WO2024251205A1 - Dérivé de quinazolinone et son utilisation médicale - Google Patents

Dérivé de quinazolinone et son utilisation médicale Download PDF

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Publication number
WO2024251205A1
WO2024251205A1 PCT/CN2024/097795 CN2024097795W WO2024251205A1 WO 2024251205 A1 WO2024251205 A1 WO 2024251205A1 CN 2024097795 W CN2024097795 W CN 2024097795W WO 2024251205 A1 WO2024251205 A1 WO 2024251205A1
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Prior art keywords
alkylene
nhc
alkyl
membered
methyl
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PCT/CN2024/097795
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English (en)
Chinese (zh)
Inventor
张晨
何平
宣兆利
廖鹏飞
宁文涛
王乐
李瑶
严庞科
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Tibet Haisco Pharmaceutical Co Ltd
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Tibet Haisco Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a compound described by general formula (I) or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and pharmaceutical compositions thereof, as well as use thereof in preparing drugs for PARP14-related diseases.
  • PARP14 is an interferon-stimulated gene that is overexpressed in multiple tumor types and affects pro-tumor macrophage polarization as well as suppresses anti-tumor inflammatory responses by regulating IFN- ⁇ and IL-4 signaling.
  • PARP14 is a 203 kDa protein with a catalytic domain responsible for the transfer of mono-ADP-ribose to its substrate.
  • PARP14 contains three macrodomains and a WE domain, which are binding modules for mono- and poly-ADP-ribose, respectively.
  • Catalytic inhibitors of PARP14 have been shown to reverse IL-4-driven pro-tumor gene expression in macrophages.
  • PARP14 is highly expressed in inflammatory disease tissues (but not constitutively in normal tissues), leading to increased primary cytokines (alarmins) and secondary cytokines (Th2 and Th17 cytokines), ultimately leading to increased tissue eosinophils and neutrophils.
  • alarmins primary cytokines
  • Th2 and Th17 cytokines secondary cytokines
  • Targeting these inflammatory pathways with PARP14 inhibitors is expected to have better efficacy than current therapies, such as those that target only single cytokines such as IL-4, IL-5 and/or IL-13 for asthma treatment.
  • the compounds, compositions and methods described herein help to meet the unmet need for the treatment of certain cancers and inflammatory diseases characterized by aberrant expression or activity of PARP14.
  • the object of the present invention is to provide a novel compound of the general formula (I) or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods thereof, and their use in the preparation of drugs for treating diseases associated with abnormal PARP14 expression.
  • the compound of the invention has good pharmacokinetic properties and bioavailability, oral properties and good safety.
  • the present invention provides a compound or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compounds represented by general formula (I),
  • the compound represented by general formula (I) is selected from the compounds represented by general formula (Ia), (Ib), (Ic), (Id), (Ie), (If),
  • the compound represented by general formula (I) is selected from the compounds represented by general formula (Ih) and (II),
  • the compound represented by general formula (I) is selected from the compound represented by general formula (IJ),
  • Selected from m1 is selected from 0, 1, 2 or 3;
  • Y 1 , Y 2 , and Y 3 are each independently selected from N or CR y ;
  • Y 1 , Y 2 are selected from CH, and Y 3 is selected from CR y ;
  • Y 1 is selected from N
  • Y 2 is selected from CH
  • Y 3 is selected from CR y ;
  • R 1 is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, non-aromatic C 3-12 carbocyclyl, or non-aromatic 4 to 12 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with 1 to 4 R 1a ;
  • R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a : phenyl, naphthyl, 5 to 6 membered heteroaryl, 8 to 10 membered cycloheteroaryl, C 3-7 monocycloalkyl, C 4-7 monocycloalkenyl, C 5-12 cycloalkyl, C 5-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, 4 to 7 membered monoheterocycloalkyl, 6 to 12 membered cycloheterocycloalkyl, 6 to 12 membered spiroheterocycloalkyl, 6 to 12 membered bridged heterocycloalkyl;
  • R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a : phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinazolinyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridothiphenyl, pyridooxazolyl, pyridothiazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidofuranyl, pyrimidothiphenyl, pyrimidooxazolyl, pyrimidothiazolyl,
  • R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a :
  • R 1 is selected from R 1A or R 1A optionally substituted with 1 to 4 R 1A
  • R 1A is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, said aryl or heteroaryl being optionally substituted with 1 to 4 R 1a ;
  • R 1A is selected from phenyl, naphthyl, 5- to 6-membered heteroaryl, or 8- to 10-membered heteroaryl, wherein the phenyl, naphthyl, or heteroaryl is optionally substituted with 1 to 4 R 1a ;
  • R 1A is selected from one of the following groups optionally substituted with 1 to 4 R 1a : phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinazolinyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridothiphenyl, pyridooxazolyl, pyridothiazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidofuranyl, pyrimidothiphenyl, pyrimidooxazolyl, pyrimidothiazolyl, pyrimi
  • R 1A is selected from one of the following groups optionally substituted with 1 to 4 R 1a :
