WO2012064569A1 - Imidazole derivatives - Google Patents

Imidazole derivatives Download PDF

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Publication number
WO2012064569A1
WO2012064569A1 PCT/US2011/059033 US2011059033W WO2012064569A1 WO 2012064569 A1 WO2012064569 A1 WO 2012064569A1 US 2011059033 W US2011059033 W US 2011059033W WO 2012064569 A1 WO2012064569 A1 WO 2012064569A1
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Prior art keywords
pharmaceutically acceptable
compound
alkyl
acceptable salt
halogen
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PCT/US2011/059033
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French (fr)
Inventor
Donald M. Sperbeck
Robert J. Devita
James M. Balkovec
Mark L. Greenlee
Zhicai Wu
Yang Yu
Petr Vachal
Gang Zhou
Heping Wu
Rongze Kuang
Pauline Ting
Robert Aslanian
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Merck Sharp & Dohme Corp.
Schering Corporation
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Application filed by Merck Sharp & Dohme Corp., Schering Corporation filed Critical Merck Sharp & Dohme Corp.
Publication of WO2012064569A1 publication Critical patent/WO2012064569A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/14Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/04Heterocyclic 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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention is directed to novel imidazole derivative compounds.
  • the compounds act as diacylglycerol O-acyltransferase type 1 inhibitors (hereinafter also referred to as "DGAT1”), and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.
  • DGAT1 diacylglycerol O-acyltransferase type 1 inhibitors
  • Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and increased health problems.
  • obesity is recognized as an upstream risk factor for many conditions such as diabetes mellitus, lipidosis and hypertension (Journal of Japan Society for the Study of Obesity, Vol. 12, Extra Edition, 2006).
  • the need to treat obesity is recognized to be important, there are extremely limited drug therapies for obesity that are currently available, and thus, the advent of novel antiobesity drugs having more definite action and few side-effects is desired.
  • TG triacylglycerol
  • adipose tissue which is a result of lack of exercise, intake of excessive calories and ageing.
  • TG triacylglycerol
  • a glycerol phosphate pathway which is present in most organs and causes de novo TG synthesis
  • a monoacylglycerol pathway which is involved principally in absorption of aliphatic acid from the small intestine.
  • Diacylglycerol acyltransferases DGATs, EC 2.3.1.20
  • DGATs EC 2.3.1.20
  • the final reaction consists of transferring an acyl group from acyl-coenzyme A to the 3-position of 1 ,2-diacylglycerol to generate TG (Prog. Lipid Res., 43,134-176, 2004 and Ann. Med., 36, 252-261, 2004).
  • DGAT1 subtypes of DGATs: DGAT1 and DGAT2.
  • DGAT2 which are encoded by different genes (Proc. Natl. Acad. Sci.USA., 95, 13018-13023, 1998 and JBC, 276, 38870-38876, 2001).
  • DGAT1 is present in the small intestine, adipose tissue and liver and is believed to be involved in lipid absorption in the small intestine; lipid accumulation in the fat cell; and VLDL secretion and lipid accumulation in the liver (Ann. Med., 36, 252-261, 2004 and JBC, 280, 21506-21514, 2005).
  • a DGAT1 inhibitor is expected to be an effective obesity treatment through inhibition of lipid absorption in the small intestine, lipid accumulation in the adipose tissue and the liver, and lipid secretion from the liver.
  • DGAT1 -knockout mice deficient in DGAT1 at the genetic level were produced and analyzed.
  • the DGAT1 -knockout mice have been found to have smaller fat masses than those of wild-type mice and became resistant to obesity, abnormal glucose tolerance, insulin resistance and fatty liver due when fed a high-fat diet (Nature Genetics, 25, 87-90, 2000 and JCI, 109, 1049-1055, 2002).
  • DGAT1 inhibitors are likely to be therapeutic drugs with efficacy for obesity, type 2 diabetes mellitus, lipidosis, hypertension, fatty liver, arteriosclerosis, cerebrovascular disorder, coronary artery disease and metabolic syndrome, associated with obesity.
  • X is selected from the group consisting of - CH- or ⁇ N-;
  • Z is selected from the group consisting of phenyl and nitrogen containing heterocycle, wherein the phenyl and nitrogen containing heterocycle can be unsubstituted or substituted with 1-3 substituents selected from a;
  • R ⁇ R 2 and R 3 are independently selected from the group consisting of a;
  • a is selected from the group consisting of halogen, Ct-Cealkyl, halogen- substitutedCi ⁇ C 6 alkyl, COCi-Cgalkyl, COhalogen-substitutedCrC 6 alkyl 5 oxo, -OH, Cp
  • n independently selected from the list consisting of 1 or 2, DETAILED DESCRIPTION OF THE INVENTION
  • X is -CH- or -N-. In certain embodiments, X is -
  • X is -N-.
  • each occurrence of n is independently selected from the list consisting of 1 or 2. In other embodiments, n is 1. In still other embodiments, n is 2.
  • Z is selected from the group consisting of phenyl and nitrogen containing heterocycle, wherein the phenyl and nitrogen containing heterocycle can be unsubstituted or substituted with 1-3 substituents selected from a.
  • Z is unsubstituted.
  • Z is substituted with 1 substituent selected from a.
  • Z is substituted with 2 substituents selected from the group consisting of a.
  • Z is substituted with 3 substituents selected from the group consisting of a.
  • Z is substituted with 1 or 2 substituents selected from the group consisting of a.
