WO2026008045A1 - Composé spiro contenant un groupe alcynyle et son utilisation - Google Patents

Composé spiro contenant un groupe alcynyle et son utilisation

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Publication number
WO2026008045A1
WO2026008045A1 PCT/CN2025/107015 CN2025107015W WO2026008045A1 WO 2026008045 A1 WO2026008045 A1 WO 2026008045A1 CN 2025107015 W CN2025107015 W CN 2025107015W WO 2026008045 A1 WO2026008045 A1 WO 2026008045A1
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WIPO (PCT)
Prior art keywords
alkyl
alkoxy
compound
halogen
hydroxyl
Prior art date
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Pending
Application number
PCT/CN2025/107015
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English (en)
Chinese (zh)
Inventor
王仁林
吴政
马奔
魏海阳
胡永韩
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.)
Evopoint Biosciences Co Ltd
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Evopoint Biosciences Co Ltd
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Application filed by Evopoint Biosciences Co Ltd filed Critical Evopoint Biosciences Co Ltd
Publication of WO2026008045A1 publication Critical patent/WO2026008045A1/fr
Pending legal-status Critical Current
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/499—Spiro-condensed pyrazines or piperazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • This invention relates to the field of pharmaceuticals, and more specifically to spirocyclic compounds containing an alkyne group and their uses.
  • Triglycerides are one of the main forms of energy storage in animals and a major component of the fat we ingest. After eating, triglycerides in food are digested by lipases in the intestines, producing free fatty acids and monoacylglycerols, which are then absorbed by intestinal epithelial cells.
  • the absorbed free fatty acids and monoacylglycerols are regenerated into triglycerides by monoacylglycerol acyltransferases and diacylglycerol acyltransferases on the endoplasmic reticulum membrane.
  • the newly generated triglycerides, apolipoproteins and other lipids are packaged into chylomicrons in the endoplasmic reticulum.
  • the chylomicrons are then secreted into the blood and utilized by other organs (Ko CW et al. Regulation of intestinal lipid metabolism: current concepts and relevance to disease. Nat Rev Gastroenterol Hepatol. 2020 Mar; 17(3):169-183; Mansbach CM et al.
  • MOGAT2 knockout mice exhibit a series of beneficial metabolic phenotypic changes, including reduced body weight in high-fat fed mice, a slower rate of triglyceride entry into the bloodstream from the small intestine, reduced triglyceride levels in the liver, and increased energy expenditure (Yen CL et al. Deficiency of the intestinal enzyme acyl CoA:monoacylglycerol acyltransfer).
  • MOGAT2 is a potential target for treating obesity.
  • MOGAT2 inhibitors can help reduce weight and treat non-alcoholic fatty liver disease (Cheng D et al. MGAT2 inhibitor decreases liver fibrosis and inflammation in murine NASH models and reduces body weight in human adults with obesity. Cell Metab. 2022 Nov 1; 34(11):1732-1748.e5.).
  • Example 2-1 of Patent WO2013082345 discloses a compound (BMS-963272) with MGAT2 inhibitory activity, the structure of which is shown below. This compound has completed Phase I clinical trials.
  • Example 14 of Patent WO2019013311 discloses compound II-203 (S-309309) with MGAT2 inhibitory activity, the structure of which is shown below. This compound has completed Phase II clinical trials; however, the efficacy of this drug in Phase II clinical trials was not significant, and it has not yet entered Phase III clinical trials.
  • the present invention aims to provide a spirocyclic compound containing an alkyne group.
  • This compound can effectively inhibit MOGAT2 enzyme activity and has good metabolic properties, exhibiting excellent performance in terms of efficacy, safety, and stability.
  • R 1 is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorothio, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;
  • R 2 is selected from halogen, hydroxyl, carboxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocycle, C6-10 aryl or C6-10 heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocycle, C6-10 aryl, and C6-10 heteroaryl are optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;
  • R 3 is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorothio, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;
  • R 4 is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorothio, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;
  • R 5 is selected from H, halogen, hydroxyl, carboxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic, C6-10 aryl or C6-10 heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic, C6-10 aryl, and C6-10 heteroaryl are optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;
  • R6 is selected from -NHCO-( CH2 ) mR7 ;
  • R7 is selected from C1-C6 alkylsulfonyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocycle, C6-10 aryl or C6-10 heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocycle, C6-10 aryl, or C6-10 heteroaryl are optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, or phenyl.
