WO2023061368A1 - Dérivé d'acide hydroximique et son utilisation - Google Patents

Dérivé d'acide hydroximique et son utilisation Download PDF

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WO2023061368A1
WO2023061368A1 PCT/CN2022/124637 CN2022124637W WO2023061368A1 WO 2023061368 A1 WO2023061368 A1 WO 2023061368A1 CN 2022124637 W CN2022124637 W CN 2022124637W WO 2023061368 A1 WO2023061368 A1 WO 2023061368A1
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substituted
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group
alkyl
ring
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周鑫
叶兵
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成都自豪药业有限公司
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    • 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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to the field of biomedicine, in particular to a class of hydroxamic acid derivatives and applications thereof.
  • Polyadenosine diphosphate-ribose polymerase is an important DNA repair enzyme that exists in eukaryotic cells and has a protease that catalyzes the ribosylation of polyadenosine diphosphate (poly ADP). It recognizes DNA single-strand breaks and initiates repair. This repair acts on many proteins, involving chromosome stability, DNA damage repair, gene transcription, cell growth, death and apoptosis, and is closely related to inflammation, tumors, aging and other diseases in terms of physiology and pathology.
  • PARP Polyadenosine diphosphate-ribose polymerase
  • PARP inhibitors can inhibit PARP activity, enhance the effect of radiotherapy and DNA damage chemotherapy drugs, and can also selectively kill tumor cells with DNA repair defects when used alone.
  • the application of PARP inhibitors in tumor therapy is mainly based on two mechanisms: first, PARP inhibitors can inhibit the repair process of DNA single-strand damage, but this DNA single-strand damage can be transformed into double-strand damage during DNA replication to form a replication fork. Strand damage (DSB), and this DSB can still be repaired by homologous recombination (HR) pathway. If tumor cells have homologous recombination repair defects (including BRCA1/2 mutations), making DSB damage irreparable, it will lead to the synthetic lethal effect of PARP inhibitors and homologous recombination repair defects on tumor cells.
  • Single-drug PARP inhibitors have significant inhibitory effects on BRCA1 and BRCA2 mutated breast and ovarian cancer cells.
  • BRCA1/2 is only a part of HR repair, and other proteins such as EMSY and PTEN are also important for the HR pathway. If these genes are mutated or silenced in the HR repair pathway, PARP inhibitors may produce single-drug resistance through synthetic lethal effects. tumor activity.
  • Histone deacetylase is a class of proteases that play an important role in the structural modification of chromosomes and the regulation of gene expression. In general, the acetylation of histones is conducive to the dissociation of DNA and histone octamers, and the relaxation of nucleosome structure, so that various transcription factors and co-transcription factors can specifically bind to DNA binding sites and activate genes transcription.
  • HAT histone acetyltransferase
  • HDAC histone deacetylase
  • HDAC double-strand break repair
  • Tumor cells that have not been deleted in the pathway also have a good killing effect.
  • the combined drug has the disadvantages of complex pharmacokinetics, possible drug interactions, and more toxic and side effects.
  • a single small molecule with multi-target inhibitory activity promises to avoid these problems. Therefore, it is of great significance to study a small molecular compound with PARP/HDAC dual-target inhibitory activity.
  • the invention provides a class of hydroxamic acid derivatives and applications thereof, and its technical scheme is as follows:
  • the present invention provides a compound represented by formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof:
  • X 1 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • X 2 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • Z 1 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • Z 2 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • Y 1 and Y 2 are independently selected from N and CR 5 ;
  • R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, C 1 -C 8 alkyl;
  • Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups;
  • R 1 is a substituent on ring A, independently selected from substituted or unsubstituted C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogen, substituted or unsubstituted 3-10 membered cycloalkyl , substituted or unsubstituted 3-10 membered saturated heterocyclic group, substituted or unsubstituted 3-10 membered unsaturated heterocyclic group;
  • the substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups;
  • the substituents of the cycloalkyl and heterocyclic groups are selected from C 1 ⁇ C 8 alkyl, C 1 ⁇ C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom
  • the substituent of the heteroaryl group is selected from C 1 ⁇ C 8 alkyl, C 1 ⁇ C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom
  • the substituent forms a double bond connecting O;
  • n represents the number of substituents R 1 on the A ring, an integer selected from 0 to 5, and when n is 0, it means that there is no substituent on the A ring.
