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WO2025176107A1 - Dérivés de pyridone et leur utilisation médicale - Google Patents

Dérivés de pyridone et leur utilisation médicale

Info

Publication number
WO2025176107A1
WO2025176107A1 PCT/CN2025/077785 CN2025077785W WO2025176107A1 WO 2025176107 A1 WO2025176107 A1 WO 2025176107A1 CN 2025077785 W CN2025077785 W CN 2025077785W WO 2025176107 A1 WO2025176107 A1 WO 2025176107A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
alkoxy
mobile phase
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/077785
Other languages
English (en)
Chinese (zh)
Inventor
张晨
何平
王乐
黄江坤
黄清平
宣兆利
孟庆元
李瑶
严庞科
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.)
Tibet Haisco Pharmaceutical Co Ltd
Original Assignee
Tibet Haisco Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tibet Haisco Pharmaceutical Co Ltd filed Critical Tibet Haisco Pharmaceutical Co Ltd
Publication of WO2025176107A1 publication Critical patent/WO2025176107A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a compound described by general formula (I) or its stereoisomers, racemates, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and use of the compounds in preparing drugs for treating diseases related to integrin ⁇ 4 ⁇ 7 activity or expression.
  • the integrin family consists of dimers formed by two subunits: ⁇ (120-185 kDa) and ⁇ (90-110 kDa). There are 18 ⁇ subunits and 8 ⁇ subunits in mammals. Different combinations of these subunits can form over 20 different integrins.
  • ⁇ 4 ⁇ 7 is a member of the integrin family. Intestinal inflammatory diseases associated with ⁇ 4 ⁇ 7 include Crohn's disease and ulcerative colitis.
  • the primary ligand for ⁇ 4 ⁇ 7 is mucosal addressin cell adhesion molecule-1 (MADCAM-1).
  • MAdCAM-1 is a transmembrane glycoprotein selectively expressed in high endothelial veins of mucosal lymphoid organs and veins in the intestinal lamina intestinal. Under inflammatory conditions, various cytokines promote high expression of MAdCAM-1 on endothelial cells, which then mediate the migration of ⁇ 4 ⁇ 7-expressing leukocytes to the site of inflammation. Targeting either integrin ⁇ 4 ⁇ 7 or MAdCAM-1 can reduce intestinal inflammation. Currently, there are no small molecule compounds specifically targeting ⁇ 4 ⁇ 7-mediated inflammation on the market.
  • Natalizumab a humanized monoclonal antibody targeting the ⁇ 4 subunit, is used clinically to treat multiple sclerosis and Crohn's disease, but has been associated with PML (progressive multifocal leukoencephalopathy) as a side effect. Therefore, there is a need to develop a small molecule compound that can inhibit the integrin ⁇ 4 ⁇ 7 protein for the treatment of diseases associated with integrin ⁇ 4 ⁇ 7 activity or expression.
  • the present invention develops a novel, highly effective, and safer integrin ⁇ 4 ⁇ 7 inhibitor.
  • These compounds have good pharmacokinetic properties (e.g., good AUC, bioavailability, low clearance, and good liver microsomal stability) and good safety, have good selectivity for ⁇ 4 ⁇ 7, and exhibit better permeability in the Caco2 test. They are used to treat diseases associated with integrin ⁇ 4 ⁇ 7, such as intestinal inflammatory diseases.
