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WO2018190643A1 - Dérivés d'isoxazole en tant qu'agonistes du récepteur nucléaire et leur utilisation - Google Patents

Dérivés d'isoxazole en tant qu'agonistes du récepteur nucléaire et leur utilisation Download PDF

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Publication number
WO2018190643A1
WO2018190643A1 PCT/KR2018/004277 KR2018004277W WO2018190643A1 WO 2018190643 A1 WO2018190643 A1 WO 2018190643A1 KR 2018004277 W KR2018004277 W KR 2018004277W WO 2018190643 A1 WO2018190643 A1 WO 2018190643A1
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Prior art keywords
cyclopropyl
phenyl
chloro
ethynyl
methoxy
Prior art date
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Ceased
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PCT/KR2018/004277
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English (en)
Inventor
Jae-Hoon Kang
Hong-Sub Lee
Yoon-Suk Lee
Jin-Ah Jeong
Sung-Wook Kwon
Jeong-Guen KIM
Kyung-Sun Kim
Dong-Keun Song
Sun-Young Park
Kyeo-Jin KIM
Ji-Hye Choi
Hey-Min HWANG
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IL Dong Pharmaceutical Co Ltd
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IL Dong Pharmaceutical Co Ltd
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Priority to JP2020506694A priority Critical patent/JP6886074B2/ja
Priority to LTEPPCT/KR2018/004277T priority patent/LT3612520T/lt
Priority to US16/604,180 priority patent/US10988449B2/en
Priority to NZ758117A priority patent/NZ758117A/en
Priority to ES18785171T priority patent/ES2904294T3/es
Priority to MYPI2019006047A priority patent/MY198265A/en
Priority to RS20211546A priority patent/RS62711B1/sr
Priority to SG11201908235R priority patent/SG11201908235RA/en
Application filed by IL Dong Pharmaceutical Co Ltd filed Critical IL Dong Pharmaceutical Co Ltd
Priority to CN201880024769.3A priority patent/CN110678450B/zh
Priority to PE2019002025A priority patent/PE20191792A1/es
Priority to SI201830504T priority patent/SI3612520T1/sl
Priority to RU2019132135A priority patent/RU2741306C1/ru
Priority to SM20220175T priority patent/SMT202200175T1/it
Priority to HRP20220026TT priority patent/HRP20220026T1/hr
Priority to PL18785171T priority patent/PL3612520T3/pl
Priority to BR112019021320-1A priority patent/BR112019021320B1/pt
Priority to IL269896A priority patent/IL269896B/en
Priority to CA3059869A priority patent/CA3059869C/fr
Priority to DK18785171.2T priority patent/DK3612520T3/da
Priority to MX2019012167A priority patent/MX394743B/es
Priority to EP18785171.2A priority patent/EP3612520B1/fr
Priority to AU2018252880A priority patent/AU2018252880B2/en
Priority claimed from KR1020180042545A external-priority patent/KR102168543B1/ko
Publication of WO2018190643A1 publication Critical patent/WO2018190643A1/fr
Priority to ZA2019/06541A priority patent/ZA201906541B/en
Priority to PH12019502326A priority patent/PH12019502326A1/en
Anticipated expiration legal-status Critical
Priority to US17/191,806 priority patent/US11912674B2/en
Priority to CY20221100082T priority patent/CY1124936T1/el
Priority to US18/420,478 priority patent/US20240262799A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to compounds useful as agonists for Farnesoid X receptor(FXR, NR1H4), pharmaceutical formulation comprising such compounds and its study for medicinal uses.
  • Farnesoid X receptor (FXR, NR1H4)is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. FXR is highly expressed in the liver, intestine, kidney, adrenal glands, white adipose tissue and in induced during adipocyte differentiation in vitro . (Cariu B. et al., J. Biol. Chem., 2006, 16, 11039-11049).
  • FXR regulates various physiological processed such as modulates regulrated of bile acid(BA) regulation, lipids/glucose metabolism, inflammation/fibrosis, but recently it has also been linked to the pathology of FXR receptors.
  • This nuclear receptor is the intracellular bile acid ⁇ “sensor” and its major physiological role is to protect liver cells from the deleterious effect of bile acids(BA) overload.
  • Intestine is the tissue expressing the first FXR target gene identified. Indeed IBAB-P is expressed in enterocytes and binds bile acids, thus limiting the free concentration of BA intracellularly and consequently their toxicity.(Makishima M, et al., Science, 1999, 284(5418), 1362-1365).
  • FXR is highly expressed in the liver and regulates key genes involved in BA synthesis, metabolism and transport including CYP7A1, UGT2B4, BSEP, MDR3, MRP2, ASBT, NTCP, OST ⁇ and OST ⁇ in humans.
  • FXR activation is down regulation of CYP7A1 and thus bile acid synthesis; this is accomplished through induction of SHP(Small Heterodimer Partner) which then represses CYP7A1 transcription(Claude T, et al., Arterioscler. Thromb. Vasc. Biol., 2005, 25, 2020-2031). Altered expression or malfunction of these genes has been described in patients with cholestatic liver disease.
  • FXR agonist 6-ethyl-chenodeoxycholic acid (6EtCDCA) was found to fully reverse the impairment of bile flow and to protect the hepatocytes against liver cell injury caused by the cytotoxic lithocholic acid.(Pelliciari R, et al., J. Med. Chem., 2002, 45(17), 3569-3572).
  • FXR also induces expression of SHP which represses transcription of the apical sodium dependent bile acid transporter(ASBT, SLC10A2) gene which encodes the hight affinity apical sodium dependent bile acid transporter that mouse bile acids from the intestinal lumen into the enterocyte as part of the enterohepatic recycling of bile acids.
  • ASBT apical sodium dependent bile acid transporter
  • SLC10A2 apical sodium dependent bile acid transporter
  • IBABP Ileal bile acid binding protein
  • FXR Fibroblast Growth Factor 15(rodents) or 19(monkeys, humans).
  • FXR activation has also been described to downregulate proinflammatory enzymes iNOS and COX-2, as well as migration of vascular smooth muscle cell migration.(Li YTY, et al., Arterioscler Thromb Vasc Biol., 2007, 27(12), 2606-2611). FXR is also expressed in hepatic stellate cells(HSC) which play a role in deposition of extracellular matrix during the fibrotic process. Treatment of cultured HSCs with the FXR agonist 6-ethyl-chenodeoxycholic acid(6EtCDCA) results in decreased expression of fibrotic markers such as ⁇ -smooth muscle actin and ⁇ 1(I)collagen.
  • HSC hepatic stellate cells
  • 6EtCDCA has also been reported to precent development and promote resolution of hepatic fibrosis in multiple rodent models of this disease.(Fiorucci S, et al., Gastroenterology, 2004, 127(5), 1497-1512; Fiorucci S, et al., J. Pharmacol. Exp. Ther., 2005, 314(2), 584-595).
  • bile acid(BA) are secreted with nile into the lumen of the small intestine to aid in the digestion and absorption of fat and fat-soluble vitamins,
  • the ratio of different BA determines the hydrophilicity of the bile acid pool and its ability to solubilize cholesterol.
  • FXR activation increases the hydrophilicity of the pool, decreasing the intestinal solubilization of cholesterol, effectively blocking its absorption.
  • FXR activation affects Triglyceride(TG) metabolism via several pathways such as Sterol regulatory element-binding transcription factor 1 (SREBF1), apoC-III, apoC-II, syndecan-1 and the VLDL receptor.
  • SREBF1 Sterol regulatory element-binding transcription factor 1
  • apoC-III apoC-III
  • apoC-II syndecan-1
  • VLDL receptor VLDL receptor
  • FXR agonist GW4064 or cholic acid treatment reduced plasma glucose levels and improved insulin sensitivity in three diabetic models(db/db, ob/ob and KK-A(y)mice)(Cariu B,et al., J. Biol. Chem., 2006, 281(16), 11039-11049 Zhang Y, et al., Proc. Natl. Acad. Sci., 2006, 103(4), 1006-1011; Ma K, et al., J. Clin. Invest., 2006, 116, 1102-1109). This demonstrates that FXR is involved in glucose metabolism.
  • FXR activity has been implicated in variety of diseases, including, but not limited to disorder of bile acid homeostasis, inflammation/fibrosis and hight levels of plasma triglyceride(TG)/ cholesterol.
  • FXR agonists INT-747(OCA) and EDP-305 are modified bile acid(BA),developed for the treatment of diseases caused by disorder of bile acid homeostasis such as Nonalcoholic fatty liver disease(NASH), Alcoholic disorders, Primary biliary cirrhosis(PBC), Primary sclerosing cholangitis(PSC) and caused clinical side effects for the accumulation of substances in the body.
  • diseases caused by disorder of bile acid homeostasis such as Nonalcoholic fatty liver disease(NASH), Alcoholic disorders, Primary biliary cirrhosis(PBC), Primary sclerosing cholangitis(PSC) and caused clinical side effects for the accumulation of substances in the body.