  • L is selected from a bond, -O-, -S-, -NH-, -N(C 1-4 alkyl)-, -OC 1-4 alkylene-, -NH-C 1-4 alkylene-, -N(C 1-4 alkyl)-C 1-4 alkylene-, -C 1-4 alkylene-, said alkylene or alkyl being optionally substituted with 1 to 4 R k ;
  • L is selected from a bond, -O-, -S-, -NH-, -OCH2- , -OCH2CH2-, -OCH2CH2CH2- , -NHCH2- , -NHCH2CH2-, -NHCH2CH2- , -NHCH2CH2CH2- , said -CH2- being optionally substituted with 1 to 4 Rk ;
  • L is selected from -OCH 2 -;
  • Ring B is selected from C 3-7 cycloalkyl, C 8-12 cycloalkyl, 4 to 10 membered heterocycloalkyl, 11 to 13 membered heterocycloalkyl, 11 to 13 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl;
  • ring B is selected from C 3-7 cycloalkyl, C 8-12 cycloalkyl, C 8-12 spirocycloalkyl, C 8-12 bridged cycloalkyl, 4 to 7 membered monoheterocycloalkyl, 6 to 10 membered benzoheterocycloalkyl, 6 to 10 membered spiroheterocycloalkyl, 6 to 10 membered bridged heterocycloalkyl, 11 to 13 membered bicyclic heterocycloalkyl, 11 to 13 membered tricyclic heterocycloalkyl, phenyl, naphthyl, 5 to 6 membered heteroaryl, 8 to 10 membered benzoheterocycloaryl, benzo7 to 9 membered heterocycloalkyl, 5 to 6 membered heteroaryl and 7 to 9 membered heterocycloalkyl;
  • ring B is selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinazolinyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridothiphenyl, pyridooxazolyl, pyridothiazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidofuranyl, pyrimidothiphenyl, pyrimidooxazolyl, pyrimidothiazolyl, Cyclopropyl, cyclobutyl, cyclopent
  • Ring B is selected from or ring B 1 , and the left side is directly connected to L;
  • Ring B is selected from or ring B 1 , and the left side is directly connected to L;
  • Ring B 1 is selected from C 8-12 cycloalkyl 11 to 13 membered heterocyclyl or 11 to 13 membered heterocycloalkyl;
  • Ring B1 is selected from
  • R2 is selected from or R 2A ;
  • R 2a is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-4 alkylene-C 3-12 carbocyclyl, -C 0-4 alkylene-4 to 12 membered heterocyclyl, -C 1-6 alkylene-NHC( ⁇ O)-C 1-6 alkylene-NR 2aa R 2ab , -C 1-6 alkylene-C( ⁇ O)NR 2aa R 2ab , -C 1-4 alkylene-NR 2aa C( ⁇ O)R 2ab , -C 1-6 alkylene-N(C 1-6 alkylene)R 2aa , -C 1-6 alkylene-SR 2ac , -C 1-6 alkylene-NHC( ⁇ NR 2ad )NR 2aa R 2ab , -C 1-6 alkylene-R 2ae , -C 1-6 alkylene- -C 0-6 alky
  • R 2a is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-4 to 6 membered heterocyclyl, -C 1-4 alkylene-NHC( ⁇ O)-C 1-4 alkylene-NR 2aa R 2ab , -C 1-4 alkylene- C ( ⁇ O)NR 2aa R 2ab , -C 1-4 alkylene-NR 2aa C( ⁇ O)R 2ab , -C 1-4 alkylene-N(C 1-4 alkylene)R 2aa , -C 1-4 alkylene-SR 2ac , -C 1-4 alkylene-NHC( ⁇ NR 2ad )NR 2aa R 2ab , -C 1-6 alkylene-R 2ae , -C 1-4 alkylene- 0-4 alkylene-C
  • R 2A is selected from
  • R 2B is selected from
  • R 2C is selected from
  • R 3B is selected from
  • Q is selected from O, NR q , S, S( ⁇ O), S( ⁇ O) 2 ;
  • Q is selected from O, NH or S
  • Q 1 is selected from O or NH
  • R 3 and R 4 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 3 and R 4 are each independently selected from H, halogen, CN, OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 3 and R 4 are directly linked to form a C 3-6 carbocyclyl or a 4- to 7-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, CN, OH, methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl, wherein the -CH 2 -, methyl, ethyl, cyclopropyl are optionally substituted with 1 to 4 R k ;
  • R 3 and R 4 are directly connected to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with 1 to 4 R k ;
  • R 3 and R 4 are each independently selected from H, F or methyl
  • R q , R 5 are each independently selected from H or methyl
  • R 5 is selected from H
  • R 2aa , R 2ab , R 2ac , R 2ad , R q , and R 5 are each independently selected from H, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 carbocyclyl, and -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 2aa , R 2ab , R 2ac , R 2ad , R q , and R 5 are each independently selected from H, C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 2aa , R 2ab , R 2ac , R 2ad are each independently selected from H, methyl, ethyl, CF 3 , -CH 2 -cyclopropyl, cyclopropyl;
  • R 2aa , R 2ab , R 2ac , and R 2ad are each independently selected from H, methyl, and ethyl;
  • R 2ae is selected from NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -NHC( ⁇ O)-C 1-6 alkyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 2ae is selected from NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -NHC( ⁇ O)-C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 2ae is selected from -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -NHC( ⁇ O)-CH 3 , -NHC( ⁇ O)-CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -pipe
  • R y , R 1a , and R b are each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, ⁇ O, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, and —CH 2 -cyclopropyl, wherein the —CH 2 -, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propynyl, and cyclopropyl are optionally substituted with 1 to 4 R k ;
  • each R y is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH 2 -cyclopropyl, -CH 2 OCH 3 , -CH 2 OH, -CH 2 CN;
  • R y is selected from F, Cl, Br, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;
  • each R 1a is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH 2 -cyclopropyl, -CH 2 OCH 3 , -CH 2 OH, -CH 2 CN;
  • R b is selected from H, deuterium, halogen, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;
  • R b1 is selected from -CH 2 OH, -CH 2 -OCH 3 , -CH 2 CN;
  • n is selected from 1, 2 or 3;
  • m is selected from 0, 1, 2, 3 or 4.
