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WO2025247412A1 - INHIBITEUR DOUBLE CIBLE DE PHÉNYLTHIAZOLAMINE PI4KIIIβ/HDAC, SON PROCÉDÉ DE PRÉPARATION, COMPOSITION PHARMACEUTIQUE ET UTILISATION ASSOCIÉES - Google Patents

INHIBITEUR DOUBLE CIBLE DE PHÉNYLTHIAZOLAMINE PI4KIIIβ/HDAC, SON PROCÉDÉ DE PRÉPARATION, COMPOSITION PHARMACEUTIQUE ET UTILISATION ASSOCIÉES

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Publication number
WO2025247412A1
WO2025247412A1 PCT/CN2025/100070 CN2025100070W WO2025247412A1 WO 2025247412 A1 WO2025247412 A1 WO 2025247412A1 CN 2025100070 W CN2025100070 W CN 2025100070W WO 2025247412 A1 WO2025247412 A1 WO 2025247412A1
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WO
WIPO (PCT)
Prior art keywords
methyl
methoxy
phenyl
hydroxy
sulfonamido
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Pending
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PCT/CN2025/100070
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English (en)
Chinese (zh)
Inventor
周庆发
姚圣法
王恩源
胡庆兰
韩芳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Hongshun Pharmaceutical Technology Co Ltd
China Pharmaceutical University
Original Assignee
Nanjing Hongshun Pharmaceutical Technology Co Ltd
China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • This invention relates to a phenylthiazolamine PI4KIII ⁇ /HDAC dual-target inhibitor, its preparation method, pharmaceutical composition, and applications, belonging to the field of pharmaceutical technology.
  • PI4Ks phosphatidylinositol 4-kinases
  • Phosphatidylinositol (PI) is phosphorylated by PI4Ks to produce phosphatidylinositol 4-phosphate (PI4P), which plays a crucial role in Golgi apparatus function, protein sorting, and membrane transport. It also plays a significant role in the replication and amplification of exogenous pathogens (such as viruses) within the host. Therefore, research on broad-spectrum antiviral inhibitors of PI4Ks has become a hot topic in current medicinal chemistry research.
  • Lipid phosphatidylinositol is an important regulator of numerous cellular processes, including signal transduction, membrane transport, and cytokinesis. Phosphatidylinositol is produced through phosphorylation of the inositol ring. In mammals, there are four different PI4K enzymes: two type II enzymes (PI4KII ⁇ and PI4KII ⁇ ) and two type III enzymes (PI4KIII ⁇ and PI4KIII ⁇ ).
  • PI4KIII ⁇ is a peripheral membrane protein distributed in the Golgi apparatus and plasma membrane, playing a crucial role in mediating lipid transport and cell division.
  • the PI4KIII ⁇ protein consists of 801 amino acid residues, including a helical domain, a lipid kinase domain, and three disordered regions that mediate binding with regulatory proteins.
  • the N-terminus of PI4KIII ⁇ is primarily responsible for interacting with and recruiting Golgi proteins (such as acyl-CoA binding domain protein 3, ACBD3); its C-terminus contains an amphiphilic lipid-accumulating sensor motif responsible for viral signal sensing and transport.
  • PI4KIII ⁇ is also a key factor in the replication of many viruses.
  • the virus hijacks PI4KIII ⁇ to form PI4P-containing organelles (ROs), thereby inducing viral proteins to form replication structures on the biomembrane.
  • ROs PI4KIII ⁇ also plays a crucial role in human genetic diseases.
  • PI4KIII ⁇ affects the transcriptional activation of target genes, including HES-related family bHLH transcription factors and YRPW motif 1 (hey1), by regulating bone morphogenetic protein membrane type II receptor (BMPR2) and signal transduction proteins 1/5/9 (Smad1/5/9), ultimately influencing the development of the vestibular organ in zebrafish.
  • STING is a key signal transduction factor in innate immune responses. Activation of the cGAS-STING pathway triggers exogenous DNA, thereby regulating spontaneous anti-tumor and anti-DNA virus immune responses.
  • ARMH3 is a key factor in STING activation; ARMH3 activates STING by recruiting PI4KIII ⁇ .
