WO2019089664A1 - Multicyclic compounds as farnesoid x receptor modulators - Google Patents

Multicyclic compounds as farnesoid x receptor modulators Download PDF

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Publication number
WO2019089664A1
WO2019089664A1 PCT/US2018/058312 US2018058312W WO2019089664A1 WO 2019089664 A1 WO2019089664 A1 WO 2019089664A1 US 2018058312 W US2018058312 W US 2018058312W WO 2019089664 A1 WO2019089664 A1 WO 2019089664A1
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mmol
cyclopropyl
alkyl
independently
phenyl
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English (en)
French (fr)
Inventor
Joseph E. CARPENTER
Jianxin Feng
Ji Jiang
Soong-Hoon Kim
Ying Wang
Gang Wu
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Priority to KR1020207015277A priority Critical patent/KR102731925B1/ko
Priority to ES18804794T priority patent/ES2944601T3/es
Priority to CN201880069870.0A priority patent/CN111278817B/zh
Priority to JP2020544331A priority patent/JP7264905B2/ja
Priority to EP18804794.8A priority patent/EP3704107B1/en
Priority to US16/759,782 priority patent/US11370785B2/en
Publication of WO2019089664A1 publication Critical patent/WO2019089664A1/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • A61K31/41—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
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D413/08—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 carbon chain containing alicyclic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • R 14a and R 14b are each independently hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,
  • X 1 is C; X 2 is N; and X 3 is O. In one embodiment of Formula X 1 is C: one of X 2 and X 3 is N and the other of
  • L 3 is a covalent bond, Ci-2 alkylene, or -0(Ci- 2 alkylene)-; and R z is selected from -CN, -C(0)R 16 , - 13 , -C(0)NR 14a R 14b , -NR 12 C(0)R 12 , methyltetrazolyl,
  • L 3 is a covalent bond, Ci-2 alkylene, or -0(Ci- 2 alkylene)-; and R z is selected from -CN, -C(0)R 16 , - 13 , -C(0)NR 14a R 14b , -NR 12 C(0)R 12 , methyltetrazolyl, R 12 is each independently hydrogen or C1-3 alkyl; R 13 is hydrogen and C1-4 alkyl; R 14a and R 14b are each independently hydrogen C1-4 alkyl, or Ci-6 alkoxyalkyl; and R 16 is C1-3 alkyl, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, or 4- to 6- membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl, carbocyclyl, and heterocyclyl are independently substituted with 0 to 5 R 8 .
  • hepatocellular carcinoma colorectal cancer, prostate cancer, leukemia, Kaposi's sarcoma, solid tumors.
  • the present invention provides a compound of the present invention for use in therapy for the treatment of a fibrotic disorder, an inflammatory disorder, or a cell-proliferative disorder thereof.
  • embodiments of the present invention may also be used in combination with one or more therapeutic agents such as CCR2/5 inhibitors (for example, cenicriviroc), Galectin-3 inhibitors (for example, TD-139, GR-MD-02), leukotriene receptor antagonists (for example, tipelukast, montelukast), SGLT2 inhibitors (for example, dapagliflozin, remogliflozin), GLP-1 receptor agonists (for example, liraglutide and semaglutide), FAK inhibitors (for example, GSK-2256098), CBl inverse agonists (for example, JD-5037), CB2 agonists (for example, APD-371 and JBT-101), autotaxin inhibitors (for example,
  • CCR2/5 inhibitors for example, cenicriviroc
  • Galectin-3 inhibitors for example, TD-139, GR-MD-02
  • leukotriene receptor antagonists for example, tipelukast
  • a typical injectable preparation is produced by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.
  • the compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving FXR agonists.
  • Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving FXR agonist activity.
  • a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound.
  • compounds according to the present invention could be used to test their effectiveness.
  • lower alkyl as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons containing 1 to 8 carbons
  • alkyl and alk as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons containing 1 to 20 carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4- dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like.
  • a terminal carbon atom of the alkyl group is replaced with a heteroatom (e.g., O, N, or S)
  • the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g., -CH2CH2-OH), an aminoalkyl group (e.g. , -CH2NH2), or an alkyl thiol group (e.g. , -CH2CH2-SH).
  • a heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • a Ci- Ce heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms.
  • carbamate as used herein alone or as part of another group refers to oxygen linked to an amido group.
  • carbamate may be represented by
  • cycloalkyl refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. "C3 to C7 cycloalkyl” or “C3-7 cycloalkyl” is intended to include C3, C 4 , C5, Ce, and Ci cycloalkyl groups.
  • Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1 -methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl".
  • Branched cycloheteroalkyl groups such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, and
  • a bridged ring occurs when one or more, preferably one to three, carbon atoms link two non-adjacent carbon atoms.
  • Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
  • one ring is a benzo ring fused to a second ring; and the second ring is a 5- or 6-membered carbon ring which is saturated or partially unsaturated.
  • the bicyclic carbocyclic group may be attached to its pendant group at any carbon atom which results in a stable structure.
  • the bicyclic carbocyclic group described herein may be substituted on any carbon if the resulting compound is stable. Examples of a bicyclic carbocyclic group are, but not limited to, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.
  • Scheme 3 describes a method of preparing intermediate lc, a subset of intermediate 1.
  • Ester 2 can be hydrolyzed to the corresponding carboxylic acid 8 under conditions such as but not limited to treatment of 2 with NaOH or LiOH in solvents consisting of MeOH, THF, and water at a temperature suitable to enable the hydrolysis.
  • Acid-mediated hydrolysis of particular esters, such as a tert-butyl ester may be required in some cases to obtain intermediate 8.
  • Conversion of intermediate 8 to amine 10 can be accomplished in a process consisting of in situ acyl azide formation between acid 8 and a reagent such as
  • Step 9 4-((7-Azaspiro[3.5]nonan-2-yl)methyl)-5-cyclopropyl-3-(2- (trifluoromethyl)phenyl)isoxazole
  • reaction mixture was cooled to room temperature THF (160 ⁇ ), MeOH (80 ⁇ ), 3 ⁇ 40 (80 ⁇ ), and lithium hydroxide monohydrate (9.2 mg, 0.38 mmol) were added and the resulting mixture was stirred at room temperature overnight. The excess solvents were removed in vacuo, the suspension was cooled to 0 °C and acidified with TFA.
  • Step 1 5-Cyclopropyl-4-((7-(l,2,3,4-tetrahydroisoquinolin-6-yl)-7-azaspiro[3.5]nonan-2- ylidene)methyl)-3-(2-(trifluoromethoxy)phenyl)isoxazole
  • Methyl 6-bromo-4-cyclobutoxyquinoline-2-carboxylate was prepared following the procedure described for the preparation of methyl 6-bromo-4-(cyclopen ⁇ yloxy)quinoline-2- carboxylate with replacement of iodocyclopentane with bromocyclobutane (54% yield).
  • Step 1 fert-Butyl 2-((3-(3-chloro-5-vinylpyridin-4-yl)-5-cyclopropylisoxazol-4- yl)methylene)-7-azaspiro[3.5]nonane-7-carboxylate