  • Y 1 , Y 2 , and Y 3 are each independently selected from N or CR y ;
  • R 1 is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, non-aromatic C 3-12 carbocyclyl or non-aromatic 4- to 12-membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R 1a ;
  • L is selected from a bond, -O-, -S-, -NH-, -N(C 1-4 alkyl)-, -OC 1-4 alkylene-, -NH-C 1-4 alkylene-, -N(C 1-4 alkyl)-C 1-4 Alkylene-, -C 1-4 alkylene-, said alkylene or alkyl is optionally substituted by 1 to 4 R k ;
  • Ring B is selected from C 3-7 cycloalkyl, C 8-12 cycloalkyl, 4- to 10-membered heterocycloalkyl, 11- to 13-membered heterocycloalkyl, 11- to 13-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;
  • R 2a is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-4 alkylene-C 3-12 carbocyclyl, -C 0-4 alkylene-4 to 12-membered heterocyclyl, -C 1-6 alkylene-NHC( ⁇ O)-C 1-6 alkylene-NR 2aa R 2ab , -C 1-6 alkylene-C( ⁇ O)NR 2aa R 2ab , -C 1-4 alkylene-NR 2aa C( ⁇ O)R 2ab , -C 1-6 alkylene-N(C 1-6 alkylene)R 2aa , -C 1-6 alkylene-SR 2ac , -C 1-6 alkylene-NHC( ⁇ NR 2ad )NR 2aa R 2ab , -C 1-6 alkylene-R 2ae , -C 0-6 alkylene-C 3-12 carbocycl
  • Q is selected from O, NR q , S, S( ⁇ O), S( ⁇ O) 2 ;
  • R 3 and R 4 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 3 and R 4 are directly linked to form a C 3-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;
  • R 2aa , R 2ab , R 2ac , R 2ad , R q , and R 5 are each independently selected from H, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 carbocyclyl, and -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 2ae is selected from NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -NHC( ⁇ O)-C 1-6 alkyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R y , R 1a , R b are independently selected from H, deuterium, halogen, OH, ⁇ O, CN, NH 2 , NO 2 , COOH, CONH 2 , C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , —OC 3-10 carbocyclyl, —O-4 to 10 membered heterocyclyl, —NH-C 3-10 carbocyclyl, —NH-4 to 10 membered heterocyclyl, —SC 3-10 carbocyclyl, —S-4 to 10 membered heterocyclyl, —C 0-4 alkylene-C 3-10 carbocyclyl, —C 0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycl
  • n is selected from 1, 2 or 3;
  • n is selected from 0, 1, 2, 3 or 4;
  • R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a : phenyl, naphthyl, 5 to 6 membered heteroaryl, 8 to 10 membered cycloheteroaryl, C 3-7 monocycloalkyl, C 4-7 monocycloalkenyl, C 5-12 cycloalkyl, C 5-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, 4 to 7 membered monoheterocycloalkyl, 6 to 12 membered cycloheterocycloalkyl, 6 to 12 membered spiroheterocycloalkyl, 6 to 12 membered bridged heterocycloalkyl;
  • Ring B is selected from C3-7 cycloalkyl, C8-12 cycloalkyl, C8-12 spirocycloalkyl, C8-12 bridged cycloalkyl, 4 to 7 membered monoheterocycloalkyl, 6 to 10 membered cycloheterocycloalkyl, 6 to 10 membered spiroheterocycloalkyl, 6 to 10 membered bridged heterocycloalkyl, 11 to 13 membered bicyclic heterocycloalkyl, 11 to 13 membered tricyclic heterocycloalkyl, phenyl, naphthyl, 5 to 6 membered heteroaryl, 8 to 10 membered cycloheteroaryl, benzoC7-9cycloalkyl , benzo7 to 9 membered heterocycloalkyl, 5 to 6 membered heteroaryl andC7-9cycloalkyl , 5 to 6 membered heteroaryl and7 to 9 membered heterocycloalkyl;
  • R 2a is selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-4 to 6 membered heterocyclyl, -C 1-4 alkylene-NHC( ⁇ O)-C 1-4 alkylene-NR 2aa R 2ab , -C 1-4 alkylene-C( ⁇ O)NR 2aa R 2ab , -C 1-4 alkylene-NR 2aa C( ⁇ O)R 2ab , -C 1-4 alkylene-N(C 1-4 alkylene)R 2aa , -C 1-4 alkylene-SR 2ac , -C 1-4 alkylene-NHC( ⁇ NR 2ad )NR 2aa R 2ab , -C 1-4 alkylene-R 2ae , -C 0-4 alkylene-C 3-6 carbocycl
  • R 3 and R 4 are each independently selected from H, halogen, CN, OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 3 and R 4 are directly linked to form a C 3-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;
  • R 2aa , R 2ab , R 2ac , R 2ad , R q , and R 5 are each independently selected from H, C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocyclyl, and -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 2ae is selected from NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -NHC( ⁇ O)-C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R y , R 1a , and R b are independently selected from H, deuterium, halogen, OH, ⁇ O, CN, NH 2 , NO 2 , COOH, CONH 2 , C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , —OC 3-6 carbocyclyl, -O-4 to 6-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-4 to 6-membered heterocyclyl, -SC 3-6 carbocyclyl, -S-4 to 6-membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbo
  • R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a : phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinazolinyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridothiphenyl, pyridooxazolyl, pyridothiazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidofuranyl, pyrimidothiphenyl, pyrimidooxazolyl, pyrimidothiazolyl, Cyclopropy
  • Ring B is selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinazolinyl, pyridopyrazolyl, pyrazolyl, imidazolyl, pyridofuranyl, pyridothiphenyl, pyridoxazolyl, pyridothiazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidofuranyl, pyrimidothiphenyl, pyrimidoxazolyl, pyrimidothiazolyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohex
  • R 2aa , R 2ab , R 2ac , R 2ad are each independently selected from H, methyl, ethyl, CF 3 , -CH 2 -cyclopropyl, cyclopropyl;
  • R q , R 5 are each independently selected from H or methyl
  • R y , R 1a , and R b are each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, ⁇ O, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, and —CH 2 -cyclopropyl, wherein the —CH 2 -, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propynyl, and cyclopropyl are optionally substituted by 1 to 4 R k ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, CN, OH, methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl, wherein the -CH 2 -, methyl, ethyl, cyclopropyl is optionally substituted by 1 to 4 R k ;