  • Histone deacetylases are a class of epigenetic enzymes that catalyze the removal of acetyl groups from lysine residues of histones and other proteins, thereby regulating chromatin structure and transcriptional activity.
  • Vorinostat (SAHA) a classic hydroxamic acid inhibitor of HDACs, contains sequences of three main elements forming the pharmacophore: a cap, a linker, and a zinc-binding group (ZBG).
  • the linker binds to the ZBG and facilitates its penetration into the hydrophobic “tunnel” at the HDAC active site, where it catalyzes the chelation of zinc ions at its base.
  • the linker associated with the cap-like structure, is most commonly an aryl or heteroaryl radical, which additionally interacts with the protein substrate-binding cavity, influencing the strength and selectivity of inhibition.
  • Recent proteomics studies have revealed widespread acetylation in mouse and human hepatocytes. Upregulation of HDAC activity induced by HCV infection has also been reported.
  • polymorphisms of the three HDAC enzymes (HDAC2, 3, and 5) have been shown to be independently associated with persistent virological responses to chronic HCV. Numerous observations have shown that HDAC inhibitors are promising in blocking HCV replication, and recently benzoxamic acid and the pan-HDAC inhibitor vorinostat (SAHA) have been reported as potential anti-HCV drugs.
  • SAHA pan-HDAC inhibitor vorinostat
  • the purpose of this invention is to address the deficiencies of existing technologies by proposing a phenylthiazolamine PI4KIII ⁇ /HDAC dual-target inhibitor, its preparation method, a pharmaceutical composition containing the inhibitor, and its application, thereby improving inhibitory activity.
  • a phenylthiazolamine PI4KIII ⁇ /HDAC dual-target inhibitor which is a substituted phenylthiazolamine compound of general formula I, or its stereoisomer, hydrate, or pharmaceutically acceptable salt:
  • R1 - R4 are substituents on the benzene ring selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, C1C6 alkyl, haloC1C6 alkyl, hydroxyC1C6 alkyl, C1C6 alkoxy, haloC1C6 alkoxy, hydroxyC1C6 alkoxy, or C1C6 alkoxyC1C6 alkyl;
  • R5 and R6 are selected from C1C6 alkyl, C1C6 alkyl containing one or more substituents, C1C6 alkoxy, C1C6 alkoxy containing one or more substituents, C1C6 alkyl acy
  • X is selected from sulfone or carbonyl groups
  • Y is selected from C1-C6 alkylene, C1-C6 alkylene containing one or more substituents, 4-substituted phenyl, 4-substituted benzyl, or 4-substituted phenoxyethyl, etc.
  • Z is selected from the following structures:
  • the hydrogen bonded to carbon is replaced with the hydrogen isotope deuterium.
  • the alkyl group is replaced by a deuterated alkyl group
  • the alkoxy group is replaced by a deuterated epoxy group
  • the benzene ring is replaced by a deuterated benzene ring
  • the aromatic ring is replaced by a deuterated aromatic ring.
  • a pharmaceutically acceptable salt refers to the conversion of a basic group in a parent compound into a salt form; wherein, the pharmaceutically acceptable salt is a basic group, more preferably an inorganic or organic acid salt of an amino group or amino group; the reaction is carried out by reacting a basic group in the parent compound with 1-4 equivalents of an acid in a solvent system.
  • the basic group of the compound in this invention can form a salt with an acid.
  • the salt can be formed with inorganic acids, especially hydrohalic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid), nitric acid, sulfuric acid, phosphoric acid, carbonic acid, etc.; lower alkyl sulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid; aryl sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; organic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, maleic acid, malic acid or succinic acid; or amino acids, such as aspartic acid or glutamic acid.
  • hydrohalic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid
  • nitric acid such as sulfuric acid, phosphoric acid, carbonic acid,
  • the compounds and pharmaceutically acceptable salts of the present invention also include solvates or hydrates.
  • the structural formula of the compound in the phenylthiazolamine PI4KIII ⁇ inhibitor of the present invention includes isomers, such as enantiomers, diastereomers, geometric isomers or conformational isomers, specifically R or S configurations containing an asymmetric center, (Z) or (E) isomers of double bonds, and (Z) or (E) conformational isomers.