  • R 8 is selected from H
  • X is selected from O, S, or NH
  • Y is selected from O, S, NH or CH2 ;
  • Ring A is selected from 5-6 membered heteroaromatic rings containing one or two heteroatoms, or saturated or unsaturated 4-6 membered heterocycles containing one or two heteroatoms;
  • n 0, 1, or 2;
  • n 0, 1, or 2.
  • ring A is a 5-6 membered heteroaromatic ring containing one or two heteroatoms, selected from: pyrazole, imidazole, pyrrole, furan, thiophene, thiazole, oxazole, pyridine, pyrimidine or pyrazine, preferably pyrazole.
  • ring A is a saturated or partially unsaturated 4-6 membered heterocycle containing one or two heteroatoms, selected from: oxobutane, tetrahydrofuran, piperidine, piperazine, or pyran.
  • the compound represented by Formula I of the present invention is selected from the compounds represented by Formula II:
  • R1 , R2 , R3 , R4 , R5 , R6 , R7 , R8 , m, and n are as defined above.
  • R 1 is selected from H, hydroxyl, pentafluorothiol, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl.
  • R 2 is selected from halogen, hydroxyl, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;
  • R 3 is selected from H, hydroxyl, pentafluorothiol, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl.
  • R 4 is selected from H, halogen, hydroxyl, pentafluorothio, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl.
  • R 5 is selected from H, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic or C6-8 aryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic or C6-8 aryl are optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy or phenyl;
  • R6 is selected from -NHCO-( CH2 ) mR7 ;
  • R7 is selected from C1-C6 alkylsulfonyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;
  • R 8 is selected from H
  • X is selected from O or S
  • Y is selected from O, S, or NH
  • n 0, 1, or 2;
  • n 1 or 2.
  • the compound represented by Formula I of the present invention is selected from the compounds represented by Formula III:
  • R 2 is selected from halogens or C1-C6 alkoxy groups, wherein the C1-C6 alkoxy groups are optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen;
  • R4 is selected from H or halogen
  • R 5 is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group or phenyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group or phenyl is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, hydroxyl.
  • the compound represented by Formula III of the present invention is selected from the compounds represented by Formula III-1 or Formula III-2:
  • R2 , R4 and R5 are as defined in the compounds described in Formula III above.
  • R 2 is selected from halogen or ethoxy, wherein the ethoxy is optionally substituted by 1 to 3 substituents of the following: deuterium, halogen;
  • R4 is selected from H or halogen
  • R 5 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, or oxetane, wherein methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, or oxetane is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, or hydroxyl.
  • R2 is F or -OCH2CF3 ;
  • R 4 is either H or F.
  • the compound represented by Formula I of the present invention is selected from the following compounds:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I or a stereoisomer thereof, a prodrug, a solvate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present invention also provides the use of the compound of Formula I described above, or its stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, in the preparation of an MGAT2 inhibitor medicament.
  • the MGAT2 inhibitor drug is a drug for treating and/or preventing obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDLemia, hyperfatty acidemia, diabetes, or arteriosclerosis.
  • the present invention also provides a method for treating and/or preventing MGAT2-mediated related diseases, comprising administering to a subject in need a therapeutically effective amount of a compound of Formula I above, or a stereoisomer thereof, a prodrug, a solvate thereof, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.
  • the MGAT2-mediated related diseases are selected from obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDLemia, hyperfatty acidemia, diabetes, or arteriosclerosis.
  • the present invention also provides a compound, stereoisomer thereof, prodrug, solvate thereof, or pharmaceutically acceptable salt thereof as shown in Formula I above, for use as a drug.
  • This invention also provides a compound, stereoisomer thereof, prodrug, solvate thereof, or pharmaceutically acceptable salt thereof, as shown in Formula I above, for the treatment and/or prevention of MGAT2-mediated diseases.
  • the MGAT2-mediated diseases are as defined above.
  • alkyl refers to a saturated aliphatic hydrocarbon group, including both straight-chain and branched hydrocarbon groups. Examples include C1 - C6 alkyl groups. " C1 - C6 alkyl” refers to an alkyl group having 1 to 6 carbon atoms, such as alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, including but not limited to methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl (e.g., n-hexyl), etc.