  • NASH Nonalcoholic fatty liver disease
  • PBC Primary biliary cirrhosis
  • PSC Primary sclerosing cholangitis
  • small molecule compounds such as FXR agonist were derived form GW4064, PX-102(GS-9674)/PX-104 and Global Pharmaceutical Company published various patent with various derivatives(WO2000037077, WO2003015771, WO2004048349, WO2009012125, WO2009149795, WO2011020615, WO2013037482 and WO2016097933).
  • FXR agonist is development as target for variety treatment of diseases, including, but not limited to disorder of bile acid homeostasis, inflammation/fibrosis and hight levels of plasma triglyceride(TG)/ cholesterol so that worldwide attention is focused.
  • the present invention is expected that patients with metabolic diseases, including, but not limited to cholestatic Liver Diseases, Organ Fibrosis and Liver Fibrosis, will be able to open a therapeutic field of new mechanism.
  • the present invention is related to compounds of excellent activity as FXR agonist. Particularly, the present invention relates to derivatives and processes for the preparation thereof.
  • the object of the present invention is to provide medical use for useful treatment of diseases, for modulating the activity as FXR receptors and for the treatment, prevention or amelioration of one or more symptoms of disease or disorder related to the activity of the receptors, including, but not limited to hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, cholestasis/fibrosis, cholesterol gallstone disease, gastrointestinal disease or condition, hyperglycemia, diabetes, insulin resistance, metabolic inflexibility, nephropathy, liver diseases, atherosclerosis, cancer, inflammatory disorders, osteoporosis and skin aging.
  • diseases for modulating the activity as FXR receptors and for the treatment, prevention or amelioration of one or more symptoms of disease or disorder related to the activity of the receptors, including, but not limited to hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, cholestasis/fibrosis, cholesterol gallstone disease, gastrointestinal
  • the present invention provides a compound represented by Formula I, racemic, enantiomer, diastereoisomer thereof, or pharmaceutically acceptable salt thereof.
  • Y is carbon or nitrogen
  • R 1 and R 2 are each independently hydrogen, halo or trifluoromethyl
  • n 0, 1 or 2
  • X 1 , X 2 and X 3 are each independently carbon or nitrogen
  • R 3 and R 4 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, , , , CONR a1 R a2 , NR a1 R a2 , CH 2 NR a1 R a2 , CH 2 R c3 , COR a3 , OR a3 , NR a4 COR a3 , NR a4 CO 2 R a3 , NHCONHR a3 , NHSO 2 R a3 or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • n 1 or 2
  • R a1 and R a2 are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • R a3 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, , , or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • R a4 is hydrogen or C 1-6 alkyl
  • R 5 is hydrogen, , , , , or ,
  • R 6 and R 7 are each independently hydrogen, halo, trifluoromethyl or trifluoromethoxy,
  • R c3 is hydrogen, halo, C 1-6 alkyl, C 3-6 cycloalkyl,
  • W 1 , W 2 and W 3 are each independently oxygen, nitrogen, CHR w1 , CR w1 , NR w1 or CO,
  • R w1 is hydrogen, halo, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkylamine, C 1-6 alkyl alcohol, , (CH 2 ) p heteroaryl or (CH 2 ) p aryl, wherein, p is 1, 2 or 3.
  • the present invention provides a compound represented by Formula I, racemic, enantiomer, diastereoisomer thereof, or pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition for the treatment, prevention, or amelioration of metabolic diseases, cholestatic Liver Diseases and Organ Fibrosis comprising the compound represented by Formula I, racemic, enantiomer, diastereoisomer thereof, or pharmaceutically acceptable salt thereof.
  • the present invention provides a use for the treatment, prevention, or amelioration of metabolic diseases, cholestatic Liver Diseases and Organ Fibrosis comprising the compound represented by Formula I, racemic, enantiomer, diastereoisomer thereof, or pharmaceutically acceptable salt thereof.
  • the present invention provides a method for the treatment, prevention, or amelioration of metabolic diseases, cholestatic Liver Diseases and Organ Fibrosis in a subject in need thereof, comprising administering an effective amount of the pharmaceutical composition represented by Formula I, racemic, enantiomer, diastereoisomer thereof, or pharmaceutically acceptable salt thereof to the subject(including human).
  • the compounds of the present invention are highly active as FXR agonist, and according to its pharmaceutical compositions are expected to be useful for therapeutic applications which are improved by FXR agonist, such as metabolic diseases, cholestatic Liver Diseases and Organ Fibrosis.
  • the present invention provides a compound represented by Formula I, racemic, enantiomer, diastereoisomer thereof, or pharmaceutically acceptable salt thereof.:
  • Y is carbon or nitrogen
  • R 1 and R 2 are each independently hydrogen, halo or trifluoromethyl
  • n 0, 1 or 2
  • X 1 , X 2 and X 3 are each independently carbon or nitrogen
  • R 3 and R 4 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, , , , CONR a1 R a2 , NR a1 R a2 , CH 2 NR a1 R a2 , CH 2 R c3 , COR a3 , OR a3 , NR a4 COR a3 , NR a4 CO 2 R a3 , NHCONHR a3 , NHSO 2 R a3 or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • n 1 or 2
  • R a1 and R a2 are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • R a3 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, , , or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • R a4 is hydrogen or C 1-6 alkyl
  • R 5 is hydrogen, , , , , or ,
  • R 6 and R 7 are each independently hydrogen, halo, trifluoromethyl or trifluoromethoxy,
  • R c3 is hydrogen, halo, C 1-6 alkyl, C 3-6 cycloalkyl,
  • W 1 , W 2 and W 3 are each independently oxygen, nitrogen, CHR w1 , CR w1 , NR w1 or CO,
  • R w1 is hydrogen, halo, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkylamine, C 1-6 alkyl alcohol, , (CH 2 ) p heteroaryl or (CH 2 ) p aryl, wherein, p is 1, 2 or 3.
  • the compound of Formula I is preferably selected form i) or iv) disclosed below:
  • R 3 and R 4 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, trifluoromethyl, , , , , NR a1 R a2 , CH 2 NR a1 R a2 , OR a3 , , NR a4 CO 2 R a3 , , or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein, wherein, m is 1 or 2, R a1 and R a2 are each independently hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, trifluoromethyl, , azetidine or piperidine, R a3 is hydrogen, methyl, ethyl, propyl, tert-butyl, cyclopropyl, trifluoromethyl, , , , azet
  • Z is , R c3 is hydrogen or methyl, R w1 is hydrogen, methyl, ethyl, propyl, cyclopropyl, , , , , , or .
  • R 1 and R 2 are each independently hydrogen, chloro or trifluoromethyl
  • R 3 and R 4 are each independently hydrogen, chloro, fluoro, iodo, cyano, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, , , , , NR a1 R a2 , CH 2 NR a1 R a2 , NR a4 CO 2 R a3 , azetidine, piperazine or pyrrolidine
  • R a1 and R a2 are each independently hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, trifluoroethyl, , azetidine, piperidine or oxetane
  • R a3 is hydrogen, methyl, ethyl, tert-butyl, cyclopropyl, triflu
  • Z is , R 1 and R 2 are each independently hydrogen, chloro or fluoro, n is 0 or 1, R 5 is , W 1 , W 2 and W 3 are each independently oxygen, nitrogen, CR w1 or NR w1 , wherein, R w1 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, , , , , or .
  • C 1-6 alkyl is a saturated hydrocarbonyl amine with linear or branched chains of 1-6 carbon atoms.
  • exemplary alkyl include, but are not limited, to methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 1-methylbutyl, 1,1-dimethylpropyl, 1-methylpentyl or 1,1-dimethylbutyl.
  • C 3-6 cycloalkyl is intended as a saturated hydrocarbonyl ring with 3-6 carbon atoms.
  • exemplary cycloalkyl include, but are not limited, to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • C 1-6 alkylamine is a saturated hydrocarbonyl amine with linear or branched chains of 1 ⁇ 6 carbon atoms.
  • exemplary alkylamines include, but are not limited, to methylamine, ethylamine, propylamine, butylamine, 1-methylethylamine, diethylamine or dimethylamine.
  • C 1-6 alkyl alcohol is an R-OH group with R as defined above.
  • exemplary alkyl alcohol with 1-6 carbon atoms include, but are not limited, to methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol or n-butyl alcohol.
  • halo is intended as bromine, fluorine, or chlorine atom.
  • halo C 1-6 alkyl is intended as a C 1-6 alkyl radical having one or more hydrogen atoms replaced by a halogen atom as defined above.
  • exemplary haloalkyl include, but are not limited, to difluoromethyl or trifluoromethyl.
  • aryl is intended as aromatic ring with single ring and substituted a halogen.
  • exemplary aryl include, but are not limited, to phenyl or halo phenyl.
  • heteroaryl is intended as a monocyclic ring with at least one nitrogen, oxygen or sulfur atom.