  • the inhibitor is one of the following: (1) N-hydroxy-3-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)propionamide; (2) N-hydroxy-4-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)butyramide; (3) N-hydroxy-5-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)pentamid; (4) N-hydroxy-6-((2-methoxy-5-(4-methyl-2-pentanamidothiazo-5-yl)phenyl)sulfonamido)hexanoamide; (5) N-hydroxy-7-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)
  • the above-mentioned inhibitor is prepared as follows: according to one of the preparation methods of the target compound, 4-methoxyphenylacetone is used as raw material (1).
  • Raw material (1) undergoes a substitution reaction with chlorosulfonic acid at the 3-position of the benzene ring to obtain intermediate (2); based on intermediate (2), aminocarboxylic acid methyl ester is introduced through the Hinsberg reaction to obtain intermediate (3);
  • intermediate (3) undergoes an ⁇ -bromination reaction with phenyltrimethylammonium tribromide to obtain intermediate (4);
  • thiourea (5) reacts with various acyl chlorides to obtain N-substituted thiourea (6), which is then condensed with intermediate (4) to obtain intermediate (7);
  • intermediate (7) undergoes an amide condensation reaction with hydroxylamine to obtain the target compound (8).
  • the preparation route is as follows:
  • the preparation method of the above inhibitor also includes, according to the preparation method of the target compound, using 4-methoxyphenylacetone as raw material (1), the raw material (1) undergoes a substitution reaction with chlorosulfonic acid at the 3-position of the benzene ring to obtain intermediate (2); based on intermediate (2), an aminocarboxylic acid methyl ester is introduced through the Hinsberg reaction to obtain intermediate (3); intermediate (3) undergoes an ⁇ -bromination reaction with phenyltrimethylammonium tribromide to obtain intermediate (4); thiourea (5) reacts with various acyl chlorides to obtain N-substituted thiourea (6), which is then condensed with intermediate (4) to obtain intermediate (7); intermediate (7) undergoes an amide condensation reaction with 4-fluoro-1,2-phenylenediamine to obtain the target compound (9).
  • the preparation route is as follows:
  • the preparation method of the above inhibitor also includes: using methyl 5-formyl-2-methoxybenzoate as raw material (10), intermediate (11) is obtained through a two-step reaction; intermediate (11) is heated under reflux in acetic acid and undergoes a reduction reaction with iron powder to obtain intermediate (12); intermediate (12) undergoes a hydrolysis reaction under acidic conditions to obtain intermediate (13); intermediate (13) is chlorinated with thionyl chloride to generate intermediate (14); intermediate (14) reacts with methyl aminocarboxylate to obtain intermediate (15); intermediate (15) undergoes an ⁇ -bromination reaction with phenyltrimethylammonium tribromide to obtain intermediate (16); intermediate (16) undergoes a condensation reaction with N-substituted thiourea to obtain intermediate (17); intermediate (17) undergoes an amide condensation reaction with hydroxylamine to obtain the target compound (18).
  • the preparation route is as follows:
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, adjuvant or carrier, and the above-mentioned phenylthiazolamine PI4KIII ⁇ /HDAC dual-target inhibitor.
  • the present invention further provides the use of phenylthiazolamide PI4KIII ⁇ /HDAC dual-target inhibitors or pharmaceutical compositions in the preparation of drugs for inhibiting the growth of hepatitis C virus, and for the prevention, treatment or adjunctive treatment of hepatitis C caused by HCV virus.
  • PIK-93 was selected as the lead compound for further structural modification.
  • This invention determined that phenylthiazolamine is used as the basic skeleton structure, and by screening substituents, it can achieve efficient inhibition of PI4KIII ⁇ and HDAC, thereby inhibiting the growth of HCV virus, while having low cytotoxicity, thus potentially being used as a clinical therapeutic drug.
  • Reagents were purchased from commercial suppliers such as Anhui Zesheng Technology Co., Ltd., Bailingwei Technology Co., Ltd., Aladdin Reagent Co., Ltd., and Beijing Coupling Technology Co., Ltd., and were used without further purification unless otherwise stated.
