WO2010036613A1 - Novel cyclic benzimidazole derivatives useful anti-diabetic agents - Google Patents

Novel cyclic benzimidazole derivatives useful anti-diabetic agents Download PDF

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Publication number
WO2010036613A1
WO2010036613A1 PCT/US2009/057686 US2009057686W WO2010036613A1 WO 2010036613 A1 WO2010036613 A1 WO 2010036613A1 US 2009057686 W US2009057686 W US 2009057686W WO 2010036613 A1 WO2010036613 A1 WO 2010036613A1
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WIPO (PCT)
Prior art keywords
alkyl
substituted
unsubstituted
heteroaryl
aryl
Prior art date
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Ceased
Application number
PCT/US2009/057686
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English (en)
French (fr)
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WO2010036613A8 (en
Inventor
Brett C. Bookser
Qun Dang
Tony S. Gibson
Hongjian Jiang
De Michael Chung
Jianming Bao
Jinlong Jiang
Andy Kassick
Ahmet Kekec
Ping LAN
Huagang Lu
Gergely M. Makara
F. Anthony Romero
Iyassu Sebhat
David Wilson
Dariusz Wodka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Organon Pharma UK Ltd
Metabasis Therapeutics Inc
Merck Sharp and Dohme LLC
Original Assignee
Merck Sharp and Dohme Ltd
Metabasis Therapeutics Inc
Merck Sharp and Dohme LLC
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Filing date
Publication date
Application filed by Merck Sharp and Dohme Ltd, Metabasis Therapeutics Inc, Merck Sharp and Dohme LLC filed Critical Merck Sharp and Dohme Ltd
Priority to CN200980147275.5A priority Critical patent/CN102361857B/zh
Priority to EP09792782.6A priority patent/EP3924343A1/en
Priority to AU2009296820A priority patent/AU2009296820B2/en
Priority to CA2737694A priority patent/CA2737694C/en
Priority to JP2011529149A priority patent/JP5764064B2/ja
Priority to MX2011003239A priority patent/MX2011003239A/es
Publication of WO2010036613A1 publication Critical patent/WO2010036613A1/en
Publication of WO2010036613A8 publication Critical patent/WO2010036613A8/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/28—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom 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
    • C07D413/02—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