  • exemplary heteroaryl include, but are not limited pyridinyl, quinolyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl or indazolyl.
  • heterocycle is intended as a saturated or partially unsaturated hydrocarbonyl mono-tricyclic ring with at least one nitrogen atom.
  • exemplary mono heterocycles with 5-6 atoms include, but are not limited, to pyrrolidinyl, piperidinyl, piperazinyl pyrollyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.
  • exemplary bicyclic aromatic ring include, but are not limited, to benzothiazolyl, benzoxazolyl, benzoxazinone, benzoxadiazolyl, 1,3-benzodioxolyl, benzofuryl, benzopyrazinyl, indolyl, indazolyl, benzimidazolyl, benzopyranyl, pyrolopyridanyl, furopyridinyl, or imidazothiazolyl.
  • pharmaceutically acceptable when referring to a component of a pharmaceutical composition means that the component, when administered to an animal, does not have undue adverse effects such as excessive toxicity, irritation, or allergic response commensurate with a reasonable benefit/risk ratio.
  • treatment covers any treatment of a disease in a mammal, particularly a human, and includes inhibiting the disease, i.e., arresting its development; or relieving the disease, i.e. causing regression of the disease and/or its symptoms or conditions and slowing disease progression.
  • terapéuticaally effective amount means an amount of a compound of the present invention that ameliorates, attenuates or eliminates a particular disease or condition or prevents or delays the onset of a particular disease or condition.
  • the compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic-mixture or a racemate.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • phrases "pharmaceutically acceptable salt” as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention.
  • Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate(i.e., 1,1'-methylene-bis-(
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
  • the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid
  • an inorganic acid such as hydro
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine(primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the present invention provides a method of preparing the compound represented by Formula I or a pharmaceutically approved salt thereof.
  • the compound of Formula A8, which is a compound of the present invention, may be prepared by series of steps from the compound of Formula A2 as shown in Scheme 1.
  • R 6 and R 7 of Formula A8, A2 and A7, illustrated in Scheme 1, are defined as below.
  • R 6 and R 7 is each independently hydrogen, halo, trifluoromethyl or trifluoromethoxy.
  • the preparation method of the Formula A8 according to the present invention comprise:
  • a compound of Formula A2 may be converted to Formula A3 by reductive amination under conditions of hydroxyl amine and sodium hydroxide in ethanol and distilled water at 90°C for 24 hours.
  • a compound of Formula A3, prepared as described in step 1 may be converted to Formula A4 by chlorination carried out in the presence of chlorination reagents in one or more of N,N -dimethylformamide, or chloroform at room temperature for 1 hour.
  • Example of preparing the compound of Formula A4 from the compound of Formula A3 by chlorination in the above Step 2 of the preparing method of the present invention is illustrated in the following reaction scheme.
  • the compound of Formula A4 prepared as described in step 2 may be converted to Formula A6 by cyclization with Formula A5 under basic condition at room temperature for 24 hours.
  • Example of preparing the compound of Formula A6 from the compound of Formula A4 and A5 by cyclization in the above Step 3 of the preparing method of the present invention is illustrated in the following reaction scheme.
  • the compound of Formula A6, prepared as described in step 3 may be converted to Formula A7 by reduction carried out in the presence of reducing reagent in THF at room temperature for 7 hours.
  • Example of preparing the compound of Formula A7 from the compound of Formula A6 by reduction in the above Step 4 of the preparing method of the present invention is illustrated in the following reaction scheme.
  • the compound of Formula A7 prepared as described in step 4 may be converted to Formula A8 by bromination carried out in the presence of bromination reagent in dichloromethane at room temperature for 4 hours.
  • Example of preparing the compound of Formula A8 from the compound of Formula A7 by bromination in the above Step 5 of the preparing method of the present invention is illustrated in the following reaction scheme.
  • the compound of Formula I which is a compound of the present invention, may be prepared by series of steps from the compound of Formula B2 as shown in Scheme 2.
  • Y is carbon or nitrogen
  • R 1 and R 2 are each independently hydrogen, halo or trifluoromethyl
  • n 0, 1 or 2
  • X 1 , X 2 and X 3 are each independently carbon or nitrogen
  • R 3 and R 4 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, , , , CONR a1 R a2 , NR a1 R a2 , CH 2 NR a1 R a2 , CH 2 R c3 , COR a3 , OR a3 , NR a4 COR a3 , NR a4 CO 2 R a3 , NHCONHR a3 , NHSO 2 R a3 or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • n 1 or 2
  • R a1 and R a2 are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • R a3 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, , , or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • R a4 is hydrogen or C 1-6 alkyl
  • R 5 is hydrogen, , , , , or ,
  • R 6 and R 7 are each independently hydrogen, halo, trifluoromethyl or trifluoromethoxy,
  • R c3 is hydrogen, halo, C 1-6 alkyl, C 3-6 cycloalkyl,
  • W 1 , W 2 and W 3 are each independently oxygen, nitrogen, CHR w1 , CR w1 , NR w1 or CO,
  • R w1 is hydrogen, halo, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkylamine, C 1-6 alkyl alcohol, , (CH 2 ) p heteroaryl or (CH 2 ) p aryl, wherein, p is 1, 2 or 3.
  • the preparation method of the Formula I according to the present invention comprise:
  • the compound of Formula B3 may be prepared by protection of hydroxyl group of Formula B2 using tert-Butyldimethylsilyl chloride(TBSCl) and imidazole in N,N -dimethylformamide at room temperature for 6-24 hours.
  • TBSCl tert-Butyldimethylsilyl chloride
  • the compound of Formula B3, prepared as described in step 1 may be converted to Formula B4 by Sonogashira reaction using catalytic amount of tetrakis(triphenylphosphine)palladium(0)(Pd(PPh 3 ) 4 ) or bis(triphenylphosphine)palladium(II) dichloride(PdCl 2 (PPh 3 ) 2 ) in one or more of N,N -dimethylformamide or methanol at 70-100°C for 3-24 hour.
  • Example of preparing the compound of Formula B4 from the compound of Formula B3 by Sonogashira reaction in the above Step 2 of the preparing method of the present invention is in the following reaction scheme
  • the compound of Formula B4 may be converted to Formula B5 by deprotection of tert-butyldimethyloxy( ) using either Potassium fluoride in one or more of tetrahydrofuran or methanol or Tetrabutylammonium fluoride solution at 0°C to room temperature for 1-6 hours.
  • Example of preparing the compound of Formula B5 from the compound of Formula B4 by deprotection reaction in the above Step 3 of the preparing method of the present invention is in the following reaction scheme.
  • the compound of Formula B5, prepared as described in step 3 may be converted to Formula B6 by substitution of with A8 under basic conditions in one or more of THF or N,N -dimethylformamide at room temperature for 5-24 hours.
  • Example of preparing the compound of Formula B6 from the compound of Formula B5 with A8 by substitution in the above Step 4 of the preparing method of the present invention is in the following reaction scheme.
  • the compound of Formula B6, prepared as described in step 4 may be converted to Formula I by Sonogashira reaction with B7 using catalytic amount of tetrakis(triphenylphosphine)palladium(0)(Pd(PPh 3 ) 4 ) or bis(triphenylphosphine)palladium(II) dichloride(PdCl 2 (PPH 3 ) 2 ) and Copper(I)iodide under basic condition in one or more of tetrahydrofuran or N,N -dimethylformamide at 70-100°C for 3-24 hour.
  • the compound of Formula I can be prepared from Formula B6 with B7 by Sonogashira reaction with hydrolysis using lithium hydroxide in one or more of tetrahydrofuran, 1,4-dioxane or water at 80°C for 4-48 hours.
  • Example of preparing the compound of Formula I from the compound of Formula B6 with B7 by Sonogashira reaction or hydrolysis after Sonogashira reaction from in the above Step 5 of the preparing method of the present invention is illustrated below.
  • the compound of Formula I which is a compound of the present invention, may be prepared by series of steps from the compound of Formula B6 as shown in Scheme 3.
  • R 1 , R 2 , R 6 , R 7 , Y and Z of Formula I, B2 and B7, illustrated in Scheme 3, are defined as below.
  • Y is carbon or nitrogen
  • R 1 and R 2 are each independently hydrogen, halo or trifluoromethyl
  • n 0, 1 or 2
  • X 1 , X 2 and X 3 are each independently carbon or nitrogen
  • R 3 and R 4 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, , , , CONR a1 R a2 , NR a1 R a2 , CH 2 NR a1 R a2 , CH 2 R c3 , COR a3 , OR a3 , NR a4 COR a3 , NR a4 CO 2 R a3 , NHCONHR a3 , NHSO 2 R a3 or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • n 1 or 2
  • R a1 and R a2 are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • R a3 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, , , or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • R a4 is hydrogen or C 1-6 alkyl
  • R 5 is hydrogen, , , , , or ,
  • R 6 and R 7 are each independently hydrogen, halo, trifluoromethyl or trifluoromethoxy,
  • R c3 is hydrogen, halo, C 1-6 alkyl, C 3-6 cycloalkyl,
  • W 1 , W 2 and W 3 are each independently oxygen, nitrogen, CHR w1 , CR w1 , NR w1 or CO,
  • R w1 is hydrogen, halo, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkylamine, C 1-6 alkyl alcohol, , (CH 2 ) p heteroaryl or (CH 2 ) p aryl, wherein, p is 1, 2 or 3.