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  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Liquid Crystal Substances (AREA)
PCT/US2018/058312 2017-11-01 2018-10-31 Multicyclic compounds as farnesoid x receptor modulators Ceased WO2019089664A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
KR1020207015277A KR102731925B1 (ko) 2017-11-01 2018-10-31 파르네소이드 x 수용체 조정제로서의 멀티시클릭 화합물
ES18804794T ES2944601T3 (es) 2017-11-01 2018-10-31 Compuestos multicíclicos como moduladores del receptor farnesoide X
CN201880069870.0A CN111278817B (zh) 2017-11-01 2018-10-31 作为法尼醇x受体调节剂的多环化合物
JP2020544331A JP7264905B2 (ja) 2017-11-01 2018-10-31 ファルネソイドｘ受容体モジュレーターとしての多環化合物
EP18804794.8A EP3704107B1 (en) 2017-11-01 2018-10-31 Multicyclic compounds as farnesoid x receptor modulators
US16/759,782 US11370785B2 (en) 2017-11-01 2018-10-31 Multicyclic compounds as farnesoid X receptor modulators

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US201762580064P 2017-11-01 2017-11-01
US62/580,064 2017-11-01

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CN112876491A (zh) * 2019-11-29 2021-06-01 广东东阳光药业有限公司 含氮三环化合物的无定形及其用途
WO2021144330A1 (en) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of fxr agonists for treating an infection by hepatitis d virus
US11208418B2 (en) 2018-02-02 2021-12-28 Sunshine Lake Pharma Co., Ltd. Nitrogenous tricyclic compounds and uses thereof in medicine
WO2022152770A1 (en) 2021-01-14 2022-07-21 Enyo Pharma Synergistic effect of a fxr agonist and ifn for the treatment of hbv infection
WO2022229302A1 (en) 2021-04-28 2022-11-03 Enyo Pharma Strong potentiation of tlr3 agonists effects using fxr agonists as a combined treatment
JP2023505116A (ja) * 2019-11-29 2023-02-08 ▲広▼▲東▼▲東▼▲陽▼光▲薬▼▲業▼有限公司 三環式含窒素化合物の結晶形及びその用途
WO2024013736A1 (en) * 2022-07-12 2024-01-18 Adama Makhteshim Ltd. Process for preparing substituted benzamides

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Publication number Priority date Publication date Assignee Title
KR20260032385A (ko) * 2024-08-28 2026-03-09 주식회사유한양행 Glp-1 수용체 효능제 활성을 가진 시에노이미다졸 화합물, 이의 제조 방법, 및 이들의 의약 용도

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WO2012087520A1 (en) * 2010-12-20 2012-06-28 Irm Llc Compositions and methods for modulating farnesoid x receptors
EP3034501A1 (en) * 2014-12-17 2016-06-22 Gilead Sciences, Inc. Hydroxy containing FXR (NR1H4) modulating compounds
WO2017118294A1 (zh) * 2016-01-06 2017-07-13 广州市恒诺康医药科技有限公司 Fxr受体调节剂及其制备方法和用途

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