Definitions

  • Y is selected from: benzodihydrofuran, phenyl, benzoimidazole, benzofuran, pyridine, indole, and tetrazole, wherein Y is unsubstituted or substituted with I, 2, 3 or 4 substituents selected from Rb. In a subclass of this subclass, Y is unsubstituted or substituted with 1, 2 or 3 substituents selected from Rb. In another subclass of this subclass, Y is unsubstituted or substituted with 1 or 2 substituents selected from Rb.
  • Y is heteroaryl, wherein heteroaryl is unsubstituted or substituted with 1 , 2, 3 or 4 substituents selected from Rb.
  • Y is selected from benzoimidazole, benzofuran, pyridine, indole and tetrazole, wherein Y is unsubstituted or substituted with 1 , 2 or 3 substituents selected from Rb.
  • Y is selected from pyridine, indole and tetrazole, wherein Y is unsubstituted or substituted with 1, 2 or 3 substituents selected from Rb.
  • each CH 2 is unsubstituted or substituted with 1 substituent selected from C 1-6 alkyl, -OH and -NH 2 ; each NH is unsubstituted or substituted with 1 or 2 substituents selected from R c ; and each alkyl, cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substituted with 1 or 2 substituents selected from Rc.
  • Z is selected from: - CO 2 CH3, -CO 2 CH 2 CH3, and -CH 2 CO 2 CH 2 CH3, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, -OH and -NH 2 .
  • each CH 2 is unsubstituted or substituted with 1 substituent selected from Cl _ galkyl, -OH and -NH 2 -
  • Z is selected from: -CO 2 CH3, -- CO 2 CH 2 CH3, and -CH 2 CO 2 CH 2 CH3.
  • each Rl and R2 is independently selected from: halogen, -CN, -CF 3 , -C 1-6 alkyl, -(CH 2 ) p aryI, biphenyl, -(CH 2 ) p heteroaryl, -C 2-6 &lkenyl-aryl, -C 2-6 a lkynyl-alkyl, -C 2-6 alkenyl-aryl, -C 2-6 alkenyl-heteroaryl, -C 2-6 alkenyl-C 3-7 cycloalkyl, -C 2-6 alkenyl-C 2-7 cycloheteroalkyl ; and -C 2-6 alkenyl-C 2-7 cycloheteroalkenyl, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF 3 , -OH, - NH 2 , -C 1-6 alkyl, wherein each CH
  • each Rl is selected from: -(CH 2 ) p C 3 - 1 ocycloalkyl, -(CH 2 ) p C 3-7 cycloalkyl-aryl, -(CH 2 ) p C 3-7 cycloalkyl ⁇ heteroaryl, -(CH 2 ) p C 4 _ lOcycloalkenyl, -(CH 2 ) p C 4 .
  • R 3 is selected from: hydrogen, halogen, -C 1-6 alkyl, -CN, -CF 3 , -OH, -OC 1 - 6alkyl, -SOC 1-6 alkyl, and -SO 2 C 1-6 alkyl.
  • R 3 is selected from: hydrogen, and halogen, hi another subclass of this class, R 3 and is selected from: hydrogen, Cl, Br and F.
  • R 3 is selected from: hydrogen, and F.
  • R 3 is hydrogen.
  • R? is F.
  • R 3 is hydrogen or halogen
  • R4 is hydrogen.
  • alkyl 6alkyl)2, -C 1-6 alkyl, -0C 1-6 alkyl, halogen, -CH 2 F, -CHF2, -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3 - ⁇ cycloalkyl, phenyl, CH 2 phenyl and heteroaryl, and wherein alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstltuted or substituted with 1 , 2, 3 or 4 substituents selected from: oxo, -(CH 2 )0-3OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -C 1-6 alkyl, -0C 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2
  • alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl,, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1 , 2, 3 or 4 substituents selected from: oxo, -OH, -CN, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, - CH 2 F, -CHF2, -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, and -C 3 ⁇ cycloalkyl.
  • R i is independently selected from: C 1-6 alkyl, C 4 . 7cycloalkyl, C 4-7 cycloalkenyl, C 3-7 cycloheteroalkyl, C 3-7 cycloheteroalkenyl ; , aryl, and heteroaryl, wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1.
  • Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or ethyl acetate or a mixture thereof.
  • a suitable solvent for example MeOH or ethyl acetate or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine as a resolving agent or on a chiral HPLC column.
  • a prediabetic subject is a subject with impaired fasting glucose (a fasting plasma glucose (FPG) level of greater than or equal to 110 mg/dl and less than 126 mg/dl); or impaired glucose tolerance (a 2 hour plasma glucose level of >140 mg/dl and ⁇ 200 mg/dl); or insulin resistance, resulting in an increased risk of developing diabetes.
  • FPG fasting plasma glucose
  • Atherosclerosis encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine.
  • Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease and peripheral vessel disease are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms "atherosclerosis” and "atherosclerotic disease.”
  • the combination comprised of a therapeutically effective amount of an anti-obesity agent in combination with a therapeutically effective amount of an anti-hypertensive agent may be administered to prevent or reduce the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, or intermittent claudication.
  • dyslipidemia related disorders and “lipid disorder related disorders” should be understood to mean disorders associated with, caused by, or resulting from dyslipidemia or lipid disorders.
  • dylipidemia related disorder and lipid disorder related disorders include, but are not limited to: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high density lipoprotein (HDL) levels, high plasma low density lipoprotein (LDL) levels, atherosclerosis and its sequelae, coronary artery or carotid artery disease, heart attack, and stroke.
  • BMI Body Mass Index
  • “obesity” refers to a condition whereby a subject with at least one obesity-induced or obesity-related co-morbidity, that requires weight reduction or that would be improved by weight reduction, has a BMI greater than or equal to 25 kg/n ⁇ .
  • an “obese subject” refers to a subject with at least one obesity- induced or obesity-related co-morbidity that requires weight reduction or that would be improved by weight reduction, with a BMI greater than or equal to 25 kg/m2.
  • a "subject. at risk of obesity” is a subject with a BMI of greater than 23 kg/m2 to less than 25 kg/m2,
  • comorbidities include: hypertension, hyperiipidemia, dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea, and other obesity-related conditions.
  • Treatment of obesity and obesity-related disorders refers to the administration of the compounds of the present invention to reduce or maintain the body weight of an obese subject.
  • One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds of the present invention.
  • Another outcome of treatment may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy.
  • Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases.
  • Prevention of obesity and obesity-related disorders refers to the administration of the compounds of the present invention to reduce or maintain the body weight of a subject at risk of obesity.
  • One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds of the present invention.
  • Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy.
  • Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity.
  • Another outcome of prevention may be decreasing the occurrence and/or severity of obesity-related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity.
  • the obesity-related disorders herein are associated with, caused by, or result from obesity.
  • obesity-related disorders include overeating and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH- deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia.
  • WO 97/19682 WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/107409, WO 00/185714, WO 00/185730, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/20488, WO 02/22592, WO 02/48152, WO 02/49648, WO 02/051806, WO 02/094789, WO 03/009845, WO 03/014083, WO 03/0228
  • Step B 5- ⁇ [6-chloro-5-(4-pyrrolidin-1-ylphenyl)-1H-benzimidazol-2-yl]o ⁇ yi-2-methylbenzoic acid.
  • TBAF IM in THF
  • the reaction was heated at 8O°C for 16 h.
  • the insect cell pellet from 2 liters of culture was resuspended in 50 ml lysis buffer (20 mM Tris-HCl, 50 mM NaCl, 50 mM NaF, 30 mM Na PPi, 0.25 M sucrose, 10 mM ZnCl 2 , 2 mM DTT, 0.4 mg/ml digitonin) and subjected to two cycles of freeze-thaw lysis in a dry-ice ethanol bath. Insoluble material was removed by centrifugation at
  • the total in vitro AMPK activation assay volume is 50 ⁇ l in a 96- well plate.
  • the reaction mixture contained 100 ⁇ M ATP (0.5 ⁇ C 1 33 P-ATP per reaction), and 50 ⁇ M SAMS (HMRSAMSGLHLVKRR) in a buffer (20 mM HEPES, pH7.0, 5 mM MgCl 2 , 0.01% Brij35). The reaction was initiated with addition of the enzyme.