  • the present invention provides a compound of general formula (I) or general formula (II) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein
  • R 1 is selected from H, methyl, or ethyl
  • R 2a is selected from F, Cl, Br, OH, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy or cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy or cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, C 1-4 alkyl or C 1-4 alkoxy;
  • R3 is selected from
  • R3 is selected from
  • R3 is selected from
  • R3 is selected from
  • R 3a , R 3b are each independently selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 3a , R 3b are each independently selected from H, F, Cl, Br, cyano, methyl, ethyl, isopropyl, methoxy, or ethoxy, wherein the methyl, ethyl, isopropyl, methoxy, or ethoxy group is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, CN, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy;
  • R1 is selected from H or C1-4 alkyl
  • R2 is selected from halogen, OH, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-6 cycloalkyl or 4-7 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, C1-6 alkyl or C1-6 alkoxy;
  • R 2a are each independently selected from halogen, OH, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 3 is selected from
  • R 3a and R 3b are each independently selected from H, halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy, wherein the alkyl or alkoxy group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, C 1-6 alkyl, or C 1-6 alkoxy;
  • n is selected from 0, 1, 2, 3 or 4;
  • R1 is selected from H, methyl or ethyl
  • R 2 is selected from F, methyl, CHF 2 , CH 2 F, CF 3 ;
  • R 2a is each independently selected from F, Cl, Br, OH, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy or cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy or cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3a , R 3b are each independently selected from H, F, Cl, Br, cyano, methyl, ethyl, isopropyl, methoxy or ethoxy, wherein the methyl, ethyl, isopropyl, methoxy or ethoxy group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3 is selected from
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as the "drug strength").
  • the pharmaceutical composition includes but is not limited to 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 1 25 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of a compound of the present invention or a stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.
  • a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably an intestinal inflammatory disease (preferably Crohn's disease or ulcerative colitis).
  • a method for treating a disease in a mammal comprising administering to a subject a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1000 mg/day, wherein the daily dose can be a single dose or divided doses.
  • the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, / day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments, daily doses include but are not limited to 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200 mg/day, 300 mg/day, 320 mg/day, 400 mg/day, 480 mg/day, 600 mg/day, 640 mg/day, 800 mg/day, 1000 mg/day.
  • the present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.
  • the amount of the compound of the invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present invention are optionally replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include protium
  • Halogen refers to F, Cl, Br or I.
  • Alkyl refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups appearing herein have the same definition as this one. Alkyl groups can be monovalent, divalent, trivalent, or tetravalent.
  • Alkylene refers to a substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon group, including -(CH 2 ) v - (v is an integer from 1 to 10). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Cycloalkyl groups as used herein are as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S.
  • the N and S optionally substituted in the ring of the heterocycloalkyl can be oxidized to various oxidation states.
  • the heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl group can be connected to a bridged ring or a spiro ring.
  • “Replaced by 1 to X substituents” means substituted by 11, 2, 3, ..., X substituents, where X is selected from any integer between 1 and 10.
  • “replaced by 0 to 4 substituents” means substituted by 0, 1, 2, 3, or 4 substituents.
  • “replaced by 1 to 4 R k” means substituted by 1, 2, 3, or 4 R k .
  • "a heterobridged ring is optionally substituted by 0 to 4 substituents selected from H or F” means that the heterobridged ring is optionally substituted by 0, 1, 2, 3, or 4 substituents selected from H or F.
  • Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.
  • Mobile phase A is 0.05% TFA solution
  • mobile phase B is acetonitrile
  • 1a-3 (1580 mg, 6.05 mmol) and R-tert-butylsulfenamide (1100 mg, 9.07 mmol) were dissolved in tetrahydrofuran (35 mL), and tetraethyl titanate (2070 mg, 9.07 mmol) was slowly added.
  • the reaction was carried out at 45 ° C for 15 h, and the mixture was concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by silica gel flash column chromatography to obtain 1a-4 (2100 mg, yield 95.29%).
  • Zinc powder (1.2 g, 18.34 mmol) was added to dry tetrahydrofuran (8 mL), and the nitrogen atmosphere was replaced three times.
  • CuCl (389 mg, 3.93 mmol) was added, and the reaction was carried out at 60°C for 2 h.
  • ethyl bromoacetate (1.09 g, 6.55 mmol) was slowly added, and the reaction was carried out at 60°C for 1 h.
  • a solution of 1a-4 (478 mg, 1.31 mmol) in tetrahydrofuran (3 mL) was added, and the mixture was stirred at 0°C for 3 h.
