 8.05 mmol), and the mixture was stirred at 25° C. for 16 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was directly concentrated under reduced pressure to obtain product 18c. MS m/z: 335.0 [M+H] + .
步骤3：化合物18d盐酸盐的合成Step 3: Synthesis of Compound 18d Hydrochloride
向18c(2.70g，8.07mmol)的单口瓶中加入HCl/EtOAc(4M，50mL)，25℃搅拌24小时。LCMS检测原料反应完全，停止继续反应。反应液直接过滤，收集固体得18d的盐酸盐。MS m/z：235.0[M+H] +。 To a single-neck flask of 18c (2.70 g, 8.07 mmol), HCl/EtOAc (4 M, 50 mL) was added, and the mixture was stirred at 25° C. for 24 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was directly filtered, and the solid was collected to obtain the hydrochloride of 18d. MS m/z: 235.0 [M+H] + .
步骤4：化合物1A的三氟乙酸盐的合成Step 4: Synthesis of Trifluoroacetate Salt of Compound 1A
向5d(100mg，385.90μmol)，18d(114.93mg，424.49μmol)的DMF(5mL)溶液中加入K 2CO 3(160.00mg，1.16mmol)，KI(12.81mg，77.18μmol)。50℃搅拌2小时。LCMS检测原料反应完全，停止反应。将反应液冷却至室温，加50mL水，用3*10mL DCM萃取，合并有机层，无水硫酸钠干燥得粗品，经制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(三氟乙酸)-乙腈]；乙腈％：7％-37％，8min)纯化得到目标产物1A的三氟乙酸盐。MS m/z：421.3[M+H] +。 1H NMR(400MHz，CD 3OD)δ8.63(d，J＝2.01Hz，1H)，8.33(d，J＝2.51Hz，1H)，7.99(d，J＝8.53Hz，1H)，7.95(d，J＝1.76Hz，1H)，7.87(s，1H)，7.52(dd，J＝2.51， 8.78Hz，1H)，4.56(s，2H)，4.35(br s，1H)，3.78(br d，J＝11.29Hz，1H)，3.57(br d，J＝11.80Hz，1H)，3.37-3.50(m，3H)，3.35(s，1H)，2.94(s，3H)，2.68(dq，J＝1.00，7.45Hz，2H)，1.29(t，J＝7.53Hz，3H)，1.22(d，J＝6.78Hz，3H)。 To a solution of 5d (100 mg, 385.90 μmol), 18d (114.93 mg, 424.49 μmol) in DMF ( 5 mL) was added K2CO3 (160.00 mg, 1.16 mmol), KI (12.81 mg, 77.18 μmol). Stir at 50°C for 2 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was cooled to room temperature, 50 mL of water was added, extracted with 3*10 mL of DCM, the organic layers were combined, and dried over anhydrous sodium sulfate to obtain the crude product, which was subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [ H 2 O (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 7%-37%, 8 min) was purified to give the target product 1A as the trifluoroacetic acid salt. MS m/z: 421.3 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δ 8.63 (d, J=2.01 Hz, 1H), 8.33 (d, J=2.51 Hz, 1H), 7.99 (d, J=8.53 Hz, 1H), 7.95 ( d, J=1.76Hz, 1H), 7.87(s, 1H), 7.52(dd, J=2.51, 8.78Hz, 1H), 4.56(s, 2H), 4.35(br s, 1H), 3.78(br d , J=11.29Hz, 1H), 3.57(br d, J=11.80Hz, 1H), 3.37-3.50(m, 3H), 3.35(s, 1H), 2.94(s, 3H), 2.68(dq, J = 1.00, 7.45 Hz, 2H), 1.29 (t, J=7.53 Hz, 3H), 1.22 (d, J=6.78 Hz, 3H).
实施例19Example 19
Figure PCTCN2022088181-appb-000134
Figure PCTCN2022088181-appb-000134
步骤1：化合物19b的合成Step 1: Synthesis of Compound 19b
将19a(500.00mg，4.38mmol)、1h(945.95mg，4.38mmol)、RuPhos(204.33mg，437.87μmol)、Pd 2(dba) 3(400.97mg，437.87μmol)、Cs 2CO 3(2.85g，8.76mmol)加入甲苯(30mL)中，N 2保护，升温100℃反应5小时。LCMS检测原料反应完全，停止继续反应。将反应液冷却至室温，用HCl调节为酸性，用2*15mL乙酸乙酯萃取杂质，然后用Na 2CO 3溶液将水层调为碱性，用3*15mL DCM∶MeOH＝10∶1萃取，干燥得化合物19b。MS m/z：249.9[M+H] +。 1H NMR(400MHz，DMSO-d 6)δppm 8.36(d，J＝3.01Hz，1H)7.84(d，J＝8.78Hz，1H)7.31(dd，J＝9.03，3.01Hz，1H)3.76-3.84(m，5H)2.73-2.84(m，2H)2.17-2.34(m，3H)1.02(d，J＝6.27Hz，6H)。 19a (500.00 mg, 4.38 mmol), 1 h (945.95 mg, 4.38 mmol), RuPhos (204.33 mg, 437.87 μmol), Pd2(dba) 3 (400.97 mg, 437.87 μmol), Cs2CO3 ( 2.85 g , 8.76 mmol) was added to toluene (30 mL), protected by N 2 , and the temperature was increased to 100 °C for 5 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was cooled to room temperature, adjusted to be acidic with HCl, the impurities were extracted with 2*15 mL of ethyl acetate, then the aqueous layer was made basic with Na 2 CO 3 solution, and extracted with 3 * 15 mL of DCM:MeOH=10:1 , and dried to obtain compound 19b. MS m/z: 249.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δppm 8.36 (d, J=3.01 Hz, 1H) 7.84 (d, J=8.78 Hz, 1H) 7.31 (dd, J=9.03, 3.01 Hz, 1H) 3.76-3.84 (m, 5H) 2.73-2.84 (m, 2H) 2.17-2.34 (m, 3H) 1.02 (d, J=6.27 Hz, 6H).
步骤2：化合物19c的合成Step 2: Synthesis of Compound 19c
将19b(223.00mg，894.46μmol)加入甲胺的EtOH(462.99mg，4.47mmol，30％含量)中，25℃搅拌反应2小时。LCMS检测原料反应完全，停止继续反应。蒸干溶剂得化合物19c。MS m/z：249.0[M+H] +。 19b (223.00 mg, 894.46 μmol) was added to methylamine in EtOH (462.99 mg, 4.47 mmol, 30% content), and the reaction was stirred at 25° C. for 2 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The solvent was evaporated to dryness to obtain compound 19c. MS m/z: 249.0 [M+H] + .
步骤3：化合物19A三氟乙酸盐的合成Step 3: Synthesis of Compound 19A Trifluoroacetate Salt
25℃将19c(21.98mg，88.51μmol)、K 2CO 3(32.00mg，231.54μmol)和KI(2.56mg，15.44μmol)加入DMF(3mL)中，加入5d(20mg，77.18μmol)，升温50℃，继续搅拌2小时。LCMS检测原料反应完全，停止继续反应。将反应液冷却至室温，加80mL水，用3*15mL DCM萃取，合并有机层，无水硫酸钠干燥，减压浓缩得粗品，粗品经制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(三氟乙酸)-乙腈]；乙腈％：10％-40％，8min)分离得化合物19A的三氟乙酸盐。MS m/z：435.1[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 8.57(d，J＝1.88Hz，1H)8.24(br d，J＝2.50Hz，1H)7.82-7.92(m，2H)7.77(s，1H)7.40(dd，J＝8.76，2.63Hz，1H)4.73(br s，2H)3.99(br d，J＝13.13Hz，2H)3.52(br s，2H)3.01-3.12(m，2H)2.83(s，3H)2.52-2.64(m，2H)1.58(d，J＝6.38Hz，6H)1.16-1.20(m，3H)。 19c (21.98 mg, 88.51 μmol), K 2 CO 3 (32.00 mg, 231.54 μmol) and KI (2.56 mg, 15.44 μmol) were added to DMF (3 mL) at 25°C, 5d (20 mg, 77.18 μmol) was added, and the temperature was increased to 50 °C, stirring was continued for 2 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was cooled to room temperature, 80 mL of water was added, extracted with 3*15 mL of DCM, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40mm*3μm ; mobile phase: [H 2 O (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 10%-40%, 8 min) to isolate the trifluoroacetic acid salt of compound 19A. MS m/z: 435.1 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.57 (d, J=1.88 Hz, 1H) 8.24 (br d, J=2.50 Hz, 1H) 7.82-7.92 (m, 2H) 7.77 (s, 1H) 7.40 ( dd, J=8.76, 2.63Hz, 1H) 4.73(br s, 2H) 3.99(br d, J=13.13Hz, 2H) 3.52(br s, 2H) 3.01-3.12(m, 2H) 2.83(s, 3H ) 2.52-2.64 (m, 2H) 1.58 (d, J=6.38 Hz, 6H) 1.16-1.20 (m, 3H).
实施例20Example 20
Figure PCTCN2022088181-appb-000135
Figure PCTCN2022088181-appb-000135
步骤1：化合物13B的三氟乙酸盐的合成Step 1: Synthesis of the trifluoroacetate salt of compound 13B
25℃将14d(32.95mg，121.71μmol)，KI(3.67mg，22.13μmol)和K 2CO 3(45.88mg，331.93μmol)加入DMF(4mL)中，加入11b(30mg，110.64μmol)，升温50℃，继续搅拌2小时。LCMS检测原料反应完全，停止反应。将反应液冷却至室温，加40mL水，用3*10mL DCM萃取，合并有机层，无水硫酸钠干燥，经制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(三氟乙酸)-乙腈]；乙腈％：10％-40％，8min)纯化得到目标产物13B的三氟乙酸盐。MS m/z：433.1[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 8.62(d，J＝1.88Hz，1H)8.35(d，J＝2.63Hz，1H)8.00(d，J＝8.63Hz，1H)7.92(d，J＝1.50Hz，1H)7.49-7.58(m，2H)4.97(br d，J＝3.25Hz，2H)4.54(s，2H)3.78(br s，1H)3.56(br d，J＝12.26Hz，1H)3.51-3.61(m，1H)3.40-3.49(m，3H)2.96(s，3H)2.21-2.30(m，1H)1.23(br d，J＝6.63Hz，3H)1.10-1.17(m，2H)0.87-0.94(m，2H)。化合物13B的三氟乙酸盐经手性HPLC分析(色谱柱：Chiralcel OJ-3 100*4.6mm I.D.，3μm；流动相：A：CO 2B：甲醇(0.05％二乙胺)；梯度洗脱：4min B从5％升到40％，40％B保持2.5min，然后5％B保持1.5min；流速：2.8mL/min；柱温：35℃；压力：1500psi)，确定其保留时间Rt＝5.239min，ee％＝97.76％。 14d (32.95 mg, 121.71 μmol), KI (3.67 mg, 22.13 μmol) and K 2 CO 3 (45.88 mg, 331.93 μmol) were added to DMF (4 mL) at 25°C, 11b (30 mg, 110.64 μmol) was added, and the temperature was increased to 50 °C, stirring was continued for 2 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was cooled to room temperature, 40 mL of water was added, extracted with 3*10 mL of DCM, the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [H 2 O(trifluoroacetic acid)-acetonitrile]; acetonitrile %: 10%-40%, 8 min) was purified to obtain the trifluoroacetic acid salt of the target product 13B. MS m/z: 433.1 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.62 (d, J=1.88 Hz, 1H) 8.35 (d, J=2.63 Hz, 1H) 8.00 (d, J=8.63 Hz, 1H) 7.92 (d, J= 1.50Hz, 1H) 7.49-7.58(m, 2H) 4.97(br d, J=3.25Hz, 2H) 4.54(s, 2H) 3.78(br s, 1H) 3.56(br d, J=12.26Hz, 1H) 3.51-3.61(m, 1H) 3.40-3.49(m, 3H) 2.96(s, 3H) 2.21-2.30(m, 1H) 1.23(br d, J=6.63Hz, 3H) 1.10-1.17(m, 2H) 0.87-0.94 (m, 2H). The trifluoroacetate salt of compound 13B was analyzed by chiral HPLC (column: Chiralcel OJ-3 100*4.6 mm ID, 3 μm; mobile phase: A: CO 2 B: methanol (0.05% diethylamine); gradient elution: 4min B increased from 5% to 40%, 40% B was maintained for 2.5min, and then 5%B was maintained for 1.5min; flow rate: 2.8mL/min; column temperature: 35°C; pressure: 1500psi), determine its retention time Rt=5.239 min,ee%=97.76%.
实施例21Example 21
Figure PCTCN2022088181-appb-000136
Figure PCTCN2022088181-appb-000136
步骤1：化合物21b的合成Step 1: Synthesis of Compound 21b
0℃将21a(4g，18.49mmol)，咪唑(1.51g，22.19mmol)加入DCM(50mL)，缓慢滴加TBSCl(3.07g，20.34mmol，2.49mL)，滴毕，升至室温，反应12小时。TLC检测原料反应完全，停止继续反应。反应液用2*30mL水洗涤，无水硫酸钠干燥，浓缩得粗品，经柱层析(PE∶EA＝1∶1)纯化得化合物21b。21a (4 g, 18.49 mmol), imidazole (1.51 g, 22.19 mmol) were added to DCM (50 mL) at 0°C, TBSCl (3.07 g, 20.34 mmol, 2.49 mL) was slowly added dropwise, the dropping was completed, the temperature was raised to room temperature, and the reaction was carried out for 12 hours. . TLC detected that the reaction of the raw materials was complete, and the reaction was stopped. The reaction solution was washed with 2*30 mL of water, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by column chromatography (PE:EA=1:1) to obtain compound 21b.
步骤2：化合物21c的合成Step 2: Synthesis of Compound 21c
向1h(1.96g，9.08mmol)的二氧六环(50mL)溶液中，加入21b(3.0g，9.08mmol)，Pd-Xphos-G3(759.10mg，907.61μmol)，Cs 2CO 3(8.87g，27.23mmol)，100℃反应8小时。LCMS检测原料反应完全，停止继续反应。反应液经硅藻土过滤，再用DCM洗涤，滤液浓缩得粗品。粗品经硅胶柱层析(PE∶EA＝1∶1)纯化得产物21c。MS m/z：466.1[M+H] +。 To a solution of 1 h (1.96 g, 9.08 mmol) in dioxane (50 mL) was added 21b (3.0 g, 9.08 mmol), Pd-Xphos-G3 (759.10 mg, 907.61 μmol), Cs 2 CO 3 (8.87 g) , 27.23 mmol), and reacted at 100 °C for 8 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was filtered through celite, washed with DCM, and the filtrate was concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (PE:EA=1:1) to obtain product 21c. MS m/z: 466.1 [M+H] + .
步骤3：化合物21d的合成Step 3: Synthesis of Compound 21d
25℃将21c(1.4g，3.01mmol)加入甲胺的乙醇溶液(1.41g，15.03mmol，33％含量)，搅拌反应12小 时。LCMS检测原料反应完全，停止继续反应。蒸出有机溶剂得目标产物21d。MS m/z：465.2[M+H] +。 21c (1.4 g, 3.01 mmol) was added to a solution of methylamine in ethanol (1.41 g, 15.03 mmol, 33% content) at 25°C and the reaction was stirred for 12 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The organic solvent was evaporated to obtain the target product 21d. MS m/z: 465.2 [M+H] + .
步骤4：化合物21e的合成Step 4: Synthesis of Compound 21e
向21d(1.4g，3.01mmol)的THF(30mL)中加入TBAF(1M，6.03mL)，25℃反应12小时。LCMS检测原料反应完全，停止继续反应.向反应液中加入水(50mL)，加入乙酸乙酯(50mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得粗品。粗品经制备硅胶柱层析分离(DCM∶MeOH＝10∶1)得到目标产物21e。MS m/z：351.0[M+H] +。 TBAF (1 M, 6.03 mL) was added to 21d (1.4 g, 3.01 mmol) in THF (30 mL), and the mixture was reacted at 25°C for 12 hours. LCMS detected that the reaction of the raw materials was complete, and the continued reaction was stopped. Water (50 mL) was added to the reaction solution, ethyl acetate (50 mL*3) was added for extraction, the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative silica gel column chromatography (DCM:MeOH=10:1) to obtain the target product 21e. MS m/z: 351.0 [M+H] + .
步骤5：化合物21f盐酸盐的合成Step 5: Synthesis of Compound 21f Hydrochloride
将HCl/EtOAc(4M，8.77mL)加入21e(1.0g，2.85mmol)的EtOAc(10mL)中，25℃搅拌反应。LCMS检测原料反应完全，停止继续反应。过滤、收集滤饼、干燥得化合物21f的盐酸盐。MS m/z：250.9[M+H] +。 HCl/EtOAc (4M, 8.77 mL) was added to 21e (1.0 g, 2.85 mmol) in EtOAc (10 mL) and the reaction was stirred at 25°C. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. Filter, collect the filter cake, and dry to obtain the hydrochloride salt of compound 21f. MS m/z: 250.9 [M+H] + .