  • R 3 and R 4 are directly linked to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted by 1 to 4 R k ;
  • L is selected from a bond, -O-, -S-, -NH-, -OCH2- , -OCH2CH2- , -OCH2CH2CH2- , -NHCH2-, -NHCH2CH2-, -NHCH2CH2- , -NHCH2CH2CH2- , said -CH2- being optionally substituted with 1 to 4 Rk ;
  • Q is selected from O, NH or S
  • R 3 and R 4 are each independently selected from H, F or methyl
  • R5 is selected from H
  • R 1 is selected from one of the following groups optionally substituted by 1 to 4 R 1a :
  • R 2aa , R 2ab , R 2ac , and R 2ad are each independently selected from H, methyl, and ethyl;
  • R b1 is selected from -CH 2 OH, -CH 2 -OCH 3 , -CH 2 CN;
  • the compound represented by the general formula (I) is selected from the compounds represented by the general formulas (Ia), (Ib), (Ic), (Id), (Ie), and (If),
  • R 1A is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, said aryl or heteroaryl being optionally substituted by 1 to 4 R 1a ;
  • Q 1 is selected from O or NH
  • Ring B1 is selected from C8-12 cycloalkyl, 11 to 13 membered heterocyclyl or 11 to 13 membered heterocycloalkyl;
  • n 1;
  • p is selected from 2 or 3;
  • R 2A is selected from
  • Ring B 1 is selected from
  • R 1A is selected from one of the following groups optionally substituted with 1 to 4 R 1a : phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinazolinyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridothiphenyl, pyridooxazolyl, pyridothiazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidofuranyl, pyrimidothiphenyl, pyrimidooxazolyl, pyrimidothiazolyl,
  • L is selected from -OCH 2 -;
  • R 2 is selected from or R 2A ;
  • R 1 is selected from R 1A or R 1A optionally substituted by 1 to 4 R 1A
  • Ring B is selected from or ring B 1 , and the left side is directly connected to L;
  • the compound represented by the general formula (I) is selected from the compounds represented by the general formula (Ih) and (II),
  • Ring B2 is selected from C8-12 bridged cycloalkyl or 6 to 10 membered spiro heterocycloalkyl, preferably, Ring B2 is selected from The left side is connected to the methylene group;
  • R b is selected from H, deuterium, halogen, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;
  • R y is selected from F, Cl, Br, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;
  • R 2B is selected from
  • R 2C is selected from
  • the compound represented by the general formula (I) is selected from the compounds represented by the general formula (IJ),
  • R y is selected from F, Cl, Br, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;
  • R 3B is selected from
  • R b is selected from H, deuterium, halogen, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;
  • the present invention relates to the following compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures in Table S.
  • the present invention relates to a pharmaceutical composition, comprising the above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.
  • the present invention relates to use of the above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of drugs for PARP14-related diseases, preferably tumors, atopic dermatitis and autoimmune diseases.
  • the present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal and a pharmaceutical excipient.
  • the pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").
  • the present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition.
  • the mammal of the present invention includes a human.
  • an "effective amount” or “therapeutically effective amount” as used herein refers to administering a sufficient amount of the compound disclosed herein to alleviate to some extent one or more symptoms of the disease or condition being treated (e.g., tumors, atopic dermatitis, and autoimmune diseases).
  • the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired effect of a biological system.
  • an "effective amount” for therapeutic uses is the amount of a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg, 4-500 mg, 5-5 00mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg
  • the pharmaceutical composition includes but is not limited to 1-1500 mg, 1-600 mg, 20-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg of a compound of the invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.
  • a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a PARP14-related disease (such as a tumor, atopic dermatitis).
  • a method for treating a disease in a mammal comprising administering a drug compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof to a subject at a daily dose of 1-1500 mg/day
  • the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day , 200-800 mg/day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments, daily doses include but are not limited to 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 200 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1500 mg/day, 2000 mg
  • the present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as that in the above-mentioned pharmaceutical composition.
  • the amount of the compound of the invention or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more other
  • the isotopes of carbon include 12 C, 13 C and 14 C
  • the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen) and tritium (T, also called super tritium)
  • the isotopes of oxygen include 16 O, 17 O and 18 O
  • the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S
  • the isotopes of nitrogen include 14 N and 15 N
  • the isotopes of fluorine include 17 F and 19 F
  • the isotopes of chlorine include 35 Cl and 37 Cl
  • the isotopes of bromine include 79 Br and 81 Br.