  • Common reagents were purchased from Xilong Chemical Co., Ltd., Nanjing Chemical Reagent Co., Ltd., Sinopharm Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Co., Ltd. In the examples, all temperatures are set to Celsius unless otherwise stated.
  • silica gel columns were used.
  • Silica gel 200-300 mesh
  • Nuclear magnetic resonance spectroscopy was performed using Chloroform-d or DMSO-d 6 as solvents (in ppm), with TMS (0 ppm) as the reference standard.
  • TMS 0. ppm
  • s sensinglet
  • d doublet
  • t triplet
  • m multiplet
  • br broadened
  • dd doublet of doublets
  • dt doublet of triplets
  • Coupling constants are expressed in Hertz (Hz).
  • MS data were analyzed using an Agilent 6120 series LC-MS equipped with a G1329B autosampler and a G4212B detector, with an ESI source used in the LC-MS spectrometer.
  • DCM CH2Cl2 , i.e., dichloromethane
  • Chloroform-d and CDCl3 are deuterated chloroform
  • PE is petroleum ether
  • EtOAc and EA are both ethyl acetate
  • MeOH and CH3OH are both methanol
  • ClSO3H is chlorosulfonic acid
  • TEA and Et3N are triethylamine
  • DMSD- d6 is hexadeuterated dimethyl sulfoxide
  • THF is tetrahydrofuran
  • NaCl sodium chloride
  • NaSO4 sodium sulfate
  • CDI is N,N-carbonyldiimidazole.
  • Step 1 Synthesis of 2-methoxy-5-(2-oxopropyl)benzenesulfonyl chloride, structural formula: measure 10 mL of ClSO3H (132 mmol, 11.0 eq.) was added to a 25 mL pear-shaped reaction flask and pre-cooled in an ice bath for 30 min. 2.02 g (12.0 mmol) of 4-methoxyphenylacetone was slowly added dropwise to the ClSO3H .
  • Step 2 Synthesis of methyl 3-((2-methoxy-5-(2-oxopropyl)phenyl)sulfonamide)propionate, structural formula: 5 mmol of 2-methoxy-5-(2-oxopropyl)benzenesulfonyl chloride was dissolved in 20 mL of dichloromethane.
  • Step 3 Synthesis of methyl 3-((2-methoxy-5-(4-methyl-2-pentamidothiazolyl-5-yl)phenyl)sulfonamido)propionate, Structural formula: 1 mmol of methyl 3-((2-methoxy-5-(2-oxopropyl)phenyl)sulfonamide)propionate was dissolved in 5 mL of tetrahydrofuran solution and placed in a round-bottom flask. Under ice bath conditions, 10 mL of tetrahydrofuran solution containing 1.1 mmol of phenyltrimethylammonium tribromide was slowly added dropwise to the above reaction solution.
  • N-tervaline thiourea was prepared by dissolving 10 mmol of thiourea in 30 mL of anhydrous toluene solution and placing it in a 100 mL round-bottom flask.
  • Step 4 Synthesis of N-hydroxy-3-((2-methoxy-5-(4-methyl-2-pentamidothiazolyl-5-yl)phenyl)sulfonamido)propionamide, with the following structural formula: First, 3-((2-methoxy-5-(4-methyl-2-pentamidothiazol-5-yl)phenyl)sulfonamide)propionic acid was prepared.
  • Example 1 N-hydroxy-4-((2-methoxy-5-(4-methyl-2-propamidothiazo-5-yl)phenyl)sulfonamido)butyramide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionate hydrochloride fragment in step 2 was replaced with methyl 4-aminobutyrate hydrochloride, and the pentanoyl chloride in step 3 was replaced with propionyl chloride.
  • Other steps and operations were the same as in Example 1.
  • Example 1 N-hydroxy-4-((2-methoxy-5-(4-methyl-2-butamidothiazo-5-yl)phenyl)sulfonamido)butyramide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminobutyrate hydrochloride, and the pentanoyl chloride in step 3 was replaced with butyryl chloride.
  • Other steps and operations were the same as in Example 1.