  • X 1 is selected from none, O or NR 2 ;
  • X 2 is selected from none or CR 3 R 4 ;
  • Z 1 is selected from none or CR 3 R 4 ;
  • Z 2 is selected from none, O or NR 2 ;
  • Y 1 and Y 2 are independently selected from N and CR 5 ;
  • R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, C 1 -C 4 alkyl;
  • Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • R 1 is a substituent on ring A, independently selected from substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • the substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • the substituents of the cycloalkyl and heterocyclic groups are selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom
  • the substituent of the heteroaryl group is selected from C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom
  • the substituent forms a double bond connecting O;
  • n represents the number of substituents R1 on the A ring, an integer selected from 0, 1, 2 or 3, and when n is 0, it means that there is no substituent on the A ring.
  • X 1 is selected from none, O or NR 2 ;
  • X 2 is selected from none or CR 3 R 4 ;
  • Z 1 is selected from none or CR 3 R 4 ;
  • Z 2 is selected from none, O or NR 2 ;
  • X 2 and Z 1 cannot be CR 3 R 4 or none at the same time;
  • Y 1 and Y 2 are independently selected from N and CR 5 ;
  • Y 1 and Y 2 cannot be selected from N at the same time, but can be selected from CR 5 at the same time;
  • R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, C 1 -C 4 alkyl;
  • X 1 and X 2 are both nil or not nil at the same time;
  • Z 1 and Z 2 are both nil or not nil at the same time
  • Y1 and Y2 are not the same.
  • Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;
  • R 1 is a substituent on ring A, independently selected from substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;
  • the substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;
  • the substituents of the cycloalkyl and heterocyclic groups are selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom
  • the substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C 1 -C 4 alkane group, C 1 -C 4 alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;
  • n represents the number of substituents R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;
  • R 1 ' is selected from halogen.
  • X 1 is selected from O or NR 2 ;
  • X 2 is selected from CR 3 R 4 ;
  • Y 1 and Y 2 are independently selected from N and CR 5 ; and Y 1 and Y 2 cannot be selected from N at the same time, but can be selected from CR 5 at the same time;
  • R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, C 1 -C 4 alkyl;
  • Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • R 1 is a substituent on ring A, independently selected from substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • the substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • the substituents of the cycloalkyl and heterocyclic groups are selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom
  • the substituent of the heteroaryl group is selected from C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom
  • the substituent forms a double bond connecting O;
  • n represents the number of substituents R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;
  • Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;
  • R 1 is a substituent on ring A, independently selected from substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;
  • the substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;
  • the substituents of the cycloalkyl and heterocyclic groups are selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom
  • the substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C 1 -C 4 alkane group, C 1 -C 4 alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;
  • n represents the number of substituents R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;
  • R 1 ' is selected from halogen.
  • X 1 is selected from O or NR 2 ;
  • Y 1 and Y 2 are independently selected from N and CR 5 ; and Y 1 and Y 2 cannot be selected from N at the same time, but can be selected from CR 5 at the same time;
  • R 2 and R 5 are independently selected from hydrogen, C 1 -C 4 alkyl
  • Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • R 1 is a substituent on ring A, independently selected from substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • the substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • the substituents of the cycloalkyl and heterocyclic groups are selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom
  • the substituent of the heteroaryl group is selected from C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom
  • the substituent forms a double bond connecting O;
  • n represents the number of substituents R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;
  • Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;
  • R 1 is a substituent on ring A, independently selected from substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;
  • the substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;
  • the substituents of the cycloalkyl and heterocyclic groups are selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom
  • the substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C 1 -C 4 alkane group, C 1 -C 4 alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;
  • n represents the number of substituents R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;
  • R 1 ' is selected from halogen.
  • X 1 is selected from O or NR 2 ;
  • R 2 is selected from hydrogen, C 1 -C 4 alkyl
  • Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • R 1 is a substituent on ring A, independently selected from substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • the substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • the substituents of the cycloalkyl and heterocyclic groups are selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom
  • the substituent of the heteroaryl group is selected from C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom
  • the substituent forms a double bond connecting O;
  • n represents the number of substituents R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;
  • Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;
  • R 1 is a substituent on ring A, independently selected from substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;
  • the substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;
  • the substituents of the cycloalkyl and heterocyclic groups are selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom
  • the substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C 1 -C 4 alkane group, C 1 -C 4 alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;
  • n represents the number of substituents R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;
  • R 1 ' is selected from halogen.
