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WO2022222995A1 - Composé picolinamide - Google Patents

Composé picolinamide 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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English (en)
Chinese (zh)
Inventor
陈正霞
戴美碧
赵立雨
张杨
陈曙辉
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Medshine Discovery Inc
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Medshine Discovery Inc
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Priority to CN202280004848.4A priority Critical patent/CN115702156A/zh
Publication of WO2022222995A1 publication Critical patent/WO2022222995A1/fr
Anticipated expiration legal-status Critical
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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.

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Abstract

L'invention concerne un composé picolinamide, et spécifiquement un composé représenté par la formule (V) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2022/088181 2021-04-23 2022-04-21 Composé picolinamide Ceased WO2022222995A1 (fr)

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EP4466269A1 (fr) 2022-01-21 2024-11-27 Xinthera, Inc. Inhibiteurs de parp1 et leurs utilisations
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WO2023207284A1 (fr) * 2022-04-28 2023-11-02 Ningbo Newbay Technology Development Co., Ltd Dérivés de pipérazine utilisés comme inhibiteurs de parp1
US11795173B1 (en) 2022-04-28 2023-10-24 Xinthera, Inc. Substituted pyridines as PARP1 inhibitors
WO2023217045A1 (fr) * 2022-05-07 2023-11-16 南京明德新药研发有限公司 Dérivé de fluoroquinoxalinone pour l'inhibition selective de parp1
WO2024046366A1 (fr) * 2022-09-01 2024-03-07 浙江文达医药科技有限公司 Inhibiteur de parp1 sélectif
WO2024067694A1 (fr) * 2022-09-30 2024-04-04 中国医药研究开发中心有限公司 Composé hétérocyclique contenant de l'azote et son utilisation pharmaceutique
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WO2024082654A1 (fr) * 2022-10-20 2024-04-25 上海海和药物研究开发股份有限公司 Composés à activité inhibitrice de parp1 et leurs utilisations
WO2024099364A3 (fr) * 2022-11-09 2024-06-13 Laekna Therapeutics Shanghai Co., Ltd. Composés multicycliques fusionnés et leur utilisation en tant qu'inhibiteurs de parp1

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