  • the alkyl group may optionally be further substituted with one or more substituents.
  • halogen refers to fluorine, chlorine, bromine or iodine; preferably fluorine or chlorine.
  • C3 - C8 cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; preferably cyclopropyl.
  • the cycloalkyl group may optionally be further substituted with one or more substituents.
  • C1 - C6 alkoxy refers to a group formed by the bonding of a C1 - C6 alkyl group with an oxygen atom, i.e., a " C1 - C6 alkyl-O-" group, wherein C1 - C6 alkyl is the same as the " C1 - C6 alkyl" defined above. This includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy; preferably methoxy and ethoxy.
  • the alkoxy group may optionally be further substituted by one or more substituents.
  • Heterocyclic refers to a substituted or unsubstituted saturated or partially unsaturated non-aromatic cyclic group, which can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic, a 6- to 12-membered (e.g., 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1, 2, or 3 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group.
  • heterocyclic group can be attached to a heteroatom or a carbon atom; the “heterocyclic group” can be a bridged ring or a spirocyclic ring.
  • heterocyclic groups include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexacycloyl, aziridineheptyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyran, 1,3-dithiaalkyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, aziridine[3.2.1]octyl, azi
  • Aromatic ring or “aryl” refers to a substituted or unsubstituted aromatic ring, which can be a 6- to 8-membered monocyclic ring (e.g., 6, 7, 8-membered), a 6- to 12-membered (e.g., 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system. It can be a bridged ring or a spirocyclic ring. Non-limiting examples include phenyl, naphthyl, etc.
  • the aromatic ring may optionally be further substituted by one or more substituents.
  • Heteroaromatic ring refers to an aromatic ring having a conjugated planar ring system and containing heteroatoms. It can be a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, an 8- to 12-membered (e.g., 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S.
  • heteroaryl groups include oxazolyl, triazolyl, pyridyl, furanyl, thiophenyl, pyrroloyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, etc.
  • the heterocyclic ring may optionally be further substituted by one or more substituents.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention, prepared by combining a compound of the invention having specific substituents with a pharmaceutically acceptable acid or base.
  • stereoisomer refers to compounds that have the same chemical composition but differ in the spatial arrangement of atoms and groups. These include enantiomers, diastereomers, geometric isomers, transisomers, or conformational isomers.
  • solvent as used in this invention describes a molecular complex comprising a compound having any of the above chemical formulas or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol).
  • solvent e.g., ethanol
  • hydrate is used.
  • prodrug used in this invention, also known as a precursor drug, drug precursor, or predrug, refers to a compound obtained by chemically modifying a drug, which has no or low activity in vitro, but releases an active drug in vivo through enzymatic or non-enzymatic conversion to exert its therapeutic effect.
  • the compounds of the present invention may also contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds.
  • the compounds may be radiolabeled with radioactive isotopes such as deuterium (D), tritium ( 3H ), iodine-125 ( 125I ), or carbon-14 ( 14C ). All isotopic variations of the compounds of the present invention, whether radioactive or not, are covered within the scope of the present invention.
  • the compounds of this invention effectively inhibit MOGAT2 enzyme activity and exhibit favorable metabolic properties, demonstrating excellent performance in terms of efficacy, safety, and stability.
  • the compounds of this invention exhibit excellent inhibitory activity against MOGAT2, showing significant inhibition of MOGAT2 activity in cells, good plasma stability, stability in liver microsomes, good PPB results with a high proportion of free compounds contributing to the therapeutic effect, good CYP properties without inhibiting any CYP subtypes, low permeability and high efflux rate which facilitates intestinal accumulation, significant weight loss effect, good oil absorption inhibition effect, good PK properties, good bioavailability and apparent volume of distribution, high distribution in the jejunum, and relatively low distribution in the liver. Therefore, the compounds of this invention have promising clinical applications.
  • the structure of the compound was determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR measurements were performed using a Bruker Avance III 400 NMR spectrometer.
  • the solvents used were deuterated dimethyl sulfoxide (DMSO- d6 ) and deuterated chloroform ( CDCl3 ), with tetramethylsilane (TMS) as the internal standard.