  • CN refers to cyano
  • Halogen refers to F, Cl, Br or I.
  • Halogen substituted refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I.
  • Halogen substituted is abbreviated as "halo”.
  • Alkyl refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups can be monovalent, divalent, trivalent, or tetravalent.
  • Heteroalkyl refers to a substituted or unsubstituted alkyl in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S).
  • Non-limiting examples include -X-( CH2 )vX-( CH2 )vX-( CH2 )vH (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom, the heteroatom includes but is not limited to N, O or S, and at least one X is selected from a heteroatom, and the N or S in the heteroatom can be oxidized to various oxidation states).
  • the heteroalkyl group can be monovalent, divalent, trivalent or tetravalent.
  • Alkylene refers to a substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon group, including -(CH 2 ) v - (v is an integer from 1 to 10). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene.
  • Heteroalkylene refers to a substituted or unsubstituted alkylene in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S).
  • Non-limiting examples include -X-(CH 2 )vX-(CH 2 )vX-(CH 2 )v-(CH 2 )v-, v is an integer from 1 to 5, each X is independently selected from a bond, N, O or S, and at least one X is selected from N, O or S.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms, and the cycloalkyl radical can be a monocyclic, cyclic, bridged, and spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, adamantane, etc.
  • the cycloalkyl radical can be monovalent, divalent, trivalent, or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S, and the C, N, S on the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocyclic, cyclic, bridged and spirocyclic.
  • Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxadiazole, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazininyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,
  • the heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.
  • Alkenyl refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon double bonds, with a main chain including but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms.
  • alkenyl groups include but are not limited to but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1- methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and
  • Alkynyl refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, 2 to 4 carbon atoms in the backbone, examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13
  • Alkoxy refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.
  • Carbocyclyl or “carbocycle” refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, a 10-15-membered tricyclic ring, or a 12-18-membered quaternary system.
  • the carbocyclyl can be attached to an aromatic ring or a non-aromatic ring, and the ring can be optionally a monocyclic ring, a cyclic ring, a bridged ring, or a spirocyclic ring.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl” or “carbocycle” can be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S.
  • the C, N, S selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states.
  • the heterocyclic group can be connected to a heteroatom or a carbon atom, and can be connected to an aromatic ring or a non-aromatic ring.
  • the heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring.
  • Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, te
  • Spiro or “spirocyclic group” refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom).
  • "Spirocycle” or “spirocyclyl” can be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms in the cyclic system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, 5 to 10.
  • Non-limiting examples include: "Bicyclic" or "bicyclic group” can be monovalent, divalent, trivalent or tetravalent.
  • Carbospirocycle refers to a “spirocycle” wherein the ring system consists of only carbon atoms.
  • Carbocyclic refers to a “cyclic” ring system consisting of only carbon atoms.
  • Carbobridged ring refers to a “bridged ring” wherein the ring system consists of only carbon atoms.
  • Heteromonocycle refers to a monocyclic ring system of "heterocyclyl” or “heterocycle”,
  • Heterocyclic ring refers to a "cyclo" containing a heteroatom.
  • Heterospirocycle refers to a “spirocycle” containing a heteroatom.
  • Heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • Aryl or “aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms.
  • the aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl” or “aromatic ring” can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.
  • heteroaryl examples include but are not limited to pyridyl, furanyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl, etc.
  • the heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include
  • the heteroaryl groups appearing in this article have the same definition as this definition.
  • the heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment site is located on the aromatic ring.
  • X-Y membered rings (X, Y are integers, and 3 ⁇ X ⁇ Y, X ⁇ Y ⁇ 20 are selected from any integer between 4 and 20) include X, X+1, X+2, X+3, X+4....Y membered rings.
  • Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings or heterobridged rings.
  • 4--7 membered heteromonocyclic rings refer to 4-, 5-, 6- or 7-membered heteromonocyclic rings
  • 5--10 membered heterocyclic rings refer to 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic rings
  • Cxy carbocycle (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, cyclic carbocycle or bridged carbocycle) includes Cx , Cx +1 , Cx+2 , Cx +3 , Cx +4 ...
  • Cy -membered ring (x is an integer, and 3 ⁇ x ⁇ y, y is selected from any integer between 4 and 20), for example.
  • C3-6 cycloalkyl refers to C3 , C4 , C5 or C6 cycloalkyl;
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection is non-positional and there are hydrogen atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds and become a group with the corresponding valence.
  • any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes
  • connection directions include connection from left to right and from right to left in reading order, for example, A-L-B, when L is selected from -M-W-, includes A-M-W-B and A-W-M-B.
  • alkyl optionally substituted with F means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • Carrier refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • Prodrug refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism.
  • the prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the modified compounds, which can be removed by conventional manipulation or in vivo to obtain the parent compound.
  • the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.
  • Co-crystal refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.
  • Stepoisomers refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers (such as trans/cis, Z/E), enantiomers, diastereomers and conformational isomers.
  • Tautomers refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.
  • IC50 is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of such a process, such as an enzyme, receptor, cell, etc.) by half.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;
  • Boc tert-butoxycarbonyl
  • Ts p-toluenesulfonyl
  • DIPEA CAS: 7087-68-5;
  • HATU CAS: 148893-10-1;
  • LAH CAS: 16853-85-3;
  • Dess-Martin oxide CAS: 87413-09-0.