  • Z 1 is selected from CR 3 R 4 ;
  • Z 2 is selected from O or NR 2 ;
  • Y 1 and Y 2 are independently selected from N and CR 5 ; and Y 1 and Y 2 cannot be selected from N at the same time, but can be selected from CR 5 at the same time;
  • R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, C 1 -C 4 alkyl;
  • Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • R 1 is a substituent on ring A, independently selected from substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • the substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • the substituents of the cycloalkyl and heterocyclic groups are selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom
  • the substituent of the heteroaryl group is selected from C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom
  • the substituent forms a double bond connecting O;
  • n represents the number of substituents R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;
  • Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;
  • R 1 is a substituent on ring A, independently selected from substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;
  • the substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;
  • the substituents of the cycloalkyl and heterocyclic groups are selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom
  • the substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C 1 -C 4 alkane group, C 1 -C 4 alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;
  • n represents the number of substituents R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;
  • R 1 ' is selected from halogen.
  • Z 2 is selected from O or NR 2 ;
  • Y 1 and Y 2 are independently selected from N and CR 5 ; and Y 1 and Y 2 cannot be selected from N at the same time, but can be selected from CR 5 at the same time;
  • R 2 and R 5 are independently selected from hydrogen, C 1 -C 4 alkyl
  • Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • R 1 is a substituent on ring A, independently selected from substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • the substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • the substituents of the cycloalkyl and heterocyclic groups are selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom
  • the substituent of the heteroaryl group is selected from C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom
  • the substituent forms a double bond connecting O;
  • n represents the number of substituents R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;
  • Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;
  • R 1 is a substituent on ring A, independently selected from substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;
  • the substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;
  • the substituents of the cycloalkyl and heterocyclic groups are selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom
  • the substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C 1 -C 4 alkane group, C 1 -C 4 alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;
  • n represents the number of substituents R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;
  • R 1 ' is selected from halogen.
  • Z 2 is selected from O or NR 2 ;
  • R 2 is selected from hydrogen, C 1 -C 4 alkyl
  • Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • R 1 is a substituent on ring A, independently selected from substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • the substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • the substituents of the cycloalkyl and heterocyclic groups are selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom
  • the substituent of the heteroaryl group is selected from C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom
  • the substituent forms a double bond connecting O;
  • n represents the number of substituents R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;
  • Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;
  • R 1 is a substituent on ring A, independently selected from substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;
  • the substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;
  • the substituents of the cycloalkyl and heterocyclic groups are selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom
  • the substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C 1 -C 4 alkane group, C 1 to C 4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two substituents on the same carbon atom form a double bond to connect O;
  • n represents the number of substituents R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;
  • R 1 ' is selected from halogen.
  • X 1 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • X 2 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • Z 1 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • Z 2 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • Y 1 and Y 2 are independently selected from N and CR 5 ;
  • R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, C 1 -C 8 alkyl;
  • X 1 is selected from none, O or NR 2 ;
  • X 2 is selected from none or CR 3 R 4 ;
  • Z 1 is selected from none or CR 3 R 4 ;
  • Z 2 is selected from none, O or NR 2 ;
  • X 2 and Z 1 cannot be CR 3 R 4 or none at the same time;
  • Y 1 and Y 2 are independently selected from N and CR 5 ;
  • Y 1 and Y 2 cannot be selected from N at the same time, but can be selected from CR 5 at the same time;
  • R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, C 1 -C 4 alkyl;
  • X 1 is selected from O or NR 2 ;
  • R 2 is selected from hydrogen, C 1 -C 4 alkyl
  • Z 2 is selected from O or NR 2 ;
  • R 2 is selected from hydrogen, C 1 -C 4 alkyl.
