WO2023061051A1 - Sulfamide inhibiteur d'usp8 et son utilisation - Google Patents

Sulfamide inhibiteur d'usp8 et son utilisation Download PDF

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WO2023061051A1
WO2023061051A1 PCT/CN2022/114208 CN2022114208W WO2023061051A1 WO 2023061051 A1 WO2023061051 A1 WO 2023061051A1 CN 2022114208 W CN2022114208 W CN 2022114208W WO 2023061051 A1 WO2023061051 A1 WO 2023061051A1
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compound
acid
group
iii
trifluoromethyl
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PCT/CN2022/114208
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Chinese (zh)
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李志裕
卞金磊
田于成
刘康
刘若依
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中国药科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the application relates to the field of medical technology, in particular to a class of compounds containing thiazole or thiadiazole structures and their application in the preparation of inhibitors of ubiquitin-specific protease USP8.
  • Ubiquitination is an important post-translational modification process.
  • the regulation of protein stability and activity can be achieved by transferring ubiquitin to substrate proteins, and the ubiquitination process is also closely related to the functional localization of proteins and the normal functioning of protein-protein interactions (Han J et al.Bioorganic Chemistry, 2020, 101:103962).
  • ubiquitination is a reversible process.
  • Deubiquitinating enzymes can remove ubiquitin from substrates and protect substrates from degradation.
  • USP8 belongs to a family of ubiquitin-specific proteases (USPs). Studies have shown that USP8 gene mutation or protein overexpression is closely related to the occurrence of various adenocarcinomas and gastric cancers.
  • Each exemplary embodiment of the present application utilizes pharmacophore splitting and recombination to optimize the structure of the lead compound, and obtains a series of USP8 inhibitors with new skeletons containing thiazole or thiadiazole structures, and their activity, selectivity and physical and chemical properties Compared with the previously reported USP8 inhibitors with thiourea structure, they have been greatly improved.
  • n and i are each independently selected from 0, 1 or 2
  • m is selected from 1, 2 or 3
  • n 1 , n 2 , m 1 , m 2 are each independently selected from 1, 2 or 3;
  • R 1 and R 2 are each independently selected from one or more of a hydrogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a halogen, and an ester group; and
  • Ar is a substituted or unsubstituted aromatic ring, aromatic heterocycle, aromatic ring, and aromatic ring, wherein the substituent is selected from one of alkyl, trifluoromethyl, halogen, cyano, amino, hydroxyl, carboxyl, and ester or more;
  • X is C or N, when X is C, Z is H, and the A fragment is a substituted aromatic ring, wherein the substituent is selected from hydrogen atom, alkyl, alkoxy, trifluoromethyl, cyano, nitro, amino , one or more of hydroxyl, halogen or ester groups; when X is N, the A segment does not exist, and Z is selected from substituted aromatic rings, wherein the substituents are selected from hydrogen atoms, alkyl groups, alkoxy groups, trifluoromethane One or more of nitrile, nitro, amino, hydroxyl, halogen or ester groups;
  • Y selected from wherein n and i are each independently selected from 0, 1 or 2, m is selected from 1, 2 or 3, and n 1 , n 2 , m 1 , m 2 are each independently selected from 1, 2 or 3;
  • R is selected from one or more of a hydrogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a halogen or an ester group;
  • Ar is a substituted or unsubstituted aromatic ring, aromatic heterocyclic ring, aromatic ring, aromatic ring, wherein the substituent is selected from one of alkyl, trifluoromethyl, halogen, cyano, amino, hydroxyl, carboxyl or ester group or more; and
  • Fragment A is selected from phenylthiazole ring, phenylthiadiazole ring or benzothiazole ring;
  • X is -C(O)-, -S(O) 2 - or absent;
  • Ar is a substituted or unsubstituted aromatic ring, aromatic heterocycle, aromatic ring, aromatic ring, wherein the substituent is selected from one of alkyl, trifluoromethyl, halogen, nitrile, amino, hydroxyl, carboxyl or ester or more.
  • the pharmaceutically acceptable salt of the compound of general formula (I), (II), (III) refers to the compound of general formula (I), (II), (III) and Acid addition salts with pharmaceutically acceptable acids or base addition salts with pharmaceutically acceptable bases, including: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid , phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid;
  • the base addition salts include: sodium salt, potassium salt, ammonium salt, calcium salt , aluminum salt, magnesium salt or other metal salts, ethylenediamine, ethanolamine or other common base addition salts.