  • Z is substituted with 1-3 substituents independently selected from the group consisting of halogen, Ci-C 6 alk l, halogen-substitutedQ- Cealkyl, -OC C 6 alkyl, -COOH, -COOC Cealkyl, -d-CealkylCOOCrCealkyl, -C r
  • Z is phenyl. In some embodiments, the phenyl Is unsubstituted. In other embodiments, the phenyl is substituted. In embodiments, Z is phenyl, wherein the phenyl is substituted with halogen, CrCsalkyl, halogen- substitutedCi-C 6 alkyl, -OCrQalkyl, -COOH, ⁇ COOCi-C 6 alkyl, -C r C 6 alkylCOOCi-C 6 alkyl ; - C r C 6 alkylCOOH, -S0 2 C r C 6 alkyl, -CN, Ci-C 6 alkylCON3 ⁇ 4 and -CON3 ⁇ 4.
  • Z is phenyl, wherein the phenyl can be substituted with -COOH, -CH 2 COOH, -(CH 2 ) 2 COOH, -C(CH 3 ) 2 COOH, -COOMe, - C(CH 3 ) 2 COOCH 3 , -OMe, -COOMe, -CH 2 COOCH 2 CH 3 , fluorine, methyl, -OH, triflouromethyl, -S0 2 Me, -CH 2 CONH 2 , -C(CH 3 ) 2 CONH 25 CONH 2 or -CN.
  • the nitrogen-containing heterocycle is N-containing heterocycle. In some embodiments, the nitrogen-containing heterocycle is N-containing heterocycle.
  • the nitrogen-containing heterocycle is substituted.
  • Suitable examples of a nitrogen-containing heterocycle include, but are not limited to, benzimidazole, pyrimidine or pyridine.
  • Z is nitrogen-containing heterocycle, wherein the nitrogen-containing heterocycle is substituted with substitutedCi-Cealkyl, -COOH, - COOCi-Cgalkyl, -CrQalkylCOOH, -CN and ⁇ CONH 2 ,
  • Z benzimidazole, pyrimidine or pyridine wherein the benzimidazole, pyrimidine or pyridine can be substituted with -COOH, halogen-substitutedC]- C 6 alkyl or -C CealkylCOOH.
  • Z is benzimidazole, pyrimidine or pyridine, wherein the benzimidazole, pyrimidine or pyridine can be unsubstituted
  • R 1 is selected from a.
  • R 1 is selected from the group consisting of halogen, -OCrC 6 alkyl, halogen-substitutedCi-Cealkyl.
  • Suitable examples of R 1 include, but are not limited to, chlorine, fluorine, methoxy and trifluromethyl.
  • R 1 can be positioned as follows:
  • R is selected from the group consisting of a.
  • R z is selected from the group consisting of hydrogen, halogen and halogen- substitutedC]-C 6 alkyL
  • R is hydrogen.
  • R is halogen.
  • Suitable halogens include, but are not limited to, chlorine and fluorine.
  • R 2 is halogen-substitutedCi-C 6 alkyl. Suitable examples include, but are not limited to, trifluoromethyl.
  • R is selected from the group consisting of hydrogen and -Cgalkyl.
  • R 2 is hydrogen.
  • R 3 is C Cealkyl. Suitable examples include, but are not limited to, methyl.
  • a is selected from the group consisting of halogen, Ci ⁇ C 6 alkyl, halogen-substitutedCrCealkyl, COCrCgalkyl, COhalogen-substitutedC C 6 alkyl, oxo, -OH, C r C 6 alkylOH, Cj-CealkylOHCOOH, halogen-substitutedC C 6 alkylOH, - OC C 6 alkyl, -Ohalogen-substitutedd-Cealkyl, -COOH, -COCOOH, -COOC C 6 alkyl, -C r C 6 alkylCOOCi-C 6 aikyl, -C C 6 alkylCOOH, -OC C 6 alkylCOOH, -CN ; d-CealkylCN, -NO 3 ⁇ 4 NH 2 , NHC,-C 6 alkyl, N(C r C 6
  • R 1 , R 3 and Z are defined as above.
  • halogen examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • CpC galkyl encompasses straight alk l having a carbon number of 1 to 6 and branched alkyl having a carbon number of 3 to 6. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1 ,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1 ,2-dimethylbutyl, 2,2- dimethylbutyl, 1-ethylbutyl, 1, ,2-trimethylpropyl, 1,2,2-trimethylpropyl, l-
  • Cycloalkyl encompasses cycloalkyls having 3 to 10 carbons, forming one or more carbocyclic rings that are fused. “Cycloalkyl” also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. In one embodiment, the cycloalkyl can include 3-6 carbons, i.e. C3-C 6 cycloalkyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl,
  • -OCi -C 6 alkyl refers to an alkyl group having 1 to 6 carbons linked to oxygen, also known as an alkoxy group. Examples include methoxy, ethoxy, butoxy and propoxy.
  • -OCi-C 6 alkylCOOH refers to an alkoxy group having 1 to 6 carbons substituted with a carboxylic acid (-COOH) group.
  • halogen-substitutedCrC 6 alkyl encompasses CpC 6 alkyl with the hydrogen atoms thereof being partially or completely substituted with halogen, examples thereof including fluoromethyl, difluoromethyl, trifiuoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl and the like.
  • -Ohalogen-substitutedCpCealky means a -OCpCealkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different, and specifically includes, for example, a trifluoromethoxy group.
  • -COCpC 6 arky means groups having CpC 6 alkyl bonded to carbonyl, and encompasses alkylcarbonyl having a carbon number of 1 to 6. Specific examples thereof include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and the like.
  • -COhalogen-substi ted -Cealkyl means a -COCi ⁇ C 6 alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different.
  • Ci-C 6 alkylOH means a Q-Cealkyl substituted with an alcohol (-OH).
  • Examples include methanol, propanol, butanol and t-butanoL
  • halogen-substitutedCrCealkylOH means a halogen- substitedQ-Qatkyl, as defined above, substituted with an alcohol (-OH).