  • Example 1 N-hydroxy-4-((2-methoxy-5-(4-methyl-2-isobutyramamidothiazo-5-yl)phenyl)sulfonamido)butyramide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminobutyrate hydrochloride, and the pentanoyl chloride in step 3 was replaced with isobutyryl chloride.
  • Other steps and operations were the same as in Example 1.
  • Example 1 N-hydroxy-4-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)butyramide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminobutyrate hydrochloride, and the pentanoyl chloride in step 3 was replaced with pentanoyl chloride.
  • Other steps and operations were the same as in Example 1. The solid was white, with a yield of 43%.
  • Example 1 N-hydroxy-4-((2-methoxy-5-(4-methyl-2-isovaleramidothiazo-5-yl)phenyl)sulfonamido)butyramide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminobutyrate hydrochloride, and the pentovaleryl chloride in step 3 was replaced with isovaleryl chloride.
  • Other steps and operations were the same as in Example 1.
  • the solid was white, with a yield of 45%.
  • Example 1 N-hydroxy-4-((2-methoxy-5-(4-methyl-2-hexamidothiazo-5-yl)phenyl)sulfonamido)butyramide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminobutyrate hydrochloride, and the pentanoyl chloride in step 3 was replaced with hexanoyl chloride.
  • Other steps and operations were the same as in Example 1. The solid was white, with a yield of 46%.
  • Example 1 N-hydroxy-5-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)pentanamide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 5-aminovalerate hydrochloride, and the pentanoyl chloride in step 3 was replaced with pentanoyl chloride.
  • Other steps and operations were the same as in Example 1: white solid, yield 40%.
  • Example 1 N-hydroxy-6-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)hexanoamide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 6-aminohexanoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with pentanoyl chloride.
  • Other steps and operations were the same as in Example 1.
  • Example 1 N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)methyl)benzamide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminomethylbenzoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with pentanoyl chloride.
  • Other steps and operations were the same as in Example 1: white solid, yield: 30%.
  • Example 1 N-hydroxy-7-((2-methoxy-5-(4-methyl-2-acetamidothiazo-5-yl)phenyl)sulfonamido)heptanoamide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 7-aminoheptanoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with acetyl chloride.
  • Other steps and operations were the same as in Example 1.
  • Example 1 N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-butamidothiazo-5-yl)phenyl)sulfonamido)methyl)benzamide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminomethylbenzoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with butyryl chloride.
  • Other steps and operations were the same as in Example 1.
  • Example 1 N-hydroxy-5-((2-methoxy-5-(4-methyl-2-isobutyramamidothiazo-5-yl)phenyl)sulfonamido)pentanamide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 5-aminovalerate hydrochloride, and the pentanoyl chloride in step 3 was replaced with isobutyryl chloride.
  • Other steps and operations were the same as in Example 1.
  • the solid was white, with a yield of 45%.
  • Example 1 N-hydroxy-7-((2-methoxy-5-(4-methyl-2-isovaleramidothiazo-5-yl)phenyl)sulfonamido)heptamide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 7-aminoheptanoate hydrochloride, and the pentovaleryl chloride in step 3 was replaced with isovaleryl chloride.
  • Other steps and operations were the same as in Example 1.
  • the solid was white, with a yield of 45%.
  • Example 1 N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-isovaleramidothiazo-5-yl)phenyl)sulfonamido)methyl)benzamide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminomethylbenzoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with isovaleryl chloride.
  • Other steps and operations were the same as in Example 1.
  • Example 1 N-hydroxy-6-((2-methoxy-5-(4-methyl-2-hexamidothiazo-5-yl)phenyl)sulfonamido)hexanoamide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 6-aminohexanoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with hexanoyl chloride.
  • Other steps and operations were the same as in Example 1.
  • Example 1 N-hydroxy-7-((2-methoxy-5-(4-methyl-2-hexamidothiazo-5-yl)phenyl)sulfonamido)heptamide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 7-aminoheptanoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with hexanoyl chloride.
  • Other steps and operations were the same as in Example 1.
  • Example 1 N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-hexamidothiazo-5-yl)phenyl)sulfonamido)methyl)benzamide, with the following structural formula:
  • Example 1 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminomethylbenzoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with hexanoyl chloride.