  • DMSO- d6 deuterated dimethyl sulfoxide
  • CDCl3 deuterated chloroform
  • TMS tetramethylsilane
  • solution refers to an aqueous solution.
  • the room temperature is 20°C ⁇ 30°C.
  • EVO38054-A0 (1.2 g, 5.45 mmol, synthesized according to patent WO2016126935) and cyclopropylacetylene (1.8 g, 27.27 mmol) were dissolved in anhydrous 1,4-dioxane (6 mL), followed by the sequential addition of triethylamine (1.66 g, 16.36 mmol), CuI (103.87 mg, 0.54 mmol), and Pd(dppf)Cl2 . (400mg, 0.54mmol), oil bath at 80°C, sealed tube and stirred for 3 hours. Liquid chromatography-mass spectrometry monitoring showed that the ratio of reactant to product was 4:1.
  • the reaction solution was extracted with water (20mL) and ethyl acetate (10mL) to separate the layers.
  • the aqueous phase was extracted with ethyl acetate (10mL*2).
  • the organic phases were combined and washed with saturated sodium chloride solution (*2).
  • the solution was dried and evaporated to dryness.
  • EVO38054-A1 50 mg, 0.24 mmol
  • EVO38028-A1 92 mg, 0.24 mmol, synthesized according to patent WO2019122129
  • anhydrous DMF 6 mL
  • potassium carbonate 50 mg, 0.36 mmol
  • the reaction mixture was heated to 100 °C and reacted for 5 hours.
  • the reaction mixture was monitored by liquid chromatography-mass spectrometry until the starting material disappeared.
  • the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL * 3), and the organic phases were combined and washed with saturated sodium chloride solution (* 2).
  • EVO38054-A2 80 mg, 0.16 mmol was dissolved in dioxane hydrochloride solution (6 mL) and stirred for 2 hours. The disappearance of the starting material was monitored by liquid chromatography-mass spectrometry. The reaction solution was directly concentrated to obtain a yellow oily substance EVO38054-A3 (64 mg, yield: 100%).
  • EVO38054-A4 (15 mg, 0.04 mmol) and 2-(methanesulfonyl)acetic acid (12 mg, 0.08 mmol) were dissolved in anhydrous tetrahydrofuran (4 mL), and HATU (30.8 mg, 0.08 mmol) and triethylamine (16.4 mg, 0.16 mmol) were added, and the reaction was carried out for 4 hours.
  • the reaction mixture was monitored by liquid chromatography-mass spectrometry (LC-MS) to detect the disappearance of the starting material. Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution to separate the phases.
  • the aqueous phase was extracted with ethyl acetate (10 mL * 2).
  • the organic phases were combined and washed with saturated sodium chloride solution (* 2), dried, and the solvent was evaporated.
  • the mixture was then subjected to high-performance liquid chromatography (HPLC) (column: YMC Triart C18 12nm 10um , 30*250mm; mobile phase A: 10mM NH4HCO3 solution, mobile phase B: ACN; flow rate: 40 mL/min; gradient: 30% B to 80% B over 30 min; wavelength: 200-400 nm).
  • HPLC high-performance liquid chromatography
  • the monoacylglycerol acyltransferase MOGAT2 catalyzes the transfer of the fatty acyl group of fatty acyl-CoA to monoacylglycerol to generate diacylglycerol.
  • the content of the reaction product diacylglycerol can be quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • SF9 cells expressing hMOGAT2 were collected by centrifugation, and the cells were resuspended in homogenization buffer (20mM Tris-HCl, pH 7.6, 250mM sucrose, proteinase inhibitor). The cells were lysed using a Dounce homogenizer, and the cell homogenate was centrifuged at 1,000g for 10 minutes. The supernatant was collected, and then centrifuged at 100,000g for 60 minutes using an ultracentrifuge. The supernatant was discarded, and the pellet was resuspended in buffer (20mM Tris-HCl, pH 7.6, 250mM sucrose). The enzyme activity of the prepared MOGAT2-expressing microsomes was tested.
  • the reaction buffer consisted of 100 mM Tris-HCl, pH 7.6, 250 mM sucrose, and 0.01% BSA.
  • the reaction volume was 20 ⁇ L.