  • the process of preparing compound I-2 from compound I-1 is through the reaction of aromatic sulfonyl chloride and substituted aromatic amine, the solvent is preferably water, and the acid-binding agent used is sodium hydroxide; the process of preparing compound I-4 from compound I-3, Obtained by amide condensation reaction, the condensing agent is preferably HATU, the base is N,N-diisopropylethylamine, and the solvent is preferably N,N-dimethylformamide; the process of preparing compound I-6 from compound I-5, For the nucleophilic substitution reaction under basic conditions, the selected base is potassium carbonate, and the solvent is acetone or N,N-dimethylformamide; the process of preparing compound I-7 from compound I-6 is the same as compound I-4; by The process of preparing compound I-8 from compound I-5 is obtained by the nucleophilic substitution reaction of 4-Boc-aminopiperidine and aromatic halide, the base is potassium carbonate, and the solvent is acetone or N,N-
  • the process of preparing compound II-2 from compound II-1 is to generate isothiocyanate through the reaction of halogen and potassium thiocyanate, and the solvent is methanol or ethanol; the process of preparing compound II-3 from compound II-2 is through isothiocyanate
  • the thiazole ring is synthesized from cyanate ester, and the solvent is preferably 33% hydrobromic acid solution.
  • the process of preparing compound II-5 from compound II-4 uses 2-bromoacetophenone to react with thiourea, and the solvent is ethanol; the process of preparing compound II-6 from compound II-5 is the same as compound I-4.
  • the process of preparing compound II-7 from compound II-3 is the same as compound I-6; the process of preparing compound II-8 from II-7 is the same as compound I-4; the process of preparing compound II-9 from compound II-3 is The same as compound I-8; the process of preparing compound II-10 from compound II-9 is the same as compound I-9; the process of preparing compound II-11 from compound II-10 is the same as compound I-4.
  • the preparation process of compound II-14, II-17, II-20 is similar to that of compound II-11.
  • the process of preparing compound II-22 from compound II-21 is the reaction of substituted benzoic acid and thiosemicarbazide, and phosphorus oxychloride is a catalyst; the process of preparing compound II-23 from compound II-22 is the same as that of compound I-4 .
  • the process of preparing compound II-24 from compound II-22 is the substitution reaction of amino group by halogen, the reaction reagent is copper bromide, isoamyl nitrite, and the solvent is acetonitrile; the process of preparing compound II-25 from compound II-24 is the same as Compound I-6; the process for preparing compound II-26 from compound II-25 is the same as compound I-4.
  • the process of preparing compound III-2 from compound III-1 is the same as that of compound I-4; the process of preparing compound III-3 from compound III-2 is a coupling reaction between halogen and amino, and the base is N,N-diisopropyl Ethylamine, the solvent is dimethyl sulfoxide; the process of preparing compound III-4 from compound III-3 is a nitro reduction reaction, catalyzed by iron powder/concentrated hydrochloric acid, and the solvent is ethanol; compound III is prepared from compound III-4 The process of -5 is obtained by reacting amino group with acid chloride or sulfonyl chloride, the acid-binding agent is pyridine, and the solvent is dichloromethane; the preparation process of compound III-9 is the same as that of compound III-4; compound III-9 is prepared from compound III-9 The process of 10 is a coupling reaction between an amino group and a halogen, the base is cesium carbonate, and the solvent is 1,4-dioxane.
  • the pharmaceutically acceptable salt of the compound of the general formula (I), (II), (III) can be prepared by reacting with an equivalent or excess acid (inorganic acid or organic acid) in a suitable solvent or solvent composition have to.
  • acids include, but are not limited to, hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid or ferulic acid.
  • the solvent includes but not limited to methanol, ethanol, dichloromethane, acetone, ethyl acetate, toluene or tetrahydrofuran, or any mixed solvents.
  • the application provides a pharmaceutical composition, which includes a pharmaceutically effective amount of active components and pharmaceutically acceptable excipients; the active components include compounds of general formula (I), (II), (III) and pharmaceutically One or more of the acceptable salts.
  • the auxiliary materials include pharmaceutically acceptable carriers, diluents and/or excipients.
  • the pharmaceutical composition can be made into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, granules, capsules and injections (solution or suspension), etc. , preferably tablets, capsules, liquids, suspensions and injections (solution or suspension).
  • the clinical administration of the compounds described in this application can be oral administration, injection and the like.
  • the dosage range for human is 1-1000 mg/day. Depending on the dosage form and the severity of the disease, the dosage may exceed this range.
  • the application also provides the application of the compounds of the general formulas (I), (II) and (III) in the preparation of USP8 inhibitors.
  • the present application also provides the application of the compounds represented by the general formulas (I), (II) and (III) in the treatment of USP8-mediated immunosuppression-related diseases.
  • the USP8-mediated immunosuppression-related diseases described in this application include cancer, neurodegenerative diseases, blood system diseases, and endocrine system diseases.