  • Other steps and operations were the same as in Example 1.
  • Step 1 Synthesis of 2-methoxy-5-(2-oxopropyl)benzoic acid, with the following structural formula: 10 mmol of methyl 5-formyl-2-methoxybenzoate and butylamine (2.0 e.) were dissolved in toluene and refluxed for 3 h. After being dried by vacuum distillation, the mixture was dissolved in 10 mL of acetic acid.
  • Step 2 Synthesis of methyl 4-(5-(2-hexamido-4-methylthiazolyl-5-yl)-2-methoxybenzamido)butyrate, with the following structural formula: 1 mmol of 2-methoxy-5-(2-oxopropyl)benzoic acid and 1 mmol of CDI were dissolved in 10 mL of DCM solution and pre-reacted for 1 h. Then, 1.5 mmol of methyl 4-aminobutyrate was added to the reaction solution and reacted at room temperature. After the reaction was complete, the mixture was purified to obtain methyl 4-(2-methoxy-5-(2-oxopropyl)benzamido)butyrate.
  • step 3 the pentanoyl chloride in step 3 was replaced with hexanoyl chloride to obtain a white solid methyl 4-(5-(2-hexamido-4-methylthiazolyl-5-yl)-2-methoxybenzamido)butyrate, yield: 60%.
  • Step 3 Synthesis of N-(7-(hydroxyamino)-4-oxobutyl)-5-(2-hexamido-4-methylthiazolyl-5-yl)-2-methoxybenzamide, with the following structural formula: According to step 4 in Example 1, 4-(5-(2-hexamido-4-methylthiazol-5-yl)-2-methoxybenzamido)butyric acid was first prepared.
  • Example 30 N-(7-(hydroxyamino)-7-oxohepyl)-5-(2-isobutyramido-4-methylthiazo-5-yl)-2-methoxybenzamide, with the following structural formula:
  • Example 30 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 7-aminoheptanoate hydrochloride, and the hexanoyl chloride in step 3 was replaced with isovaleryl chloride.
  • Other steps and operations were the same as in Example 30.
  • Example 30 N-(7-(hydroxyamino)-7-oxohepyl)-5-(2-hexamido-4-methylthiazo-5-yl)-2-methoxybenzamide, with the following structural formula:
  • Example 30 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 7-aminoheptanoate hydrochloride; other steps and operations were the same as in Example 30.
  • Example 30 N-(4-(hydroxycarbamoyl)benzyl)-5-(2-hexanoyl-4-methylthiazolyl-5-yl)-2-methoxybenzamide, with the following structural formula:
  • Example 30 the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminomethylbenzoate hydrochloride; other steps and operations were the same as in Example 30.
  • PI4KIII ⁇ kinase inhibition experiments were conducted against the inhibitor of this invention:
  • the ADP-Glo Luminescent Kinase Assay method was used for the assay.
  • the reagents used for the kinase reaction were as follows: HEPES (50 mM). The reaction was carried out at pH 7.5 with NaCl (100 mM), EGTA (1.0 mM), MgCl2 (3.0 mM), DTT (2.0 mM), and CHAPS (0.03%). During the reaction, 50 ⁇ M PIP2 and 25 ⁇ M ATP were added to each 10 mL of the test compound at different concentrations (0.05 nM–1.0 ⁇ M).
  • the reaction system was incubated at room temperature for 1 h, and then 10 ⁇ L of ADP-Glo reagent was added to terminate the enzyme reaction. Data were collected using Envision software, and the IC50 values of the compounds were analyzed and fitted using Graphpad Prism 5.
  • HDAC1 kinase inhibition experiments were conducted against the inhibitor of this invention:
  • the HDAC1 fluorescence detection kit (Cat#50051) from BPS Corporation was used, employing a fluorescence labeling assay.
  • the HDAC1 inhibitory activity of the compounds in the examples was tested.
  • the experimental steps were as follows: (1) Preparation of 1x assay buffer (modified Tris buffer); (2) Dilution of the compounds: The compounds were transferred to the assay plate in 100% DMSO using Echo.