  • X 1 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • X 2 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • Z 1 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • Z 2 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • Y 1 and Y 2 are independently selected from N and CR 5 ;
  • R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, C 1 -C 8 alkyl;
  • X 1 is selected from none, O or NR 2 ;
  • X 2 is selected from none or CR 3 R 4 ;
  • Z 1 is selected from none or CR 3 R 4 ;
  • Z 2 is selected from none, O or NR 2 ;
  • X 2 and Z 1 cannot be CR 3 R 4 or none at the same time;
  • Y 1 and Y 2 are independently selected from N and CR 5 ;
  • Y 1 and Y 2 cannot be selected from N at the same time, but can be selected from CR 5 at the same time;
  • R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, C 1 -C 4 alkyl;
  • X 1 is selected from O or NR 2 ;
  • R 2 is selected from hydrogen, C 1 -C 4 alkyl
  • Z 2 is selected from O or NR 2 ;
  • R 2 is selected from hydrogen, C 1 -C 4 alkyl.
  • X 1 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • X 2 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • Z 1 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • Z 2 is selected from none, O, S, NR 2 or CR 3 R 4 ;
  • Y 1 and Y 2 are independently selected from N and CR 5 ;
  • R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, C 1 -C 8 alkyl;
  • R 1 ' is selected from halogen
  • X 1 is selected from none, O or NR 2 ;
  • X 2 is selected from none or CR 3 R 4 ;
  • Z 1 is selected from none or CR 3 R 4 ;
  • Z 2 is selected from none, O or NR 2 ;
  • X 2 and Z 1 cannot be CR 3 R 4 or none at the same time;
  • Y 1 and Y 2 are independently selected from N and CR 5 ;
  • Y 1 and Y 2 cannot be selected from N at the same time, but can be selected from CR 5 at the same time;
  • R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, C 1 -C 4 alkyl;
  • R 1 ' is selected from halogen
  • X 1 is selected from O or NR 2 ;
  • R 2 is selected from hydrogen, C 1 -C 4 alkyl
  • R 1 ' is selected from halogen
  • Z 2 is selected from O or NR 2 ;
  • R 2 is selected from hydrogen, C 1 -C 4 alkyl
  • R 1 ' is selected from halogen.
  • the compound is one of the following compounds:
  • the present invention also provides the aforementioned compounds, or their salts, or their stereoisomers, or their solvates, or their hydrates, or their prodrugs in the preparation of drugs for inhibiting PARP and/or HDAC activity use.
  • the medicament is a medicament for treating ischemic diseases, diabetes or inflammatory diseases.
  • the drug is a chemotherapeutic drug sensitizer, a radiotherapy sensitizer or a drug for treating tumors;
  • the tumor is breast cancer, ovarian cancer, pancreatic cancer or prostate cancer.
  • the present invention also provides a pharmaceutical preparation, which is one or more of the aforementioned compounds, or their salts, or their stereoisomers, or their solvates, or their hydrates, or their prodrugs It is a preparation prepared by adding pharmaceutically acceptable excipients or auxiliary ingredients to the active ingredient.
  • the present invention also provides a pharmaceutical composition, which comprises the aforementioned compound, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, and a chemotherapeutic drug or a radiotherapy drug .
  • the present invention also provides the use of the aforementioned compound, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its prodrug and chemotherapeutic drug or radiotherapy drug in the preparation of combined drug.
  • the preparation of the present invention is composed of the aforementioned compound, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its prodrug, or one or more of the aforementioned pharmaceutical compositions It is the active ingredient, plus pharmaceutically acceptable excipients or auxiliary ingredients prepared according to conventional methods. Its dosage form includes but not limited to: tablet, granule, capsule, oral liquid and other pharmaceutically acceptable dosage forms.
  • the pharmaceutical composition and its preparation are used in the treatment of diseases that can directly or indirectly produce clinical beneficial effects through the inhibition of PARP and/or HDAC.
  • the diseases improved by PARP and/or HDAC activity inhibition in the present invention include but not limited to the prevention and/or treatment of ischemic diseases, diabetes and inflammatory diseases.
  • the cancer includes but not limited to breast cancer, ovarian cancer, pancreatic cancer or prostate cancer.
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • the structure of the compound refers to a structure that can exist stably.
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • the minimum and maximum values of carbon atom content in hydrocarbon groups are indicated by prefixes, for example, the prefix (C a ⁇ C b ) alkyl means any alkyl group containing "a" to "b" carbon atoms .
  • C 1 -C 8 alkyl refers to straight or branched chain alkyl containing 1 to 8 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl base, tert-butyl, etc.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • Substituted or unsubstituted means that the group may be substituted or unsubstituted.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, eg, phenyl and naphthyl.