步骤6：化合物2B的三氟乙酸盐的合成Step 6: Synthesis of Trifluoroacetate Salt of Compound 2B
25℃将21f(73.04mg，254.70μmol)，KI(7.69mg，46.31μmol)和K 2CO 3(96.00mg，694.63μmol)加入DMF(4mL)中，加入5d(60mg，231.54μmol)，升温50℃，继续搅拌2小时。LCMS检测原料反应完全，停止反应。反应液减压抽滤，滤液直接送分离纯化。粗品经制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3um；流动相：[水(三氟乙酸)-乙腈；乙腈％：10％-40％，8min)纯化得到2B的三氟乙酸盐。MS m/z：437.1[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 8.66(d，J＝1.88Hz，1H)8.39(d，J＝2.75Hz，1H)7.88-8.05(m，3H)7.55(dd，J＝8.88，2.88Hz，1H)4.32-4.48(m，2H)4.14(br d，J＝13.63Hz，1H)3.92-4.05(m，2H)3.71(br d，J＝7.63Hz，1H)3.38-3.53(m，4H)3.19-3.29(m，1H)2.96(s，3H)2.66-2.78(m，2H)1.31(t，J＝7.44Hz，3H)。化合物2B的三氟乙酸盐经手性HPLC分析(色谱柱：Chiralpak IE-3 50*4.6mm I.D.，3μm，流动相：A：甲醇(0.05％二乙胺)B：乙腈，等度洗脱：A/B＝50/50，流速：1.0mL/min，柱温：35℃)，确定其保留时间Rt＝10.268min，ee％＝99.04％。 21f (73.04 mg, 254.70 μmol), KI (7.69 mg, 46.31 μmol) and K 2 CO 3 (96.00 mg, 694.63 μmol) were added to DMF (4 mL) at 25°C, 5d (60 mg, 231.54 μmol) was added, and the temperature was increased to 50 °C, stirring was continued for 2 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was filtered under reduced pressure, and the filtrate was directly sent for separation and purification. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 100*40mm*3um; mobile phase: [water (trifluoroacetic acid)-acetonitrile; % acetonitrile: 10%-40%, 8 min) to obtain the trifluoroacetate salt of 2B . MS m/z: 437.1 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.66 (d, J=1.88 Hz, 1H) 8.39 (d, J=2.75 Hz, 1H) 7.88-8.05 (m, 3H) 7.55 (dd, J=8.88, 2.88 Hz, 1H) 4.32-4.48 (m, 2H) 4.14 (br d, J=13.63Hz, 1H) 3.92-4.05 (m, 2H) 3.71 (br d, J=7.63Hz, 1H) 3.38-3.53 (m, 4H) 3.19-3.29 (m, 1H) 2.96 (s, 3H) 2.66-2.78 (m, 2H) 1.31 (t, J=7.44 Hz, 3H). The trifluoroacetate salt of compound 2B was analyzed by chiral HPLC (column: Chiralpak IE-3 50*4.6 mm ID, 3 μm, mobile phase: A: methanol (0.05% diethylamine) B: acetonitrile, isocratic elution: A/B=50/50, flow rate: 1.0 mL/min, column temperature: 35°C), determine its retention time Rt=10.268min, ee%=99.04%.
实施例22Example 22
Figure PCTCN2022088181-appb-000137
Figure PCTCN2022088181-appb-000137
步骤1：化合物8B的三氟乙酸盐的合成Step 1: Synthesis of the trifluoroacetate salt of compound 8B
25℃将21f(34.90mg，121.70μmol)，KI(3.67mg，22.13μmol)和K 2CO 3(45.88mg，331.92μmol)加入DMF(4mL)中，加入21f(30mg，110.64μmol)，升温50℃，继续搅拌2小时。LCMS检测原料反应完全，停止反应。反应液减压抽滤，滤液直接送分离纯化。粗品经制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3um；流动相：[水(三氟乙酸)-乙腈]；乙腈％：5％-35％，8min)纯化得到8B的三氟乙酸盐。MS m/z：449.1[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 8.64(d，J＝1.88Hz，1H)8.39(d，J＝2.75Hz，1H)8.00(d，J＝8.75Hz，1H)7.94(d，J＝1.63Hz，1H)7.55(s，2H)4.32-4.45(m，2H)4.13(br d，J＝13.63Hz，1H)3.92-4.05(m，2H)3.70(br d，J＝8.25Hz，1H)3.38-3.52(m，4H)3.19-3.29(m，1H)2.96(s，3H)2.19-2.30(m，1H)1.08-1.17(m，2H)0.86-0.94(m，2H)。化合物8B的三氟乙酸盐经手性HPLC分析(色谱柱：Chiralpak IE- 3 50*4.6mm I.D.，3μm；流动相：MeOH(0.05％二乙胺)；流速：1.0mL/min；柱温：35℃)，确定其保留时间Rt＝8.836min，ee％＝99.15％。 21f (34.90 mg, 121.70 μmol), KI (3.67 mg, 22.13 μmol) and K 2 CO 3 (45.88 mg, 331.92 μmol) were added to DMF (4 mL) at 25°C, 21f (30 mg, 110.64 μmol) was added, and the temperature was increased to 50 °C, stirring was continued for 2 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was filtered under reduced pressure, and the filtrate was directly sent for separation and purification. The crude product was purified by preparative HPLC (chromatographic column: Welch Xtimate C18 100*40mm*3um; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 5%-35%, 8 min) to obtain 8B of trifluoroacetic acid Salt. MS m/z: 449.1 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.64 (d, J=1.88 Hz, 1H) 8.39 (d, J=2.75 Hz, 1H) 8.00 (d, J=8.75 Hz, 1H) 7.94 (d, J= 1.63Hz, 1H) 7.55(s, 2H) 4.32-4.45(m, 2H) 4.13(br d, J=13.63Hz, 1H) 3.92-4.05(m, 2H) 3.70(br d, J=8.25Hz, 1H ) 3.38-3.52 (m, 4H) 3.19-3.29 (m, 1H) 2.96 (s, 3H) 2.19-2.30 (m, 1H) 1.08-1.17 (m, 2H) 0.86-0.94 (m, 2H). The trifluoroacetate salt of compound 8B was analyzed by chiral HPLC (column: Chiralpak IE-3 50*4.6 mm ID, 3 μm; mobile phase: MeOH (0.05% diethylamine); flow rate: 1.0 mL/min; column temperature: 35°C), determine its retention time Rt=8.836min, ee%=99.15%.
实施例23Example 23
Figure PCTCN2022088181-appb-000138
Figure PCTCN2022088181-appb-000138
步骤1：化合物23a的合成Step 1: Synthesis of Compound 23a
0℃将化合物15e(30mg，85.61μmol)加入到DCM(5mL)溶液中，将Et3N(21.66mg，214.03μmol，29.79μL)和MsCl(170mg，1.48mmol，114.86μL)加入到反应中，反应0℃搅拌1小时。LCMS检测原料反应完全，停止继续反应。反应液减压抽滤，滤液直接送制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(三氟乙酸)-乙腈]；乙腈％：5％-35％，8min)分离纯化得到23a的三氟乙酸盐。MS m/z：429.2[M+H] +。 Compound 15e (30 mg, 85.61 μmol) was added to DCM (5 mL) solution at 0°C, Et3N (21.66 mg, 214.03 μmol, 29.79 μL) and MsCl (170 mg, 1.48 mmol, 114.86 μL) were added to the reaction, and the reaction was 0 Stir at °C for 1 hour. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was filtered under reduced pressure, and the filtrate was directly sent to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [H 2 O (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 5%-35%, 8min) separation and purification to obtain the trifluoroacetic acid salt of 23a. MS m/z: 429.2 [M+H] + .
步骤2：化合物23b的合成Step 2: Synthesis of Compound 23b
将化合物23a(20mg，46.67μmol)加入到DMF(5mL)溶液中，将NaCN(60mg，1.22mmol)加入到反应液中，反应100℃搅拌10小时。TLC检测原料反应完全。向反应液加入50mL，用3*15mL乙酸乙酯进行萃取，合并有机相，无水硫酸钠干燥，浓缩得产物粗品，经柱层析纯化得到化合物23b。Compound 23a (20 mg, 46.67 μmol) was added to DMF (5 mL) solution, NaCN (60 mg, 1.22 mmol) was added to the reaction solution, and the reaction was stirred at 100° C. for 10 hours. TLC detected that the reaction of the raw materials was complete. 50 mL was added to the reaction solution, extracted with 3*15 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography to obtain compound 23b.
步骤3：化合物23c的盐酸盐的合成Step 3: Synthesis of the hydrochloride salt of compound 23c
20℃将化合物23b(16.78mg，46.67μmol)加入到EtOAc(5mL)溶液中，将HCl/EtOAc(4M，58.34μL)加入到反应液中，反应20℃搅0.5小时。TLC检测原料反应完全。反应液浓缩得产物23c的盐酸盐。Compound 23b (16.78 mg, 46.67 μmol) was added to EtOAc (5 mL) solution at 20°C, HCl/EtOAc (4M, 58.34 μL) was added to the reaction solution, and the reaction was stirred at 20°C for 0.5 hour. TLC detected that the reaction of the raw materials was complete. The reaction solution was concentrated to obtain the hydrochloride salt of product 23c.
步骤4：化合物5B的三氟乙酸盐的合成Step 4: Synthesis of the trifluoroacetate salt of compound 5B
将化合物23c的盐酸盐(15mg，57.89μmol)和化合物5d(18.92mg，63.96μmol)加入到DMF(3mL)溶液中，将K 2CO 3(40.00mg，289.43μmol)和KI(960.90μg，5.79μmol)加入到反应液中，反应50℃搅拌2小时。LCMS检测原料反应完全。反应液减压抽滤滤液直接送分离纯化。粗品经制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[水(三氟乙酸)-乙腈]；乙腈％：5％-35％，8min)纯化得到5B的三氟乙酸盐。MS m/z：446.3[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 8.63(d，J＝1.76Hz，1H)8.37(d，J＝2.51Hz，1H)7.99-8.05(m，2H)7.89(s，1H)7.59(dd，J＝9.03，2.51Hz，1H)4.63(s，1H)3.90-4.12(m，2H)3.75(br d， J＝13.30Hz，1H)3.40(s，1H)3.20(d，J＝11.29Hz，2H)3.03-3.12(m，1H)2.95-2.99(m，3H)2.79-2.91(m，2H)2.63-2.79(m，3H)1.32(t，J＝7.40Hz，3H)。 The hydrochloride salt of compound 23c (15 mg, 57.89 μmol) and compound 5d (18.92 mg, 63.96 μmol) were added to DMF (3 mL) solution, K 2 CO 3 (40.00 mg, 289.43 μmol) and KI (960.90 μg, 5.79 μmol) was added to the reaction solution, and the reaction was stirred at 50° C. for 2 hours. The reaction of the raw materials was detected by LCMS. The reaction solution was filtered under reduced pressure and the filtrate was directly sent for separation and purification. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [water(trifluoroacetic acid)-acetonitrile]; % acetonitrile: 5%-35%, 8min) to give 5B of trifluoroacetic acid Salt. MS m/z: 446.3 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.63 (d, J=1.76 Hz, 1H) 8.37 (d, J=2.51 Hz, 1H) 7.99-8.05 (m, 2H) 7.89 (s, 1H) 7.59 (dd , J=9.03, 2.51Hz, 1H) 4.63(s, 1H) 3.90-4.12(m, 2H) 3.75(br d, J=13.30Hz, 1H) 3.40(s, 1H) 3.20(d, J=11.29Hz , 2H) 3.03-3.12 (m, 1H) 2.95-2.99 (m, 3H) 2.79-2.91 (m, 2H) 2.63-2.79 (m, 3H) 1.32 (t, J=7.40Hz, 3H).
实施例24Example 24
Figure PCTCN2022088181-appb-000139
Figure PCTCN2022088181-appb-000139
步骤1：化合物24a的合成Step 1: Synthesis of Compound 24a
将9b(966mg，4.13mmol)溶于甲苯(25mL)中，然后加入18a(827.14mg，4.13mmol)，Ruphos(192.62mg，413.00μmol)，Pd 2(dba) 3(189.00mg，206.50μmol)，Cs 2CO 3(4.03g，12.39mmol)。氮气氛围下100℃搅拌16小时。LCMS显示原料反应完全，主峰为目标产物。反应完成后，反应液通过硅藻土抽滤，将滤液减压旋干得到粗品。粗品通过硅胶柱层析分离(PE∶EA＝5∶1)，得到目标产物24a。MS m/z：354.2[M+H] +。 1H NMR(400MHz，CDCl 3)δppm 1.19-1.21(m，3H)1.51(s，9H)3.01-3.20(m，1H)3.21-3.33(m，2H)3.43-3.53(m，1H)3.95-4.00(m，3H)4.04-4.54(m，3H)6.74-6.82(m，1H)8.13-8.18(m，1H)。 9b (966 mg, 4.13 mmol) was dissolved in toluene (25 mL), followed by the addition of 18a (827.14 mg, 4.13 mmol), Ruphos (192.62 mg, 413.00 μmol), Pd2(dba)3 ( 189.00 mg, 206.50 μmol), Cs2CO3 ( 4.03 g, 12.39 mmol). Stir at 100°C for 16 hours under nitrogen atmosphere. LCMS showed that the reaction of the starting materials was complete, and the main peak was the target product. After the completion of the reaction, the reaction solution was suction filtered through celite, and the filtrate was spin-dried under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (PE:EA=5:1) to obtain the target product 24a. MS m/z: 354.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δppm 1.19-1.21(m,3H)1.51(s,9H)3.01-3.20(m,1H)3.21-3.33(m,2H)3.43-3.53(m,1H)3.95- 4.00 (m, 3H) 4.04-4.54 (m, 3H) 6.74-6.82 (m, 1H) 8.13-8.18 (m, 1H).
步骤2：化合物24b的合成Step 2: Synthesis of Compound 24b
将24a(1.19g，3.37mmol)溶解于EtOH(10mL)，加入甲胺(3.49g，33.67mmol，30％purity)乙醇溶液，25℃搅拌反应16小时。LCMS显示原料反应完全。反应结束，将反应液直接旋干得到粗品。将粗品通过硅胶柱层析分离(PE∶EA＝2∶1)得到目标产物24b。MSm/z：353.2[M+H] +。 1H NMR(400MHz，CDCl 3)δppm 1.09(d，J＝6.63Hz，3H)1.42(s，9H)2.92(d，J＝5.00Hz，3H)2.98-3.23(m，3H)3.29-3.39(m，1H)3.86-4.00(m，2H)4.03-4.09(m，1H)6.66-6.78(m，1H)7.45-7.56(m，1H)7.84-7.91(m，1H)。 24a (1.19 g, 3.37 mmol) was dissolved in EtOH (10 mL), methylamine (3.49 g, 33.67 mmol, 30% purity) ethanol solution was added, and the reaction was stirred at 25° C. for 16 hours. LCMS showed complete reaction of starting material. After the reaction was completed, the reaction solution was directly spin-dried to obtain a crude product. The crude product was separated by silica gel column chromatography (PE:EA=2:1) to obtain the target product 24b. MS m/z: 353.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δppm 1.09 (d, J=6.63 Hz, 3H) 1.42 (s, 9H) 2.92 (d, J=5.00 Hz, 3H) 2.98-3.23 (m, 3H) 3.29-3.39 ( m, 1H) 3.86-4.00 (m, 2H) 4.03-4.09 (m, 1H) 6.66-6.78 (m, 1H) 7.45-7.56 (m, 1H) 7.84-7.91 (m, 1H).
步骤3：化合物24c盐酸盐的合成Step 3: Synthesis of Compound 24c Hydrochloride
将24b(829mg，2.35mmol)溶于乙酸乙酯(10mL)，将HCl/EtOAc(4M，5.88mL)滴加至反应液中，25℃下搅拌反应2小时。LCMS显示原料反应完全。将反应液抽滤，滤饼用乙酸乙酯洗涤三次，干燥后即得24c的盐酸盐。MS m/z：253.3[M+H] +。 24b (829 mg, 2.35 mmol) was dissolved in ethyl acetate (10 mL), HCl/EtOAc (4 M, 5.88 mL) was added dropwise to the reaction solution, and the reaction was stirred at 25° C. for 2 hours. LCMS showed complete reaction of starting material. The reaction solution was suction filtered, the filter cake was washed three times with ethyl acetate, and the hydrochloride of 24c was obtained after drying. MS m/z: 253.3 [M+H] + .