  • r C 6 alkyIOHCOOH means a C C 6 alkyl substituted with an alcohol (-OH) and a carboxylic acid group (-COOH).
  • CrC 6 alkylCN means a C
  • COOCi-Cealkyl means a -COOH group wherein the -OH is replaced with an alkoxy group as defined above. Examples include methoxycarbonyl, eihoxycarbonyl and butoxycarbonyl.
  • the term means a group having Ci-C 6 alkyl bonded to sulfonyl (-S0 2 ⁇ ). Specific examples thereof include methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl, tert-butanesulfonyl, and the like.
  • NHQ-Cealkyl means a group with one of the hydrogen atoms of amino (- N3 ⁇ 4) being substituted with a C 1-6 alkyl group. Specific examples thereof include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino, and the like.
  • NCCi-Cealk iy means a group with the two amino hydrogen atoms each being substituted with a C 1-6 alkyl group. Specific examples thereof include dimethylamino, diethylamino, ethylmethyiamino, di(n-propyl)amino, methyl(n-propyl)amino, diisopropylamino, and the like.
  • NHCOiCrQalkyl means a group with one of the amino hydrogen atoms being substituted with C 1-6 alkoxycarbonyl and encompasses alkoxycarbonylamino having a carbon number of 1 to 6. Specific examples thereof include methoxycafbonylamino, ethoxycarbonylamino, n-propyloxycarbonylamino, isopropyloxycarbonylamino, n- butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, n- pentyloxycarbonylamino, and the like.
  • NRCOCrC 6 alkyr means a group with one of the amino hydrogen atoms being substituted with Ci-6 alkylcarbonyl. Specific examples thereof include acetylamino, propionylamino, isobutyryl amino, valerylamino, isovalerylamino, pivaloylamino, and the like.
  • CONHCrC 6 alkyl means a group with one of the hydrogen atoms of carbamoyl (-CONH 2 ) being substituted with Ci -6 alkyl. Specific examples thereof include methylcarbamoyl, ethylcarbarnoyl, n-propyl carbamoyl, isopropylcarbamoyl, n-butylcarbamoyl ⁇ sec-butylcarbamoyl, tert-butylcarbamoyl, and the like.
  • CONtCi-Csalkyiy means a group with the two carbamoyl hydrogen atoms each being substituted with Ci -6 alkyt. Specific examples thereof include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl,, di(n-propyl)carbamoyl, methyl (n-propyl)carbamoyl s diisopropylcarbamoyl, and the like.
  • NHSChQ-Cgalkyl means a group with one of the amino hydrogen atoms being substituted with C 1-6 alkylsulfonyl. Specific examples thereof include
  • Heterocycle unless otherwise specified, means an aromatic, partially aromatic or non- aromatic monocyclic or polycyclic (including bicyclic) ring having at least one ring heteroatom selected from O, S and N.
  • heterocyclic groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazoJyl, pyridinyi, 2-oxo-(lH) ⁇ pyridinyl (2-hydroxy-pyridinyl), oxazolyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, ihienyl, pyrimidinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indoliny
  • heterocycle also include tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2 J 3-dihydrofuro(2,3-£>)pyridyi, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2,l-&]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, 2- or 4-pyridones attached through the nitrogen or jV-substituted-(lH, 3H)-pyrimidine-2,4-diones (JV-substituted uracils).
  • the term also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2 ⁇ azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 2- azabicyclo[2.2.2]octyl, and 3-azabicyclo[3.2.2]nonyl, and azabicyclo[2.2.1]heptanyl.
  • pharmaceutically acceptable salt refers to salts prepared from
  • salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbro
  • suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as argi ine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamme, N-ethylmorpholine, N-ethylpiperidme, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion-exchange resins such as argi ine, betaine, caffeine,
  • the compounds of the present invention contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers.
  • the present invention is meant to comprehend all such isomeric forms of these compounds.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomericaliy pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racermc mixture of the compounds can also be separated directly by
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • references to the compounds of the structural formulas described herein are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.
  • Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts.
  • a ketone and its enol form are keto-enol tautomers.
  • the individual tautomers as well as mixtures thereof are encompassed with compounds of the present invention.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of the formulas described herein.
  • different isotopic forms of hydrogen (H) include protium ( ⁇ ) and deuterium (2H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic formula can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • DGATl -related diseases are effective in preventing or treating various DGATl -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatos
  • One aspect of the invention described herein provides a method for the treatment and control of obesity or metabolic syndrome, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having the formulas described herein or a pharmaceutically acceptable salt thereof.
  • the compounds described herein are useful for treating or preventing obesity by administering to a subject in need thereof a composition comprising a compound of formula I, formula la or formula lb.
  • Methods of treating or preventing obesity and conditions associated with obesity refer to the administration of the pharmaceutical formulations described herein to reduce or maintain the body weight of an obese subject or to reduce or maintain the body weight of an individual at risk of becoming obese.
  • 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 or combinations of the present invention.
  • Another outcome of treatment may be preventing body weight gain, regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy and preventing weight gain from cessation of smoking.
  • Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases.
  • Yet another outcome of treatment may be decreasing the risk of developing diabetes in an overweight or obese subject.
  • the treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof.
  • the treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.
  • Prevention of obesity and obesity-related disorders refers to the administration of the pharmaceutical formulations described herein 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 or combinations 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.
  • such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, type 2 diabetes, polycystic ovary disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
  • arteriosclerosis such as, but not limited to, arteriosclerosis, type 2 diabetes, polycystic ovary disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
  • Another aspect of the invention that is of interest relates to a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat hyperglycemia, diabetes or insulin resistance.