  • the final fraction of DMSO was 1%; (3) Preparation of enzyme solution: The enzyme solution was prepared in 1x assay buffer; (4) Preparation of substrate solution: Trypsin and Ac peptide substrate were added to 1x assay buffer to prepare the substrate solution; (5) 15 ⁇ L of enzyme solution was transferred to the assay plate, or 15 ⁇ L of 1x assay buffer was transferred for the low control. The plate was incubated at room temperature for 15 min. 10 ⁇ L of substrate solution was added to each well to start the reaction; (6) Data collection was performed using Envision software, and the IC50 values of the compounds were analyzed and fitted using Graphpad Prism 5.
  • HDAC1 enzyme inhibitory activity ( IC50 , nM) of the compounds in the examples As shown in Table 2, some compounds of the present invention exhibit nanomolar inhibitory activity against HDAC1, and some compounds are significantly superior to the positive control Vorinostat. In particular, the inhibitory activity of compounds 10, 11, 13, 23, and 26 against HDAC1 kinase is superior to that of the positive control Vorinostat. This demonstrates that some of the compounds in the embodiments of the present invention are highly effective HDAC inhibitors.
  • Example 11 has the best kinase inhibitory activity against PI4KIII ⁇ and HDAC1, which are 2.3 nM and 1 nM, respectively.
  • Kinase selectivity experiments were conducted on Example 11 using the same experimental methods as described above.
  • the results of kinase subtype inhibitory activity of the example are shown in Tables 3 and 4.
  • Example 11 Based on the experimental data in Tables 3 and 4, analysis shows that Example 11 exhibits the best inhibitory activity against PI4KIII ⁇ , with an IC50 value reaching [value missing]. At 2.3 nM, it can also inhibit the activity of PI3K ⁇ , with an IC50 value of 47.8 nM. Meanwhile, Example 11 is also a broad-spectrum HDAC inhibitor, showing good inhibitory activity against HDAC1, 2, 3, 6 and 10, with IC50 values of 11, 17, 20, 23 and 75 nM, respectively.
  • the anti-HCV virus activity test of the inhibitor of this invention was conducted using the following experimental method: (1) Sample preparation: Dissolve the sample to be tested in DMSO, and then use 0.22 ⁇ m... Sterilization is achieved through membrane filtration, with the original drug concentration at 20 mg/mL.
  • Virus culture Add J6/JFH1 virus solution to Huh-7.5.1 cell culture flasks in the exponential growth phase, incubate for 5-8 hours, discard the supernatant, replace with fresh culture medium, change the medium every two days, discard the culture medium after 6 days, then add about 15 mL of culture medium and culture until the 7th day, centrifuge at 3000 rpm/min for 10 min, collect the clear culture medium, aliquot and store at -80°C.
  • Detection method MTT assay.
  • Huh-7.5.1 cells in logarithmic growth phase were digested with 0.25% trypsin, centrifuged at 1000 rpm for 3 min, counted using a hemocytometer, and adjusted to a cell concentration of 9 ⁇ 104 cells/mL. The cells were then seeded into 96-well plates (100 ⁇ L/well) and cultured at 37°C in a 5% CO2 incubator. After 5 h of adhesion, serially diluted DMSO was added, resulting in eight dilutions, with three replicates for each dilution.
  • a blank control (containing only culture medium), DMSO control, cell control, positive drug control, and drug color control were also included, bringing the final culture medium volume to 200 ⁇ L/well.
  • the culture plates were then placed in a 37°C 5% CO2 incubator for further culture.
  • On the third day add 20 ⁇ L of 5 mg/mL LMT solution to each well and incubate at 37°C with 5% CO2 for 4 hours. Discard the supernatant, add 100 ⁇ L/well of DMSO, shake to dissolve for 10 min, and then measure the OD 490 value using a microplate reader. Calculate the IC50 ( IC50 : half-maximal inhibitory concentration, the concentration required to inhibit cell growth by 50%) using GraphPad Prism 5.0 software.
  • HCV replication inhibition rate formula (OD Control OD Drug) / (OD Control OD Blank) ⁇ 100%)
  • Table 5 shows the anti-HCV virus activity of compounds in some of the examples.