步骤4：化合物24A的三氟乙酸盐的合成Step 4: Synthesis of the Trifluoroacetate Salt of Compound 24A
将24c的盐酸盐(70mg，270.13μmol)和5d(85.80mg，297.15μmol)溶于DMF(3mL)中，加入KI(4.48mg，27.01μmol)和K 2CO 3(186.68mg，1.35mmol)，50℃下搅拌反应2小时。LCMS监测反应显示原料反应完全。反应液减压抽滤滤液直接送分离纯化。粗品通过制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[水(三氟乙酸)-乙腈]；乙腈％：8％-38％，8min)纯化得到目标产物24A的三氟乙酸盐。 MS m/z：439.3[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 1.27-1.34(m，6H)2.66-2.76(m，2H)2.93(s，3H)3.29(br s，1H)3.35-3.66(m，5H)3.91(br d，J＝13.63Hz，1H)4.50(br d，J＝7.38Hz，1H)4.55(s，2H)7.18-7.29(m，1H)7.87-7.94(m，1H)7.93-8.02(m，1H)8.14-8.25(m，1H)8.60-8.68(m，1H)。 The hydrochloride salt of 24c (70 mg, 270.13 μmol) and 5d (85.80 mg, 297.15 μmol) were dissolved in DMF (3 mL), KI (4.48 mg, 27.01 μmol) and K 2 CO 3 (186.68 mg, 1.35 mmol) were added , and the reaction was stirred at 50 °C for 2 hours. Monitoring the reaction by LCMS showed that the starting material was complete. The reaction solution was filtered under reduced pressure and the filtrate was directly sent for separation and purification. The crude product was purified by preparative HPLC (chromatographic column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 8%-38%, 8min) to obtain the target product 24A trifluorocarbon acetate. MS m/z: 439.3 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 1.27-1.34 (m, 6H) 2.66-2.76 (m, 2H) 2.93 (s, 3H) 3.29 (br s, 1H) 3.35-3.66 (m, 5H) 3.91 ( br d, J=13.63Hz, 1H) 4.50 (br d, J=7.38Hz, 1H) 4.55(s, 2H) 7.18-7.29(m, 1H) 7.87-7.94(m, 1H) 7.93-8.02(m, 1H) 8.14-8.25 (m, 1H) 8.60-8.68 (m, 1H).
实施例25Example 25
Figure PCTCN2022088181-appb-000140
Figure PCTCN2022088181-appb-000140
步骤1：中间体25b的合成Step 1: Synthesis of Intermediate 25b
向化合物25a(220mg，973.15μmol)，原料3b(217.50mg，1.17mmol)的甲苯(10mL)溶液中加入Pd 2(dba) 3(89.11mg，97.32μmol)，RuPhos(90.82mg，194.63μmol，)，Cs 2CO 3(951.22mg，2.92mmol)。氮气保护下100℃搅拌16小时。反应液冷却至室温，过滤，滤液减压浓缩得粗品。粗品经柱层析分离纯化(PE∶EA＝1∶2)得中间体25b。MS m/z：331.9[M+1] +。 To a solution of compound 25a (220 mg, 973.15 μmol), starting material 3b (217.50 mg, 1.17 mmol) in toluene (10 mL) was added Pd2(dba )3 ( 89.11 mg, 97.32 μmol), RuPhos (90.82 mg, 194.63 μmol,) , Cs2CO3 ( 951.22 mg, 2.92 mmol). Stir at 100°C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (PE:EA=1:2) to obtain intermediate 25b. MS m/z: 331.9 [M+1] + .
步骤2：中间体25c盐酸盐的合成Step 2: Synthesis of Intermediate 25c Hydrochloride
向中间体25b(30mg，90.52μmol)的乙酸乙酯(2mL)溶液中加入HCl/EtOAc(4M，5mL)，25℃搅拌16小时。反应液直接减压浓缩得中间体25c的盐酸盐。MS m/z：231.9[M+1] +。 To a solution of intermediate 25b (30 mg, 90.52 μmol) in ethyl acetate (2 mL) was added HCl/EtOAc (4 M, 5 mL) and stirred at 25° C. for 16 hours. The reaction solution was directly concentrated under reduced pressure to obtain the hydrochloride of intermediate 25c. MS m/z: 231.9 [M+1] + .
步骤3：化合物25三氟乙酸盐的合成Step 3: Synthesis of Compound 25 Trifluoroacetate
向化合物25c(30mg，112.04μmol，HCl)，中间体11b(30.38mg，112.04μmol，HCl)的DMF(2mL)溶液中加入碘化钾(3.72mg，22.41μmol)，碳酸钾(61.94mg，448.16μmol)。50℃搅拌16小时。反应液直接过滤，滤液直接送分离纯化。粗品通过制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[水(三氟乙酸)-乙腈]；乙腈％：12％-42％，8min)分离得化合物25的三氟乙酸盐。MS m/z：430.3[M+1] +。 1H NMR(400MHz，CD 3OD)δ8.60(d，J＝1.76Hz，1H)，7.89(s，1H)，7.63(d，J＝8.53Hz，1H)，7.53(s，1H)，7.10-7.17(m，2H)，4.59(s，2H)，4.42(s，2H)，3.40-3.81(m，8H)，3.15(s，3H)，2.17-2.32(m，1H)，1.06-1.16(m，2H)，0.81-0.93(m，2H)。 To a solution of compound 25c (30 mg, 112.04 μmol, HCl), intermediate 11b (30.38 mg, 112.04 μmol, HCl) in DMF (2 mL) was added potassium iodide (3.72 mg, 22.41 μmol), potassium carbonate (61.94 mg, 448.16 μmol) . Stir at 50°C for 16 hours. The reaction solution was directly filtered, and the filtrate was directly sent for separation and purification. The crude product was separated by preparative HPLC (chromatographic column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile%: 12%-42%, 8min) to obtain the trifluoroacetate of compound 25 acid salt. MS m/z: 430.3 [M+1] + . 1 H NMR (400 MHz, CD 3 OD) δ 8.60 (d, J=1.76 Hz, 1H), 7.89 (s, 1H), 7.63 (d, J=8.53 Hz, 1H), 7.53 (s, 1H), 7.10-7.17(m, 2H), 4.59(s, 2H), 4.42(s, 2H), 3.40-3.81(m, 8H), 3.15(s, 3H), 2.17-2.32(m, 1H), 1.06- 1.16 (m, 2H), 0.81-0.93 (m, 2H).
实施例26Example 26
Figure PCTCN2022088181-appb-000141
Figure PCTCN2022088181-appb-000141
步骤1：中间体26b的合成Step 1: Synthesis of Intermediate 26b
将26a(1g，5.71mmol)溶于甲苯中(10mL)中，然后加入3b(1.28g，6.86mmol)，Ruphos(266.65mg，0.57mmol)，Pd 2(dba) 3(261.64mg，0.29mmol)，Cs 2CO 3(5.59g，17.14mmol)。氮气氛围下100℃搅拌16小时。反应液过滤，将滤液减压旋干得到粗品。粗品经柱层析分离(PE∶EA＝5∶1)，得到中间体26b。MSm/z：280.9[M+1] +。 1H NMR(400MHz，CDCl 3)δppm 1.48-1.51(m，9H)，3.02-3.10(m，4H)，3.56-3.63(m，4H)，6.86-6.93(m，2H)，6.95-7.02(m，2H)。 26a (1 g, 5.71 mmol) was dissolved in toluene (10 mL), then 3b (1.28 g, 6.86 mmol), Ruphos (266.65 mg, 0.57 mmol), Pd2(dba)3 ( 261.64 mg, 0.29 mmol) were added , Cs2CO3 ( 5.59 g, 17.14 mmol). Stir at 100°C for 16 hours under nitrogen atmosphere. The reaction solution was filtered, and the filtrate was spin-dried under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (PE:EA=5:1) to yield intermediate 26b. MSm/z: 280.9[M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δppm 1.48-1.51 (m, 9H), 3.02-3.10 (m, 4H), 3.56-3.63 (m, 4H), 6.86-6.93 (m, 2H), 6.95-7.02 ( m, 2H).
步骤2：中间体26c盐酸盐的合成Step 2: Synthesis of Intermediate 26c Hydrochloride
将26b(1g，3.57mmol)溶于乙酸乙酯(10mL)中，将HCl/EtOAc(4M，8.92mL)滴加至反应液中，25℃下搅拌反应2小时。LCMS显示原料反应完全。将反应液抽滤，滤饼用乙酸乙酯洗涤三次，干燥得中间体26c的盐酸盐。MS m/z：180.8[M+1] +。 26b (1 g, 3.57 mmol) was dissolved in ethyl acetate (10 mL), HCl/EtOAc (4 M, 8.92 mL) was added dropwise to the reaction solution, and the reaction was stirred at 25° C. for 2 hours. LCMS showed complete reaction of starting material. The reaction solution was suction filtered, and the filter cake was washed three times with ethyl acetate and dried to obtain the hydrochloride salt of intermediate 26c. MS m/z: 180.8 [M+1] + .
步骤3：化合物26三氟乙酸盐的合成Step 3: Synthesis of Compound 26 Trifluoroacetate
将26c盐酸盐(30mg，0.11mmol)和11b(23.97mg，110.64μmol)加入至DMF(2mL)中，加入KI(1.84mg，0.011mmol)，K 2CO 3(76.46mg，0.55mmol)，50℃下搅拌反应2小时。LCMS监测反应显示原料反应完全。反应液减压抽滤，滤液直接送分离纯化。粗品通过制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[水(三氟乙酸)-乙腈]；乙腈％：18％-48％，8min)纯化得到化合物26的三氟乙酸盐。MS m/z：379.0[M+1] +。 1H NMR(400MHz，CD 3OD)δppm 0.87-0.96(m，2H)，1.09-1.17(m，2H)，2.18-2.31(m，1H)，3.33-3.92(m，8H)，4.57-4.62(m，2H)，7.02-7.08(m，4H)，7.54-7.58(m，1H)，7.88-7.93(m，1H)，8.58-8.64(m，1H)。 26c hydrochloride (30 mg, 0.11 mmol) and 11b (23.97 mg, 110.64 μmol) were added to DMF (2 mL), KI (1.84 mg, 0.011 mmol), K 2 CO 3 (76.46 mg, 0.55 mmol) were added, The reaction was stirred at 50°C for 2 hours. Monitoring the reaction by LCMS showed that the starting material was complete. The reaction solution was filtered under reduced pressure, and the filtrate was directly sent for separation and purification. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 18%-48%, 8 min) to give compound 26 in trifluoroacetate acid salt. MS m/z: 379.0 [M+1] + . 1 H NMR (400 MHz, CD 3 OD) δppm 0.87-0.96 (m, 2H), 1.09-1.17 (m, 2H), 2.18-2.31 (m, 1H), 3.33-3.92 (m, 8H), 4.57-4.62 (m, 2H), 7.02-7.08 (m, 4H), 7.54-7.58 (m, 1H), 7.88-7.93 (m, 1H), 8.58-8.64 (m, 1H).
实施例27Example 27
Figure PCTCN2022088181-appb-000142
Figure PCTCN2022088181-appb-000142
步骤1：中间体27b的合成Step 1: Synthesis of Intermediate 27b
将原料27a(1g，4.81mmol)加到THF(10mL)中，-10℃氮气保护下搅拌反应，将异丙基氯化镁(2M，3.61mL)加入到反应液中，反应搅拌1小时，将三正丁基氯化锡(1.620g，4.98mmol)滴加到反应液中，25℃反应搅拌2小时。向反应液中加入20mL氯化铵饱和溶液淬灭反应，搅拌15min，乙酸乙酯(40mL*2)萃取，有机相用水(2*40mL)和饱和食盐水(2*10mL)洗涤，合并有机相，无水硫酸钠干燥，减压浓缩得中间体27b。MS m/z：373.3[M+1] +。 The raw material 27a (1 g, 4.81 mmol) was added to THF (10 mL), and the reaction was stirred under nitrogen protection at -10°C. n-Butyltin chloride (1.620 g, 4.98 mmol) was added dropwise to the reaction solution, and the reaction was stirred at 25° C. for 2 hours. 20mL of saturated ammonium chloride solution was added to the reaction solution to quench the reaction, stirred for 15min, extracted with ethyl acetate (40mL*2), the organic phase was washed with water (2*40mL) and saturated brine (2*10mL), and the organic phases were combined , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 27b. MS m/z: 373.3 [M+1] + .
步骤2：中间体27c的合成Step 2: Synthesis of Intermediate 27c
将27b(300mg，0.81mol)，2，4-二溴吡啶(287.22mg，1.21mmol)，Pd(PPh 3) 4(93.40mg，0.08mmol)加入甲苯(3mL)中，N 2置换三次，升温至100℃反应3小时。将反应液旋干后溶解于DCM，分别用饱和KF溶液、水、饱和氯化钠溶液洗涤一次，有机相旋干得到粗品。粗品经柱层析(DCM∶MeOH＝40∶1)纯化得到中 间体27c。MS m/z：237.8[M+1] +；239.8[M+1] +。 1H NMR(400MHz，DMSO-d 6)δppm 3.67-3.78(m，3H)，7.65-7.76(m，2H)，7.77-7.88(m，1H)，7.94-8.07(m，1H)，8.52-8.65(m，1H)。 27b (300 mg, 0.81 mol), 2,4-dibromopyridine (287.22 mg, 1.21 mmol), Pd(PPh 3 ) 4 (93.40 mg, 0.08 mmol) were added to toluene (3 mL), N 2 was replaced three times, and the temperature was increased. The reaction was carried out at 100°C for 3 hours. The reaction solution was spin-dried, dissolved in DCM, washed once with saturated KF solution, water, and saturated sodium chloride solution, respectively, and the organic phase was spin-dried to obtain a crude product. The crude product was purified by column chromatography (DCM:MeOH=40:1) to give intermediate 27c. MS m/z: 237.8[M+1] + ; 239.8[M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) δppm 3.67-3.78 (m, 3H), 7.65-7.76 (m, 2H), 7.77-7.88 (m, 1H), 7.94-8.07 (m, 1H), 8.52- 8.65 (m, 1H).
步骤3：中间体27d的合成Step 3: Synthesis of Intermediate 27d
依次将27c(80mg，336.02mol)，3b(75.10mg，403.22μmol)，Pd 2(dba) 3(15.38mg，16.80μmol)，RuPhos(15.68mg，33.60μmol)，Cs 2CO 3(328.44mg，1.01mmol)加入甲苯(2mL)中，置换N 2三次，升温至100℃搅拌反应16小时。将反应液过滤，减压浓缩滤液得到粗品。粗品经柱层析(DCM∶MeOH＝40∶1)纯化得中间体27d。MS m/z：344.0[M+1] +。 1H NMR(400MHz，CDCl 3)δppm 1.49-1.52(m，9H)，3.10-3.25(m，4H)，3.58-3.66(m，4H)，3.73-3.80(m，3H)，7.29-7.32(m，1H)，7.44-7.56(m，2H)，7.80-7.93(m，1H)，8.18-8.29(m，1H)。 27c (80 mg, 336.02 mol), 3b (75.10 mg, 403.22 μmol), Pd 2 (dba) 3 (15.38 mg, 16.80 μ mol), RuPhos (15.68 mg, 33.60 μ mol), Cs 2 CO 3 (328.44 mg, 1.01 mmol) was added to toluene (2 mL), N 2 was replaced three times, the temperature was raised to 100 °C and the reaction was stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM:MeOH=40:1) to give intermediate 27d. MS m/z: 344.0 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δppm 1.49-1.52 (m, 9H), 3.10-3.25 (m, 4H), 3.58-3.66 (m, 4H), 3.73-3.80 (m, 3H), 7.29-7.32 ( m, 1H), 7.44-7.56 (m, 2H), 7.80-7.93 (m, 1H), 8.18-8.29 (m, 1H).
步骤4：中间体27e盐酸盐的合成Step 4: Synthesis of Intermediate 27e Hydrochloride
将27d(33mg，96.09μmol)溶解于乙酸乙酯(2mL)中，缓慢滴加HCl/EtOAc(4M，240.23uL)，25℃搅拌反应2小时。LCMS监测显示原料反应完全，直接将反应液旋干得中间体27e的盐酸盐。MS m/z：244.0[M+1] +。 27d (33 mg, 96.09 μmol) was dissolved in ethyl acetate (2 mL), HCl/EtOAc (4 M, 240.23 uL) was slowly added dropwise, and the reaction was stirred at 25° C. for 2 hours. LCMS monitoring showed that the reaction of the raw materials was complete, and the reaction solution was directly spin-dried to obtain the hydrochloride of the intermediate 27e. MS m/z: 244.0 [M+1] + .