  • Another aspect of the invention that is of interest relates to a method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising
  • Yet another aspect of the invention that is of interest relates to a method of treating non- insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat non-insulin dependent diabetes mellitus.
  • the present invention is also directed to the use of a compound of structural formula I, formula la or formula lb in the manufacture of a medicament for use in treating various DGAT1- related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congesti e cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and
  • the present invention is directed to the use of a compound of structural formula I, formula la or formula lb in the manufacture of a medicament for use in treating obesity, diabetes, hormone secretion disorder, hyperlipemia, gout and fatty liver.
  • the present invention is directed to the use of a compound of structural formula I, formula la or formula lb in the manufacture of a medicament for use in treating obesity.
  • Compounds of the invention may be administered orally or parenterally.
  • the compound of the invention can be used as a pharmaceutical composition for the prevention, treatment, or remedy of the above diseases.
  • the compound of the invention In clinical use of the compound of the invention, usually, the compound is formulated into various preparations together with pharmaceutically acceptable additives according to the dosage form, and may then be administered.
  • pharmaceutically acceptable it is meant the additive, carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • additives various additives ordinarily used in the field of pharmaceutical preparations are usable.
  • gelatin lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, corn starch, macrocrystalline wax, white petrolatum, magnesium metasiiicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropyleellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, poiyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic acid anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, and the like.
  • Preparations to be formed with those additives include, for example, solid preparations such as tablets, capsules, granules, powders, suppositories; and liquid preparations such as syrups, elixirs, injections. These may be formulated according to conventional methods known in the field of pharmaceutical preparations.
  • the liquid preparations may also be in such a form that may be dissolved or suspended in water or in any other suitable medium for their use.
  • the preparations may be dissolved or suspended in physiological saline or glucose liquid, and a buffer or a preservative may be optionally added thereto.
  • the pharmaceutical compositions may contain the compound of the invention in an amount of from 1 to 99.9 % by weight, preferably from 1 to 60 % by weight of the composition.
  • compositions may further contain any other therapeutically-effective compounds.
  • the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the patient and on the type and the range of the intended remedial effect.
  • the dose when orally administered, may be from 0.001 to 50 mg/kg of body weight/day, and it may be administered at one time or at several times.
  • the dose is preferably from about 0.01 to about 25 mg kg/day, more preferably from
  • compositions are preferably
  • the compounds of the present invention are further useful in methods for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other therapeui agents.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of formula I, formula la or formula lb or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of formula I, formula la or formula lb.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of formula I, formula . or formula lb is preferred.
  • the combination therapy may also include therapies in which the compound of formula I, formula la or formula lb and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or mc other active ingredients, the compounds of the present invention and the other active ingredients may t used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions oft present invention include those that contain one or more other active ingredients, in addition to a compound of formula I, formula la or formula lb. Examples of other active ingredients that may be administered in combination with a compounc of formula I, formula la or formula lb, and either administered separately or in the same pharmaceutical composition, include, but are not limited to:
  • insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g. pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligands, including (1) PPARa/ ⁇ dual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPA a agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), such as those disclosed in WO
  • salts in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and GlucophageXR®;
  • PTP-1B protein tyrosine phosphatase- IB
  • insulin or insulin analogs such as insulin lispro, insulin detemir, insulin glargine, insulin glulisine, and inhalable formulations of each thereof;
  • amylin and amylin analogs such as pramlintide
  • sulfonylurea and non-sulfonylurea insulin secretagogues such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;
  • ⁇ -glucosidase inhibitors such as acarbose, voglibose and miglitol
  • glucagon receptor antagonists such as those disclosed in WO 1998/04528, WO 1999/0142; WO 2000/39088, and WO 2000/69810;
  • incretin mimetics such as GLP-1, GLP- analogs, derivatives, and mimetics
  • GLP-1 receptor agonists such as exenatide, liraglutide, taspoglutide, AVE0010, CJC- 1131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof;
  • LDL cholesterol lowering agents such as (i) H G-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fiuvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, coiesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl CoA:cholesterol acyltransferase inhibitors, such as avasimibe;
  • H G-CoA reductase inhibitors lovastatin, simvastatin, pravastatin, cerivastatin, fiuvastatin, atorvastatin, pitavastatin, and rosuvastatin
  • HDL-raising drugs such as niacin or a salt thereof and extended-release versions thereof
  • MK-524A which is a combination of niacin extended-release and the DP-1 antagonist MK-524
  • nicotinic acid receptor agomsts nicotinic acid receptor agomsts
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • antihypertensive agents such as ACE inhibitors (such as enalapril, iisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta
  • ACE inhibitors such as enalapril, iisinopril, ramipril, captopril, quinapril, and tandolapril
  • A-II receptor blockers such as losartan, candesartan,
  • GKAs glucokinase activators
  • Patent No. 6,730,690 WO 2003/104207; and WO 2004/058741;
  • CETP cholesteryl ester transfer protein
  • inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2);
  • AMPK AMP-activated Protein Kinase
  • neuromedin U receptor agonists such as those disclosed in WO 2009/042053, including, b not limited to, neuromedin S (NMS);
  • GPR-105 antagonists such as those disclosed in WO 2009/000087;
  • inhibitors of glucose uptake such as sodium-glucose transporter (SGLT) inhibitors and its various isoforrns, such as SGLT-1; SGLT-2, such as dapagliflozm and remogliflozin; and SGLT-3;
  • SGLT sodium-glucose transporter
  • agonists of the TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR131, and h BAR.