  • the preparation method of the Formula I according to the present invention comprise:
  • the compound of Formula B6, prepared as described in step 4 in scheme 2 may be converted to Formula D2 by Sonogashira reaction with Formula D1 using catalytic amount of tetrakis(triphenylphosphine)palladium(0)(Pd(PPh 3 ) 4 ) or bis(triphenyl phosphine)palladium(II) dichloride(PdCl 2 (PPH 3 ) 2 ) and Copper(I)iodide under basic condition in one or more of tetrahydrofuran or N,N -dimethylformamide at 70-100°C for 3-24 hour
  • Example of preparing the compound of Formula D2 from the compound of Formula B6 with D1 by Sonogashira reaction in the above Step 1 of the preparing method of the present invention is illustrated in the following reaction scheme.
  • the compound of Formula D2 prepared as described in step 1 may be converted to Formula I by hydrolysis using lithium hydroxide in one or more of tetahydrofuran, 1,4-dioxane or water at rt-80°C for 4-48 hours followed by deprotection in the presence of boron tribromide solution or hydrogen chloride solution in dichloromethane or tetahydrofuran(THF) at 0-80°C for 2-24 hours.
  • Example of preparing the compound of Formula I from the compound of Formula D2 by hydrolysis and deprotection reaction in the above Step 2 of the preparing method of the present invention is illustrated in the following reaction scheme.
  • the compound of Formula I which is a compound of the present invention, may be prepared by series of steps from the compound of Formula B6 as shown in Scheme 4.
  • R 1 , R 2 , R 6 , R 7 , R e1 , R e2 , Y and Z of Formula I, B6 and E3, illustrated in Scheme 4, are defined as below:
  • Y is carbon or nitrogen
  • R 1 and R 2 are each independently hydrogen, halo or trifluoromethyl
  • n 0, 1 or 2
  • X 1 , X 2 and X 3 are each independently carbon or nitrogen
  • R 3 and R 4 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, , , , CONR a1 R a2 , NR a1 R a2 , CH 2 NR a1 R a2 , CH 2 R c3 , COR a3 , OR a3 , NR a4 COR a3 , NR a4 CO 2 R a3 , NHCONHR a3 , NHSO 2 R a3 or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • n 1 or 2
  • R a1 and R a2 are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • R a3 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, , , or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • R a4 is hydrogen or C 1-6 alkyl
  • R 5 is hydrogen, , , , , or ,
  • R 6 and R 7 are each independently hydrogen, halo, trifluoromethyl or trifluoromethoxy,
  • R c3 is hydrogen, halo, C 1-6 alkyl, C 3-6 cycloalkyl,
  • W 1 , W 2 and W 3 are each independently oxygen, nitrogen, CHR w1 , CR w1 , NR w1 or CO,
  • R w1 is hydrogen, halo, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkylamine, C 1-6 alkyl alcohol, , (CH 2 ) p heteroaryl or (CH 2 ) p aryl, wherein, p is 1, 2 or 3.
  • the preparation method of the Formula I according to the present invention comprise:
  • the compound of Formula B6, prepared as described in step 4 in scheme 2 may be converted to Formula E2 by Sonogashira reaction with Formula E1 using catalytic amount of tetrakis(triphenylphosphine) palladium(0)(Pd(PPh 3 ) 4 ) or bis(triphenylphosphine)palladium(II) dichloride (PdCl 2 (PPh 3 ) 2 ) and Copper(I) iodide under basic condition in one or more of tetrahydrofuran or N,N -dimethylformamide at 70-100°C for 3-24 hour.
  • Example of preparing the compound of Formula E2 from the compound of Formula B6 with E1 by Sonogashira reaction in the above Step 1 of the preparing method of the present invention is illustrated in the following reaction scheme.
  • the compound of Formula E2 prepared as described in step 1 may be converted to Formula E3 by reduction or reductive amination depending on the type of the substituent R e1 .
  • the desired compound of Formula E3 may be prepared by reduction or reductive amination.
  • the above reduction reaction may be carried out by Tin(II) chloride dehydrate in ethyl acetate or ethanol with the compound of Formula E2(When R e2 is nitro in the above Formula) at room temperature for one day and it is illustrated in the following reaction scheme.
  • the compound of Formula E2 (When R e1 is aldehyde in the above Formula) also may be converted to Formula E3(A substituent maybe introduced in the presence of sodium carbonate and R c4 -I in N,N -dimethylformamide) by reductive amination in the presence of sodiumtriacetoxyborohydride(NaBH(OAc) 3 ) or acetic acid in one or more of dichloromethane or 1,2-dichloroethane at room temperature for overnight and it is illustrated in the following reaction scheme.
  • the compound of Formula E3, prepared as described in step 2 may be converted to Formula I by hydrolysis using lithium hydroxide in one or more of tetrahydrofuran, 1,4-dioxane or water at rt - 80°C for 4-48 hours.
  • Example of preparing the compound of Formula I from the compound of Formula E3 by hydrolysis in the above Step 3 of the preparing method of the present invention is illustrated in the following reaction scheme.
  • the compound of Formula I which is a compound of the present invention, may be prepared by series of steps from the compound of Formula B6 as shown in Scheme 5.
  • R 1 , R 2 , R 3 , R 6 , R 7 , Y and Z of Formula I, B6 and G4, illustrated in Scheme 5, are defined as below:
  • Y is carbon or nitrogen
  • R 1 and R 2 are each independently hydrogen, halo or trifluoromethyl
  • n 0, 1 or 2
  • X 1 , X 2 and X 3 are each independently carbon or nitrogen
  • R 3 and R 4 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, , , , CONR a1 R a2 , NR a1 R a2 , CH 2 NR a1 R a2 , CH 2 R c3 , COR a3 , OR a3 , NR a4 COR a3 , NR a4 CO 2 R a3 , NHCONHR a3 , NHSO 2 R a3 or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • n 1 or 2
  • R a1 and R a2 are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • R a3 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, , , or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • R a4 is hydrogen or C 1-6 alkyl
  • R 5 is hydrogen, , , , , or ,
  • R 6 and R 7 are each independently hydrogen, halo, trifluoromethyl or trifluoromethoxy,
  • R c3 is hydrogen, halo, C 1-6 alkyl, C 3-6 cycloalkyl,
  • W 1 , W 2 and W 3 are each independently oxygen, nitrogen, CHR w1 , CR w1 , NR w1 or CO,
  • R w1 is hydrogen, halo, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkylamine, C 1-6 alkyl alcohol, , (CH 2 ) p heteroaryl or (CH 2 ) p aryl, wherein, p is 1, 2 or 3.
  • the preparation method of the Formula I according to the present invention comprise:
  • the compound of Formula B6, prepared as described in step 4 in scheme 2 may be converted to Formula G2 by Sonogashira reaction with Formula G1 using catalytic amount of tetrakis(triphenylphosphine)palladium(0)(Pd(PPh 3 ) 4 ) or bis(triphenyl phosphine)palladium(II) dichloride(PdCl 2 (PPh 3 ) 2 ) and Copper(I) iodide under basic condition in one or more of tetrahydrofuran or N,N -dimethylformamide at 70-100°C for 3-24 hour.
  • Example of preparing the compound of Formula G2 from the compound of Formula B6 with G1 by Sonogashira reaction in the above Step 1 of the preparing method of the present invention is illustrated in the following reaction scheme.
  • the compound of Formula G2 prepared as described in step 1 may be converted to Formula G3 using Tin(II) chloride dehydrate in ethyl acetate or ethanol at room temperature for one day and it is illustrated in the following reaction scheme.
  • the compound of Formula G3 prepared as described in step 2 may be converted to Formula G4 by substitution or addition.
  • the desired compound of Formula G4 may be prepared by substitution or addition.
  • the compound of Formula G3 may be converted to Formula G4 by the above substitution in the presence of tert-butylnitrile with iodine in toluene at room temperature for 3 hours or by iodo substitution followed by substitution with amine compound using L-proline, cesium carbonate, copper(I) iodide in dimethylsulfoxide.
  • Example of preparing the compound of Formula G4 from the compound of Formula G3 by substitution or iodo substitution followed by amine substitution in the above Step 3 of the preparing method of the present invention is illustrated in the following reaction scheme.
  • the compound of Formula G4 may be prepared by addition reaction which is carried out with the compound of Formula G3 and , or (R c3 in the Formula is same as that defined in the above Formula I) in dichloromethane or N,N -dimethylformamide at room temperature for 3-6 hours and it is illustrated in the following reaction scheme.