  • MOGAT2 microsomes, the test compound, and the substrate were added sequentially to a final concentration of 0.01 mg/mL MOGAT2 microsomes, 100 ⁇ M lithium oleoyl-CoA, and 200 ⁇ M 2-oleoylglycerol.
  • the reaction was carried out at room temperature for 60 minutes, and 180 ⁇ L of methanol was added to terminate the reaction.
  • the mixture was centrifuged at 13,000 rpm for 15 minutes, and 150 ⁇ L of the supernatant was collected for LC-MS/MS analysis of the dioleoylglycerol content.
  • the product concentrations with and without substrate were defined as DAG concentration (control+) / DAG concentration (control-) .
  • A represents IC 50 ⁇ 100 nM
  • B represents 100 nM ⁇ IC 50 ⁇ 500 nM
  • C represents 500 nM ⁇ IC 50 ⁇ 1000 nM
  • D represents 1000 nM ⁇ IC 50 ⁇ 5000 nM.
  • Caco-2 cells lack endogenous monoacylglycerol acyltransferase activity. Therefore, a Caco-2 cell line stably expressing hMOGAT2 (human monoacylglycerol acyltransferase 2) was first established to make it a cell line with monoacylglycerol acyltransferase activity. Then, 2-O-hexadecylglycerol (HDG), an analog of MAG (monoacylglycerol), was added exogenously and packaged into liposomes with DOPC (dioleoyl lecithin) for delivery into the cells. HDG can serve as a substrate for MOGAT2. The product catalyzed by HDG and MOGAT2 is relatively stable and can be distinguished from endogenous DAG. Mass spectrometry detection of the product catalyzed by HDG and MOGAT2 can reflect the cellular MOGAT2 activity.
  • hMOGAT2 human monoacylglycerol acy
  • DMEM/F12 mixed medium DMEM and F12 mixed at a 3:1 ratio
  • DMEM and F12 mixed at a 3:1 ratio DMEM and F12 mixed at a 3:1 ratio
  • DMEM/F12 mixed medium containing oleic acid, HDG/DOPC liposomes, the corresponding concentration of the test compound, and 2% BSA (final oleic acid concentration 1200 ⁇ M, final HDG concentration 400 ⁇ M).
  • Discard the medium centrifuge at 1000 rpm for 1 min, aspirate the residual liquid, wash with 160 ⁇ L of methanol and scrape off cells from each well.
  • A represents IC 50 ⁇ 100 nM
  • B represents 100 nM ⁇ IC 50 ⁇ 500 nM
  • C represents 500 nM ⁇ IC 50 ⁇ 1000 nM
  • D represents 1000 nM ⁇ IC 50 ⁇ 5000 nM.
  • Blank plasma samples (from C57 mice, SD rats, and humans, sourced from Shanghai Runno Biotechnology Co., Ltd.) were thawed, preheated at 37°C for 15 minutes, and then incubated at 37°C, 5% CO2 , and 100 rpm. Samples were taken at 0, 5, 15, 30, 60, and 120 minutes. All samples were mixed with 300 ⁇ L of stop solution and centrifuged at 4000 rpm for 15 minutes. After centrifugation, 100 ⁇ L of the supernatant was collected, diluted with 100 ⁇ L of water, and the concentration of the compound was determined by LC-MS/MS. The remaining amount of the compound was calculated. The experimental results are shown in Table 3, indicating that the test compound exhibited good plasma stability.
  • the reaction system was prepared with the following final concentrations: 0.5 mg/mL for CD-1 mice, SD rats, beagles, cynomolgus monkeys, and human liver microsomes (from Kanglong Pharmaceutical (Beijing) New Drug Technology Co., Ltd.); 100 mM phosphate buffer; 5 mM magnesium chloride; 25 ⁇ g/mL promethazine; 1 mM NADPH; 2 mM UDPGA; and 1 ⁇ M of the test compound.
  • the reaction was started by incubation at 37°C, with 10 ⁇ L samples taken at 0, 15, 30, 45, and 60 minutes. All samples were mixed with 120 ⁇ L of stop solution and centrifuged at 3220 g for 45 minutes.
  • the protein binding rate of the compound in C57 mice, Sprague-Dawley (SD) rats, and human plasma was determined using the equilibrium dialysis method. After dialysis, 20 ⁇ L of the post-dialysis plasma sample was transferred to a sample receiving plate, and 80 ⁇ L of PBS was added. Another 20 ⁇ L of the post-dialysis PBS sample was transferred to the same plate, and 80 ⁇ L of blank plasma was added. All samples were mixed with 480 ⁇ L of stop solution and centrifuged at 3220 g at 4 °C for 30 min.