  • the compounds of the present application can be prepared by the following synthesis method:
  • the compound (Z-4) is subjected to removal of 2,4-dimethoxybenzyl to obtain the compound (Z-5);
  • the compound of the general formula (Z-6) reacts with the compound (Z-7) to obtain the compound of the general formula (Z);
  • R z1 is selected from Cl, Br, I, OMs, OTs, OTf and the like.
  • compound 2b (synthetic route according to document WO2022206795) (1.5 g, 7.50 mmol) was dissolved in 20 mL of dichloromethane, triethylamine (1.52 g, 15.0 mmol), and methylsulfonyl chloride (1.14 g, 10 mmol) was added dropwise and reacted at room temperature for 3 h.
  • the reaction mixture was poured into 100 mL of water and extracted with DCM (30 mL ⁇ 2).
  • the combined organic phase was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
  • the residue was purified by silica gel column to obtain compound 2c (2.0 g, yield: 71.94%)
  • compound 2d (1.20 g, 3.24 mmol) was dissolved in 50 mL of N-methylpyrrolidone, 2,4-dimethoxybenzylamine (0.82 g, 4.86 mmol), potassium carbonate (0.90 g, 6.48 mmol), and the temperature was raised to 80 ° C.
  • the reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (100 mL ⁇ 2). The combined organic phase was washed with brine (100 mL ⁇ 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 2e (1.2 g, yield: 71.56%).
  • compound 2e (1.20 g, 2.32 mmol) was dissolved in 10 mL of dichloromethane and 2 mL of trifluoroacetic acid, triethylsilane (0.54 g, 4.64 mmol), and reacted at room temperature for 2 h. Vacuum concentration was performed. The mixture was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column to obtain compound 2f (0.6 g, yield: 70.43%).
  • compound 2f (0.6 g, 1.63 mmol) was dissolved in 10 mL 2N hydrochloric acid 1,4-dioxane solution, chloroacetonitrile (0.24 g, 3.26 mmol), reacted at 80 ° C for 2 h, and concentrated under reduced pressure. Dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column to obtain compound 2g (0.2 g, yield: 29.83%)
  • compound 2g (0.2g, 0.49mmol) was dissolved in tetrahydrofuran, 1mL of 2N sodium hydroxide solution was added dropwise to the reaction flask, and intermediate 1 (0.16g, 0.98mmol) was reacted at room temperature for 2h. The residue was concentrated under reduced pressure and purified by silica gel column to obtain compound 2 (25mg, yield: 10.41%).
  • compound 3b (1.4 g, 6.22 mmol) was dissolved in 20 mL of tetrahydrofuran, and 2.5 N lithium aluminum tetrahydride tetrahydrofuran solution (5.0 mL, 12.5 mmol) was added dropwise to the reaction bottle at 0°C and reacted at room temperature for 3 h.
  • the reaction mixture was poured into 100 mL of water and extracted with DCM (30 mL ⁇ 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 3b (1.2 g, yield: 97.93%).
  • compound 4d (0.70 g, 1.43 mmol) was dissolved in 10 mL of dichloromethane and 2 mL of trifluoroacetic acid, triethylsilane (0.54 g, 4.64 mmol), and reacted at room temperature for 2 h. Vacuum concentration was performed. Dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column to obtain compound 4e (0.25 g, yield: 51.47%)
  • compound 5b (4.5 g, 15.23 mmol) was dissolved in acetonitrile (30 mL) and water (3 mL), trifluoroacetic acid (40.26 mmol, 3 mL) was added, and the reaction was allowed to proceed at room temperature for one hour.
  • the pH of the reaction solution was adjusted to 7-8 with sodium bicarbonate aqueous solution, poured into 100 mL of water and extracted with ethyl acetate (30 mL ⁇ 2).
  • the combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude product of compound 5c, which was directly used in the next step.
  • compound 5c (4 g, 14.22 mmol) was dissolved in methanol (20 mL), and then sodium borohydride (800 mg, 21.21 mmol) was slowly added at 0°C and reacted at 0°C for one hour.
  • the pH of the reaction solution was adjusted to 6-7 with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate (30 mL ⁇ 2).
  • the combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by silica gel column to obtain compound 5d (3.5 g, 86.85%).
  • compound 10b (4.0 g, 13.94 mmol) was dissolved in 100 mL of tetrahydrofuran, and 2.5 M LAH (13.94 mL, 34.85 mmol) was added dropwise to the reaction bottle at 0°C, and the reaction was carried out at room temperature for 3 h.
  • the reaction mixture was poured into 100 mL of water and extracted with DCM (100 mL ⁇ 2).
  • the combined organic phase was washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
  • the residue was purified by silica gel column to obtain compound 10c (3.0 g, yield: 83.11%).
  • compound 10d (3.0 g, 8.90 mmol) was dissolved in 30 mL of dichloromethane, and 10 mL of 4N HCl in 1,4-dioxane was added dropwise, and the mixture was reacted at room temperature for 1 h. The reaction mixture was concentrated in vacuo to obtain compound 10e, which was used directly in the next step (3.0 g, crude product).
  • compound 10f (1.0 g, 3.58 mmol) was dissolved in 10 mL DMSO, methyl 2,6-difluoro-4-hydroxybenzoate (1.01 g, 5.37 mmol), potassium carbonate (1.38 g, 10 mmol), microwave heated to 120 ° C, and reacted for 2 h.
  • the reaction mixture was poured into 30 mL of water and extracted with ethyl acetate (30 mL ⁇ 2).