  • the drug concentrations are: CC 50 (half-maximal toxic concentration), IC 50 (half-maximal effective concentration), and SI (selectivity).
  • the SI value is the ratio of CC 50 to IC 50 and is used to assess a drug's therapeutic potential. A higher SI value indicates greater efficacy against HCV. A "-" indicates that 10 ⁇ M initial screening showed no inhibitory effect on HCV or could not fit the IC 50 value.
  • some embodiments of the present invention exhibit high levels of inhibitory activity against HCV virus and low cytotoxicity, with Example 2 achieving an inhibition level of 18.41 nM against HCV virus.
  • Examples 4 and 31 show SI values greater than 2000, CC 50 values greater than 100 ⁇ M, and IC 50 values below 60 nM, significantly superior to the positive control PIK93-10. Therefore, the compounds of some embodiments of the present invention have the potential for clinical use in the treatment of HCV.

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Abstract

La présente invention concerne un inhibiteur double cible de phénylthiazolamine PI4KIIIβ/HDAC, son procédé de préparation, une composition pharmaceutique et une utilisation associées, se rapportant au domaine technique des médicaments. La présente invention concerne un inhibiteur double cible de phénylthiazolamine PI4KIIIβ/HDAC qui est un composé phénylthiazolamine substitué représenté par la formule générale I ou un stéréoisomère de celui-ci, un hydrate de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci. La présente invention présente les effets bénéfiques suivants : (1) L'inhibiteur est caractérisé par l'inhibition efficace de la voie de signalisation PI3K/Akt/mTOR de PI4KIIIβ et a une activité inhibitrice de double enzyme efficace et excellente contre PI4KIIIβ/HDAC. (2) Le coût est réduit, l'efficacité est bonne, et la toxicité est faible. De plus, le rendement en produits intermédiaires dans le procédé de synthèse est élevé, ce qui réduit le gaspillage de ressources et aide ainsi à réduire le coût. (3) L'inhibiteur présente une activité anti-virus de l'hépatite C relativement élevée et est utilisé à petites doses.
PCT/CN2025/100070 2024-05-27 2025-06-10 INHIBITEUR DOUBLE CIBLE DE PHÉNYLTHIAZOLAMINE PI4KIIIβ/HDAC, SON PROCÉDÉ DE PRÉPARATION, COMPOSITION PHARMACEUTIQUE ET UTILISATION ASSOCIÉES Pending WO2025247412A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101331125A (zh) * 2005-12-12 2008-12-24 健亚生物科技公司 N-(5-元杂芳香环)-酰胺基抗病毒化合物
WO2013052845A1 (fr) * 2011-10-05 2013-04-11 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteurs de pi-kinase à activité anti-infectieuse à large spectre
US20190062323A1 (en) * 2016-02-26 2019-02-28 The Board Of Trustees Of The Leland Stanford Junior University PI-Kinase Inhibitors with Anti-Infective Activity
CN117534631A (zh) * 2024-01-09 2024-02-09 南京市鸿舜医药科技有限公司 一种苯基噻唑胺类PI4KIIIβ抑制剂、制法及其药物组合物和应用
CN118221610A (zh) * 2024-05-27 2024-06-21 南京市鸿舜医药科技有限公司 一种苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂、制备方法及其药物组合物和应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101331125A (zh) * 2005-12-12 2008-12-24 健亚生物科技公司 N-(5-元杂芳香环)-酰胺基抗病毒化合物
WO2013052845A1 (fr) * 2011-10-05 2013-04-11 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteurs de pi-kinase à activité anti-infectieuse à large spectre
US20190062323A1 (en) * 2016-02-26 2019-02-28 The Board Of Trustees Of The Leland Stanford Junior University PI-Kinase Inhibitors with Anti-Infective Activity
CN117534631A (zh) * 2024-01-09 2024-02-09 南京市鸿舜医药科技有限公司 一种苯基噻唑胺类PI4KIIIβ抑制剂、制法及其药物组合物和应用
CN118221610A (zh) * 2024-05-27 2024-06-21 南京市鸿舜医药科技有限公司 一种苯基噻唑胺类PI4KIIIβ/HDAC双靶抑制剂、制备方法及其药物组合物和应用

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