步骤5：化合物27三氟乙酸盐的合成Step 5: Synthesis of Compound 27 Trifluoroacetate
将27e盐酸盐(35mg，129.08μmol)，11b(26mg，92.93μmol)溶解于DMF(2mL)中，加入KI(2.14mg，12.91μmol)，K 2CO 3(89.20mg，645.42μmol)后，升温至50℃搅拌反应2小时。将反应液过滤，取滤液通过制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[水(三氟乙酸)-乙腈]；乙腈％：5％-35％，8min)分离纯化得化合物27的三氟乙酸盐。MSm/z：442.0[M+1] +。 1H NMR(400MHz，CD 3OD)δppm0.88-0.92(m，2H)，1.10-1.16(m，2H)，2.21-2.29(m，1H)，3.48-3.54(m，4H)，3.53-3.82(m，4H)，3.97-4.01(m，3H)，4.55-4.61(m，2H)，7.54-7.57(m，1H)，7.58-7.63(m，1H)，7.76-7.85(m，1H)，7.89-7.96(m，1H)，7.97-8.04(m，1H)，8.40-8.46(m，1H)，8.60-8.65(m，1H)，8.80-8.88(m，1H)。 27e hydrochloride (35 mg, 129.08 μmol), 11b (26 mg, 92.93 μmol) were dissolved in DMF (2 mL), KI (2.14 mg, 12.91 μmol), K 2 CO 3 (89.20 mg, 645.42 μmol) were added, The temperature was raised to 50°C and the reaction was stirred for 2 hours. The reaction solution was filtered, and the filtrate was separated and purified by preparative HPLC (chromatographic column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile%: 5%-35%, 8min) The trifluoroacetate salt of compound 27 was obtained. MSm/z: 442.0[M+1] + . 1 H NMR (400 MHz, CD 3 OD) δppm 0.88-0.92 (m, 2H), 1.10-1.16 (m, 2H), 2.21-2.29 (m, 1H), 3.48-3.54 (m, 4H), 3.53- 3.82(m, 4H), 3.97-4.01(m, 3H), 4.55-4.61(m, 2H), 7.54-7.57(m, 1H), 7.58-7.63(m, 1H), 7.76-7.85(m, 1H) ), 7.89-7.96 (m, 1H), 7.97-8.04 (m, 1H), 8.40-8.46 (m, 1H), 8.60-8.65 (m, 1H), 8.80-8.88 (m, 1H).
实施例28Example 28
Figure PCTCN2022088181-appb-000143
Figure PCTCN2022088181-appb-000143
步骤1：中间体28b的合成Step 1: Synthesis of Intermediate 28b
将28a(1.77g，9.66mmol)、3b(2g，10.74mmol)、Pd 2(dba) 3(983.32mg，1.07mmol)、RuPhos(501.08mg，1.07mmol)、Cs 2CO 3(7.00g，21.48mmol)加入至甲苯(60mL)中，N 2保护，升温至100℃搅拌反应16小时。LCMS监测显示原料反应完全。反应液用硅藻土抽滤，旋干得到粗品。粗品通过柱层析(PE∶EA＝4∶1)分离纯化得到中间体28b。MS m/z：289.3[M+1] +。 1H NMR(400MHz，CDCl 3)δppm 1.35-1.43(m，9H)，3.25-3.35(m，4H)，3.49-3.58(m，4H)，6.98-7.08(m，1H)，7.40-7.51(m，1H)，8.18-8.28(m，1H)。 28a (1.77 g, 9.66 mmol), 3b ( 2 g, 10.74 mmol), Pd2(dba) 3 (983.32 mg, 1.07 mmol), RuPhos (501.08 mg, 1.07 mmol), Cs2CO3 (7.00 g, 21.48 mmol) was added to toluene (60 mL), protected with N 2 , warmed to 100 °C and stirred for 16 h. LCMS monitoring showed complete reaction of starting material. The reaction solution was suction-filtered with celite and spin-dried to obtain the crude product. The crude product was isolated and purified by column chromatography (PE:EA=4:1) to obtain intermediate 28b. MS m/z: 289.3 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δppm 1.35-1.43 (m, 9H), 3.25-3.35 (m, 4H), 3.49-3.58 (m, 4H), 6.98-7.08 (m, 1H), 7.40-7.51 ( m, 1H), 8.18-8.28 (m, 1H).
步骤2：中间体28c的合成Step 2: Synthesis of Intermediate 28c
-78℃，N 2保护下，将DIBALH(1M，26.01mL)缓慢滴加至中间体28b(5g，17.34mmol)的DCM(50mL)溶液中，-78℃搅拌1.5小时。LCMS显示原料反应完全。-78℃下缓慢加1mL水，缓慢加入1mL15％NaOH溶液，再加入10mL水。25℃搅拌15min，加入适量无水硫酸钠搅拌10min，滤除固体旋干得到粗品，粗品柱层析(PE∶EA＝3∶1)分离得到中间体28c。MS m/z：291.9[M+1] +。 1H NMR(400MHz，CDCl 3)δppm 1.38-1.46(m，9H)，3.28-3.41(m，4H)，3.49-3.59(m，4H)，7.05-7.13(m，1H)，7.75-7.86(m，1H)，8.24-8.33(m，1H)，9.78-9.92(m，1H)。 DIBALH (1 M, 26.01 mL) was slowly added dropwise to a solution of intermediate 28b (5 g, 17.34 mmol) in DCM (50 mL) at -78 °C under N2 protection, and stirred at -78 °C for 1.5 h. LCMS showed complete reaction of starting material. Slowly add 1 mL of water at -78°C, slowly add 1 mL of 15% NaOH solution, and then add 10 mL of water. Stir at 25°C for 15 min, add an appropriate amount of anhydrous sodium sulfate and stir for 10 min, filter out the solid and spin dry to obtain the crude product, which is separated by column chromatography (PE:EA=3:1) to obtain intermediate 28c. MS m/z: 291.9 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δppm 1.38-1.46 (m, 9H), 3.28-3.41 (m, 4H), 3.49-3.59 (m, 4H), 7.05-7.13 (m, 1H), 7.75-7.86 ( m, 1H), 8.24-8.33 (m, 1H), 9.78-9.92 (m, 1H).
步骤3：中间体28d的合成Step 3: Synthesis of Intermediate 28d
将PPh3(7.20g，27.46mmol)、CBr4(4.55g，13.73mmol)置于反应瓶中，置换N 2三次，加入DCM(40mL)，25℃下搅拌30min；降温至0℃将28c(2g，6.86mmol)缓慢加入反应液，搅拌1小时。将反应液缓慢滴加至饱和碳酸氢钠溶液，搅拌后分液；水相再用2*15mL DCM萃取，合并有机相，并用无水硫酸钠干燥后浓缩得到粗品。粗品经柱层析分离纯化(PE∶EA＝4∶1)得到28d。MSm/z：445.8[M+1] +；447.8[M+1] +； 449.8[M+1] +。 1H NMR(400MHz，CDCl 3)δppm 1.42(s，9H)，3.13-3.20(m，4H)，3.50-3.57(m，4H)，7.06-7.11(m，1H)，7.46-7.56(m，1H)，7.61-7.67(m，1H)，8.16-8.25(m，1H)。 PPh3 (7.20 g, 27.46 mmol), CBr4 (4.55 g, 13.73 mmol) were placed in a reaction flask, N was replaced three times, DCM (40 mL) was added, and stirred at 25 ° C for 30 min; 6.86 mmol) was slowly added to the reaction solution and stirred for 1 hour. The reaction solution was slowly added dropwise to saturated sodium bicarbonate solution, stirred and separated; the aqueous phase was extracted with 2*15 mL of DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (PE:EA=4:1) to obtain 28d. MSm/z: 445.8[M+1] + ; 447.8[M+1] + ; 449.8[M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δppm 1.42 (s, 9H), 3.13-3.20 (m, 4H), 3.50-3.57 (m, 4H), 7.06-7.11 (m, 1H), 7.46-7.56 (m, 1H), 7.61-7.67 (m, 1H), 8.16-8.25 (m, 1H).
步骤4：中间体28e的合成Step 4: Synthesis of Intermediate 28e
将28d(1.7g，3.80mmol)加入至TBAF(1M四氢呋喃溶液，19.01mL)，25℃搅拌反应2小时。反应完全后，浓缩反应液，柱层析分离(PE∶EA＝3∶1)得到中间体28e。MSm/z：365.9[M+1] +；367.9[M+1] +。 1H NMR(400MHz，CDCl 3)δppm 1.50-1.53(m，9H)，3.21-3.29(m，4H)，3.57-3.65(m，4H)，7.05-7.14(m，1H)，7.32-7.39(m，1H)，8.20-8.28(m，1H)。 28d (1.7 g, 3.80 mmol) was added to TBAF (1M tetrahydrofuran solution, 19.01 mL), and the reaction was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was concentrated and separated by column chromatography (PE:EA=3:1) to obtain intermediate 28e. MSm/z: 365.9[M+1] + ; 367.9[M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δppm 1.50-1.53 (m, 9H), 3.21-3.29 (m, 4H), 3.57-3.65 (m, 4H), 7.05-7.14 (m, 1H), 7.32-7.39 ( m, 1H), 8.20-8.28 (m, 1H).
步骤5：中间体28f的合成Step 5: Synthesis of Intermediate 28f
将28e(1g，2.73mmol)、AgF(692.78mg，5.46mmol)加入至乙腈(2mL)和水(0.1mL)中，升温至80℃，搅拌反应4小时。反应完成后浓缩反应液得到粗品，柱层析分离(PE∶EA＝5∶1)得到中间体28f。MS m/z：385.9[M+1] +；387.9[M+1] +。 1H NMR(400MHz，CDCl 3)δppm 1.48-1.53(m，9H)，3.19-3.31(m，4H)，3.56-3.69(m，4H)，6.52-6.68(m，1H)，7.12-7.20(m，1H)，7.39-7.46(m，1H)，8.22-8.30(m，1H)。 28e (1 g, 2.73 mmol), AgF (692.78 mg, 5.46 mmol) were added to acetonitrile (2 mL) and water (0.1 mL), the temperature was raised to 80°C, and the reaction was stirred for 4 hours. After the completion of the reaction, the reaction solution was concentrated to obtain the crude product, which was separated by column chromatography (PE:EA=5:1) to obtain the intermediate 28f. MS m/z: 385.9[M+1] + ; 387.9[M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δppm 1.48-1.53 (m, 9H), 3.19-3.31 (m, 4H), 3.56-3.69 (m, 4H), 6.52-6.68 (m, 1H), 7.12-7.20 ( m, 1H), 7.39-7.46 (m, 1H), 8.22-8.30 (m, 1H).
步骤6：中间体28g的合成Step 6: Synthesis of Intermediate 28g
将28f(30mg，77.67μmol)、MeB(OH) 2(9.30mg，155.34μmol)、Pd(dppf)Cl 2(5.68mg，7.77μmol)、K 2CO 3(32.20mg，233.00μmol)、Ag 2O(45.00mg，194.17μmol)加入THF(0.5mL)中，N 2置换三次，升温至70℃搅拌反应3小时。LCMS检测反应完全。将反应液用硅藻土抽滤，滤液减压浓缩后经柱层析分离纯化(PE∶EA＝5∶1)得到中间体28g。MS m/z：321.9[M+1] +。 1H NMR(400MHz，CDCl 3)δppm 1.39-1.44(m，9H)，1.69-1.82(m，3H)，3.04-3.17(m，4H)，3.47-3.62(m，4H)，5.70-5.93(m，1H)，7.08-7.14(m，1H)，7.25-7.34(m，1H)，8.13-8.23(m，1H)。 28f (30 mg, 77.67 μmol), MeB(OH) 2 (9.30 mg, 155.34 μmol), Pd(dppf)Cl 2 (5.68 mg, 7.77 μmol), K 2 CO 3 (32.20 mg, 233.00 μmol), Ag 2 O (45.00 mg, 194.17 μmol) was added to THF (0.5 mL), N 2 was replaced three times, the temperature was raised to 70 °C and the reaction was stirred for 3 hours. The reaction was complete by LCMS. The reaction solution was suction filtered with celite, the filtrate was concentrated under reduced pressure, and then separated and purified by column chromatography (PE:EA=5:1) to obtain 28 g of intermediate. MS m/z: 321.9 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δppm 1.39-1.44 (m, 9H), 1.69-1.82 (m, 3H), 3.04-3.17 (m, 4H), 3.47-3.62 (m, 4H), 5.70-5.93 ( m, 1H), 7.08-7.14 (m, 1H), 7.25-7.34 (m, 1H), 8.13-8.23 (m, 1H).
步骤7：中间体28h盐酸盐的合成Step 7: Synthesis of intermediate 28h hydrochloride
将28g(20mg，62.23μmol)溶解于乙酸乙酯(2mL)中，加入HCl/EA(4M，155.57gL)，25℃搅拌反应2小时。反应完毕后将反应液减压旋干得到中间体28h的盐酸盐。MS m/z：221.8[M+1] +。 28 g (20 mg, 62.23 μmol) was dissolved in ethyl acetate (2 mL), HCl/EA (4 M, 155.57 gL) was added, and the reaction was stirred at 25° C. for 2 hours. After the completion of the reaction, the reaction solution was spin-dried under reduced pressure to obtain the hydrochloride salt of the intermediate 28h. MS m/z: 221.8 [M+1] + .
步骤8：化合物28三氟乙酸盐的合成Step 8: Synthesis of Compound 28 Trifluoroacetate Salt
将11b(16mg，59.01μmol)，28h(15.21mg，59.01μmol)，KI(979.57ug，5.90μmol)，K 2CO 3(40.78mg，295.05μmol)溶解于DMF(2mL)中，升温至50℃搅拌反应2小时。LCMS显示原料反应完全。过滤反应液，取滤液减压浓缩，将粗品经柱层析分离(DCM∶MeOH＝40∶1)得到化合物28三氟乙酸盐。MSm/z：420.1[M+1] +。 1H NMR(400MHz，CD 3OD)δppm 0.72-0.76(m，2H)，0.95-1.01(m，2H)，1.67-1.72(m，3H)，2.05-2.12(m，1H)，2.55-2.61(m，4H)，3.61-3.65(m，2H)，4.51-4.53(m，4H)，5.59-5.80(m，1H)，7.23-7.33(m，2H)，7.38-7.41(m，1H)，7.63-7.67(m，1H)，8.06-8.10(m，1H)，8.35-8.39(m，1H)。 11b (16 mg, 59.01 μmol), 28h (15.21 mg, 59.01 μmol), KI (979.57ug, 5.90 μmol), K 2 CO 3 (40.78 mg, 295.05 μmol) were dissolved in DMF (2 mL), and the temperature was raised to 50° C. The reaction was stirred for 2 hours. LCMS showed complete reaction of starting material. The reaction solution was filtered, the filtrate was collected and concentrated under reduced pressure, and the crude product was separated by column chromatography (DCM:MeOH=40:1) to obtain compound 28 trifluoroacetic acid salt. MSm/z: 420.1[M+1] + . 1 H NMR (400 MHz, CD 3 OD) δppm 0.72-0.76 (m, 2H), 0.95-1.01 (m, 2H), 1.67-1.72 (m, 3H), 2.05-2.12 (m, 1H), 2.55-2.61 (m, 4H), 3.61-3.65 (m, 2H), 4.51-4.53 (m, 4H), 5.59-5.80 (m, 1H), 7.23-7.33 (m, 2H), 7.38-7.41 (m, 1H) , 7.63-7.67 (m, 1H), 8.06-8.10 (m, 1H), 8.35-8.39 (m, 1H).
实施例29Example 29
Figure PCTCN2022088181-appb-000144
Figure PCTCN2022088181-appb-000144
步骤1：中间体29b的合成Step 1: Synthesis of Intermediate 29b
将29a(1g，5.46mmol)溶解在四氢呋喃(THF)(20mL)溶液中，-20℃下滴加乙基溴化镁(3M，2.00mL)，再缓慢升温至25℃搅拌2小时。0℃滴加1mol/L盐酸水溶液淬灭反应液，再加入乙酸乙酯萃取，有机相用饱和食盐水洗涤，再用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经硅胶柱层析(PE∶EA＝10∶1)纯化得中间体29b。MS m/z：213.7[M+1] +；215.7[M+1] +。 29a (1 g, 5.46 mmol) was dissolved in tetrahydrofuran (THF) (20 mL) solution, ethylmagnesium bromide (3M, 2.00 mL) was added dropwise at -20°C, and the temperature was slowly raised to 25°C and stirred for 2 hours. 1 mol/L aqueous hydrochloric acid solution was added dropwise at 0°C to quench the reaction solution, and then ethyl acetate was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to obtain intermediate 29b. MS m/z: 213.7[M+1] + ; 215.7[M+1] + .
步骤2：中间体29c的合成Step 2: Synthesis of Intermediate 29c
将化合物29b(2.2g，10.28mmol)，3b(1.91g，10.28mmol)加入到甲苯(22mL)溶液中，再加入Pd 2(dba) 3(1.88g，2.06mmol)，RuPhos(959.17mg，2.06mmol)，Cs 2CO 3(10.05g，30.83mmol)，氮气置换后，于氮气保护下100℃搅拌16小时。反应液体过滤，减压浓缩得粗品。粗品经硅胶柱层析分离(PE∶EA＝5∶1)得中间体29c。MS m/z：320.0[M+1] +。 Compounds 29b (2.2 g, 10.28 mmol), 3b (1.91 g, 10.28 mmol) were added to a solution of toluene (22 mL), followed by Pd 2 (dba) 3 (1.88 g, 2.06 mmol), RuPhos (959.17 mg, 2.06 mmol), Cs 2 CO 3 (10.05 g, 30.83 mmol), after nitrogen replacement, stirred at 100° C. for 16 hours under nitrogen protection. The reaction liquid was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (PE:EA=5:1) to obtain intermediate 29c. MS m/z: 320.0 [M+1] + .