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  • Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
PCT/US2009/057686 2008-09-26 2009-09-21 Novel cyclic benzimidazole derivatives useful anti-diabetic agents Ceased WO2010036613A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CN200980147275.5A CN102361857B (zh) 2008-09-26 2009-09-21 可用作抗糖尿病剂的环状苯并咪唑衍生物
EP09792782.6A EP3924343A1 (en) 2008-09-26 2009-09-21 Novel cyclic benzimidazole derivatives useful anti-diabetic agents
AU2009296820A AU2009296820B2 (en) 2008-09-26 2009-09-21 Novel cyclic benzimidazole derivatives useful anti-diabetic agents
CA2737694A CA2737694C (en) 2008-09-26 2009-09-21 Novel cyclic benzimidazole derivatives useful anti-diabetic agents
JP2011529149A JP5764064B2 (ja) 2008-09-26 2009-09-21 抗糖尿病薬として有用な新規な環状ベンゾイミダゾール誘導体
MX2011003239A MX2011003239A (es) 2008-09-26 2009-09-21 Nuevos derivados de bencimidazol ciclicos utiles como agentes anti-diabeticos.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US19433708P 2008-09-26 2008-09-26
US61/194,337 2008-09-26

Publications (2)

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WO2010036613A1 true WO2010036613A1 (en) 2010-04-01
WO2010036613A8 WO2010036613A8 (en) 2010-11-18