  • the cancer is preferably but not limited to non-small cell lung cancer, liver cancer, gastric cancer, bile duct cancer, breast cancer, pancreatic cancer, cervical cancer, pituitary tumor, multiple myeloma, leukemia, melanoma, glioma; nervous system degenerative diseases are preferred But not limited to Parkinson's disease, Alzheimer's disease; blood system disease is preferably but not limited to Fanconi anemia; endocrine system disease is preferably but not limited to Cushing's disease.
  • aromatic ring refers to a monocyclic or fused polycyclic or biphenyl group containing 1-12 carbon atoms, having a fully conjugated ⁇ -electron system.
  • aromatic rings are phenyl, naphthyl and biphenyl, which may be substituted or unsubstituted.
  • heteromatic ring refers to a monocyclic ring system containing 1-6 atoms, the system contains one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms are C, and have Completely conjugated ⁇ -electron system.
  • unsubstituted aromatic heterocycles include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, thiadiazole, pyrazole, pyridine, pyrimidine, tetrazole, and triazine.
  • Heteroaromatic rings can be substituted or unsubstituted.
  • alkyl denotes a saturated aliphatic group of 1 to 20 carbon atoms, including straight and branched chain groups. Alkyl groups can be substituted or unsubstituted. In the case of substituted alkyl groups, the substituents are preferably one or more.
  • alkoxy denotes -O-(unsubstituted alkyl) and -O-(unsubstituted cycloalkyl).
  • Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • trifluoromethyl denotes a -CF3 group.
  • nitro denotes a -NO2 group.
  • amino denotes a -NH2 group.
  • cyano denotes a -CN group.
  • hydroxyl denotes a -OH group.
  • ester group denotes a formate group such as -COOCH3 .
  • halogen means fluorine, chlorine, bromine or iodine. Preferred are fluorine, chlorine, bromine.
  • Benzoic acid (0.43g, 2.44mmol), thiosemicarbazide (1.8g, 19.67mmol), and phosphorus oxychloride (20ml) were added into a three-necked flask, and reacted at 75°C for 5 hours, and the reaction was complete as monitored by TLC. After the reaction solution was cooled to room temperature, 1 mol/L hydrochloric acid solution was slowly added dropwise to the reaction solution in an ice bath to quench phosphorus oxychloride. After extraction with ethyl acetate, the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • reaction solution was poured into 5V volume of 1mol/L hydrochloric acid, a light yellow solid precipitated out, filtered with suction, the filter cake was dried and purified by column chromatography to obtain 0.14 g of a beige solid with a yield of 75%.
  • the raw material II-20 (0.3g, 0.97mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (0.38g, 1.45mmol), N,N-dimethylformamide (3ml), potassium carbonate (0.4g, 2.9mmol), reacted overnight at 110°C, after the reaction was completed, the reaction solution was cooled to room temperature, poured into 5 times the volume of water, and extracted with dichloromethane (8ml x 3) , the organic layers were combined, the solvent was evaporated under reduced pressure, and purified by column chromatography to obtain 0.23 g of a light yellow solid with a yield of 71%.
  • a light yellow solid was prepared by the same method as compound L68 except that 1-Boc-3-aminopyrrolidine was replaced with 3-(Boc-amino)pyrrolidine, and the yield was 69%.
  • a high-throughput screening system targeting USP8 was established by using the substrate Ubiquitin-Rho-110.
  • the substrate powder was dissolved to a concentration of 200 ⁇ M using DMSO.
  • the components include 50mM Tris-HCl, pH 7.5, 1mM EDTA, 100mM NaCl and 0.05% (w/v) CHAPS.
  • USP8 protein, USP2 protein and USP7 protein were diluted to 1nM, 2nM and 1nM with assay buffer, respectively, and 2.5 ⁇ L were added to 384-well plates. Then 2.5 ⁇ L of compound dilution buffer was added.
  • the cell survival assay was used to determine the inhibitory effect of the compound on the proliferation of the MCF-7 cell line.
  • the MCF-7 cell line was selected, and a plurality of key compounds were selected to treat the cells, and the detection of cell proliferation inhibition was carried out.
  • the cells were cultured in a 96-well transparent plate at a density of 3 ⁇ 104mL-1, and the cells were treated with the compound or the same volume of DMSO. After 3 days of treatment, the fluorescence of each well was measured with the Envision multiwell microplate detector using the CellTiter-Glo reagent. Intensity, indicative of cell viability.
  • the GI 50 value of the half-proliferation inhibitory concentration was calculated by GraphPad Prism 5.0 software fitting. The results are shown in Table 2.

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Abstract

La présente invention concerne une classe de composés contenant une structure thiazole ou thiadiazole et leur utilisation, appartenant au domaine technique de la médecine. Selon la présente invention, la structure d'un composé de plomb est optimisée par division, recombinaison de pharmacophores, etc., pour obtenir une série d'inhibiteurs d'USP8 ayant un nouveau squelette et contenant une structure thiazole ou thiadiazole, enrichissant la diversité structurale des inhibiteurs d'USP8.
PCT/CN2022/114208 2021-10-12 2022-08-23 Sulfamide inhibiteur d'usp8 et son utilisation WO2023061051A1 (fr)

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