步骤3：中间体29d盐酸盐的合成Step 3: Synthesis of Intermediate 29d Hydrochloride
向化合物29c(300mg，939.27μmol)的乙酸乙酯(10mL)溶液中加入HCl/EtOAc(4M，11.74mL)，25℃搅拌16小时。减压浓缩得中间体29d的盐酸盐。MS m/z：219.9[M+1] +。 To a solution of compound 29c (300 mg, 939.27 μmol) in ethyl acetate (10 mL) was added HCl/EtOAc (4 M, 11.74 mL), followed by stirring at 25° C. for 16 hours. Concentration under reduced pressure gave the hydrochloride salt of intermediate 29d. MS m/z: 219.9 [M+1] + .
步骤4：化合物29三氟乙酸盐的合成Step 4: Synthesis of Compound 29 Trifluoroacetate
向化合物29d盐酸盐(20mg，78.20μmol)，11b(20mg，73.76μmol，HCl)的DMF(2mL)溶液中加入碳酸钾(43.23mg，312.81μmol)，碘化钾(2.60mg，15.64μmol)。50℃搅拌3小时。反应液直接过滤。粗品经制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[水(三氟乙酸)-乙腈]；乙腈％：8％-38％，8min)分离得化合物29的三氟乙酸盐。MS m/z：418.2[M+1] +； 1H NMR(400MHz，CD 3OD)δ8.60(d，J＝1.76Hz，1H)，8.41(d，J＝3.02Hz，1H)，8.10(d，J＝9.04Hz，1H)，7.89-7.95(m，1H)，7.65(dd，J＝3.02，9.04Hz，1H)，7.53(s，1H)，4.58(s，2H)，3.78(br s，4H)，3.44-3.60(m，4H)，3.13(q，J＝7.28Hz，2H)，2.15-2.32(m，1H)，1.18(t，J＝7.28Hz，3H)，1.07-1.15(m，2H)，0.83-0.91(m，2H)。 To a solution of compound 29d hydrochloride (20 mg, 78.20 μmol), 11b (20 mg, 73.76 μmol, HCl) in DMF (2 mL) was added potassium carbonate (43.23 mg, 312.81 μmol), potassium iodide (2.60 mg, 15.64 μmol). Stir at 50°C for 3 hours. The reaction solution was directly filtered. The crude product was separated by preparative HPLC (chromatographic column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile%: 8%-38%, 8min) to obtain the trifluoroethyl compound of compound 29 acid salt. MS m/z: 418.2 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.60 (d, J=1.76 Hz, 1H), 8.41 (d, J=3.02 Hz, 1H), 8.10 (d, J=9.04Hz, 1H), 7.89-7.95(m, 1H), 7.65(dd, J=3.02, 9.04Hz, 1H), 7.53(s, 1H), 4.58(s, 2H), 3.78( br s, 4H), 3.44-3.60 (m, 4H), 3.13 (q, J=7.28Hz, 2H), 2.15-2.32 (m, 1H), 1.18 (t, J=7.28Hz, 3H), 1.07- 1.15 (m, 2H), 0.83-0.91 (m, 2H).
实施例30Example 30
Figure PCTCN2022088181-appb-000145
Figure PCTCN2022088181-appb-000145
步骤1：中间体30a的合成Step 1: Synthesis of Intermediate 30a
将中间体28b(0.1g，346.81μmol)、甲醇钠(56.21mg，1.04mmol)加入MeOH(2mL)，65℃反应2h。LCMS显示原料反应完全，停止反应。得到中间体30a，反应液无需后处理，直接进行下一步。MS m/z：320.9[M+H] +。 Intermediate 28b (0.1 g, 346.81 μmol) and sodium methoxide (56.21 mg, 1.04 mmol) were added to MeOH (2 mL) and reacted at 65° C. for 2 h. LCMS showed complete reaction of starting material and the reaction was stopped. Intermediate 30a is obtained, and the reaction solution does not need post-treatment, and directly proceeds to the next step. MS m/z: 320.9 [M+H] + .
步骤2：中间体30b的合成Step 2: Synthesis of Intermediate 30b
将2，2-二乙氧基乙胺(207.86mg，1.56mmol)、醋酸(93.72mg，1.56mmol)加入中间体30a(0.5g，1.56mmol，1eq)的MeOH(10mL)中，65℃反应0.5小时。LCMS显示原料反应完全，停止反应。得到中间体30b，反应液无需后处理，直接进行下一步。MS m/z：422.1[M+H] +。 2,2-diethoxyethylamine (207.86 mg, 1.56 mmol) and acetic acid (93.72 mg, 1.56 mmol) were added to intermediate 30a (0.5 g, 1.56 mmol, 1 eq) in MeOH (10 mL), and reacted at 65°C 0.5 hours. LCMS showed complete reaction of starting material and the reaction was stopped. Intermediate 30b is obtained, and the reaction solution does not need post-treatment, and proceeds directly to the next step. MS m/z: 422.1 [M+H] + .
步骤3：中间体30c的合成Step 3: Synthesis of Intermediate 30c
将HCl(5M，4.29mL)、CaCl 2(15.80mg，142.34μmol)加入中间体30b(0.6g，1.42mmol)的MeOH(5mL)中，升温65℃反应4h。LCMS检测原料反应完全，停止继续反应。用饱和NaHCO 3调节反应液pH＝7～8，用3*10mL二氯甲烷萃取，除去水层中的杂质，得到中间体30c的水溶液粗品，直接用于下步反应。MS m/z：229.9[M+H] +。 HCl (5M, 4.29 mL), CaCl 2 (15.80 mg, 142.34 μmol) were added to intermediate 30b (0.6 g, 1.42 mmol) in MeOH (5 mL), and the temperature was increased to 65° C. to react for 4 h. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. Adjust the pH of the reaction solution to 7-8 with saturated NaHCO 3 , extract with 3*10 mL of dichloromethane, remove impurities in the aqueous layer, and obtain a crude aqueous solution of intermediate 30c, which is directly used in the next step. MS m/z: 229.9 [M+H] + .
步骤4：中间体30d的合成Step 4: Synthesis of Intermediate 30d
在25℃下，将(Boc) 2O(1.14g，5.23mmol)、三乙胺(529.60mg，5.23mmol)加入中间体30c(0.4g，1.74mmol)的水(20mL)中，反应3小时。LCMS检测原料反应完全，停止继续反应。用3*15mLDCM进行萃取，无水硫酸钠干燥，浓缩得中间体30d。MS m/z：330.0[M+H] +。 At 25°C, (Boc) 2 O (1.14 g, 5.23 mmol) and triethylamine (529.60 mg, 5.23 mmol) were added to intermediate 30c (0.4 g, 1.74 mmol) in water (20 mL) and reacted for 3 hours . The reaction of the raw materials was detected by LCMS, and the reaction was stopped. Extract with 3*15mL DCM, dry over anhydrous sodium sulfate, and concentrate to obtain intermediate 30d. MS m/z: 330.0 [M+H] + .
步骤5：中间体30e盐酸盐的合成Step 5: Synthesis of Intermediate 30e Hydrochloride
在25℃下，将HCl/EtOAc(4M，1.21mL)加入中间体30d(0.4g，1.21mmol)的乙酸乙酯(10mL)中，反应2小时。LCMS检测原料反应完全，停止继续反应。将反应液抽滤，用2ml乙酸乙酯洗涤滤饼，干燥得中间体30e盐酸盐。MS m/z：229.9[M+H] +。 1H NMR(400MHz，DMSO)δppm 15.01(br s，1H)9.57(br s，2H)8.53(d，J＝2.76Hz，1H)8.37(d，J＝9.03Hz，1H)7.64(dd，J＝8.91，2.89Hz，1H)3.65-3.74(m，4H)3.23(br s，5H)。 HCl/EtOAc (4M, 1.21 mL) was added to Intermediate 30d (0.4 g, 1.21 mmol) in ethyl acetate (10 mL) at 25°C for 2 hours. The reaction of the raw materials was detected by LCMS, and the reaction was stopped. The reaction solution was suction filtered, the filter cake was washed with 2 ml of ethyl acetate, and dried to obtain the hydrochloride of intermediate 30e. MS m/z: 229.9 [M+H] + . 1 H NMR (400 MHz, DMSO) δppm 15.01 (br s, 1H) 9.57 (br s, 2H) 8.53 (d, J=2.76 Hz, 1H) 8.37 (d, J=9.03 Hz, 1H) 7.64 (dd, J = 8.91, 2.89 Hz, 1H) 3.65-3.74 (m, 4H) 3.23 (br s, 5H).
步骤6：化合物30三氟乙酸盐的合成Step 6: Synthesis of Compound 30 Trifluoroacetate
在25℃下，将30e盐酸盐(22.65mg，85.22μmol)、KI(2.83mg，17.04μmol)和K 2CO 3(70.67mg，511.33μmol)加入DMF(4mL)中，加入11b(0.02g，85.22μmol)，升温50℃，继续搅拌2小时.将反应液冷却至室温，过滤，滤液用高效液相制备色谱分离纯化(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[水(三氟乙酸)-乙腈]；乙腈％：8％-38％，8min)得化合物30的三氟乙酸盐。MS m/z：428.3[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 8.62(d，J＝1.88Hz，1H)8.58(d，J＝2.63Hz，1H)8.00(d，J＝8.88Hz，1H)7.94(d，J＝1.38Hz，1H)7.57-7.65(m，3H)7.55(s，1H)4.60(s，2H)3.50-3.91(m，8H)2.20-2.31(m，1H)1.10-1.17(m，2H)0.87-0.94(m，2H)。 At 25°C, 30e hydrochloride (22.65 mg, 85.22 μmol), KI (2.83 mg, 17.04 μmol) and K2CO3 ( 70.67 mg, 511.33 μmol) were added to DMF (4 mL), 11b (0.02 g) was added , 85.22μmol), heat up at 50°C, and continue to stir for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was separated and purified by preparative high-performance liquid chromatography (chromatographic column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile%: 8%-38%, 8 min) to obtain the trifluoroacetic acid salt of compound 30. MS m/z: 428.3 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.62 (d, J=1.88 Hz, 1H) 8.58 (d, J=2.63 Hz, 1H) 8.00 (d, J=8.88 Hz, 1H) 7.94 (d, J= 1.38Hz, 1H)7.57-7.65(m,3H)7.55(s,1H)4.60(s,2H)3.50-3.91(m,8H)2.20-2.31(m,1H)1.10-1.17(m,2H)0.87 -0.94 (m, 2H).
实施例31Example 31
Figure PCTCN2022088181-appb-000146
Figure PCTCN2022088181-appb-000146
步骤1：化合物31三氟乙酸盐的合成Step 1: Synthesis of Compound 31 Trifluoroacetate
在25℃下，将中间体30c(29.84mg，112.27μmol)、KI(3.73mg，22.45μmol，0.2eq)和K 2CO 3(93.10mg，673.64μmol)加入DMF(4mL)中，加入5d(0.025g，112.27μmol)，升温50℃，继续搅拌2小时。将反应液冷却至室温，过滤，滤液用制备制备HPLC(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[水(三氟乙酸)-乙腈]；乙腈％：0％-30％，8min)分离纯化得化合物31的三氟乙酸盐。MS m/z：416.1[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 8.66(s，1H)8.57(d，J＝2.51Hz，1H)7.95-8.04(m，2H)7.89(s，1H)7.56-7.64(m，3H)4.64(s，2H)3.77(br s，3H)3.57(br s，3H)3.33(dt，J＝3.26，1.63Hz，2H)2.65-2.74(m，2H)1.31(t，J＝7.53Hz，3H)。 Intermediate 30c (29.84 mg, 112.27 μmol), KI (3.73 mg, 22.45 μmol, 0.2 eq) and K 2 CO 3 (93.10 mg, 673.64 μmol) were added to DMF (4 mL) at 25 °C, 5d ( 0.025g, 112.27μmol), the temperature was increased to 50°C, and the stirring was continued for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was subjected to preparative HPLC (chromatographic column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 0%-30%, 8min) separation and purification to obtain the trifluoroacetic acid salt of compound 31. MS m/z: 416.1 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.66 (s, 1H) 8.57 (d, J=2.51 Hz, 1H) 7.95-8.04 (m, 2H) 7.89 (s, 1H) 7.56-7.64 (m, 3H) 4.64(s, 2H) 3.77(br s, 3H) 3.57(br s, 3H) 3.33(dt, J=3.26, 1.63Hz, 2H) 2.65-2.74(m, 2H) 1.31(t, J=7.53Hz, 3H).
实施例32Example 32
Figure PCTCN2022088181-appb-000147
Figure PCTCN2022088181-appb-000147
步骤1：化合物32A三氟乙酸盐的合成Step 1: Synthesis of Compound 32A Trifluoroacetate Salt
将11b(20mg，73.76μmol)和24c的盐酸盐(20.47mg，70.89μmol)加入DMF(2mL)溶液中，将K 2CO 3(30.58mg，221.29μmol)和KI(2.45mg，14.75μmol)加入反应液，于50℃搅拌2小时。反应液直接40℃减压浓缩得到粗品。粗品经制备HPLC制备(色谱柱：Welch Xtimate C18 100*40mm*3μm；流动相：[H 2O(三氟乙酸)-乙腈]；乙腈％：8％-38％，8min)分离纯化得到化合物32A的三氟乙酸盐。MS m/z：451.2[M+H] +。 1H NMR(400MHz，CD 3OD)δppm 8.63(d，J＝1.76Hz，1H)8.18(s，1H)7.96(s，1H)7.54(s，1H)7.23(br d，J＝14.05Hz，1H)4.56(s，2H)4.51(br d，J＝16.31Hz，1H)3.91(br d，J＝13.55Hz，1H)3.39-3.64(m，4H)3.25-3.31(m，1H)2.93(s，3H)2.20-2.32(m，1H)1.30(d，J＝7.03Hz，3H)1.09-1.18(m，2H)0.86-0.95(m，2H)。 11b (20 mg, 73.76 μmol) and the hydrochloride salt of 24c (20.47 mg, 70.89 μmol) were added to a solution of DMF ( 2 mL), K2CO3 (30.58 mg, 221.29 μmol) and KI (2.45 mg, 14.75 μmol) were added The reaction solution was added, and the mixture was stirred at 50°C for 2 hours. The reaction solution was directly concentrated under reduced pressure at 40°C to obtain the crude product. The crude product was prepared by preparative HPLC (chromatographic column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [H 2 O (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 8%-38%, 8 min) to obtain compound 32A of trifluoroacetate. MS m/z: 451.2 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 8.63 (d, J=1.76 Hz, 1H) 8.18 (s, 1H) 7.96 (s, 1H) 7.54 (s, 1H) 7.23 (br d, J=14.05 Hz, 1H) 4.56(s, 2H) 4.51(br d, J=16.31Hz, 1H) 3.91(br d, J=13.55Hz, 1H) 3.39-3.64(m, 4H) 3.25-3.31(m, 1H) 2.93( s, 3H) 2.20-2.32 (m, 1H) 1.30 (d, J=7.03 Hz, 3H) 1.09-1.18 (m, 2H) 0.86-0.95 (m, 2H).
生物测试数据：Biological test data:
实验例1：PARP1酶活性测试实验Experimental Example 1: PARP1 Enzyme Activity Test Experiment
测试平台：武汉合研生物医药科技有限公司。Test platform: Wuhan Heyan Biomedical Technology Co., Ltd.
1.实验材料：1. Experimental materials:
PARP1化学荧光检测试剂盒购自BPS Bioscience；EnVision多标记分析仪(PerkinElmer)。PARP1 chemiluminescence detection kit was purchased from BPS Bioscience; EnVision Multilabel Analyzer (PerkinElmer).
2.实验步骤：2. Experimental steps:
试剂配制：Reagent preparation:
PBST缓冲液配制：1X PBS中包含0.05％Tween-20，即10mL PBS中加入5μL 100％Tween-20PBST buffer preparation: 1X PBS contains 0.05% Tween-20, that is, 5μL of 100% Tween-20 is added to 10mL of PBS
1X测试缓冲液配制：将10X PARP测试缓冲液用双蒸水进行10倍稀释1X test buffer preparation: Dilute 10X PARP test buffer 10 times with double distilled water
化合物配制：Compound formulation:
化合物溶液配制：将待测化合物用100％DMSO进行5倍稀释至第8个浓度，即从1000μM稀释至12.8nM。内控化合物使用100％DMSO进行5倍稀释至第8个浓度，即从200μM稀释至2.56nM。再用1X测试缓冲液将待测化合物各梯度稀释成DMSO为10％的工作液。Compound solution preparation: The compounds to be tested were diluted 5-fold with 100% DMSO to the 8th concentration, that is, from 1000 μM to 12.8 nM. Internal control compounds were diluted 5-fold with 100% DMSO to the 8th concentration, ie, from 200 μM to 2.56 nM. Then use 1X test buffer to dilute each compound to be tested into a working solution with 10% DMSO.