  • Step 4 Synthesis of Compound 1-1 and Compound 1-2
  • 1d (190 mg, 0.50 mmol) was dissolved in dry DMF (10 mL), and EDCI (CAS: 7084-11-9) (190 mg, 1.0 mmol), HOBt (CAS: 2592-95-2) (140 mg, 1.0 mmol), and DIPEA (260 mg, 2.0 mmol) were added sequentially. After stirring at room temperature for 40 min, 2b (200 mg, 0.50 mmol) was added. The reaction was allowed to proceed overnight at room temperature, and ethyl acetate (80 mL) was added.
  • Step 4 Synthesis of Compound 2-1 and Compound 2-2
  • 8c (2.8 g, 6.78 mmol) was dissolved in THF (30 mL) and water (10 mL), lithium hydroxide (331.55 mg, 13.85 mmol) was added, and the reaction was continued for 30 min. 8c was purified by reverse phase chromatography to obtain 8c (2.0 g, yield: 76.80%).
  • compound 9-1 50 mg, SFC retention time: 1.181 min
  • compound 9-2 50 mg, SFC retention time: 1.708 min
  • SFC preparation conditions instrument: Waters 150 Prep-SFC; chromatographic column: Chiral IK column; mobile phase: A is CO 2 ; B is a methanol solution containing 0.1% ammonia; elution conditions: 35% B isocratic elution; flow rate: 100 mL/min; pressure: 100 bar; column temperature: room temperature; detection wavelength: 220 nm.
  • HPLC preparation conditions Instrument: Waters 2767 preparative column: SunFire@Prep C18 (19 mm ⁇ 150 mm); Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 0.1% ammonium acetate)
  • compound 13-1 (44 mg, yield 11.35%, HPLC retention time: 4.289 min) and compound 13-2 (44 mg, yield 11.35%, HPLC retention time: 4.378 min) were obtained by preparative HPLC purification.
  • HPLC preparation conditions Instrument: Waters 2767 preparative column: SunFire@Prep C18 (19 mm ⁇ 150 mm); Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 0.1% ammonium acetate)
  • compound 14-1 45 mg, yield 11.80%, HPLC retention time: 4.289 min
  • compound 14-2 45 mg, yield 11.80%, HPLC retention time: 4.378 min
  • HPLC preparation conditions Instrument: Waters 2767 preparative column: SunFire@Prep C18 (19 mm ⁇ 150 mm); Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 0.1% ammonium acetate)
  • Instrument Waters 150 Prep-SFC; chromatographic column: Chiral OD column; mobile phase: A is CO 2 ; B is methanol solution; elution conditions: 15% B isocratic elution; flow rate: 120 mL/min; pressure: 100 bar; column temperature: room temperature; detection wavelength: 220 nm.
  • compound 16-1 46 mg, yield 11.71%, HPLC retention time: 4.389 min
  • compound 16-2 46 mg, yield 11.71%, HPLC retention time: 4.470 min
  • HPLC preparation conditions Instrument: Waters 2767 preparative column: SunFire@Prep C18 (19 mm ⁇ 150 mm); Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 0.1% ammonium acetate)
  • compound 17-1 40 mg, yield 10.03%, SFC retention time: 1.147 min
  • compound 17-2 40 mg, SFC retention time: 1.599 min
  • SFC preparation conditions instrument: Waters 150 Prep-SFC; chromatographic column: Chiral OD column; mobile phase: A is CO 2 ; B is methanol solution; elution conditions: 25% B isocratic elution; flow rate: 120 mL/min; pressure: 100 bar; column temperature: room temperature; detection wavelength: 220 nm.
  • compound 18-1 40 mg, yield 10.32%, HPLC retention time: 4.500 min
  • compound 18-2 40 mg, yield 10.32%, HPLC retention time: 4.594 min
  • HPLC preparation conditions instrument: Waters 2767 preparative column: SunFire@Prep C18 (19 mm ⁇ 150 mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% ammonium acetate).