  • Dipeptidyl peptidase-IY (DPP-4) inhibitors that can be used in combination with compounds c formula I, formula la or formula lb include, but are not limited to, sitagliptin (disclosed in US Patent IS 6,699,871), vildagliptin, saxagliptin, alogliptin, denagiiptin, carmegliptin, dutogliptin, melogliptin, linagliptin, and pharmaceutically acceptable salts thereof, and fixed-dose combinations of these compounds with metformin hydrochloride, pioglitazone, rosiglitazone, simvastatin, atorvastatin, or a sulfonylurea.
  • DPP-4 dipeptidyl peptidase-IV
  • Other dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of formula I, formula la or formula lb include, but are not limited to: (2i?3 ⁇ 5J?)-5-(l-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)-2-(2 I 4,5- trifluorophenyl)tetrahydro-2H-pyran-3 -amine ;
  • Antiobesity compounds that can be combined with compounds of formula I, formula la or formula lb include topiramate; zonisamide; naltrexone; phentermine; bupropion; the combination of bupropion and naltrexone; the combination of bupropion and zonisamide; the combination of topirama and phentermine; fenfluramine; dexfenfiuramine; sibutramine; lipase inhibitors, such as oriistat and cetilistat; melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists; CC -1 agonists; melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Y or Y5 antagonists (such as MK-0557); CBl receptor inverse agonists and antagonists (such as rimonabant am taranabant); ⁇ 3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (
  • Glucagon receptor antagonists that can be used in combination with the compounds of formula formula la or formula lb include, but are not limited to:
  • Inhibitors of stearoyl-coenzyme A delta-9 desaturase that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
  • Glucokinase activators that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
  • Agonists of the GPR-119 receptor that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
  • rac-c is 5 -chloro-2- ⁇ 4- [2-(2- ⁇ [5-(methylsulfonyl)pyridin-2-yl] oxy ⁇ ethyl)cyclopropyl] piperidin- 1 - yl ⁇ pyrimidine;
  • Selective PPARy modulators that can be used in combination with the compoun of formula I, formula la or formula lb include, but are not limited to:
  • Inhibitors of 1 ⁇ -hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
  • Somatostatin subtype receptor 3 (SSTR3) antagonists that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
  • AMP-activated Protein Kinase (AMPK) activators that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
  • Inhibitors of acetyl-CoA carboxylase- 1 and 2 that can be used in combination with the compounds of formula 1, formula la or formula lb include, but are not limited to: 3- ⁇ r-[(l-cyclopropyl-4-methoxy-lH-indol-6-yl)carbonyi]-4-oxospiro[chroman- 2,4'-piperidm]- 6-yl ⁇ benzoic acid;
  • composition which comprises one or more of the following agents:
  • DPP-4 dipeptidyl peptidase-IV
  • insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g.
  • PPARa/ ⁇ dual agonists such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar
  • PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrat and bezaflbrate)
  • SPPARyM's selective PPARy modulators
  • PPARy partial agonists include (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and GlucophageXR®; (iii) protein tyrosine phosphatas
  • sulfonylurea and non-sulfonylurea insulin secretagogues such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;
  • a-glucosidase inhibitors such as acarbose, voglibose and miglitol
  • LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pravastatin, and rosuvastatir (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelara hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl CoA:cholesterol acyltransferase inhibitors, such as avasimibe;
  • HMG-CoA reductase inhibitors lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pravastatin, and rosuvastatir
  • HDL-raising drugs such as niacin or a salt thereof and extended-release versions thereof;
  • MK.-524A which is a combination of niacin extended-release and the DP-1 antagonist MK-52 and nicotinic acid receptor agonists;
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal an inflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • NSAIDs non-steroidal an inflammatory drugs
  • COX-2 selective cyclooxygenase-2
  • antihypertensive agents such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta;
  • ACE inhibitors such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril
  • A-II receptor blockers such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan
  • renin inhibitors such as aliskiren
  • GKAs glucokmase activators
  • LY2599506 LY2599506
  • inhibitors of 1 ⁇ -hydroxysteroid dehydrogenase type 1 LY2599506
  • CETP cholesteryl ester transfer protein
  • inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2);
  • AMPK AMP-activated Protein Kinase
  • neuromedin U receptor agonists including, but not limited to, neuromedin S (NMS)
  • (22) inhibitors of glucose uptake such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2, such as dapagliflozin and remogliflozin; and SGLl 3;
  • SGLT sodium-glucose transporter
  • TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPRI31 and M-BAR
  • compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of the compound of the present invention to the second active ingredient may vary and will depend upon the effective dose of each ingredient. Generally, an effective dose of eacl will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1 : 1000, preferably about 200:1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • Na 2 S0 4 sodium sulfate
  • Step 1 methyl 6-fpiperazin-l-yl pyrazine-2-carboxylate
  • Step 2 ethyl 6-(4-(5-(5-(trifluoromethvI -lH-berizofd]imidazol-2-yl)pyridin-2-yl)piperazin-l- yl)pyrazine-2-carboxyiate
  • Step 3 6-(4-(5 -(5 -f trifluororoethvO- 1 H-benzo [dl imidazol-2- yl)pyridin-2-yl)piperazin- 1 - yl)pyrazine-2-carboxylic acid
  • 5-((l-(5-(5-chloro-lH-benzo[d]imidazol-2-yl)pyridin-2-yl)piperidi yl)methoxy)isophthalate 48 mg, 0.10 mmol
  • MeOH 3.0 mL
  • THF 3.0 mL
  • water 2.0 mL
  • the reaction mixture was stirred at RT for 5 h then 1 N HCl (2.5 mL) was added, and the solution was concentrated.