  • the aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of connection to the parent must be in a conjugated ⁇ -electron system on the carbon atoms in the ring.
  • the 6-10 membered aryl group means that the aryl group contains 6-10 carbon atoms.
  • Heteroaryl refers to an aryl group in which one or more carbon atoms are replaced by a heteroatom (such as nitrogen, oxygen, or sulfur, etc.).
  • the 5-10 membered heteroaryl group means that the number of atoms on the heteroaryl skeleton is 5-10.
  • Cycloalkyl means an all-carbon monocyclic alkyl group or a bridged, fused, spirocycloalkyl group. 3-10 members means that the cycloalkyl group consists of 3-10 carbon atoms.
  • “Saturated heterocyclyl” means that one or more carbon atoms in a cycloalkyl group are replaced by heteroatoms (such as nitrogen, oxygen, or sulfur, etc.).
  • Unsaturated heterocyclyl is a partially unsaturated cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms (such as nitrogen, oxygen, or sulfur, etc.).
  • Salt in the present invention means “pharmaceutically acceptable salt”.
  • “Pharmaceutically acceptable salts” means those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
  • Salt formation with acid obtained by reacting the free base of the parent compound with inorganic or organic acids.
  • Inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, phosphoric acid, metaphosphoric acid, sulfuric acid, Sulfurous acid and perchloric acid, etc.
  • Organic acids include acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid, methoxy Benzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, tea-1-sulfonic acid, tea-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, Succinic acid or malonic acid, etc.
  • the acidic proton present in the parent compound is replaced by a metal ion or a salt formed by coordination with an organic base, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, an organic base such as ethylamine, diethylamine Amine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, tromethamine, N -Methylglucamine etc.
  • an organic base such as ethylamine, diethylamine Amine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, trometh
  • solvate means that the compound of the present invention forms a solvate with a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent includes but is not limited to water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran , Dichloromethane.
  • stereoisomer means that the chiral carbon atom involved in the compound of the present invention can be in R configuration, or S configuration, or a combination thereof.
  • PARP plays a key role in the repair of cellular DNA damage.
  • PARP is also involved in DNA methylation modification and transcription, cell signal transduction, cell cycle regulation and cell mitosis.
  • PARP inhibitors have anticancer effects, and more importantly, PARP inhibitors can cause synthetic lethal effects when used in combination with other anticancer drugs.
  • the combined use of PARP inhibitors and chemotherapy drugs can not only reduce the adverse reactions of chemotherapy drugs, but also improve their therapeutic effect. Therefore, PARP inhibitors can not only treat PARP-related diseases, but also act as drugs for treating tumors, as well as chemotherapeutic drug sensitizers and radiotherapy sensitizers, and have a remarkable effect in tumor treatment.
  • the present invention provides a class of compounds that have good inhibitory activity on both HDAC and PARP. These compounds have good inhibitory effects on both HDAC and PARP, and can be used to prepare PARP/HDAC dual-target inhibitors for the prevention and/or treatment of Diseases improved by inhibition of PARP and/or HDAC activity, such as tumors, local ischemic diseases, diabetes, inflammatory diseases, etc.
  • the compound of the invention has a synthetic lethal effect, can be used as a chemotherapeutic drug sensitizer and a radiotherapy sensitizer, and can be used in combination with other antitumor drugs to improve the therapeutic effect and reduce adverse reactions.
  • the compound of the invention improves the patient's compliance, has advantages in pharmacoeconomics, and has good application prospects.
  • the raw materials and equipment used in the specific embodiment of the present invention are all known products, obtained by purchasing commercially available products.
  • the compounds listed in Table 1 can all be prepared by methods similar to the above examples.
  • the reaction process was monitored by TLC, and the purification was carried out by conventional column chromatography or recrystallization.
  • PARP is a nuclear enzyme present in eukaryotic cells that catalyzes poly ADP ribosylation. PARP plays an important role in DNA damage repair and maintenance of genome stability. When DNA is damaged, the PARP enzyme is activated, binds to DNA, and catalyzes polyadenosine diphosphate-ribosylation, thereby initiating the damage control and repair process of DNA.
  • PARP-1 is involved in the recognition of DNA gaps. After recognizing DNA gaps, the activated PARP-1 forms a homodimer and catalyzes the decomposition of NAD+ into nicotinamide and ADP ribose, and uses the latter as raw materials to poly-ADP-ribosylate nuclear receptor proteins.