实验方法：experimental method:
a)将试剂盒中的组蛋白溶液用1X PBS进行5倍稀释，取25μL/孔稀释液到微孔板中，置于4℃过夜孵育；a) Dilute the histone solution in the kit 5-fold with 1X PBS, take 25 μL/well of the dilution into a microplate, and incubate at 4°C overnight;
b)结束孵育后，弃去孔中液体，取100μL/孔PBST洗板3次，弃去孔中残留液体；b) After the incubation, discard the liquid in the well, wash the plate 3 times with 100 μL/well PBST, and discard the residual liquid in the well;
c)取100μL/孔封闭液到微孔板中，置于25℃孵育90分钟；结束孵育后，弃去孔中液体，取100μL/孔PBST洗板3次，弃去孔中残留液体；c) Take 100 μL/well of blocking solution into the microplate and incubate at 25°C for 90 minutes; after the incubation, discard the liquid in the well, take 100 μL/well of PBST to wash the plate 3 times, and discard the residual liquid in the well;
d)取12.5μL/孔底物混合溶液(1.25μL 10X PARP测试缓冲液；1.25μL 10X PARP测试混合液；2.5μl Activated DNA；7.5μL双蒸水)到微孔板。d) Take 12.5μL/well substrate mixture solution (1.25μL 10X PARP test buffer; 1.25μL 10X PARP test mixture; 2.5μL Activated DNA; 7.5μL double distilled water) to the microplate.
e)取2.5μL/孔的化合物工作溶液到微孔板，设置双复孔实验。e) Take 2.5 μL/well of the compound working solution to the microplate, and set up a double-well experiment.
f)将PARP1酶稀释到2ng/μL，取10μL/孔加入到微孔板，此时待测化合物终浓度梯度为10μM至0.128nM，内控化合物终浓度梯度为2μM至0.0256nM，PARP1(20ng/孔)，反应体系置于25℃孵育60分钟；f) Dilute the PARP1 enzyme to 2ng/μL, and add 10μL/well to the microplate. At this time, the final concentration gradient of the compound to be tested is 10μM to 0.128nM, and the final concentration gradient of the internal control compound is 2μM to 0.0256nM. PARP1 (20ng/ well), the reaction system was incubated at 25°C for 60 minutes;
g)结束孵育后，弃去孔中液体，取100μL/孔PBST洗板3次，弃去孔中残留液体；g) After the incubation, discard the liquid in the well, wash the plate three times with 100 μL/well PBST, and discard the residual liquid in the well;
h)将Streptavidin-HRP用封闭液进行50倍稀释，然后取25μL/孔到微孔板，置于25℃孵育30分钟；h) Dilute Streptavidin-HRP 50-fold with blocking solution, then take 25 μL/well into a microplate, and incubate at 25°C for 30 minutes;
i)结束孵育后，弃去孔中液体，取100μL/孔PBST洗板3次，弃去孔中残留液体；i) After the incubation, discard the liquid in the well, wash the plate 3 times with 100 μL/well PBST, and discard the residual liquid in the well;
j)按照1∶1(v/v)混匀ELISA ECL底物A和ELISA ECL底物B，取50μL/孔到微孔板，读取化学发光值。j) Mix ELISA ECL Substrate A and ELISA ECL Substrate B at 1:1 (v/v), take 50 μL/well to the microplate, and read the chemiluminescence value.
3.实验数据处理方法3. Experimental data processing method
利用方程式(Sample-Min)/(Max-Min)*100％将原始数据换算成酶活，IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(inhibitor)vs.response--Variable slope模式得出)。Using the equation (Sample-Min)/(Max-Min)*100% to convert the raw data into enzyme activity, the IC50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response- in GraphPad Prism -Variable slope mode derived).
Max：含有1％DMSO，PARP1和底物混合溶液Max: Mixed solution containing 1% DMSO, PARP1 and substrate
Min：不含有PARP1酶Min: Does not contain PARP1 enzyme
实验结果：见表1。Experimental results: see Table 1.
表1.本发明化合物PARP-1激酶活性Table 1. PARP-1 Kinase Activity of Compounds of the Invention
化合物编号Compound number PARP1(IC 50，nM) PARP1 ( IC50 , nM)
化合物1的三氟乙酸盐Trifluoroacetate salt of compound 1 8.618.61
化合物2的三氟乙酸盐Trifluoroacetate salt of compound 2 8.288.28
化合物3的三氟乙酸盐Trifluoroacetate salt of compound 3 3.423.42
化合物4的三氟乙酸盐Trifluoroacetate salt of compound 4 9.729.72
化合物5的三氟乙酸盐Trifluoroacetate salt of compound 5 7.997.99
化合物6的三氟乙酸盐Trifluoroacetate salt of compound 6 10.8410.84
化合物8的三氟乙酸盐Trifluoroacetate salt of compound 8 20.4020.40
化合物9的盐酸盐The hydrochloride salt of compound 9 1.151.15
化合物10的三氟乙酸盐Trifluoroacetate salt of compound 10 3.783.78
化合物11的三氟乙酸盐Trifluoroacetate salt of compound 11 1.631.63
化合物12的三氟乙酸盐Trifluoroacetate salt of compound 12 6.026.02
化合物13ACompound 13A 1.561.56
化合物16B的盐酸盐The hydrochloride salt of compound 16B 5.915.91
化合物25的三氟乙酸盐Trifluoroacetate salt of compound 25 8.388.38
化合物26的三氟乙酸盐Trifluoroacetate salt of compound 26 3.943.94
化合物27的三氟乙酸盐Trifluoroacetate salt of compound 27 10.2510.25
化合物30的三氟乙酸盐Trifluoroacetate salt of compound 30 2.722.72
结论：本发明化合物具有较好的PARP1抑制作用。Conclusion: The compounds of the present invention have good PARP1 inhibitory effect.
实验例2：本发明化合物的PARP1和PARP2结合力研究Experimental Example 2: Study on the PARP1 and PARP2 Binding Ability of the Compounds of the Invention
PARP1实验操作：PARP1 experimental operation:
表面等离子共振(SPR)实验在Biacore 8K(GE Healthcare)仪器上进行。Surface plasmon resonance (SPR) experiments were performed on a Biacore 8K (GE Healthcare) instrument.
首先，在25℃条件下通过链霉亲和素包被的SA芯片(Cytiva，29699622)对生物素化的PARP1蛋白(序列：655-end)进行偶联，具体步骤为：用1mM NaCl/50mM NaOH对芯片进行表面活化；用偶联缓冲液(50mM Tris-HCl pH 8.0，150mM NaCl，10mM MgCl2，0.05％P20)稀释PARP1蛋白配制成10ug/mL的配体溶液，其流经芯片表面(进样时间为50s，进样流速为5μL/min)，将PARP1蛋白偶联到芯片表面；用50％异丙醇/1M NaCl/50mM NaOH溶液封闭芯片上多余的活性位点。实验的最终偶联水平是2000～3000RU(Response Units).First, the biotinylated PARP1 protein (sequence: 655-end) was coupled with a streptavidin-coated SA chip (Cytiva, 29699622) at 25°C. The specific steps were: using 1 mM NaCl/50 mM The chip was surface activated with NaOH; the PARP1 protein was diluted with coupling buffer (50mM Tris-HCl pH 8.0, 150mM NaCl, 10mM MgCl2, 0.05% P20) to prepare a 10ug/mL ligand solution, which flowed over the chip surface (into the The sample time was 50 s, and the injection flow rate was 5 μL/min) to couple the PARP1 protein to the surface of the chip; the excess active sites on the chip were blocked with 50% isopropanol/1M NaCl/50mM NaOH solution. The final coupling level of the experiment is 2000-3000RU (Response Units).
用缓冲液(50mM Tris pH 8.0，150mM NaCl，10mM MgCl2，0.05％Tween 20)对小分子化合物进行梯 度稀释获得不同浓度的化合物溶液，该溶液流经已偶联蛋白的芯片表面，进样流速为50μL/min，进样时间为60s，解离时间为20min。仪器检测到蛋白-小分子化合物的结合解离曲线。The small molecule compounds were serially diluted with buffer (50mM Tris pH 8.0, 150mM NaCl, 10mM MgCl2, 0.05% Tween 20) to obtain compound solutions of different concentrations. 50 μL/min, the injection time was 60 s, and the dissociation time was 20 min. The instrument detects the binding and dissociation curves of protein-small molecule compounds.
样品通道和参比通道的数据通过Biacore 8K评价软件分析生成传感图，基于1∶1结合模式进行数据拟合。The data of the sample channel and reference channel were analyzed by Biacore 8K evaluation software to generate sensorgrams, and data fitting was performed based on the 1:1 binding mode.
PARP2实验操作：PARP2 experimental operation:
表面等离子共振(SPR)实验在Biacore 8K(GE Healthcare)仪器上进行。Surface plasmon resonance (SPR) experiments were performed on a Biacore 8K (GE Healthcare) instrument.
首先，在25℃条件下通过链霉亲和素包被的SA芯片(Cytiva，29699622)对生物素化的PARP2蛋白(序列：223-end)进行偶联，具体步骤为：用1mM NaCl/50mM NaOH对芯片进行表面活化；用偶联缓冲液(50mM Tris-HCl pH 8.0，150mM NaCl，10mM MgCl2，0.05％P20)稀释PARP2蛋白配制成10ug/mL的配体溶液，其流经芯片表面(进样时间为60s，进样流速为10μL/min)，将PARP2蛋白偶联到芯片表面；用50％异丙醇/1M NaCl/50mM NaOH溶液封闭芯片上多余的活性位点。实验的最终偶联水平是3000～4000RU(Response Units).First, the biotinylated PARP2 protein (sequence: 223-end) was coupled with a streptavidin-coated SA chip (Cytiva, 29699622) at 25°C. The specific steps were: 1mM NaCl/50mM The chip was surface activated with NaOH; the PARP2 protein was diluted with coupling buffer (50mM Tris-HCl pH 8.0, 150mM NaCl, 10mM MgCl2, 0.05% P20) to prepare a 10ug/mL ligand solution, which flowed over the chip surface (into the The sample time was 60 s, and the injection flow rate was 10 μL/min), and the PARP2 protein was coupled to the chip surface; the excess active sites on the chip were blocked with 50% isopropanol/1 M NaCl/50 mM NaOH solution. The final coupling level of the experiment was 3000-4000RU (Response Units).
用缓冲液(50mM Tris pH 8.0，150mM NaCl，10mM MgCl2，0.05％Tween 20)对小分子化合物进行梯度稀释获得不同浓度的化合物溶液，该溶液流经已偶联蛋白的芯片表面，进样流速为30μL/min，进样时间为60s，解离时间为400s.仪器检测到蛋白-小分子化合物的结合解离曲线。The small molecule compounds were serially diluted with buffer (50mM Tris pH 8.0, 150mM NaCl, 10mM MgCl2, 0.05% Tween 20) to obtain compound solutions of different concentrations. 30μL/min, the injection time is 60s, and the dissociation time is 400s. The instrument detects the binding and dissociation curves of protein-small molecule compounds.
样品通道和参比通道的数据通过Biacore 8K评价软件分析生成传感图，基于1∶1结合模式进行数据拟合。The data of the sample channel and reference channel were analyzed by Biacore 8K evaluation software to generate sensorgrams, and data fitting was performed based on the 1:1 binding mode.
实验结果：如表2所示。Experimental results: as shown in Table 2.
表2.本发明化合物PARP1和PARP2结合力研究Table 2. Study on the binding ability of the compounds of the present invention to PARP1 and PARP2
Figure PCTCN2022088181-appb-000148
Figure PCTCN2022088181-appb-000148
结论：本发明化合物对PARP2结合力显著低于PARP1结合力，是PARP1选择性抑制剂。Conclusion: The compound of the present invention has significantly lower binding ability to PARP2 than PARP1, and is a selective inhibitor of PARP1.
实验例3：本发明化合物的PARP ELISA活性测试实验Experimental Example 3: PARP ELISA activity test experiment of the compounds of the present invention
实验操作：Experimental operation:
测试平台：北京爱思益普生物科技股份有限公司。用ELISA方法测试化合物对PARP1/PARP3的酶活性抑制实验。将50微升组蛋白(BPS，52029)用PBS(Solarbio，P1022)稀释后添加到96反应板(Greiner，781074)上4℃包被过夜。PBST(1XPBS+0.05％Tween-20)清洗后，添加200微升缓冲液(BPS，79743)于室温封闭90分钟。分别将PARP1(BPS，80501)、PARP3(BPS，80503)与5微升化合物、生物素标记的底物(BPS，80601)以及DNA(BPS，80605)混合液添加进96反应板中，混合液在PARP缓冲溶液(BPS，80602)中进行稀释， 室温孵育1小时。PBST进行清洗，添加50做升辣根过氧化物酶标记链霉亲和素(BPS，80611)，室温孵育30分钟。PBST清洗板子，添加100微升ELISA底物A和底物B混合溶液(BPS，79670)，10分钟后用PHERAstar FSX BMG读取化学发光信号值。通过GraphPad Prism8.0软件中的抑制-剂量(四参数)方程进行IC 50计算。 Test platform: Beijing Aisipu Biotechnology Co., Ltd. ELISA method was used to test compounds for inhibition of PARP1/PARP3 enzymatic activity. Fifty microliters of histone (BPS, 52029) diluted in PBS (Solarbio, P1022) were added to a 96 reaction plate (Greiner, 781074) for coating overnight at 4°C. After washing with PBST (1XPBS+0.05% Tween-20), 200 microliters of buffer (BPS, 79743) was added for blocking at room temperature for 90 minutes. PARP1 (BPS, 80501), PARP3 (BPS, 80503) and 5 microliters of compound, biotin-labeled substrate (BPS, 80601) and DNA (BPS, 80605) mixture were added into the 96 reaction plate, and the mixture was Dilutions were performed in PARP buffer solution (BPS, 80602) and incubated for 1 hour at room temperature. Wash with PBST, add 50 liters of horseradish peroxidase-labeled streptavidin (BPS, 80611), and incubate at room temperature for 30 minutes. The plate was washed with PBST, and 100 microliters of ELISA substrate A and substrate B mixed solution (BPS, 79670) was added. After 10 minutes, the chemiluminescence signal value was read with PHERAstar FSX BMG. IC50 calculations were performed by the inhibition-dose (four-parameter) equation in GraphPad Prism 8.0 software.
实验结果：如表3所示。Experimental results: as shown in Table 3.
表3.本发明化合物PARP ELISA活性测试实验Table 3. PARP ELISA activity test experiment of the compounds of the present invention
Figure PCTCN2022088181-appb-000149
Figure PCTCN2022088181-appb-000149
结论：本发明化合物6对PARP3抑制比AZD5305弱，对PARP1具有更高的选择性。Conclusion: Compound 6 of the present invention has weaker inhibition on PARP3 than AZD5305, and has higher selectivity for PARP1.
实验例4：本发明化合物的小鼠体内药代动力学评价Experimental Example 4: In vivo pharmacokinetic evaluation of the compounds of the present invention in mice
实验过程：将0.04mg/mL 2％DMSO/10％PEG400/88％水试验化合物的澄清溶液经尾静脉注射到雌性Balb/c小鼠体内(过夜禁食，7-9周龄)，给药剂量为0.2mg/kg。将0.10mg/mL 2％DMSO/10％PEG400/88％水试验化合物的澄清溶液灌胃给予雌性Balb/c小鼠(过夜禁食，7-9周龄)，给药剂量为1mg/kg。两组动物分别于给药后0.0833、0.25、0.5、1.0、2.0、4.0、8.0、24h从颈静脉和0.25、0.5、1.0、2.0、4.0、8.0、24h从尾静脉采血约30μL置于添加了EDTA-K2的抗凝管中，离心分离血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3(Pharsight，Mountain View，CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。 Experimental procedure: A clear solution of 0.04 mg/mL 2% DMSO/10% PEG400/88% water test compound was injected into female Balb/c mice (overnight fasted, 7-9 weeks old) via tail vein, and administered The dose is 0.2 mg/kg. Female Balb/c mice (overnight fasted, 7-9 weeks old) were administered 0.10 mg/mL of a clear solution of test compound in 2% DMSO/10% PEG400/88% water by gavage at a dose of 1 mg/kg. About 30 μL of blood was collected from the jugular vein at 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours after administration and from the tail vein at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours after administration. Plasma was separated by centrifugation in an anticoagulant tube of EDTA-K2. The plasma concentration was determined by LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated by non-compartmental model linear logarithmic trapezoidal method using WinNonlin ™ Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software.