  • Step 1 5-chloro-2-(6-fluoropyridin-3 -ylV 1 H-benzo [d] imidazole
  • Step 2 5-chloro-2-[6-[4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin- 1 -yl]pyridin-3-yl "
  • - IH- benzo [(flimidazole
  • Stepl To a solution of 4-trifluoromet yl-l ⁇ 2-phenylenediamine (l.Og, 5.68mmoI) in THF (lOmL) was added 6-chloro-3-pyridinecarboxaldehyde (800mg, 5.68mmol). The mixture was stirred at T for 2 hours and the solvent was evaporated. The solids were washed with a minimum of methylene chloride and filtered to give 2-(6-chloropyridin-3-yl)-5-(trifiuoromethyl)- lH-benzimidazole as a yellow solid.
  • Step 1 To a solution of ethyl (4-bromophenylacetate)(1.02g, 4.20mmol), 1- benzylpiperazine(740mg, 4.20 ⁇ 1), palladium acetate (47mg, 0.21mmol) s
  • Step 1 A solution of 6-chloropyridme-3-carboxamide (lOOmg, 0.639mmol), /ert-butyl piperazine-1-car.boxylate (119mg, 0.639mmol) and ⁇ , ⁇ -diisopropylethylamine (248mg, 1.91mmol) in dry DMA (3mL) was heated to 150° C in a microwave for 2 hours. The cooled mixture was partitioned between ethyl acetate and water. The organic layer was twice washed with water and dried over Na 2 S0 4 . The solvent was evaporated to give /eri-butyl 4-(5- carbamoylpyridin-2-yl)piperazine-l-carboxylate as a tan solid.
  • LC-MS (M+H) 307
  • Step 2 To a suspension of fert-butyl 4-(5-carbamoylpyridin-2"yl)piperazine-l-carboxylate (120mg, 0.392mmol) was added 4M HCl in dioxane (4mL). The mixture was stirred at RT for 3 hours and evaporated to dryness to give a tan solid. The solid was dissolved in DMA (2mL) and 5-chloro-2- (6-chloropyridin-3-yl)- lH-benzimidaole (55mg, 0.208mmol) was added followed by ⁇ , ⁇ -diisopropylethylamine (27mg, 0.208mmol). The mixture was heated to 110° C overnight.
  • the mixture was purified by reverse phase Prep HPLC using 30-100% CH 3 CN/H 2 O/0.1%TFA as gradient to give 6- ⁇ 4- 5-(5- cWoro-lH-beixzimidazol-2-yl)pyridin-2-yl]piperazin-l-yl ⁇ pyridi as the TFA salt.
  • Step 1 A solution of 2-methyl-2-(4-nitrophenyl)propanoic acid (1.02g, 4.88mrnol) in 1.25M methanolic HCL (lOmL) was stirred at RT overnight. The mixture was partitioned between ethyl acetate and sodium bicarbonate soln. The organic layer was dried over Na 2 S0 4 and concentrated to give methyl 2-methyl-2-(4-nitrophenyl)propanoate which was dissolved in methanol (lOmL). The solution was treated with 10% palladium on carbon (lOOmg) and stirred under latm of hydrogen for 3 hours.
  • lOOmg 10% palladium on carbon
  • Step 5 A solution of methyl 2-(4- ⁇ 4-[5-(5-cWoro ⁇ lH-benzimidazol-2-yl)pyridin-2-yl]piperazin- l-yl ⁇ phenyl)-2-methylpropanoate (30mg, 0.061mmol) in methanol (2mL) was treated with 5N NaOH (122uL, 0. 1rnmol) and the mixture was heated to 50° C overnight. An additional lOOuL of 5N NaOH solution was added and the mixture was heated to reflux for 2 hours. The solvent was evaporated and the residue was taken up in water (2mL). The pH was adjusted to 7 by addition of IN HC1.
  • Step 2 To a solution of 5-chloro-2-(6-cWoro-5-fluoropyridin-3-yl)-lH-beri2imidazole (60mg, 0.213mmol) in dry DMA (2mL) was added ethyl [4-(piperazin-l-yl)phenyl] acetate (53 ⁇ 3 ⁇ 4, 0.213mmol) and ⁇ , ⁇ -diisopropyletliylamine (82mg, 0.638mmol). The mixture was heated to 150° C for 90 min. The cooled mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na 2 S0 4 and concentrated.
  • Step 3 A solution of ethyl (4- ⁇ 4-[5-(5-cUoro-lH-benzimidazol-2-yl)-3-fluoropyridin-2- yljpiperazin-l-yl ⁇ phenyl)acetate (40mg 5 0.081mmol) in ethanol (4mL) was treated with 5N NaOH (O.SlOmmol). The mixture was heated to 60° C for 2 hours. The solvent was evaporated and the residue was taken up in water (5mL). The solution was neutralized with I N HC1 and extracted with ethyl acetate containing 10% ethanol.
  • Step 1 To a solution of 1 -benzylpiperazine (500mg, 2.84mmol) and methyl 3-(4- bromophenyl)propanoate (690mg, 2.84mmol) in dry DMA (5mL) was added
  • Step 2 A solution of methyl 3-[4-(4-benzylpiperazin-l-yl)phenyl]propanoate (720mg >
  • Step 3 To a solution of 2-(6-chloropyridin-3-yl)-5-chloro-lH-benzimidazole (60mg,
  • Step 4 A suspension of methyl 3-(4- ⁇ 4-[5 ⁇ (5-chloro-lH-benzimidazol-2-yl)pyridin-2- yl]piperazin-l-yl ⁇ phenyl)propanoate TFA salt (12mg, 0.025mmol) in methanol and treated with 5N NaOH (200uL). The mixture was heated to 50° C for 4 hours.
  • Step, 1 To a solution of 2-(6-bromopyridin-3-yl)-5-(trifluoromemyi)-lH-benzimidazoie, prepared in the same manner as Example 4, (300mg, 0.877mmol) in dry DMA (3mL) was added 1-benzylpiperazine (155mg, 0.877mmol) and N s N-diisopropylethylamine (227mg, 1.75mmoI).