  • the combined organic phase was washed with brine (20 mL ⁇ 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
  • the residue was purified by silica gel column to obtain compound 10g (0.3 g, yield: 20.94%).
  • compound 10h (0.25 g, 0.48 mmol) was dissolved in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid, triethylsilane (0.11 g, 0.96 mmol) was added, and the reaction was carried out at room temperature for 2 h. Vacuum concentration was performed. The product was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column to obtain compound 10i (0.15 g, yield: 84.46%).
  • compound 10i (0.15 g, 0.41 mmol) was dissolved in 5 mL 2N hydrochloric acid 1,4-dioxane solution and chloroacetonitrile (0.06 g, 0.82 mmol) and reacted at 80 °C for 2 h. Concentrated in vacuo. Dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column to obtain compound 10j (0.10 g, yield: 59.69%).
  • compound 10j (0.10 g, 0.24 mmol) was dissolved in tetrahydrofuran, 1 mL of 2N sodium hydroxide solution was added dropwise to the reaction flask, intermediate 1 (0.08 g, 0.48 mmol) was added, and the mixture was reacted at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column to obtain compound 10 (50 mg, yield: 41.68%).
  • 1,1-Dibromo-3,3,3-trifluoroacetone (4.98 g, 18.49 mmol) was placed in a 250 mL single-mouth bottle, 30 mL of water and sodium acetate (1.89 g, 23.09 mmol) were added, and the temperature was raised to 90 °C for 1 hour. After cooling to room temperature, 60 mL of methanol, 11C (3.02 g, 15.39 mmol) and concentrated aqueous ammonia (15 mL) were added in sequence, and the temperature was raised to 90 °C for 2 hours. After cooling to room temperature, the reaction solution was poured into 200 mL of water, filtered, and the filter cake was washed with water (2 ⁇ 10 mL). The filter cake was dried under reduced pressure to obtain 11D (2.9 g, yield: 62%).
  • 11D (2.0 g, 6.62 mmol) was dissolved in 30 mL DMF at room temperature, and isopropyl iodide (4.50 g, 26.48 mmol) and cesium carbonate (6.47 g, 19.86 mmol) were added in sequence, and the temperature was raised to 90°C for overnight reaction. After cooling to room temperature, water and ethyl acetate were added for extraction, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 11E (1.2 g, yield: 52%).
  • 11D (5.0 g, 16.54 mmol) was dissolved in 30 mL DMF at room temperature, iodomethane (10.78 g, 33.10 mmol) and cesium carbonate (3.52 g, 24.74 mmol) were added in sequence, and the temperature was raised to 80 °C for 16 hours.
  • the reaction solution was cooled to room temperature, water (30 mL) was added, and it was extracted twice with ethyl acetate (30 mL ⁇ 2), and the organic phases were combined.
  • compound 14a (5 g, 27.29 mmol) was dissolved in 20 mL of tetrahydrofuran, and 2.5 N tetrahydrogen lithium aluminum tetrahydrofuran solution (10.0 mL, 255.6 mmol) was added dropwise to the reaction bottle at 0°C. After the addition, the reaction was allowed to react at room temperature for 3 h. The reaction mixture was poured into 100 mL of water and extracted with DCM (30 mL ⁇ 2). The combined organic phase was washed with brine (30 mL), then dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column to obtain compound 14b (3 g, yield: 70.83%).
  • the organic phases were combined, and the organic phases were washed twice with water (20 mL ⁇ 2) and once with a saturated aqueous solution of NaCl (20 mL ⁇ 1) in sequence, and then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain the target compound 15e (0.30 g, yield 58.50%).
  • 16b (1.4 g, 6.27 mmol) was dissolved in 35 mL of toluene, and methyl 2,6-difluoro-4-hydroxybenzoate (1.42 g, 7.52 mmol) and cyanomethylenetri-n-butylphosphine (4.54 g, 18.81 mmol) were added in sequence, and the mixture was reacted at 100°C for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain the target compound 16c (1 g, yield 40.54%).
  • 16e (0.3 g, 0.77 mmol) was dissolved in 6 mL 1,4-dioxane, and chloroacetonitrile (170 mg, 2.31 mmol) and dioxane hydrochloride solution (0.5 mL, 4 mol/L) were added in sequence, and the mixture was reacted at 80°C for 4 hours.
  • the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, and the residue was chromatographed on a silica gel column to obtain compound 16f (0.3 g, yield 89.99%).
  • 16f (0.3 g, 0.69 mmol) was dissolved in 4 mL of tetrahydrofuran, and intermediate 1 (0.44 g, 2.76 mmol) and sodium hydroxide solution (0.5 mL, 3N) were added in sequence, and the mixture was reacted at room temperature for 3 hours. The reaction solvent was removed by concentration under reduced pressure, and the residue was chromatographed on a silica gel column to obtain compound 16 (42 mg, yield 11.78%).
  • the ELISA method was used to test the inhibitory effect of compounds on the enzyme activity of PARP14.
  • 50 ⁇ L of histone (BPS, 52029) was diluted with PBS (Solarbio, P1022) and added to a 384 reaction plate (Greiner, 781074) and coated overnight at 4°C. After washing with PBST (1XPBS + 0.05% Tween-20), 200 ⁇ L of Blocking buffer (BPS, 79743) was added and blocked at room temperature for 90 minutes.
  • the compounds of the present invention have an inhibitory effect on PARP14.
  • compounds 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15 and 16 have good inhibitory activity on PARP14.
  • mice Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice On the day of the experiment, 6 SD rats/compound were randomly divided into groups according to body weight. The rats were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.2% Tween 80 + 99.8% 0.5% MC.