  • HT Universal Chemiluminescent PARP Assay Kit With Histone-coated Strip Wells (Cat#4676-096-K) was purchased from TREVIGEN, and the activity of PARP1 was determined by detecting polyadenosine diphosphate-ribose bound to biotin on histone by chemiluminescent method .
  • AZD2281 is a positive drug.
  • Histone deacetylase inhibitors can cause the accumulation of acetylated nucleosomal histones in vitro and in vivo, increase the expression level of p21 gene, inhibit the proliferation of tumor cells, induce cell differentiation or apoptosis, and can be used for various Treatment of hematologic malignancies and solid tumors.
  • HDAC can deacetylate the substrate Boc-lys(AC)-AMC under certain conditions, and then hydrolyze the substrate under the action of trypsin to generate AMC, which can emit fluorescence with a wavelength of 460nm at an excitation wavelength of 355nm , so the activity of the enzyme can be reflected by detecting the change of the product amount.
  • HDAC enzyme was extracted from Hela cell nucleus. LBH-589 is a positive drug.
  • Test example 2 MTT method cell proliferation inhibitory activity test
  • In vitro cell proliferation inhibition test adopts MMT method, using the following 9 cell lines: human breast cancer cell MDA-MB-436, human breast cancer cell HCC1937, human breast ductal carcinoma cell HCC1395, human breast cancer cell HCC1428, human breast cancer cell SUM -149PT, human breast cancer MDA-MB-231, human breast cancer MCF7, human cervical cancer Hela, non-mutated triple-negative breast cancer MDA-MB-157.
  • the detection principle is that succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-purple crystal formazan (Formazan) and deposit in the cells, while dead cells have no such function.
  • Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, and its light absorption value is measured at a wavelength of 490nm with a microplate reader.
  • the amount of MTT crystal formation is proportional to the number of cells. According to the measured absorbance value (OD value), the number of living cells is judged. The larger the OD value, the stronger the cell activity (if the drug toxicity is measured, it means that the drug toxicity is less).
  • test results show that the compound involved in the present invention has good in vitro tumor cell proliferation inhibitory activity and has good application prospects.
  • the present invention provides a class of compounds that have good inhibitory activity on both HDAC and PARP. These compounds have good inhibitory effects on both HDAC and PARP, and can be used to prepare PARP/HDAC dual-target inhibitors, prevent and/or Or treat diseases improved by inhibition of PARP and/or HDAC activity, such as tumors, local ischemic diseases, diabetes, inflammatory diseases and the like.
  • the compound of the invention has a synthetic lethal effect, can be used as a chemotherapeutic drug sensitizer and a radiotherapy sensitizer, and can be used in combination with other antitumor drugs to improve the therapeutic effect and reduce adverse reactions.
  • the compound of the invention improves the patient's compliance, has advantages in pharmacoeconomics, and has good application prospects.

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Abstract

La présente invention concerne un dérivé d'acide hydroximique et son utilisation, se rapportant au domaine de la biomédecine. Le dérivé d'acide hydroximique est un composé représenté par la formule I, ou un sel, ou un stéréoisomère, ou un solvate, ou un hydrate, ou un promédicament de celui-ci. La présente invention concerne un composé ayant une bonne activité inhibitrice sur HDAC et PARP. Le composé a un bon effet d'inhibition à la fois sur HDAC et PARP, et peut être utilisé pour préparer un inhibiteur double cible de PARP/HDAC qui peut prévenir et/ou traiter des maladies atténuées par l'inhibition de PARP et/ou d'activité de HDAC, telles que des tumeurs, des maladies ischémiques, le diabète, des maladies inflammatoires et similaires. Le composé a un effet de létalité synthétique, et peut être utilisé en tant que sensibilisateur de médicament chimiothérapeutique et sensibilisateur de radiothérapie en combinaison avec d'autres médicaments antitumoraux pour améliorer l'effet de traitement et réduire des réactions indésirables. De plus, le composé selon la présente invention améliore la compliance des patients, présente des avantages pharmacoéconomiques supérieurs, et a une bonne perspective d'application.
PCT/CN2022/124637 2021-10-11 2022-10-11 Dérivé d'acide hydroximique et son utilisation WO2023061368A1 (fr)

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