  • Step 2 A solution of 2-[6-(4-benzylpiperazin- 1 -yl)pyridin-3 -yl] -5 -(trifluoromethyl)- 1 H- benzimidazole (200mg, 0.457mmol) in methanol (5mL) was treated with 20% Pd(OH) 2 on carbon (80mg). The mixture was stirred under 1 aim of hydrogen for 16 hours. The catalyst was filtered and the solvent evaporated to give 2-[6-(piperazin-l-yl)pyridin-3-yl]-5-(trifluoromethyl)- lH-benzimidazole.
  • Step 1 To a solution of 6-fluoro-3-pyridinecarboxaldehyde (1.76g, 14.0mmol) and 4-chloro ⁇ l,2- phenylenediamine (2.0g, 14.0mmol) in DMF (20mL) was added water (2mL).
  • Step 3 To a solution of 5-cMoro-2-[6- ⁇ iperazin-l-yl)pyridin-3-yl]-lH-benzimidazole (200mg, 0.637mraol) in dry NMP (2mL) under argon was added ethyl (5,6-difiuoropyridin-3-yl)acetate, prepared in the same manner as in patent WO 2007/120729, (128mg, 0.637mmol). Sodium bicarbonate (268mg, 3.19mmol) was added and the mixture was heated to 150° C for 90 min. in a microwave.
  • Step 4 A solution of ethyl (6- ⁇ 4-[5-(5-cMoro-lH-benzimidazol-2-yl)pyridin-2-yl]piperazin-l- yl ⁇ -5-fluoropyridin-3-yl)acetate TFA salt (lOOmg, 0.202mmol) in ethanol (5mL) was treated with 5N NaOH (404uL, 2.02mmol) and the mixture was heated to 50° C for 2 hours.
  • Acetic acid 16uL, 2.02mmol was added and the mixture was purified by reverse phase Prep HPLC using 10-100% C3 ⁇ 4CN/H 2 O/0.1%TFA as gradient to give (6- ⁇ 4-[5-(5-chloro-lH-benzimidazol-2- yl)pyridin-2-yl]piperazin-l-yl ⁇ -5-fluoropyridin-3-yl)acetic acid as the TFA salt.
  • LC-MS (M+H) 467
  • Step 2 To a solution of 2-(6-fluoropyridin-3-yl)-5-methoxy-3H-imidazo[4,5-&]pyridine (44mg, O.lSlmmol) in dry DMA (2mL) under argon was added ethyl [4-(piperazin-l-yl)phenyl]acetate (45mg, O.lSlmmol). Sodium bicarbonate (46mg, 0.543mmol) was added and the mixture was heated to 150° C for 90 min. in a microwave.
  • Step 1 To a solution of 2-(6-fluoropyridm-3-yl)-5-methoxy-3H-imidazo[4,5-&]pyridine (400mg, 1.64mmol) in dry DMA (1 OmL) under argon was added 1 -benzylpiperazine (289mg > 1.64mmol) and sodium bicarbonate (688mg, 8.19mmol). The mixture was heated to 150° C for 60 min. in a microwave. The mixture was partitioned between ethyl acetate and water and the organic layer was dried over Na 2 S0 4 .
  • Step 3 To a solution of 5-methoxy-2-[6-(piperazin-l-yl)pyridin-3-yl]-3H-imidazo[4,5- £>]pyridine (54mg ? 0.174mmol) in dry DMA(2mL) degassed with argon was added methyl 5,6- difluoropyridine-3-carboxylate (30mg, 0.174mmol) and sodium bicarbonate (73mg, 0.87mmol). The mixture was heated to 150° C for 60 min. in a microwave.
  • Step 2 To a solution of 3-nitro-6-(trifLuoromethyl)pyridin-2-amine (838mg, 4.05mmol) in methanol (30mL) was added 10% palladium on carbon (400mg). The mixture was hydrogenated on a Parr shaker at 40 psi for 90 min. The catalyst was filtered and the solvent was evaporated to give 6 ⁇ (trifluoromethyl)pyridine-2,3-diamine as a yellow solid.
  • LC-MS (M+H) 178
  • Step 3 To a solution of 5,6-difluoropyridine-3-carboxylic acid (348mg, 2.19mmol) in dry NMP(3mL) was added l-hydroxybenzotriazole (335mg, 2.19mmol),and iV-[3- (dimethylamino)propyl3-N'-ethyicarbodiimide hydrochloride (420mg > 2.19mmol). The mixture was stirred for 10 min. and 6-(trifluoromethyl)pyridine-2, 3 -diamine (388mg, 2.19mmol) was added. The mixture was stirred at RT for 16 hours. Acetic acid (2mL) was added and the mixture was heated to 120° C for 60 min. in a microwave. The cooled mixture was partitioned between ethyl acetate and sodium bicarbonate solution. The organic layer was dried over Na 2 S0 4 and concentrated. The mixture was purified by phase Prep HPLC using 10-100%
  • the in vitro assay to identify DGAT1 inhibitors uses human DGAT1 enzyme expressed in Sf9 insect cells prepared as microsomes.
  • the reaction is initiated by the addition of the combined substrates 1,2-dioleoyl-sn-glycerol and [ 1 C]-palmitoyl-Co A and incubated with test compounds and microsomal membranes for 2 hours at room temperature.
  • the assay is stopped by adding 0.5 mg wheat germ agglutinin beads in assay buffer with 1% Brij-35 and 1% 3 -cholamidopropyldimemyl-ammomo-1 -propane sulfonate. Plates are sealed with TopSeal and incubated for 18 hours to allow the radioactive triglyceride product to come into proximity with the bead. Plates are read on a TopCount instrument.