  • DMA dimethylacetamide
  • Solutol polyethylene glycol-15-hydroxystearate
  • Saline physiological saline
  • 0.5% MC 0.5% aqueous solution of methylcellulose.
  • the compounds of the present invention have good pharmacokinetic properties in rats. Specifically, compound 3 has better oral absorption performance and/or lower clearance rate in rats.
  • mice Male BALB/c mice, 20-25 g, 6 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice On the day of the experiment, six BALB/c mice were randomly divided into groups according to their body weight. They were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.2% Tween 80 + 99.8% 0.5% MC.
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic properties in mice.
  • mice Male beagle dogs, about 8-11 kg, 5-6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.
  • Test method On the test day, 5-6 beagle dogs/compound were randomly divided into groups according to body weight. The dogs were fasted but not watered for 12-14 hours one day before administration, and food was given 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.2% Tween 80 + 99.8% 0.5% MC.
  • the compounds of the present invention such as the compounds in the examples, have good oral absorption properties in beagle dogs.
  • mice Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4-6 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.
  • Test method On the test day, 4-6 monkeys/compound were randomly divided into groups according to body weight. The monkeys were fasted but not watered for 14-18 hours one day before administration and were fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.2% Tween 80 + 99.8% 0.5% MC.
  • DMA dimethylacetamide
  • Solutol polyethylene glycol-15-hydroxystearate
  • Saline physiological saline
  • 0.5% MC 0.5% aqueous solution of methylcellulose.
  • 1.0 mL of blood was collected from the limb veins and placed in an EDTAK2 centrifuge tube.
  • the blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma.
  • the blood collection time points for the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h.
  • all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.
  • the compounds of the present invention such as the compounds in the examples, have good oral absorption properties in monkeys.
  • the experiment used a monolayer of Caco-2 cells and three parallel incubations were performed in a 96-well Transwell plate.
  • a transport buffer solution (HBSS, 10mM HEPES, pH 7.4 ⁇ 0.05) containing the compound of the present invention (5 ⁇ M) was added to the dosing port hole on the apical side or the basolateral side.
  • a transport buffer solution containing DMSO was added to the corresponding receiving port hole.
  • the cell plate was removed and appropriate amounts of samples were taken from the top and bottom ends to a new 96-well plate. Subsequently, acetonitrile containing an internal standard was added to precipitate the protein.
  • the samples were analyzed using LC MS/MS and the concentrations of the compounds of the present invention and the control compounds were determined.
  • the concentration data were used to calculate the apparent permeability coefficients for transport from the apical side to the basolateral side of the monolayer cells and from the basolateral side to the apical side, thereby calculating the efflux rate.
  • the integrity of the monolayer cells after 2 hours of incubation was evaluated by leakage of fluorescent yellow.
  • the compounds of the present invention have good Caco2 permeability. Compared with the control compound 1, for example, compound 3 has better permeability and lower efflux rate.
  • liver microsomes from five species including humans, dogs, rats and mice, were used as in vitro models to evaluate the metabolic stability of the test substances.
  • test substance was incubated with microsomal proteins and coenzyme NADPH. After a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS/MS. T 1/2 was calculated by the ln value of the drug residual rate in the incubation system and the incubation time, and the liver microsomal intrinsic clearance CLint(mic) and liver intrinsic clearance CLint(Liver) were further calculated.
  • the compounds of the present invention such as the compounds in the examples, have good metabolic stability in liver microsomes.

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Abstract

La présente invention concerne un composé tel que représenté par la formule générale (I) ou un stéréoisomère, une substance deutérée, un solvate, un promédicament, un métabolite, un sel pharmaceutiquement acceptable ou un co-cristal de celui-ci, ainsi qu'un intermédiaire et une composition pharmaceutique associés, et son utilisation dans la préparation d'un médicament pour des maladies associées à PARP14.
PCT/CN2024/097795 2023-06-06 2024-06-06 Dérivé de quinazolinone et son utilisation médicale Pending WO2024251205A1 (fr)

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CN202311343202.1 2023-10-17
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019126443A1 (fr) * 2017-12-21 2019-06-27 Ribon Therapeutics Inc. Quinazolinones en tant qu'inhibiteurs de parp14
WO2020257416A1 (fr) * 2019-06-19 2020-12-24 Ribon Therapeutics, Inc. Dégradation de protéine ciblée de parp14 pour une utilisation en thérapie
WO2022165118A1 (fr) * 2021-01-29 2022-08-04 Ribon Therapeutics, Inc. Méthodes de traitement de maladies inflammatoires

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019126443A1 (fr) * 2017-12-21 2019-06-27 Ribon Therapeutics Inc. Quinazolinones en tant qu'inhibiteurs de parp14
WO2020257416A1 (fr) * 2019-06-19 2020-12-24 Ribon Therapeutics, Inc. Dégradation de protéine ciblée de parp14 pour une utilisation en thérapie
WO2022165118A1 (fr) * 2021-01-29 2022-08-04 Ribon Therapeutics, Inc. Méthodes de traitement de maladies inflammatoires

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LAURIE B. SCHENKEL ET AL.: "A Potent and Selective PARP14 Inhibitor Decreases Protumor Macrophage Gene Expression and Elicits Inflammatory Responses in Tumor Explants", CELL CHEMICAL BIOLOGY, vol. 28, 19 August 2021 (2021-08-19), XP055924628, DOI: 10.1016/j.chembiol.2021.02.010 *

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