  • compound 19-1 (40 mg, yield 10.49%, HPLC retention time: 4.244 min) and compound 19-2 (40 mg, yield 10.49%, HPLC retention time: 4.314 min) were obtained by preparative HPLC purification.
  • HPLC preparation conditions Instrument: Waters 2767 preparative column: SunFire@Prep C18 (19 mm ⁇ 150 mm); Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 0.1% ammonium acetate)
  • a crude product of compound 20 was obtained.
  • the crude product was separated and purified by prep-HPLC to obtain the trifluoroacetate salt of compound 20-1 (102 mg, yield 21%, HPLC retention time: 3.978 min) and the trifluoroacetate salt of compound 20-2 (68 mg, yield 14%, HPLC retention time: 4.180 min).
  • HPLC preparation conditions Instrument: Waters 2767 preparative column: SunFire@Prep C18 (19 mm ⁇ 150 mm); Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 0.1% trifluoroacetic acid)
  • a crude product of compound 22 was obtained.
  • the crude product was separated and purified by prep-HPLC to obtain the trifluoroacetate salt of compound 22-1 (87 mg, yield 31%, HPLC retention time: 4.300 min) and the trifluoroacetate salt of compound 22-2 (86 mg, yield 31%, HPLC retention time: 4.508 min).
  • HPLC preparation conditions Instrument: Waters 2767 preparative column: SunFire@Prep C18 (19 mm ⁇ 150 mm); Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 0.1% trifluoroacetic acid)
  • HPLC preparation conditions Instrument: Waters 2767 preparative column: SunFire@Prep C18 (19 mm ⁇ 150 mm); Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 0.1% trifluoroacetic acid)
  • HPLC preparation conditions Instrument: Waters 2767 preparative column: SunFire@Prep C18 (19 mm ⁇ 150 mm); Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 0.1% trifluoroacetic acid)
  • a crude product of compound 25 was obtained.
  • the crude product was separated and purified by prep-HPLC to give the trifluoroacetate salt of compound 25-1 (87 mg, yield 32%, HPLC retention time: 4.307 min) and the trifluoroacetate salt of compound 25-2 (73 mg, yield 27%, HPLC retention time: 4.516 min).
  • HPLC preparation conditions Instrument: Waters 2767 preparative column: SunFire@Prep C18 (19 mm ⁇ 150 mm); Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 0.1% trifluoroacetic acid)
  • HPLC preparation conditions Instrument: Waters 2767 preparative column: SunFire@Prep C18 (19 mm ⁇ 150 mm); Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 0.1% trifluoroacetic acid)
  • the crude product of compound 27 was obtained, and the crude product was separated and purified by prep-HPLC (instrument: waters 2767 preparative chromatography column: SunFire@Prep C18 (19mm ⁇ 150mm); (mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% ammonium acetate) to obtain compound 27-1 (157 mg, yield 42%, HPLC retention time: 4.385 min) and compound 27-2 (65 mg, yield 19%, HPLC retention time: 4.504 min).
  • prep-HPLC instrument: waters 2767 preparative chromatography column: SunFire@Prep C18 (19mm ⁇ 150mm
  • mobile phase composition mobile phase A: acetonitrile
  • mobile phase B water (containing 0.1% ammonium acetate)
  • a crude compound 28 was obtained, which was separated and purified by prep-HPLC (instrument: waters 2767 preparative chromatographic column: SunFire@Prep C18 (19 mm ⁇ 150 mm); (mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% ammonium acetate) to obtain compound 28-1 (40 mg, yield 21%, HPLC retention time: 4.111 min) and compound 28-2 (21 mg, yield 12%, HPLC retention time: 4.233 min).
  • prep-HPLC instrument: waters 2767 preparative chromatographic column: SunFire@Prep C18 (19 mm ⁇ 150 mm
  • mobile phase composition mobile phase A: acetonitrile
  • mobile phase B water (containing 0.1% ammonium acetate) to obtain compound 28-1 (40 mg, yield 21%, HPLC retention time: 4.111 min) and compound 28-2 (21 mg, yield 12%, HPLC retention time: 4.233 min).