  • EVO38023-R protocol The specific probe substrate for the P450 isoenzyme and human liver microsomes (from Shanghai Runno Biotechnology Co., Ltd.) were preheated at 38°C for 7 minutes. Then, the test compound was added, and the mixture was vortexed at 1000 rpm for 10 seconds. 60 ⁇ L of NADPH was added to initiate the reaction, and the mixture was incubated at 38°C and 300 rpm for 10 minutes. After the reaction, all samples were mixed with 500 ⁇ L of stop solution at 1000 rpm for 90 seconds and centrifuged at 4000 rpm for 15 minutes. After centrifugation, 300 ⁇ L of the supernatant was collected, and the concentration of the compound was determined by LC-MS/MS. The inhibition rates of the compound against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A were calculated.
  • EVO38054-P2 protocol A specific probe substrate for the P450 isoenzyme (from WuXi AppTec Co., Ltd.) was preheated with human liver microsomes (from WuXi AppTec Co., Ltd.) and the analyte compound at 37°C for 10 minutes. Then, 20 ⁇ L of NADPH was added to initiate the reaction, and the mixture was incubated in a 37°C water bath for 10 minutes. After the reaction, all samples were mixed with 400 ⁇ L of stop solution and centrifuged at 3220 g for 20 minutes. After centrifugation, 200 ⁇ L of the supernatant was collected, diluted with 100 ⁇ L of water, and the concentration of the compound was determined by LC-MS/MS. The inhibition rates of the compound against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A were calculated.
  • the bidirectional permeability of compounds and their efflux transport in the absence of inhibitors were determined using a Caco-2 monolayer cell model (from Pharmaron (Beijing) New Drug Technology Co., Ltd.). After removing the culture medium from the Caco-2 cells, the cells were rinsed with pre-warmed transport buffer. 75 ⁇ L of HEPES dosing solution containing 5 ⁇ M of the test compound and 235 ⁇ L of HEPES receiving solution were added to the top and base wells, respectively. The cell plates were incubated at 37°C for 120 minutes. After incubation, the final samples were collected from the dosing and receiving ends, mixed with transport buffer and stop solution in a specific ratio, and vortexed for 5 minutes.
  • the samples were then centrifuged at 3220 g for 30 minutes. After centrifugation, 100 ⁇ L of the supernatant was diluted with 100 ⁇ L of water, and the compound concentration was determined by LC-MS/MS. The apparent permeability coefficient and efflux rate were calculated. The experimental results are shown in Table 7. The results indicate that the test compound has low permeability and a high efflux rate, which is beneficial for intestinal enrichment.
  • the weight-loss effect of compounds on obese mice was tested in a high-fat diet-induced obesity (DIO) mouse model.
  • Male SPF-grade DIO mice aged 16–17 weeks were purchased from Shanghai Southern Model Biotechnology Co., Ltd. They were fed a 60 kcal high-fat diet. After one week of acclimatization, the weight of each mouse was measured, and they were grouped according to weight before administration.
  • the solvent was a mixture of 0.5% hydroxypropyl methylcellulose (HPMC) and 0.1% Tween-80 aqueous solution. The test compound was dissolved in the solvent, and the dosage volume was calculated at 10 ⁇ L/g mouse body weight. Mouse weight was recorded daily during the experiment.
  • the weight reduction in the compound-treated group relative to the solvent control group reflected the weight-loss efficacy of the compound in obese mice.
  • the dosage, administration method, and experimental results are shown in Tables 8 and 9. The results indicate that the tested compound had a significant weight-loss effect.
  • mice under starvation were administered compounds and corn oil orally.
  • the inhibitory effect of the compounds on MGAT2 in mice was evaluated by detecting triglycerides (TG) in the blood.
  • Male C57BL/6 mice aged 6–8 weeks were purchased from Changzhou Cavens Laboratory Animal Co., Ltd.
  • the solvent was 0.5% hydroxypropyl methylcellulose (HPMC) + 0.1% Tween-80 aqueous solution.