  • the compound of Formula G3 may be converted to Formula G4 by another method of the addition reaction which is carried out with (R c3 in the Formula is same as that defined in the above Formula I) in the presence of triphosgene or 1,1'-carbonyldiimiazole in dichloromethane or tetrahydrofuran(THF) at room temperature for 2-6 hours and it is illustrated in the following reaction scheme.
  • the compound of Formula G4 prepared as described in step 3 may be converted to Formula I by hydrolysis using lithium hydroxide in one or more of tetrahydrofuran, 1,4-dioxane or water at rt-80°C for 4-48 hours.
  • Example of preparing the compound of Formula I from Formula G4 by hydrolysis in the above Step 4 of the preparing method of the present invention is illustrated in the following reaction scheme.
  • the compound of Formula I which is a compound of the present invention, may be prepared by series of steps from the compound of Formula B6 as shown in Scheme 6.
  • R 1 , R 2 , R 3 , R 6 , R 7 , R j1 , Y and Z of Formula I, B6 and J3, illustrated in Scheme 6, are defined as below:
  • Y is carbon or nitrogen
  • R 1 and R 2 are each independently hydrogen, halo or trifluoromethyl
  • n 0, 1 or 2
  • X 1 , X 2 and X 3 are each independently carbon or nitrogen
  • R 3 and R 4 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, , , , CONR a1 R a2 , NR a1 R a2 , CH 2 NR a1 R a2 , CH 2 R c3 , COR a3 , OR a3 , NR a4 COR a3 , NR a4 CO 2 R a3 , NHCONHR a3 , NHSO 2 R a3 or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • n 1 or 2
  • R a1 and R a2 are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • R a3 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, , , or 3- or 8- membered heterocycles containing one or two oxygen or nitrogen atom(s) therein,
  • R a4 is hydrogen or C 1-6 alkyl
  • R 5 is hydrogen, , , , , or ,
  • R 6 and R 7 are each independently hydrogen, halo, trifluoromethyl or trifluoromethoxy,
  • R c3 is hydrogen, halo, C 1-6 alkyl, C 3-6 cycloalkyl,
  • W 1 , W 2 and W 3 are each independently oxygen, nitrogen, CHR w1 , CR w1 , NR w1 or CO,
  • R w1 is hydrogen, halo, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkylamine, C 1-6 alkyl alcohol, , (CH 2 ) p heteroaryl or (CH 2 ) p aryl, wherein, p is 1, 2 or 3.
  • the preparation method of the Formula I according to the present invention comprise:
  • the compound of Formula B6, prepared as described in step 4 in scheme 2 may be converted to Formula J2 by Sonogashira reaction with Formula J1 using catalytic amount of tetrakis(triphenylphosphine) palladium(0)(Pd(PPh 3 ) 4 ) or bis(triphenyl phosphine)palladium(II)dichloride (PdCl 2 (PPh 3 ) 2 ) and Copper(I)iodide under basic condition in one or more of tetrahydrofuran or N,N -dimethylformamide at 70-100°C for 3-24 hour.
  • Example of preparing the compound of Formula J2 from the compound of Formula B6 with J1 by Sonogashira reaction in the above Step 1 of the preparing method of the present invention is illustrated in the following reaction scheme.
  • the compound of Formula J2 prepared as described in step 1 may be converted to Formula J3 by reduction reaction with Tin(II) chloride dehydrate in ethyl acetate or ethanol at room temperature for one day and it is illustrated in the following reaction scheme.
  • the compound of Formula J3, prepared as described in step 2 may be converted to Formula I by hydrolysis or addition reaction.
  • the desired compound of Formula I may be prepared by hydrolysis or addition reaction.
  • the compound of Formula J3 may be converted to Formula I by above hydrolysis reaction under the condition of lithium hydroxide in one or more of tetrahydrofuran, 1,4-dioxane or water at rt-80°C for 4-48 hours and it is illustrated in the following reaction scheme.
  • the compound of Formula I may be prepared by addition reaction with Formula J3 under basic condition in N,N -dimethylformamide or tetrahydrofuran at room temperature or heating condition for 3 or 24 hours in the present invention and it is illustrated in the following reaction scheme.
  • the present invention provides a pharmaceutical compostion for the treatment, prevention, or amelioration of the metabolic diseases, cholestatic Liver Diseases and Organ Fibrosis comprising the compound of Formula I, racemic, enantiomer, diastereoisomer thereof, or pharmaceutically acceptable salt thereof.
  • the metabolic diseases, cholestatic Liver Diseases and Organ Fibrosis may be caused by FXR receptor activity.
  • Exemplary diseases include hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, cholestasis/fibrosis, cholesterol gallstone disease, gastrointestinal disease or condition, hyperglycemia, diabetes, insulin resistance, metabolic inflexibility, nephropathy, liver diseases, atherosclerosis, cancer, inflammatory disorders, osteoporosis and skin aging.
  • the present invention provides a method of the treatment, prevention, or amelioration of metabolic diseases, cholestatic Liver Diseases and Organ Fibrosis in a subject in need thereof, comprising administering an effective amount of the pharmaceutical composition to the subject.
  • the dosage of pharmaceutical composition of the present invention may vary depending on the patient's weight, age, gender, physical condition, diet, the time and mode of administration, excretion rates, and the severity of illness. Mammals(including human) are desirable for the individual without limit.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition(Mack Publishing Company, 1995).
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid plugs, solid microparticulates, semi-solid and liquid(including multiple phases or dispersed systems) such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, emulsions or powders; lozenges(including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.
  • Liquid(including multiple phases and dispersed systems) formulations include emulsions, suspensions, solutions, syrups and elixirs.
  • Such formulations may be presented as fillers in soft or hard capsules(made, for example, from gelatin or hydroxypropyl methyl cellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents.
  • a carrier for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose, or a suitable oil
  • emulsifying agents and/or suspending agents may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001)
  • the immediate release portion may comprise a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, powdered cellulose, loweralkyl-substituted hydroxypropyl cellulose, polacrilin potassium, starch, pregelatinizedstarch, sodium alginate, and mixtures thereof.
  • the disintegrant will comprise from 1 wt% to 80 wt%, preferably from 5 wt% to 60 wt% of the layer.
  • matrix materials, fillers, or diluents include lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers, polyethylene oxide, hydroxypropyl methyl cellulose and mixtures thereof.
  • the compounds may also be blended with conventional excipients such as binders, including gelatin, pregelatinized starch, and the like; lubricants, such as hydrogenated vegetable oil, stearic acid, and the like; diluents, such as lactose, mannose, and sucrose; disintegrants, such as carboxymethyl cellulose and sodium starch glycolate; suspending agents, such as povidone, polyvinyl alcohol, and the like; absorbants, such as silicon dioxide; preservatives, such as methylparaben, propylparaben, and sodium benzoate; surfactants; such as sodium lauryl sulfate, polysorbate 80, and the like; flavorants; and sweeteners.
  • binders including gelatin, pregelatinized starch, and the like
  • lubricants such as hydrogenated vegetable oil, stearic acid, and the like
  • diluents such as lactose, mannose, and sucrose
  • disintegrants such as carboxymethyl
  • the surfactants would comprise of 0.2 wt% to 5 wt% and the absorbants would comprise from 0.2 wt% to 1 wt%.
  • Another excipients include one or more of: anti-oxidants, colorant, flavouring agents, preservatives and taste-masking agents.
  • Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration includes needle(including micro needle) injectors, needle-free injectors and infusion techniques.
  • needle free injection is Powderject TM .
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents(preferably, to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non aqueous solution or as a powdered, dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents(preferably, to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • a proper dosage form such as combination with solubility enhancer can increase solubility of compound of formula I used in non-oral solution.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified/controlled release.
  • Controlled/modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and pro-grammed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions.
  • Li-posomes may also be used.
  • the precise daily dose administered depends on various factors such as the age, sex, weight and condition of the patient being treated.
  • the amount of dose can be selected within the bounds of goal achieving treatment effect without harmful or serious adverse effect.
  • the dosage of the compound of invention may be administered in an effective amount raging from 0.05 to 1000mg daily on patients.
  • the following dosage levels and other dosage levels herein are for the average human subject having a weight range of about 65 to 70kg. The skilled person will readily be able to determine the dosage levels required for a subject whose weight falls outside this range, such as children and the elderly.
  • Step 1 Preparation of 2,6- dichlorobenzaldehyde oxime
  • N -chlorosuccinimide(NCS, 18.4g, 140mmol) was added to a solution of the intermediate compound(Step 1)(25.9g, 140mmol) in chloroform(1000ml) and stirred for 4 hours at room temperature.
  • the reaction mixture was evaporated in vacuum, diluted with dicholrometane and washed with water.