  • the crude product of compound 30 was obtained, and the crude product was separated and purified by prep-HPLC (instrument: waters 2767 preparative chromatography column: SunFire@Prep C18 (19mm ⁇ 150mm); (mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% TFA) to obtain trifluoroacetate of compound 30-1 (17 mg, yield 7.3%, HPLC retention time: 4.066 min) and trifluoroacetate of compound 30-2 (23 mg, yield 9.9%, HPLC retention time: 4.246 min).
  • prep-HPLC instrument: waters 2767 preparative chromatography column: SunFire@Prep C18 (19mm ⁇ 150mm
  • mobile phase composition mobile phase A: acetonitrile
  • mobile phase B water (containing 0.1% TFA) to obtain trifluoroacetate of compound 30-1 (17 mg, yield 7.3%, HPLC retention time: 4.066 min) and trifluoroacetate of compound 30-2 (23 mg, yield 9.9%, HPLC retention time: 4.246 min).
  • the crude product of compound 31 was obtained, and the crude product was separated and purified by prep-HPLC (instrument: waters 2767 preparative chromatography column: SunFire@Prep C18 (19mm ⁇ 150mm); (mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% ammonium acetate) to obtain compound 31-1 (55 mg, yield 19%, HPLC retention time: 4.509 min) and compound 31-2 (42 mg, yield 14.5%, HPLC retention time: 4.589 min).
  • prep-HPLC instrument: waters 2767 preparative chromatography column: SunFire@Prep C18 (19mm ⁇ 150mm
  • mobile phase composition mobile phase A: acetonitrile
  • mobile phase B water (containing 0.1% ammonium acetate)
  • the crude product of compound 32 was obtained, and the crude product was separated and purified by prep-HPLC (instrument: waters 2767 preparative chromatography column: SunFire@Prep C18 (19mm ⁇ 150mm); (mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% ammonium acetate) to obtain compound 32-1 (15 mg, yield 7.7%, HPLC retention time: 4.483 min) and compound 32-2 (20 mg, yield 10.3%, HPLC retention time: 4.565 min).
  • prep-HPLC instrument: waters 2767 preparative chromatography column: SunFire@Prep C18 (19mm ⁇ 150mm
  • mobile phase composition mobile phase A: acetonitrile
  • mobile phase B water (containing 0.1% ammonium acetate)
  • Reference compound A prepared according to WO2021076890A1.
  • MAdCAM-1 was diluted to a final concentration of 2 ⁇ g/ml in TBS buffer, and 50 ⁇ l of the solution was transferred to a 96-well plate for overnight coating at 4°C. The plate was washed three times with TBS buffer, followed by the addition of 150 ⁇ l of blocking buffer (TBS buffer containing 1% BSA) and incubation at 37°C for 1 hour. RPMI8866 cells were harvested, washed twice with DPBS, and resuspended in TBS buffer to 4 ⁇ 10 5 cells/ml. 50 ⁇ l of the cell suspension was transferred to a 96-well plate at a cell density of 2 ⁇ 10 5 cells/well.
  • TBS buffer containing 1% BSA blocking buffer
  • VCAM was prepared with coating buffer to a final concentration of 0.5 ⁇ g/ml, and 50 ⁇ l of the solution was transferred to a 96-well plate for overnight coating at 4°C. The plate was washed three times with coating buffer, and then 150 ⁇ l of blocking buffer (containing 1% BSA in coating buffer) was added and blocked at 37°C for 1 hour. Jurkat cells were collected and washed twice with DPBS buffer, and then resuspended in the reaction buffer to 4 ⁇ 106 cells/ml. 50 ⁇ l of the cell solution was transferred to a 96-well plate to a cell density of 2 ⁇ 105 cells/well. 1 ⁇ l of the test compound or DMSO at different concentrations was added and incubated at 37°C for 1 hour.