实验结果如表4所示：The experimental results are shown in Table 4:
表4.药代动力学数据Table 4. Pharmacokinetic data
Figure PCTCN2022088181-appb-000150
Figure PCTCN2022088181-appb-000150
Figure PCTCN2022088181-appb-000151
Figure PCTCN2022088181-appb-000151
注：“-”表示该参数无法通过计算得到；C 0代表初始浓度；C max代表达峰浓度；T max代表达峰时间；T 1/2代表消除半衰期；V dss代表稳态表观分布容积；Cl代表总清除率；T last代表最后一个可定量测试药物浓度的时间点；AUC 0-last代表从0时间到最后一个可定量时间点的血浆浓度-时间曲线下面积；AUC 0-inf代表0时间外推至无穷大时的血浆浓度-时间曲线下面积；F(％)代表生物利用度，采用AUC 0-last计算。 Note: "-" indicates that this parameter cannot be calculated; C 0 represents initial concentration; C max represents peak concentration; T max represents time to peak; T 1/2 represents elimination half-life; V dss represents steady-state apparent volume of distribution ; Cl represents total clearance; T last represents the time point of the last quantifiable drug concentration; AUC 0-last represents the area under the plasma concentration-time curve from time 0 to the last quantifiable time point; AUC 0-inf represents Area under the plasma concentration-time curve at time 0 extrapolated to infinity; F (%) represents bioavailability, calculated using AUC 0-last .
本发明化合物6和13A静脉给药0.2mg/kg后均展示极慢的清除速率，Cl分别为0.103和0.0293mL/min/kg，较长的半衰期，T 1/2分别为11.4，42.8小时；口服给药1mg/kg后，能够快速达峰T max均为2.5小时，达峰药物浓度17650和20850nM，口服吸收生物利用度为106％和97.4％。 Compounds 6 and 13A of the present invention both showed extremely slow clearance rates after intravenous administration of 0.2 mg/kg, Cl were 0.103 and 0.0293 mL/min/kg, respectively, longer half-lives, T 1/2 were 11.4 and 42.8 hours, respectively; After oral administration of 1 mg/kg, it can quickly reach the peak Tmax in 2.5 hours, the peak drug concentration is 17650 and 20850 nM, and the oral absorption bioavailability is 106% and 97.4%.
结论：本发明化合物具有优异的体内代谢稳定性，优异的口服吸收药物暴露量和口服吸收生物利用度。相比AZD5305，本发明化合物能显著降低小鼠中清除率(Cl)和提高口服吸收暴露量(AUC)。Conclusion: The compounds of the present invention have excellent in vivo metabolic stability, excellent oral absorption drug exposure and oral absorption bioavailability. Compared to AZD5305, the compounds of the present invention can significantly reduce clearance (Cl) and increase oral absorbed exposure (AUC) in mice.
实验例5：本发明化合物的大鼠体内药代动力学评价Experimental Example 5: In vivo pharmacokinetic evaluation of the compounds of the present invention in rats
实验过程：将0.04mg/mL 2％DMSO/10％PEG400/88％水试验化合物的澄清溶液经尾静脉注射到雄性SD大鼠体内(过夜禁食，7周龄)，给药剂量为0.2mg/kg。将0.10mg/mL 2％DMSO/10％PEG400/88％水试验化合物的澄清溶液灌胃给予到雄性SD大鼠(过夜禁食)，给药剂量为1mg/kg。两组动物分别于给药后0.0833、0.25、0.5、1.0、2.0、4.0、8.0、24h从颈静脉和0.25、0.5、1.0、2.0、4.0、8.0、24h从尾静脉采血约30μL置于添加了EDTA-K2的抗凝管中，离心分离血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3(Pharsight，Mountain View，CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。 Experimental procedure: A clear solution of 0.04 mg/mL 2% DMSO/10% PEG400/88% water was injected into male SD rats via tail vein (overnight fasted, 7 weeks old), and the dose was 0.2 mg /kg. A 0.10 mg/mL 2% DMSO/10% PEG400/88% water clear solution of the test compound was administered by gavage to male SD rats (overnight fasted) at a dose of 1 mg/kg. About 30 μL of blood was collected from the jugular vein at 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours after administration and from the tail vein at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours after administration. Plasma was separated by centrifugation in an anticoagulant tube of EDTA-K2. The plasma concentration was determined by LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated by non-compartmental model linear logarithmic trapezoidal method using WinNonlin ™ Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software.
实验结果如表5所示：The experimental results are shown in Table 5:
表5.药代动力学数据Table 5. Pharmacokinetic data
Figure PCTCN2022088181-appb-000152
Figure PCTCN2022088181-appb-000152
Figure PCTCN2022088181-appb-000153
Figure PCTCN2022088181-appb-000153
注：“-”表示该参数无法通过计算得到；C 0代表初始浓度；C max代表达峰浓度；T max代表达峰时间；T 1/2代表消除半衰期；V dss代表稳态表观分布容积；Cl代表总清除率；T last代表最后一个可定量测试药物浓度的时间点；AUC 0-last代表从0时间到最后一个可定量时间点的血浆浓度-时间曲线下面积；AUC 0-inf代表0时间外推至无穷大时的血浆浓度-时间曲线下面积；F(％)代表生物利用度，采用AUC 0-last计算。 Note: "-" indicates that this parameter cannot be calculated; C 0 represents initial concentration; C max represents peak concentration; T max represents time to peak; T 1/2 represents elimination half-life; V dss represents steady-state apparent volume of distribution ; Cl represents total clearance; T last represents the time point of the last quantifiable drug concentration; AUC 0-last represents the area under the plasma concentration-time curve from time 0 to the last quantifiable time point; AUC 0-inf represents Area under the plasma concentration-time curve at time 0 extrapolated to infinity; F (%) represents bioavailability, calculated using AUC 0-last .
本发明化合物6静脉给药0.2mg/kg后展示极慢的清除速率，Cl为0.731mL/min/kg；口服给药1mg/kg后，能够快速达峰T max为3小时，达峰药物浓度4920nM，口服吸收生物利用度为88.2％。 Compound 6 of the present invention showed a very slow clearance rate after intravenous administration of 0.2 mg/kg, and Cl was 0.731 mL/min/kg; after oral administration of 1 mg/kg, it could quickly reach a peak Tmax of 3 hours, and the peak drug concentration was reached 4920nM, orally absorbed bioavailability of 88.2%.
结论：本发明化合物具有优异的体内代谢稳定性，优异的口服吸收药物暴露量和口服吸收生物利用度。相比AZD5305，本发明化合物在大鼠中显著降低清除率和显著提高口服吸收暴露量。Conclusion: The compounds of the present invention have excellent in vivo metabolic stability, excellent oral absorption drug exposure and oral absorption bioavailability. Compared to AZD5305, the compounds of the present invention significantly reduced clearance and significantly increased oral absorbed exposure in rats.
实验例6：本发明化合物的犬体内药代动力学评价Experimental Example 6: In vivo pharmacokinetic evaluation of the compounds of the present invention in dogs
实验过程：将0.20mg/mL 2％DMSO/10％PEG400/88％水试验化合物的澄清溶液经尾静脉注射到雄性比格犬体内(过夜禁食)，给药剂量为0.2mg/kg。将0.20mg/mL 2％DMSO/10％PEG400/88％水试验化合物的澄清溶液灌胃给予到雄性比格犬(过夜禁食)，给药剂量为1mg/kg。两组动物分别于给药后0.0833、0.25、0.5、1.0、2.0、4.0、8.0、24h从颈静脉和0.25、0.5、1.0、2.0、4.0、8.0、24h从尾静脉采血约30μL置于添加了EDTA-K2的抗凝管中，离心分离血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TMVersion 6.3(Pharsight，Mountain View，CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。 Experimental procedure: A clear solution of 0.20 mg/mL 2% DMSO/10% PEG400/88% water test compound was injected into male beagle dogs via tail vein (overnight fasting) at a dose of 0.2 mg/kg. A 0.20 mg/mL 2% DMSO/10% PEG400/88% water clear solution of the test compound was administered by gavage to male beagle dogs (overnight fasted) at a dose of 1 mg/kg. About 30 μL of blood was collected from the jugular vein at 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours after administration and from the tail vein at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours after administration. Plasma was separated by centrifugation in an anticoagulant tube of EDTA-K2. The plasma concentration was determined by LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated by non-compartmental model linear logarithmic trapezoidal method using WinNonlin ™ Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software.
实验结果如表6所示：The experimental results are shown in Table 6:
表6.药代动力学数据Table 6. Pharmacokinetic data
Figure PCTCN2022088181-appb-000154
Figure PCTCN2022088181-appb-000154
注：“-”表示该参数无法通过计算得到；C 0代表初始浓度；C max代表达峰浓度；T max代表达峰时间；T 1/2代表消除半衰期；V dss代表稳态表观分布容积；Cl代表总清除率；T last代表最后一个可定量测试药物浓度的时间点；AUC 0-last代表从0时间到最后一个可定量时间点的血浆浓度-时间曲线下面积；AUC 0-inf代表 0时间外推至无穷大时的血浆浓度-时间曲线下面积；F(％)代表生物利用度，采用AUC 0-last计算。 Note: "-" indicates that this parameter cannot be calculated; C 0 represents initial concentration; C max represents peak concentration; T max represents time to peak; T 1/2 represents elimination half-life; V dss represents steady-state apparent volume of distribution ; Cl represents total clearance; T last represents the time point of the last quantifiable drug concentration; AUC 0-last represents the area under the plasma concentration-time curve from time 0 to the last quantifiable time point; AUC 0-inf represents Area under the plasma concentration-time curve at time 0 extrapolated to infinity; F (%) represents bioavailability, calculated using AUC 0-last .
本发明化合物6静脉给药0.2mg/kg后展示极慢的清除速率，Cl为0.319mL/min/kg；口服给药1mg/kg后，能够快速达峰T max为2.5小时，达峰药物浓度11647nM，口服吸收生物利用度为126％。 The compound 6 of the present invention showed a very slow clearance rate after intravenous administration of 0.2 mg/kg, and the Cl was 0.319 mL/min/kg; after oral administration of 1 mg/kg, it could quickly reach a peak Tmax of 2.5 hours, and the peak drug concentration was reached. 11647nM, orally absorbed bioavailability of 126%.
结论：本发明化合物具有优异的体内代谢稳定性，优异的口服吸收药物暴露量和口服吸收生物利用度。相比AZD5305，本发明化合物显著降低小鼠中清除率(Cl)和提高口服吸收暴露量(AUC)。Conclusion: The compounds of the present invention have excellent in vivo metabolic stability, excellent oral absorption drug exposure and oral absorption bioavailability. Compared to AZD5305, the compounds of the present invention significantly reduced clearance (Cl) and increased oral absorbed exposure (AUC) in mice.
实验例7：本发明化合物的DLD1 BRAC2 KO细胞抗增殖实验Experimental example 7: DLD1 BRAC2 KO cell anti-proliferation test of the compounds of the present invention
测试平台：武汉合研生物医药科技有限公司。Test platform: Wuhan Heyan Biomedical Technology Co., Ltd.
实验过程：将DLD1 BRAC2 KO细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含1000个DLD1 BRAC2 KO细胞。细胞板置于二氧化碳培养箱中过夜培养。将待测化合物用排枪进5倍稀释至第8个浓度，即从2mM稀释至0.0256μM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，混匀后转移20μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是10μM至0.128nM。细胞板置于二氧化碳培养箱中培养7天。另准备一块细胞板，在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向此细胞板每孔加入25μL细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。加入化合物的细胞板结束孵育后，向细胞板中加入每孔25μL的细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。利用方程式(Sample-Min)/(Max-Min)＊100％将原始数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中″log(inhibitor)vs.response--Variable slope″模式得出)。 Experimental process: DLD1 BRAC2 KO cells were seeded in a white 96-well plate, 80 μL of cell suspension per well, which contained 1000 DLD1 BRAC2 KO cells. Cell plates were incubated overnight in a carbon dioxide incubator. The compounds to be tested were diluted 5-fold to the 8th concentration with a row gun, that is, from 2 mM to 0.0256 μM, and a double-well experiment was set up. Add 78 μL of medium to the middle plate, and then transfer 2 μL of each well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 μL of each well to the cell plate. Compound concentrations transferred to cell plates ranged from 10 [mu]M to 0.128 nM. The cell plates were placed in a carbon dioxide incubator for 7 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis. Add 25 μL of cell viability chemiluminescence detection reagent to each well of the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer. After the incubation of the compound-added cell plate, 25 μL of cell viability chemiluminescence detection reagent was added to the cell plate, and incubated at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer. Using the equation (Sample-Min)/(Max-Min)*100% to convert the raw data into inhibition rate, the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
实验结果如表7所示：The experimental results are shown in Table 7:
表7.DLD-1 BRAC2 KO细胞增殖抑制实验Table 7. DLD-1 BRAC2 KO cell proliferation inhibition experiment
化合物编号Compound number IC 50(nM) IC50 (nM)
化合物6的三氟乙酸盐Trifluoroacetate salt of compound 6 3.833.83
化合物9盐酸盐Compound 9 hydrochloride 3.493.49
化合物11的三氟乙酸盐Trifluoroacetate salt of compound 11 3.433.43
化合物13ACompound 13A 6.476.47
实验结论：本发明的化合物对DLD-1 BRAC2 KO细胞具有优异增殖抑制活性。Experimental conclusion: The compounds of the present invention have excellent proliferation inhibitory activity on DLD-1 BRAC2 KO cells.
实验例8：本发明化合物的MDA-MB-436细胞抗增殖实验Experimental example 8: MDA-MB-436 cell anti-proliferation test of the compounds of the present invention
将MDA-MB-436细胞种于黑色(透明底)96孔板中，每孔135μL细胞悬液，其中包含3500个MDA-MB-436细胞。细胞板置于二氧化碳培养箱中过夜培养。制备400X待测化合物储存液，将待测化合物用排枪进行5倍稀释至第9个浓度，即从4mM稀释至104nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，溶媒对照和空白对照中加入2μL DMSO，混匀后转移15μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是10μM至0.26nM，DMSO终浓度为0.25％。细胞板置于二氧化碳培养箱中培养7天。取出细胞板放置30分钟使其平衡至室温，每孔加入 75μL细胞活率化学发光检测试剂，将培养板在轨道摇床上振摇3分钟以诱导细胞裂解，室温孵育10分钟使发光信号稳定。2104 En Vision读板器上检测发光信号。用下列公式来计算检测化合物的抑制率(Inhibition rate，IR)：IR(％)＝(1-(RLU化合物-RLU空白对照)/(RLU溶媒对照-RLU空白对照))*100％。在Excel中计算不同浓度化合物的抑制率，然后用GraphPad Prism软件作抑制曲线图和计算相关参数。MDA-MB-436 cells were seeded in a black (clear bottom) 96-well plate with 135 μL of cell suspension per well, which contained 3500 MDA-MB-436 cells. Cell plates were incubated overnight in a carbon dioxide incubator. Prepare 400X test compound stock solution, dilute the test compound 5-fold to the ninth concentration with a discharge gun, that is, from 4mM to 104nM, and set up a double-well experiment. Add 78 μL of medium to the middle plate, and then transfer 2 μL of the compound diluted in each well to the middle plate according to the corresponding position. Add 2 μL of DMSO to the vehicle control and blank control, and transfer 15 μL of each well to the cell plate after mixing. Compound concentrations transferred to the cell plate ranged from 10 [mu]M to 0.26 nM with a final DMSO concentration of 0.25%. The cell plates were placed in a carbon dioxide incubator for 7 days. Take out the cell plate and let it equilibrate to room temperature for 30 minutes, add 75 μL of cell viability chemiluminescence detection reagent to each well, shake the culture plate on an orbital shaker for 3 minutes to induce cell lysis, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. The luminescent signal is detected on the 2104 En Vision plate reader. The inhibition rate (IR) of the tested compound was calculated by the following formula: IR(%)=(1-(RLU compound-RLU blank control)/(RLU vehicle control-RLU blank control))*100%. The inhibition rates of different concentrations of compounds were calculated in Excel, and then the GraphPad Prism software was used to plot the inhibition curves and calculate the relevant parameters.
实验结果如表8所示：The experimental results are shown in Table 8:
表8.MDA-MB-436细胞增殖抑制实验Table 8. MDA-MB-436 cell proliferation inhibition experiment
化合物编号Compound number IC 50(nM) IC50 (nM)
化合物6的三氟乙酸盐Trifluoroacetate salt of compound 6 33
化合物9盐酸盐Compound 9 hydrochloride 55
化合物11三氟乙酸盐Compound 11 Trifluoroacetate 66
实验结论：本发明的化合物对MDA-MB-436细胞具有优异的增殖抑制活性。Experimental conclusion: The compounds of the present invention have excellent proliferation inhibitory activity on MDA-MB-436 cells.