  • the combined organic layers were dried over MgSO 4 , filtered, evaporated in vacuum and purified using silica chromatography to afford the intermediate compound 2,6-dichloro-N-hydroxybenzimidoyl chloride(29g) without any further purification.
  • Step 3 Preparation of ethyl 5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazole -4- carboxylate
  • the intermediate compound(Step 2)(29g, 129mmol) was added to ethyl 3-cyclopropyl-3-oxopropanate(25ml, 194mmol) in triethylamine(150ml)and stirred for 24 hours at room temperature.
  • the reaction mixture was diluted with ethyl acetate and washed with water.
  • the combined organic layers were dried over MgSO 4 , filtered, evaporated in vacuum and purified using silica chromatography to afford the intermediate compound ethyl 5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carboxylate (22.37g, 56%).
  • Step 4 (5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4- yl )methanol
  • Step 5 Preparation of 4-( bromomethyl )-5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazole
  • Triphenylphosphine(TPP, 16.9g, 64.53mmol) and tetrabromomethane(21.4g, 64.53mmol) was slowlly added to the intermediate compound(Step 4)(12.2g, 43.02mmol) in dichloromethane(158ml) at 0 o C and stirred for 4 hours at room temperature.
  • the reaction mixture was evaporated in vacuum and purified using silica chromatography to afford the title compound(13.44g, 90%).
  • Example 1 4-((4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4- yl ) methoxy)phenyl)ethynyl)benzoic acid; ( I-1)
  • Step 1 Preparation of tert - butyl(4-iodophenoxy)dimethylsilane
  • tert-Butyldimethylsilyl chloride (TBSCl, 2.1g, 13.6mmol) and imidazole (1.2g, 18.2mmol) were added to a solution of 4-Iodophenol(2g, 9.1mmol) in N,N -dimethylformamide (45ml) and stirred for 12 hours at room temperature.
  • the reaction mixture was diluted with ethyl acetate and washed with water.
  • the combined organic layers were dried over MgSO 4 , filtered, evaporated in vacuum and purified using silica chromatography to afford the intermediate compound tert-butyl(4-iodophenoxy)dimethylsilane(2.8g, 93%).
  • Step 2 Preparation of tert -butyl(4-((trimethylsilyl)ethyl)phenoxy)silane
  • Trimethylsilylacetylene(2.4ml, 17mmol), bis(triphenylphosphine)palladium(ii) dichloride (PdCl 2 (PPh 3 ) 2 , 0.6g, 0.85mmol), Copper(I) iodide(0.16g, 0.85mmol), and triethylamine(0.6ml, 4.25mmol) were added to a solution of the intermediate compound(Step 1)(2.8g, 8.5mmol) in N,N -dimethylformamide (50ml) and stirred for 12 hours at 80°C.
  • the reaction mixture was diluted with Ethyl acetate and washed with water.
  • Potassium fluoride (KF, 3.8g, 65mmol) was added to a solution of the intermediate compound(Step 2)( 1.99g, 6.5mmol) in methanol (65ml) at 0°C and stirred for 1 hour.
  • the reaction mixture was diluted with dichloromethane and washed with water.
  • the combined organic layers were dried over MgSO 4 , filtered, and evaporated in vacuum.
  • the resulting 4-((trimethylsilly)ethyl)phenol was used for next step without any further purification.
  • Step 4 Preparation of 5- cyclopropyl -3-(2,6- dichlorophenyl )-4-((4- ethynylphenoxy)methyl)isoxazole
  • Step 5 Preparation of methyl 4-((4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)benzoate
  • Step 6 Preparation of 4-((4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)benzoic acid
  • Step 1 Preparation of methyl 3-((4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)benzoate
  • This compound was made using the procedure described for example 2(Step 5).
  • this intermediate compound(Step 4 of Example 1)(100mg, 0.26mmol) was reacted with 3-bromobenzoate (56mg, 0.26mmol), bis(triphenylphosphine) palladium(II) dichloride (PdCl 2 (PPh 3 ) 2 , 21mg, 0.03mmol), Copper(I) iodide(5.7mg, 0.03mmol), and 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 0.2ml, 1.3mmol) to afford the intermediate compound methyl 3-((4-((5-cyclopropyl-3-(2,6- dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)benzoate(40mg, 30%).
  • Step 2 Preparation of 3-((4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol - 4-yl)methoxy)phenyl)ethynyl)benzoic acid
  • Step 1 Preparation of tert -butyl(4- iodo -3-( trifluoromethyl ) phenoxy ) dimethylsilane
  • Step 2 Preparation of tert - butyldimethyl(3- ( trifluoromethyl )-4-(( trimethylsilyl ) ethynyl)phenoxy)silane
  • This compound was made using the procedure described for example 1(Step 2).
  • this intermediate compound(Step 1)(52mg, 0.13mmol) was reacted with Trimethylsilylacetylene(0.036ml, 0.26mmol), bis(triphenylphosphine)palladium(ii) dichloride (PdCl 2 (PPh 3 ) 2 , 9.1mg, 0.013mmol), Copper(I) iodide(2.4mg, 0.013mmol) and triethylamine(0.095ml, 0.65mmol) to afford the intermediate compound tert-butyldimethyl(3-(trifluoromethyl)-4-((trimethylsilyl)ethynyl) phenoxy)silane(41.1mg, 88%).
  • Step 3 Preparation of 3-( trifluoromethyl )-4-(( trimethylsilyl ) ethynyl )phenol
  • This compound was made using the procedure described for example 1(Step 3).
  • this intermediate compound(Step 2)(41.1mg, 0.16mmol) was reacted with Potassium fluoride (KF, 93mg, 1.6mmol) to afford the intermediate compound 3-(trifluoromethyl)-4-((trimethylsilyl)ethynyl)phenol.
  • KF Potassium fluoride
  • Step 4 Preparation of 5- cyclopropyl -3-(2,6- dichlorophenyl )-4-((4- ethynyl -3 -(trifluoromethyl)phenoxy)methyl)isoxazole
  • This compound was made using the procedure described for example 1(Step 4).
  • this intermediate compound(Step 3)(0.16mmol) was reacted with 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxlazole(Intermediate 1)(50mg, 0.144mmol), and potassium carbonate (26.6mg, 0.192mmol) to afford the intermediate compound 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((4- ethynyl-3-(trifluoromethyl)phenoxy)methyl)isoxazole(36mg, 50%).
  • Step 5 Preparation of methyl 3-((4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)-2-(trifluoromethyl)phenyl)ethynyl)benzoate
  • This compound was made using the procedure described for example 1(Step 5).
  • this intermediate compound(Step 4)(36mg, 0.080mmol) was reacted with methyl 3-iodobenzoate(21mg, 0.080mmol), bis(triphenylphosphine)palladium(II) dichloride (PdCl 2 (PPh 3 ) 2 , 5.6mg, 0.008mmol), Copper(I) iodide(1.5mg, 0.008mmol) and triethylamine(0.013ml, 0.096mmol)to afford the intermediate compound methyl 3-((4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methoxy)-2-(trifluoromethyl)phenyl)ethynyl)benzoate(3mg, 75%).
  • Step 6 Preparation of 3-((4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol - 4- yl ) methoxy )-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
  • Example 4 4-((4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4- yl ) methoxy )-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid; (I-4)
  • Step 1 Preparation of methyl 4-((4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4- yl ) methoxy )-2-(trifluoromethyl)phenyl)ethynyl)benzoate
  • Step 2 Preparation of 4-((4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4- yl ) methoxy )-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
  • Example 5 4-((3- chloro -4- ethynylphenoxy )methyl)-5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazole ; (I-5)
  • Step 1 Preparation of tert-butyl(3-chloro-4-iodophenoxy)dimethylsilane
  • Step 2 Preparation of tert-butyl(3-chloro-4-((trimethylsilyl)ethynyl)phenoxy) dimethylsilane
  • Step 4 Preparation of 4-((3- chloro -4- ethyntlphenoxy ) metehyl )-5- cyclopropyl -3-(2,6- dichlorophenyl)isoxazole
  • Step 1 Preparation of 4-((3- chloro -4-( phenylethynyl ) phenoxy )methyl)-5- cyclopropyl -3-(2,6-dichlorophenyl)isoxazole
  • Step 1 Preparation of methyl 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)benzoate
  • Step 1 Preparation of methyl 3-((2- chloro -4-(( cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-5-nitrobenzoate
  • Step 2 Preparation of methyl 3-amino-5-((2- chloro -4-(( cyclopropyl -3-(2,6- dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)benzoate
  • the intermediate compound(step 1) was dissolved in ethyl acetate(70ml) and ethanol(35ml) and tin(II) chloride dihydrate(15.5g, 68.7mmol) were added. The reaction was stirred at room temperature for 1 day. The reaction mixture was extracted with ethyl acetate and washed with water.