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US (1) US8394969B2 (https=)
EP (1) EP3924343A1 (https=)
JP (1) JP5764064B2 (https=)
CN (1) CN102361857B (https=)
AR (1) AR073677A1 (https=)
AU (1) AU2009296820B2 (https=)
CA (1) CA2737694C (https=)
MX (1) MX2011003239A (https=)
TW (1) TWI393709B (https=)
WO (1) WO2010036613A1 (https=)

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012033149A1 (ja) * 2010-09-10 2012-03-15 塩野義製薬株式会社 Ａｍｐｋ活性化作用を有するヘテロ環縮合イミダゾール誘導体
WO2012116145A1 (en) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
WO2012162635A1 (en) * 2011-05-26 2012-11-29 Sunovion Pharmaceuticals Inc. Metabotropic glutamate receptors 5 modulators and methods of use thereof
US8329914B2 (en) 2008-10-31 2012-12-11 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
WO2013011932A1 (ja) 2011-07-15 2013-01-24 塩野義製薬株式会社 Ａｍｐｋ活性化作用を有するアザベンズイミダゾール誘導体
US8410284B2 (en) 2008-10-22 2013-04-02 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
EP2538784A4 (en) * 2010-02-25 2013-07-10 Merck Sharp & Dohme NEW CYCLIC BENZIMIDAZOLE DERIVATIVES AS ANTIDIABETICS
US8563746B2 (en) 2008-10-29 2013-10-22 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
WO2014022528A1 (en) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
WO2014031465A1 (en) 2012-08-22 2014-02-27 Merck Sharp & Dohme Corp. Novel azabenzimidazole tetrahydropyran derivatives
US8759535B2 (en) 2010-02-18 2014-06-24 High Point Pharmaceuticals, Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
WO2014133008A1 (ja) 2013-02-27 2014-09-04 塩野義製薬株式会社 Ａｍｐｋ活性化作用を有するインドールおよびアザインドール誘導体
WO2014139388A1 (en) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents
WO2015051725A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
WO2015095256A1 (en) 2013-12-19 2015-06-25 Merck Sharp & Dohme Corp. Antidiabetic substituted heteroaryl compounds
WO2015106164A1 (en) 2014-01-10 2015-07-16 Rgenix, Inc. Lxr agonists and uses thereof
US9290517B2 (en) 2012-08-22 2016-03-22 Merck Sharp & Dohme Corp. Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
EP2888007A4 (en) * 2012-08-22 2016-04-20 Merck Sharp & Dohme NOVEL BENZIMIDAZOLTETRAHYDROFURANDERIVATE
EP2887807A4 (en) * 2012-08-22 2016-04-20 Merck Sharp & Dohme NOVEL AZABENZIMIDAZOLE-HEXAHYDROFUR [3,2-B] FURANDERIVATE
WO2016068099A1 (ja) * 2014-10-28 2016-05-06 塩野義製薬株式会社 Ａｍｐｋ活性化作用を有する複素環誘導体
EP2906040A4 (en) * 2012-08-22 2016-07-06 Merck Sharp & Dohme Novel benzimidazoletetrahydropyran derivatives
WO2017200068A1 (ja) 2016-05-20 2017-11-23 塩野義製薬株式会社 Ａｍｐｋ活性化作用を有する５－置換ベンズイミダゾールおよび５－置換アザベンズイミダゾール誘導体
US9868733B2 (en) 2012-08-22 2018-01-16 Merck Sharp & Dohme Corp. Azabenzimidazole tetrahydrofuran derivatives
WO2018035128A1 (en) 2016-08-19 2018-02-22 Rigel Pharmaceuticals, Inc. Benzimidazole direct ampk activators
US9980948B2 (en) 2014-08-27 2018-05-29 Shionogi & Co., Ltd. Azaindole derivative having AMPK-activating activity
US10172840B2 (en) 2014-12-01 2019-01-08 Vtv Therapeutics Llc Bach1 inhibitors in combination with Nrf2 activators and pharmaceutical compositions thereof
US10478425B2 (en) 2016-02-26 2019-11-19 Shionogi & Co., Ltd. 5-phenylazaindole derivative having AMPK-activating activity
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