  • blocking buffer containing 1% BSA in coating buffer
  • Coating buffer DMEM + 20mM HEPES + 0.4mM MnCl2
  • cytochrome P450 cytochrome P450
  • CYP1A2, CYP2C9, CYP2D6, and CYP3A4 cytochrome P450 isoforms
  • CYP1A2, CYP2C9, CYP2D6, and CYP3A4 cytochrome P450 isoforms
  • CYP1A2, CYP2C9, CYP2D6, and CYP3A4 cytochrome P450
  • Specific probe substrates for each CYP450 isoform were incubated with human liver microsomes and varying concentrations of the test substances.
  • the reactions were initiated by the addition of reduced nicotinamide adenine dinucleotide phosphate (NADPH).
  • NADPH reduced nicotinamide adenine dinucleotide phosphate
  • samples were processed and metabolites generated from the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS
  • IC50 values were calculated to evaluate the inhibitory potential of the test substances against each CYP isoform, CYP1A2, CYP2C9, CYP2D6, and CYP3A4-M (using midazolam as a substrate).
  • the compounds of the present invention have no significant inhibitory effect on any subtype of CYP enzymes.
  • mice On the day of the experiment, mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 95% (20% SBE- ⁇ -CD in saline)
  • DMSO dimethyl sulfoxide
  • SBE- ⁇ -CD sulfobutyl- ⁇ -cyclodextrin
  • the compounds of the present invention such as the compounds in the examples, have good oral absorption properties in mice.
  • mice Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 95% (20% SBE- ⁇ -CD in saline)
  • DMSO dimethyl sulfoxide
  • SBE- ⁇ -CD sulfobutyl- ⁇ -cyclodextrin
  • the compounds of the present invention have better pharmacokinetic properties in rats (such as lower clearance, better Cmax, AUC and bioavailability).
  • mice Male beagle dogs, weighing about 8-11 kg, 5-6 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 95% (20% SBE- ⁇ -CD in saline)
  • DMSO dimethyl sulfoxide
  • SBE- ⁇ -CD sulfobutyl- ⁇ -cyclodextrin
  • the compounds of the present invention such as the compounds in the examples, have good oral absorption properties in beagle dogs.
  • test compound was incubated with mouse liver microsomes (0.5 mg/mL) in an NADPH-regenerating system for 5, 10, 20, 30, and 60 minutes. The resulting samples were analyzed by LC-MS/MS. The half-life (T 1/2 ) and intrinsic clearance (CL int(mic) ) of the compound in mouse liver microsomal solution were calculated by calculating the percentage of compound remaining at each time point.
  • the compounds of the present invention such as the compounds in the examples, have good stability in mouse liver microsomes.
  • the experiment used a monolayer of Caco-2 cells and was incubated in triplicate in a 96-well Transwell plate.
  • Transport buffer solution (HBSS, 10mM HEPES, pH 7.4 ⁇ 0.05) containing the compound of the present invention (2 ⁇ M) or the control compounds digoxin (10 ⁇ M), nadolol (2 ⁇ M) and metoprolol (2 ⁇ M) was added to the dosing port well on the apical or basolateral side.
  • Transport buffer solution containing DMSO was added to the corresponding receiving port well. After incubation at 37 ⁇ 1°C for 2 hours, the cell plate was removed and appropriate amounts of samples were taken from the top and bottom ends to a new 96-well plate.
  • acetonitrile containing an internal standard was added to precipitate the protein.
  • the samples were analyzed using LC MS/MS and the concentrations of the compound of the present invention and the control compound were determined. The concentration data were used to calculate the apparent permeability coefficient for transport from the apical side to the basolateral side and from the basolateral side to the apical side of the monolayer cells, thereby calculating the efflux rate.
  • the integrity of the monolayer cells after 2 hours of incubation was evaluated by leakage of fluorescent yellow.
  • CHO cells overexpressing human CCK2 were cultured in F-12 medium (supplemented with 10% fetal bovine serum and 0.2 mg/mL Hygromycin B) at 37°C in 5% CO2 until use.
  • 1 ⁇ Stimulation Buffer was prepared according to the instructions for the HTRF IP-One Gq Detection Kit (Revvity, Cat. No. 62IPAPEJ).