  • Step 3 Preparation of methyl 3-((2- chloro -4-(( cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-5-((ethoxycarbonyl)amino)benzoate
  • the intermediate compound(step 2) was dissolved in N,N -dimethylform amide(8.8ml) and ethylchloroformate(250ul, 2.64mmol), triethylamine(369ul, 2.64mmol) and 1,8-Diazabicyclo[5.4.0]undec-7-ene(DBU, 13 ul, 0.0881mmol) were added.
  • the reaction was stirred at room temperature for 4 hours.
  • the reaction mixture was extracted with ethyl acetate and washed with water.
  • the combined organic phase was dried over MgSO 4 , filtered, concentrated and purified by column chromatography on silica to give the title compound(254mg, 65%).
  • Step 1 Preparation of methyl 3-( tert - butoxycarbonyl )amino)-5-((2- chloro -4- (( cyclopropyl -3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)benzoate
  • Step 1 Preparation of methyl 3-( tert - butoxycarbonyl )amino)-5-((2- chloro -4- (( cyclopropyl -3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-5-((ethoxycarbonyl)(methyl)amino)benzoate
  • Step 1 Preparation of 4-((3- chloro -4-((3- nitrophenyl ) ethynyl ) phenoxy ) methyl)-5- cyclopropyl -3-(2,6-dichlorophenyl)isoxazole
  • Step 2 Preparation of 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)aniline
  • This compound was made using the procedure described for example 8(Step 2).
  • this intermediate compound(Step 1) (100mg, 0.19mmol) was reacted with tin(II) chloride dihydrate(208.9mg, 0.93mmol) to afford the intermediate compound 3-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4- yl)methoxy)phenyl)ethynyl)aniline(60mg, 62%).
  • Step 3 Preparation of ethyl(3-((2-chloro-4-( (5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)phenyl)carbamate
  • Triethylamine(12.3ul, 0.08mmol) and ethylchloroformate(8.3ul, 0.08mmol) was added to a suspension of the intermediate compound(Step 2)(30mg, 0.06mmol) in dichloromethane and stirred for 7 hours at room temperature. Water was added to the reaction mixture and the product was extracted into dichloromethane. The combined organic layers were dried over MgSO 4 , filtered, evaporated in vacuum and purified using silica chromatography to give the title compound(25mg, 72%).
  • Step 1 Preparation of 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)benzenesulfonamide
  • Step 1 Preparation of N -(3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)phenyl)methanesulfonamide
  • Methanesulfonyl chloride(2drops) was added to a solution of 3-((2-chloro-4- ((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)aniline(Step 2 of example 11)(35mg, 0.0686mmol) in tetrahydrofuran(1ml) and triethylamine(0.05ml, 0.343mmol) was added to the reaction mixture and stirred for 8 hours. The reaction mixture was concentrated in vacuum, added 1N HCl(aq) and extracted into ethyl acetate. The combined organic layers were dried over MgSO 4 , filtered, evaporated in vacuum and purified using silica chromatography to afford the title compound(27mg, 67%).
  • Step 1 Preparation of N -(3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichloro phenyl) isoxazol -4-yl)methoxy)phenyl)ethynyl)phenyl)sulfamide
  • Step 1 Preparation of 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)benzoic acid
  • Step 1 Preparation of methyl 4-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)benzoate
  • Step 2 Preparation of 4-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)benzoic acid
  • Example 17 6-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)nicotinic acid; (I-17)
  • Step 1 Preparation of methyl 6-((4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)nicotinate
  • Step 2 Preparation of 6-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)nicotinic acid
  • Step 1 Preparation of methyl 2-((4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)isonicotinate
  • Step 2 Preparation of 2-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)isonicotinic acid
  • Step 1 Preparation of methyl 6-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)picolinate
  • Step 2 Preparation of 6-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)picolinic acid
  • Step 1 Preparation of methyl5 -((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)nicotinate
  • Step 2 Preparation of 5-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)nicotinic acid
  • Step 1 Preparation of methyl 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-5-(dimethylamino)benzoate
  • Step 2 Preparation of 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-5-(dimethylamino)benzoic acid
  • Step 1 Preparation of methyl 4-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-3-(dimethylamino)benzoate
  • Step 2 Preparation of 6-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)picolinic acid
  • Step 1 Preparation of methyl 4-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-2-(dimethylamino)benzoate
  • Step 2 Preparation of 4-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-2-(dimethylamino)benzoic acid
  • Step 1 Preparation of Methyl 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-5-(diethylamino)benzoate
  • Step 2 Preparation of 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-5-(diethylamino)benzoic acid
  • Step 1 Preparation of 3-amino-5-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)benzoic acid
  • Step 1 Preparation of methyl 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-4-(dimethylamino)benzoate
  • Step 2 Preparation of 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-4-(dimethylamino)benzoic acid
  • Step 1 Preparation of methyl 3- chloro -5-((2- chloro -4-((5- cyclopropyl - 3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)benzoate
  • Step 2 Preparation of 3- chloro -5-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)benzoic acid
  • Example 28 4- chloro -3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichloro phenyl) isoxazol -4-yl)methoxy)phenyl)ethynyl)benzoic acid; (I-28)
  • Step 1 Preparation of methyl 4- chloro -3-((2- chloro -4-((5- cyclopropyl - 3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)benzoate
  • Step 2 Preparation of 4- chloro -3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)benzoic acid
  • Step 1 Preparation of methyl 2- chloro -5-((2- chloro -4-((5- cyclopropyl -3- (2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)benzoate
  • Step 2 Preparation of 2- chloro -5-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)benzoic acid
  • Step 1 Preparation of methyl 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-5-fluorobenzoate
  • Step 2 Preparation of 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-5-fluorobenzoic acid
  • Step 1 Preparation of methyl 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-5-(trifluoromethyl)benzoate
  • Step 2 Preparation of 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-5-(trifluoromethyl)benzoic acid
  • Step 1 Preparation of methyl 3-((2- chloro -4-(( cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-5-ethynylbenzoate
  • Step 2 Preparation of 3-((2- chloro -4-(( cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-5-ethynylbenzoic acid
  • Step 1 Preparation of methyl 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-5-cyanobenzoate
  • Step 2 Preparation of 3-((2- chloro -4-((5- cyclopropyl -3-(2,6- dichlorophenyl ) isoxazol -4-yl)methoxy)phenyl)ethynyl)-5-cyanobenzoic acid

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Abstract

La présente invention concerne des dérivés d'isoxazole, y compris des compositions pharmaceutiques, pour la préparation de dérivés d'isoxazole. Plus particulièrement, la présente invention concerne une composition pharmaceutique de dérivés d'isoxazole pour l'activation du récepteur farnésoïde X (FXR, NR1H4).