实验例9：本发明化合物的DLD1 BRAC2 KO体内药效学评价Experimental Example 9: DLD1 BRAC2 KO in vivo pharmacodynamic evaluation of the compounds of the present invention
实验方法：experimental method:
1)肿瘤组织准备1) Tumor tissue preparation
在5％CO 2、37℃、饱和湿度条件下，DLD-1(BRAC2-/-)细胞在含10％胎牛血清的RPMI-1640培养基中进行常规细胞培养。根据细胞生长情况，每周传代或补液1到2次，传代比例1∶3到1∶4 DLD-1 (BRAC2-/-) cells were routinely cultured in RPMI-1640 medium containing 10% fetal bovine serum under the conditions of 5% CO 2 , 37° C., and saturated humidity. Depending on cell growth, passage or rehydration 1 to 2 times a week at a passage ratio of 1:3 to 1:4
2)组织接种及分组2) Tissue inoculation and grouping
收取对数生长期DLD-1细胞，细胞计数后重悬于50％不含血清的RPMI-1640培养基及50％Matrigel中，调整细胞浓度至5×10 6细胞/mL；将细胞置于冰盒中，用1mL注射器吸取细胞悬液，注射到裸鼠前右侧腋窝皮下，每只动物接种200μL(8×10 6细胞/只)，建立DLD-1移植瘤模型。定期观察动物状态，使用电子游标卡尺测量瘤径，计算肿瘤体积，监测肿瘤生长情况。待瘤体积达到100～200mm 3，挑选健康状况良好、肿瘤体积相近的荷瘤鼠，采用随机区组法分，n＝8。 DLD-1 cells in logarithmic growth phase were harvested, counted and resuspended in 50% serum-free RPMI-1640 medium and 50% Matrigel, and the cell concentration was adjusted to 5×10 6 cells/mL; the cells were placed on ice In the box, draw the cell suspension with a 1 mL syringe and inject it subcutaneously into the front right armpit of nude mice. Each animal is inoculated with 200 μL (8×10 6 cells/mouse) to establish a DLD-1 xenograft model. Regular observation of animal status, use of electronic vernier calipers to measure tumor diameter, calculate tumor volume, and monitor tumor growth. When the tumor volume reached 100-200 mm 3 , tumor-bearing mice with good health status and similar tumor volume were selected and randomly divided into groups, n=8.
3)每周测量2次瘤径，计算肿瘤体积，同时称量动物体重并记录。3) The tumor diameter was measured twice a week, the tumor volume was calculated, and the body weight of the animal was weighed and recorded.
肿瘤体积(TV)计算公式如下：TV(mm 3)＝1×w 2/2其中，1表示肿瘤长径(mm)；w表示肿瘤短径(mm)。 The formula for calculating tumor volume (TV) is as follows: TV (mm 3 )=1×w 2 /2, where 1 represents the long diameter of the tumor (mm); and w represents the short diameter of the tumor (mm).
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。相对肿瘤增殖率T/C(％)＝T RTV/C RTV×100％(T RTV：治疗组平均RTV；C RTV：阴性对照组平均RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝V t/V 0，其中V 0是分组给药时(即D0)测量所得肿瘤体积，V t为对应小鼠某一次测量时的肿瘤体积，T RTV与C RTV取同一天数据。 The antitumor efficacy of the compounds was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). Relative tumor proliferation rate T/C (%) = T RTV /C RTV × 100% (T RTV : the average RTV of the treatment group; C RTV : the average RTV of the negative control group). The relative tumor volume (RTV) is calculated according to the results of tumor measurement, and the calculation formula is RTV=V t /V 0 , where V 0 is the tumor volume measured during group administration (ie D0), and V t is the corresponding The tumor volume of a mouse at one measurement, T RTV and C RTV are taken on the same day.
TGI(％)，反映肿瘤生长抑制率。TGI(％)＝[(1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100％。TGI (%), reflecting tumor growth inhibition rate. TGI(%)=[(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group))/(average tumor volume at the end of treatment in the solvent control group-the start of treatment in the solvent control group time average tumor volume)] × 100%.
4)溶媒：2％DMSO+10％PEG400+88％H 2O。 4) Solvent: 2% DMSO + 10% PEG400 + 88% H 2 O.
实验结果：Experimental results:
在小鼠结肠癌DLD-1模型上，灌胃给药，一天一次，连续给药26天。与溶媒组相比，本发明化合物表现出了显著的抗肿瘤活性且体重变化小，具体结果见表9、附图1和附图2。In the mouse colon cancer DLD-1 model, it was administered by gavage, once a day, for 26 consecutive days. Compared with the vehicle group, the compounds of the present invention showed significant anti-tumor activity and small changes in body weight. The specific results are shown in Table 9, Figure 1 and Figure 2.
表9 DLD-1肿瘤生长抑制率和相对肿瘤增殖率汇总表Table 9 Summary of DLD-1 tumor growth inhibition rate and relative tumor proliferation rate
Figure PCTCN2022088181-appb-000155
Figure PCTCN2022088181-appb-000155
实验结论：本发明化合物具有显著的抗肿瘤活性，且安全性良好。Experimental conclusion: the compound of the present invention has significant antitumor activity and good safety.

Claims (28)

  1. 式(V)所示化合物或其药学上可接受的盐，A compound represented by formula (V) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022088181-appb-100001
    Figure PCTCN2022088181-appb-100001
    其中，in,
    Figure PCTCN2022088181-appb-100002
    选自单键和双键；
    Figure PCTCN2022088181-appb-100002
    selected from single and double bonds;
    T 1选自N、NH、CH 2和CR 1； T 1 is selected from N, NH, CH 2 and CR 1 ;
    T 2选自CH和N； T 2 is selected from CH and N;
    T 3选自CH和N； T 3 is selected from CH and N;
    L 1选自键、-C(＝O)-、-C(＝O)NH-和-CF＝CH-； L 1 is selected from bond, -C(=O)-, -C(=O)NH- and -CF=CH-;
    R 1选自H、F、Cl、Br和I； R 1 is selected from H, F, Cl, Br and I;
    R 2选自H、C 1-3烷基和C 3-5环烷基，所述C 1-3烷基和C 3-5环烷基分别独立地任选被1、2或3个卤素取代； R 2 is selected from H, C 1-3 alkyl and C 3-5 cycloalkyl, each of which is independently optionally replaced by 1 , 2 or 3 halogens replace;
    R 3选自H或不存在； R is selected from H or absent;
    R 4和R 5分别独立地选自H、C 1-3烷基、C 3-5环烷基和3-5元杂环烷基，所述C 1-3烷基、C 3-5环烷基和3-5元杂环烷基分别独立地任选被1、2或3个R b取代； R 4 and R 5 are each independently selected from H, C 1-3 alkyl, C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl, the C 1-3 alkyl, C 3-5 cycloalkyl Alkyl and 3-5 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 R b ;
    R 6选自H； R 6 is selected from H;
    R 7选自H； R is selected from H;
    R 8和R 9分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个卤素取代； R 8 and R 9 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 halogens;
    R 10选自H、F、Cl、Br和I； R 10 is selected from H, F, Cl, Br and I;
    R 11选自H、F、Cl、Br、I、C 1-3烷基、C 3-5环烷基和5元杂芳基，所述C 1-3烷基、C 3-5环烷基和5元杂芳基分别独立地任选被1、2或3个R c取代； R 11 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 3-5 cycloalkyl and 5-membered heteroaryl, the C 1-3 alkyl, C 3-5 cycloalkane and 5-membered heteroaryl are each independently optionally substituted with 1, 2 or 3 R c ;
    或者R 2和R 1与相连的碳原子一起形成苯基，所述苯基任选被1、2或3个卤素取代； or R2 and R1 together with the attached carbon atoms form a phenyl group optionally substituted with 1 , 2 or 3 halogens;
    或者R 2和R 3与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个卤素取代； or R2 and R3 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
    或者R 4和R 5与相连的碳原子一起形成5元杂环烷基，所述5元杂环烷基任选被1、2或3个卤素取代； or R and R together with the attached carbon atoms form a 5 - membered heterocycloalkyl optionally substituted with 1, 2 or 3 halogens;
    或者R 4和R 6与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个卤素取代； or R4 and R6 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1 , 2 or 3 halogens;
    或者R 5和R 7与相连的碳原子一起形成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个卤素取代； or R5 and R7 together with the attached carbon atoms form a C3-5 cycloalkyl optionally substituted with 1, 2 or 3 halogens;
    或者T 3和-L 1-R 11与相连的碳原子一起形成5元杂环基，所述5元杂环基任选被1个CH 3取代； Or T 3 and -L 1 -R 11 together with the attached carbon atoms form a 5-membered heterocyclic group optionally substituted with 1 CH 3 ;
    各R b分别独立地选自F、Cl、Br、I、OH和CN； each R b is independently selected from F, Cl, Br, I, OH and CN;
    各R c分别独立地选自D、F、Cl、Br、I和CH 3； each Rc is independently selected from D, F, Cl, Br, I and CH3 ;
    条件是，requirement is,
    1)当
    Figure PCTCN2022088181-appb-100003
    选自双键，T 1选自CH，T 3选自N，R 2选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个卤素取代时，R 4、R 5和R 10不同时选自H；     1) When
    Figure PCTCN2022088181-appb-100003
    is selected from double bonds, T 1 is selected from CH, T 3 is selected from N, R 2 is selected from C 1-3 alkyl, and when the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, R 4 , R 5 and R 10 are not selected from H at the same time;
    2)当
    Figure PCTCN2022088181-appb-100004
    选自双键，T 1选自CH，T 3选自CH时，T 2选自N。     2) When
    Figure PCTCN2022088181-appb-100004
    is selected from double bonds, T 1 is selected from CH, T 3 is selected from CH, T 2 is selected from N.
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 1选自H。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H.
  3. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 2选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和环丙基分别独立地任选被1、2或3个卤素取代。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and cyclopropyl, The CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 and cyclopropyl are each independently optionally substituted with 1, 2 or 3 halogens.
  4. 根据权利要求1或3所述化合物或其药学上可接受的盐，其中，R 2选自H、CH 2CH 3和环丙基。 The compound of claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, CH 2 CH 3 and cyclopropyl.
  5. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 2和R 1与相连的碳原子一起形成苯基，所述苯基被1个F取代。 The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R2 and R1 together with the attached carbon atom form a phenyl group substituted with 1 F.
  6. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 2和R 3与相连的碳原子一起形成环丙基。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 together with the attached carbon atom form a cyclopropyl group.
  7. 根据权利要求1、5或6任意一项所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022088181-appb-100005
    选自
    Figure PCTCN2022088181-appb-100006
    Figure PCTCN2022088181-appb-100007
    The compound according to any one of claims 1, 5 or 6, or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2022088181-appb-100005
    selected from
    Figure PCTCN2022088181-appb-100006
    Figure PCTCN2022088181-appb-100007
  8. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 4和R 5分别独立地选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基和氧杂环丁基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基和氧杂环丁基分别独立地任选被1、2或3个R b取代，各R b分别独立地选自F、Cl、Br、I、OH和CN。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl and oxetanyl, each of said CH3 , CH2CH3 , CH2CH2CH3 , CH (CH3)2 , cyclopropyl and oxetanyl being independently optional Substituted with 1, 2 or 3 R b , each R b independently selected from F, Cl, Br, I, OH and CN.
  9. 根据权利要求1或8所述化合物或其药学上可接受的盐，其中，R 4和R 5分别独立地选自H、CH 3、CH 2OH、CH 2CN、环丙基、
    Figure PCTCN2022088181-appb-100008
    The compound according to claim 1 or 8 or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are independently selected from H, CH 3 , CH 2 OH, CH 2 CN, cyclopropyl,
    Figure PCTCN2022088181-appb-100008
  10. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 4和R 5与相连的碳原子一起形成
    Figure PCTCN2022088181-appb-100009
     The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are formed together with the attached carbon atom
    Figure PCTCN2022088181-appb-100009
  11. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 4和R 6与相连的碳原子一起形成环丙基。 The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R4 and R6 together with the attached carbon atom form a cyclopropyl group.
  12. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 5和R 7与相连的碳原子一起形成环丙基。 The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R5 and R7 together with the attached carbon atom form a cyclopropyl group.
  13. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 8和R 9分别独立地选自H和CH 3。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R8 and R9 are independently selected from H and CH3 , respectively.
  14. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 10选自H、F和Cl。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from the group consisting of H, F and Cl.
  15. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 11选自F、CH 3、CH 2CH 3、环丙基、
    Figure PCTCN2022088181-appb-100010
    Figure PCTCN2022088181-appb-100011
    所述CH 3、CH 2CH 3、环丙基、
    Figure PCTCN2022088181-appb-100012
    分别独立地任选被1、2或3个R c取代，各R c分别独立地选自D、F、Cl、Br、I和CH 3。     The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from F, CH 3 , CH 2 CH 3 , cyclopropyl,
    Figure PCTCN2022088181-appb-100010
    Figure PCTCN2022088181-appb-100011
    The CH 3 , CH 2 CH 3 , cyclopropyl,
    Figure PCTCN2022088181-appb-100012
    Each independently is optionally substituted with 1, 2 or 3 Rcs , each Rc is independently selected from D, F, Cl, Br, I and CH3 .
  16. 根据权利要求1或15所述化合物或其药学上可接受的盐，其中，R 11选自F、CH 3、CD 3、CH 2CH 3、环丙基、
    Figure PCTCN2022088181-appb-100013
    The compound according to claim 1 or 15 or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from F, CH 3 , CD 3 , CH 2 CH 3 , cyclopropyl,
    Figure PCTCN2022088181-appb-100013
  17. 根据权利要求1所述化合物或其药学上可接受的盐，其中，T 3和-L 1-R 11与相连的碳原子一起形成5元杂环基，使结构单元
    Figure PCTCN2022088181-appb-100014
    选自
    Figure PCTCN2022088181-appb-100015
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein T 3 and -L 1 -R 11 together with the attached carbon atoms form a 5-membered heterocyclic group, making the structural unit
    Figure PCTCN2022088181-appb-100014
    selected from
    Figure PCTCN2022088181-appb-100015
  18. 根据权利要求1～17任意一项所述化合物或其药学上可接受的盐，其化合物选自The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
    Figure PCTCN2022088181-appb-100016
    Figure PCTCN2022088181-appb-100016
    其中，L 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11如权利要求1～17任意一项所定义。 Wherein, L 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as defined in any one of claims 1 to 17 .
  19. 根据权利要求18所述化合物或其药学上可接受的盐，其化合物选自The compound according to claim 18 or a pharmaceutically acceptable salt thereof, which compound is selected from the group consisting of
    Figure PCTCN2022088181-appb-100017
    Figure PCTCN2022088181-appb-100017
    其中，R 4、R 5、R 8、R 9、R 10和R 11如权利要求18所定义。 wherein R 4 , R 5 , R 8 , R 9 , R 10 and R 11 are as defined in claim 18 .
  20. 根据权利要求19所述化合物或其药学上可接受的盐，其化合物选自The compound according to claim 19 or a pharmaceutically acceptable salt thereof, which compound is selected from the group consisting of
    Figure PCTCN2022088181-appb-100018
    Figure PCTCN2022088181-appb-100018
    其中，in,
    R 5选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代； R 5 is selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ;
    各R b分别独立地选自F、Cl、Br、I、OH和CN； each R b is independently selected from F, Cl, Br, I, OH and CN;
    R 10选自H、F、Cl、Br和I。 R 10 is selected from H, F, Cl, Br and I.
  21. 根据权利要求20所述化合物或其药学上可接受的盐，其中，R 5选自H、CH 3、CH 2OH和CH 2CN。 The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from H, CH 3 , CH 2 OH and CH 2 CN.
  22. 根据权利要求20或21所述化合物或其药学上可接受的盐，其中，R 5选自H。 The compound of claim 20 or 21, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from H.
  23. 根据权利要求20所述化合物或其药学上可接受的盐，其中，R 10选自H、F和Cl。 The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R10 is selected from the group consisting of H, F and Cl.
  24. 下列化合物或其药学上可接受的盐，The following compounds or their pharmaceutically acceptable salts,
    Figure PCTCN2022088181-appb-100019
    Figure PCTCN2022088181-appb-100019
    Figure PCTCN2022088181-appb-100020
    Figure PCTCN2022088181-appb-100020
    Figure PCTCN2022088181-appb-100021
    Figure PCTCN2022088181-appb-100021
  25. 根据权利要求1或24所述化合物或其药学上可接受的盐，其化合物选自，The compound according to claim 1 or 24 or a pharmaceutically acceptable salt thereof, which compound is selected from,
    Figure PCTCN2022088181-appb-100022
    Figure PCTCN2022088181-appb-100022
    Figure PCTCN2022088181-appb-100023
    Figure PCTCN2022088181-appb-100023
    Figure PCTCN2022088181-appb-100024
    Figure PCTCN2022088181-appb-100024
    Figure PCTCN2022088181-appb-100025
    Figure PCTCN2022088181-appb-100025
  26. 根据权利要求1～25任意一项所述的化合物或其药学上可接受的盐在制备治疗实体瘤药物中的应用。Use of the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating solid tumors.
  27. 根据权利要求26所述应用，其中，实体瘤指BRCA突变的卵巢癌和乳腺癌。The use according to claim 26, wherein the solid tumor refers to BRCA-mutated ovarian cancer and breast cancer.
  28. 一种药物组合物，包括治疗有效量的根据权利要求1～25任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier, diluent or excipient.
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