  • a 1000 ⁇ working solution of the test compound was prepared in DMSO and transferred using an ECHO655 to a 384-well plate (Greiner, Cat. No. 784075).
  • CHO cells overexpressing human CCK2 were trypsinized and centrifuged at 1000 rpm for 5 minutes.
  • the cell pellet was resuspended in 1 ⁇ Stimulation Buffer and, after counting, 10 ⁇ L of the solution was added to a 384-well plate (Greiner, Cat. No. 784075) at a density of 8,000 cells per well. Centrifuge at 1000 rpm for 1 minute at room temperature and incubate at 37°C for 60 minutes. Dilute IP1-d2 to 7 ⁇ working concentration with Lysis & Detection Buffer, take 2 ⁇ L and add to the corresponding experimental wells. Then dilute Anti-IP1-Cryptate to 7 ⁇ working concentration with Lysis & Detection Buffer, take 2 ⁇ L and add to the corresponding experimental wells.
  • the detection wavelength was 330 nm with an FSX microplate reader (BMG), and the readings were at 665 nm and 620 nm.
  • the signal ratio (Signal 665/Signal 620*10 4 ) was calculated, and the EC 50 value was fitted using Graphpad Prism software.
  • Activation% represents the percentage of the compound's agonism on the receptor. Mean values of positive controls. Mean values of negative controls (DMSO).
  • X is the test concentration of the test article
  • Y is the activation percentage at the corresponding concentration
  • Bottom and Top are the minimum and maximum activation percentages, respectively.
  • the compounds of the present invention such as the compounds in the examples, have weak agonist activity on CCK2.

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Abstract

La présente invention concerne des dérivés de pyridone et leur utilisation médicale, et concerne en particulier des composés représentés par la formule générale (I) ou des stéréoisomères, des racémates, des substances deutérées, des solvates, des promédicaments, des métabolites, des sels pharmaceutiquement acceptables ou des cristaux eutectiques de ceux-ci, et un intermédiaire de ceux-ci et leur procédé de préparation, ainsi que leur utilisation dans la préparation d'un médicament pour le traitement de maladies liées à l'activité ou au niveau d'expression de l'intégrine α4β7.
PCT/CN2025/077785 2024-02-20 2025-02-18 Dérivés de pyridone et leur utilisation médicale Pending WO2025176107A1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
CN202410188785 2024-02-20
CN202410188785.3 2024-02-20
CN202410292419.2 2024-03-14
CN202410292419 2024-03-14
CN202410456185.0 2024-04-16
CN202410456185 2024-04-16
CN202410707588 2024-06-03
CN202410707588.8 2024-06-03
CN202411137105 2024-08-19
CN202411137105.1 2024-08-19

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112312910A (zh) * 2018-04-12 2021-02-02 莫菲克医疗股份有限公司 人整合素α4β7拮抗剂
CN115087444A (zh) * 2019-10-16 2022-09-20 莫菲克医疗股份有限公司 抑制人整联蛋白α4β7
WO2023125182A1 (fr) * 2021-12-27 2023-07-06 海思科医药集团股份有限公司 Dérivé d'acide propionique et son utilisation médicale
WO2024051819A1 (fr) * 2022-09-09 2024-03-14 西藏海思科制药有限公司 Dérivé d'acide propionique et son utilisation en médecine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112312910A (zh) * 2018-04-12 2021-02-02 莫菲克医疗股份有限公司 人整合素α4β7拮抗剂
CN115087444A (zh) * 2019-10-16 2022-09-20 莫菲克医疗股份有限公司 抑制人整联蛋白α4β7
WO2023125182A1 (fr) * 2021-12-27 2023-07-06 海思科医药集团股份有限公司 Dérivé d'acide propionique et son utilisation médicale
WO2024051819A1 (fr) * 2022-09-09 2024-03-14 西藏海思科制药有限公司 Dérivé d'acide propionique et son utilisation en médecine

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