  • HPMC hydroxypropyl methylcellulose
  • Tween-80 0.1%
  • mice were injected intravenously with 100 ⁇ L of tetrabutylphenol aldehyde solution (prepared with physiological saline, concentration 5%).
  • tetrabutylphenol aldehyde solution prepared with physiological saline, concentration 5%.
  • all mice were orally administered 200 ⁇ L of corn oil.
  • Blood was collected from mice at 4h, plasma was separated, and TG content was detected using a kit.
  • the reduction in TG in the compound-treated group relative to the solvent control group reflects the inhibitory effect of the compound on MGAT2 in mice.
  • the formula for calculating TG absorption inhibition is (plasma TG in the treated group / plasma TG in the control group) x 100%.
  • the experimental results are shown in Table 10, indicating that the tested compound has a good inhibitory effect on corn oil absorption.
  • mice Male C57 mice (6-8 weeks old) (from Medicilon Pharmaceuticals (Shanghai) Co., Ltd.) were administered intravenously (IV) at a dose of 1 mg/kg via tail vein bolus or orally (PO) at a dose of 5 mg/kg via gavage.
  • IV intravenously
  • PO orally
  • the compound was prepared in 5% DMSO + 10% Solutol HS15 + 85% physiological saline (IV) or 0.5% MC water containing 0.1% Tween 80 (PO). All animals had free access to food and water during the experiment.
  • mice Male SD rats (6-8 weeks old) (from Medicilon Pharmaceuticals (Shanghai) Co., Ltd.) were administered the compound via intravenous injection (IV) at a dose of 1 mg/kg via tail vein bolus or oral administration (PO) at a dose of 10 mg/kg via gavage.
  • IV intravenous injection
  • PO oral administration
  • the compound was prepared in 5% DMSO + 10% Solutol HS15 + 85% physiological saline (IV) or 0.5% MC water containing 0.1% Tween 80 (PO). All animals had free access to food and water during the experiment.
  • test compound PK has good properties, good bioavailability, and good apparent volume of distribution.
  • Tissue samples were washed with physiological saline, dried with filter paper, and homogenized with 10 times their volume of homogenate to obtain tissue homogenate samples.
  • the obtained plasma and tissue homogenate samples were analyzed by LC-MS/MS.
  • PK parameters were analyzed using WinNonlin software. Version 8.3 was calculated using a non-compartmental model analysis method.
  • Table 14 The results indicate that the test compound is highly distributed in the jejunum and relatively lowly distributed in the liver.

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Abstract

L'invention concerne un composé tel que représenté dans la formule I, dans laquelle R1, R2, R3, R4, R5, R6, R8, X, Y, un cycle A et n sont tels que définis dans la description. Le composé tel que représenté dans la formule (I) peut inhiber efficacement l'activité enzymatique de MOGAT2, présente de bonnes propriétés métaboliques, et présente des perspectives d'application clinique.
PCT/CN2025/107015 2024-07-04 2025-07-04 Composé spiro contenant un groupe alcynyle et son utilisation Pending WO2026008045A1 (fr)

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CN111094288A (zh) * 2017-07-14 2020-05-01 盐野义制药株式会社 具有mgat-2抑制活性的稠合环衍生物
CN113557021A (zh) * 2019-01-11 2021-10-26 盐野义制药株式会社 具有mgat2抑制活性的二氢吡唑并吡嗪酮衍生物
JP2022016394A (ja) * 2020-07-10 2022-01-21 塩野義製薬株式会社 Ｍｇａｔ２阻害活性を有するジヒドロピラゾロピラジノン誘導体を含有する医薬組成物
CN118215478A (zh) * 2021-09-08 2024-06-18 盐野义制药株式会社 用于预防和治疗与抗肥胖作用有关的疾病的药物

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CN111094288A (zh) * 2017-07-14 2020-05-01 盐野义制药株式会社 具有mgat-2抑制活性的稠合环衍生物
CN113557021A (zh) * 2019-01-11 2021-10-26 盐野义制药株式会社 具有mgat2抑制活性的二氢吡唑并吡嗪酮衍生物
JP2022016394A (ja) * 2020-07-10 2022-01-21 塩野義製薬株式会社 Ｍｇａｔ２阻害活性を有するジヒドロピラゾロピラジノン誘導体を含有する医薬組成物
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