PCT/KR2018/004277 2017-04-12 2018-04-12 Dérivés d'isoxazole en tant qu'agonistes du récepteur nucléaire et leur utilisation Ceased WO2018190643A1 (fr)

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HRP20220026TT HRP20220026T1 (hr) 2017-04-12 2018-04-12 Derivati izoksazola kao agonisti nuklearnog receptora i njihove uporabe
US16/604,180 US10988449B2 (en) 2017-04-12 2018-04-12 Isoxazole derivatives as nuclear receptor agonists and uses thereof
NZ758117A NZ758117A (en) 2017-04-12 2018-04-12 Isoxazole derivatives as nuclear receptor agonists and uses thereof
ES18785171T ES2904294T3 (es) 2017-04-12 2018-04-12 Derivados de isoxazol como agonistas de receptores nucleares y usos de los mismos
MYPI2019006047A MY198265A (en) 2017-04-12 2018-04-12 Isoxazole Derivatives as Nuclear Receptor Agonists and uses Thereof
RS20211546A RS62711B1 (sr) 2017-04-12 2018-04-12 Derivati izoksazola kao agonisti nuklearnih receptora i njihova upotreba
SG11201908235R SG11201908235RA (en) 2017-04-12 2018-04-12 An isoxazole derivatives as nuclear receptor agonists and used thereof
BR112019021320-1A BR112019021320B1 (pt) 2017-04-12 2018-04-12 Composto e composição farmacêutica
CN201880024769.3A CN110678450B (zh) 2017-04-12 2018-04-12 作为核受体激动剂的异噁唑衍生物及其用途
PE2019002025A PE20191792A1 (es) 2017-04-12 2018-04-12 Derivados de isoxazol como agonistas del receptor nuclear y usos de los mismos
SI201830504T SI3612520T1 (sl) 2017-04-12 2018-04-12 Izoksazolni derivati kot agonisti nuklearnega receptorja in njihove uporabe
RU2019132135A RU2741306C1 (ru) 2017-04-12 2018-04-12 Производные изоксазола в качестве агонистов ядерных рецепторов и их применение
SM20220175T SMT202200175T1 (it) 2017-04-12 2018-04-12 Derivati di isossazolo come agonisti di recettori nucleari e relativi usi
PL18785171T PL3612520T3 (pl) 2017-04-12 2018-04-12 Pochodne izoksazolu jako agoniści receptora jądrowego i ich zastosowania
IL269896A IL269896B (en) 2017-04-12 2018-04-12 Isoxazole derivatives as nuclear receptor agonists and uses thereof
JP2020506694A JP6886074B2 (ja) 2017-04-12 2018-04-12 核受容体の効能剤であるイソオキサゾール誘導体及びその用途
LTEPPCT/KR2018/004277T LT3612520T (lt) 2017-04-12 2018-04-12 Izoksazolo dariniai, kaip branduolio receptoriaus agonistai, ir jų panaudojimas
CA3059869A CA3059869C (fr) 2017-04-12 2018-04-12 Derives d'isoxazole comme agonistes des recepteurs nucleaires et leurs utilisations
DK18785171.2T DK3612520T3 (da) 2017-04-12 2018-04-12 Isoxazolderivater som kernereceptoragonister og anvendelser deraf
MX2019012167A MX394743B (es) 2017-04-12 2018-04-12 Derivados de isoxazol como agonistas del receptor nuclear y usos de los mismos
EP18785171.2A EP3612520B1 (fr) 2017-04-12 2018-04-12 Dérivés d'isoxazole en tant qu'agonistes du récepteur nucléaire et leur utilisation
AU2018252880A AU2018252880B2 (en) 2017-04-12 2018-04-12 An isoxazole derivatives as nuclear receptor agonists and used thereof
ZA2019/06541A ZA201906541B (en) 2017-04-12 2019-10-04 Isoxazole derivatives as nuclear receptor agonists and uses thereof
PH12019502326A PH12019502326A1 (en) 2017-04-12 2019-10-11 An isoxazole derivatives as nuclear receptor agonists and used thereof
US17/191,806 US11912674B2 (en) 2017-04-12 2021-03-04 Isoxazole derivatives as nuclear receptor agonists and uses thereof
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US10689391B2 (en) 2017-12-12 2020-06-23 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
US10829486B2 (en) 2018-02-14 2020-11-10 Enanta Pharmacueticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
WO2021009332A1 (fr) 2019-07-18 2021-01-21 Enyo Pharma Procédé pour diminuer les effets secondaires de l'interféron
WO2021014349A1 (fr) 2019-07-23 2021-01-28 Novartis Ag Traitement comprenant des agonistes de fxr
WO2021014350A1 (fr) 2019-07-23 2021-01-28 Novartis Ag Traitement combiné de maladies hépatiques à l'aide d'agonistes de fxr
WO2021044287A1 (fr) 2019-09-03 2021-03-11 Novartis Ag Traitement de maladie ou de trouble hépatique comprenant des antagonistes de récepteur actrii
WO2021053618A1 (fr) 2019-09-19 2021-03-25 Novartis Ag Traitement comprenant des agonistes de fxr
WO2021064575A1 (fr) 2019-09-30 2021-04-08 Novartis Ag Traitement comprenant l'utilisation d'agonistes de fxr
WO2021109712A1 (fr) 2019-12-03 2021-06-10 Gannex Pharma Co., Ltd. Composés pour moduler l'activité de fxr et leurs utilisations
WO2021127466A1 (fr) 2019-12-20 2021-06-24 Novartis Ag Polythérapie de maladies hépatiques à l'aide d'inhibiteurs d'intégrine
WO2021144330A1 (fr) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'agonistes de fxr pour traiter une infection par le virus de l'hépatite d
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WO2022101853A1 (fr) 2020-11-16 2022-05-19 Novartis Ag Procédé de détermination de la fibrose hépatique
WO2022152770A1 (fr) 2021-01-14 2022-07-21 Enyo Pharma Effet synergique d'un agoniste de fxr et d'ifn pour le traitement d'une infection par le virus de l'hépatite b
WO2022229302A1 (fr) 2021-04-28 2022-11-03 Enyo Pharma Potentialisation forte d'effets d'agonistes de tlr3 à l'aide d'agonistes de fxr en tant que traitement combiné
US11524005B2 (en) 2019-02-19 2022-12-13 Gilead Sciences, Inc. Solid forms of FXR agonists
US11555032B2 (en) 2019-05-13 2023-01-17 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
KR20230072437A (ko) 2021-11-17 2023-05-24 일동제약(주) 아이속사졸 유도체의 제조 방법 및 그의 중간체
KR20230072438A (ko) 2021-11-17 2023-05-24 일동제약(주) 아이속사졸 유도체의 제조 방법 및 그의 신규한 중간체
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US11958879B2 (en) 2015-03-31 2024-04-16 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US10421730B2 (en) 2016-06-13 2019-09-24 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10774054B2 (en) 2016-06-13 2020-09-15 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US11739065B2 (en) 2016-06-13 2023-08-29 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10981881B2 (en) 2016-06-13 2021-04-20 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US12358903B2 (en) 2016-06-13 2025-07-15 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10329286B2 (en) 2016-06-13 2019-06-25 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US11247986B2 (en) 2016-06-13 2022-02-15 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10450306B2 (en) 2016-10-04 2019-10-22 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
US11034684B2 (en) 2016-10-04 2021-06-15 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
US10597391B2 (en) 2016-10-26 2020-03-24 Enanta Pharmaceuticals, Inc. Urea-containing isoxazole derivatives as FXR agonists and methods of use thereof
US11833150B2 (en) 2017-03-28 2023-12-05 Gilead Sciences, Inc. Methods of treating liver disease
US10689391B2 (en) 2017-12-12 2020-06-23 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
US10829486B2 (en) 2018-02-14 2020-11-10 Enanta Pharmacueticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
US11225473B2 (en) 2019-01-15 2022-01-18 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US12102625B2 (en) 2019-02-19 2024-10-01 Gilead Sciences, Inc. Solid forms of FXR agonists
US11524005B2 (en) 2019-02-19 2022-12-13 Gilead Sciences, Inc. Solid forms of FXR agonists
US11555032B2 (en) 2019-05-13 2023-01-17 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
WO2021009332A1 (fr) 2019-07-18 2021-01-21 Enyo Pharma Procédé pour diminuer les effets secondaires de l'interféron
WO2021014350A1 (fr) 2019-07-23 2021-01-28 Novartis Ag Traitement combiné de maladies hépatiques à l'aide d'agonistes de fxr
WO2021014349A1 (fr) 2019-07-23 2021-01-28 Novartis Ag Traitement comprenant des agonistes de fxr
WO2021044287A1 (fr) 2019-09-03 2021-03-11 Novartis Ag Traitement de maladie ou de trouble hépatique comprenant des antagonistes de récepteur actrii
WO2021053618A1 (fr) 2019-09-19 2021-03-25 Novartis Ag Traitement comprenant des agonistes de fxr
WO2021064575A1 (fr) 2019-09-30 2021-04-08 Novartis Ag Traitement comprenant l'utilisation d'agonistes de fxr
JP7611916B2 (ja) 2019-12-03 2025-01-10 ガンネックス ファーマ カンパニー リミテッド Ｆｘｒの調節活性のための化合物およびその使用
WO2021109712A1 (fr) 2019-12-03 2021-06-10 Gannex Pharma Co., Ltd. Composés pour moduler l'activité de fxr et leurs utilisations
EP4073070A4 (fr) * 2019-12-03 2023-10-18 Gannex Pharma Co., Ltd. Composés pour moduler l'activité de fxr et leurs utilisations
WO2021127466A1 (fr) 2019-12-20 2021-06-24 Novartis Ag Polythérapie de maladies hépatiques à l'aide d'inhibiteurs d'intégrine
WO2021144330A1 (fr) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'agonistes de fxr pour traiter une infection par le virus de l'hépatite d
WO2022101853A1 (fr) 2020-11-16 2022-05-19 Novartis Ag Procédé de détermination de la fibrose hépatique
WO2022152770A1 (fr) 2021-01-14 2022-07-21 Enyo Pharma Effet synergique d'un agoniste de fxr et d'ifn pour le traitement d'une infection par le virus de l'hépatite b
WO2022229302A1 (fr) 2021-04-28 2022-11-03 Enyo Pharma Potentialisation forte d'effets d'agonistes de tlr3 à l'aide d'agonistes de fxr en tant que traitement combiné
WO2023090858A1 (fr) * 2021-11-17 2023-05-25 일동제약(주) Procédé de préparation d'un dérivé d'isoxazole, et d'un intermédiaire de celui-ci
TWI838964B (zh) * 2021-11-17 2024-04-11 南韓商日東製藥股份有限公司 異噁唑衍生物的製備方法及其中間體
TWI833451B (zh) * 2021-11-17 2024-02-21 南韓商日東製藥股份有限公司 異噁唑衍生物的製備方法及其中間體
WO2023090859A1 (fr) * 2021-11-17 2023-05-25 일동제약(주) Procédé de préparation d'un dérivé d'isoxazole et nouvel intermédiaire associé
KR20230072438A (ko) 2021-11-17 2023-05-24 일동제약(주) 아이속사졸 유도체의 제조 방법 및 그의 신규한 중간체
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