  • Percent inhibition was calculated as the percent of (test compound inhibition minus non-specific binding) relative to (total binding minus non-specific binding). IC50 values were determined by curve fitting the data to a Sigmoidal dose-response in GraphPad Prism utilizing the following equation:
  • the solution is incubated at room temperature for 1 hour after which 20 ⁇ , of a 90 ⁇ 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin solution in 90% ethanol was added. After incubation in the dark for 30 minutes at room temperature, fluorescence was measured on a Perkin Elmer Envision multilabel reader. The IC50 is determined from a 4 parameter fit of the plot of %Inhibition vs.
  • Concentration of Test Compound in the reaction is defined as the concentration at which the curve crosses the 50% inhibition line.
  • the inhibitory activity was calculated from the following formula:
  • % inhibition [1 -(fluorescence counts from test compound- average fluorescence counts from LC)/(average fluorescence counts from HC-average fluorescence counts from LC)] x 100%
  • Examples 1 -2 were assayed, the compounds were assayed using Assay 1. If Examples 3-36 were assayed, the compounds were assayed using Assay 2.

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Abstract

Described herein are compounds of formula (I), formula la or formula lb The compounds of formula I, formula la or formula lb act as DGATl inhibitors and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.

Description

IMIDAZOLE DERIVATIVES
TECHNICAL FIELD
The present invention is directed to novel imidazole derivative compounds.
Specifically, the compounds act as diacylglycerol O-acyltransferase type 1 inhibitors (hereinafter also referred to as "DGAT1"), and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.
BACKGROUND
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and increased health problems. As such, obesity is recognized as an upstream risk factor for many conditions such as diabetes mellitus, lipidosis and hypertension (Journal of Japan Society for the Study of Obesity, Vol. 12, Extra Edition, 2006). Although the need to treat obesity is recognized to be important, there are extremely limited drug therapies for obesity that are currently available, and thus, the advent of novel antiobesity drugs having more definite action and few side-effects is desired.
In general, obesity is caused by the accumulation of triacylglycerol (TG) in adipose tissue which is a result of lack of exercise, intake of excessive calories and ageing. In the body there are two TG synthesis pathways, a glycerol phosphate pathway, which is present in most organs and causes de novo TG synthesis, and a monoacylglycerol pathway, which is involved principally in absorption of aliphatic acid from the small intestine. Diacylglycerol acyltransferases (DGATs, EC 2.3.1.20), which are membrane-bound enzymes present in the endoplasmic reticulum, catalyze the final step of the TG synthesis common to the two TG synthesis pathways. The final reaction consists of transferring an acyl group from acyl-coenzyme A to the 3-position of 1 ,2-diacylglycerol to generate TG (Prog. Lipid Res., 43,134-176, 2004 and Ann. Med., 36, 252-261, 2004). There are two subtypes of DGATs: DGAT1 and DGAT2.
There is no significant homology at the generic or amino acid level between DGAT1 and
DGAT2, which are encoded by different genes (Proc. Natl. Acad. Sci.USA., 95, 13018-13023, 1998 and JBC, 276, 38870-38876, 2001). DGAT1, is present in the small intestine, adipose tissue and liver and is believed to be involved in lipid absorption in the small intestine; lipid accumulation in the fat cell; and VLDL secretion and lipid accumulation in the liver (Ann. Med., 36, 252-261, 2004 and JBC, 280, 21506-21514, 2005). In consideration of these functions, a DGAT1 inhibitor is expected to be an effective obesity treatment through inhibition of lipid absorption in the small intestine, lipid accumulation in the adipose tissue and the liver, and lipid secretion from the liver.
. i _ In order to carry out in vivo examination of the physiological function(s) of DGAT1 and inhibitory activity against DGAT1, DGAT1 -knockout mice deficient in DGAT1 at the genetic level were produced and analyzed. As a result, the DGAT1 -knockout mice have been found to have smaller fat masses than those of wild-type mice and became resistant to obesity, abnormal glucose tolerance, insulin resistance and fatty liver due when fed a high-fat diet (Nature Genetics, 25, 87-90, 2000 and JCI, 109, 1049-1055, 2002). In addition, energy expense has been reported to be accelerated in the DGAT1 -knockout mice; and transplantation of the adipose tissues of DGAT1 -knockout mice into wild-type mice has been reported to make the wild-type mice resistant to obesity and abnormal glucose tolerance, induced by a high-fat diet (JCI, '1 11. 1715-1722, 2003 and Diabetes, 53, 1445-1451, 2004). In contrast, obesity and diabetes mellitus due to a high-fat diet have been reported to worsen in mice with overexpression of DGAT1 in adipose tissue (Diabetes, 51, 3189-3195, 2002 and Diabetes, 54, 3379-3386, 2005).
From these results, DGAT1 inhibitors are likely to be therapeutic drugs with efficacy for obesity, type 2 diabetes mellitus, lipidosis, hypertension, fatty liver, arteriosclerosis, cerebrovascular disorder, coronary artery disease and metabolic syndrome, associated with obesity.
SUMMARY OF THE INVENTION
Figure imgf000003_0001
I
or pharmaceutically acceptable salts thereof, wherein X is selected from the group consisting of - CH- or ~N-;
Z is selected from the group consisting of phenyl and nitrogen containing heterocycle, wherein the phenyl and nitrogen containing heterocycle can be unsubstituted or substituted with 1-3 substituents selected from a;
R\ R2 and R3 are independently selected from the group consisting of a;
a is selected from the group consisting of halogen, Ct-Cealkyl, halogen- substitutedCi~C6alkyl, COCi-Cgalkyl, COhalogen-substitutedCrC6alkyl5 oxo, -OH, Cp
C6alkylOH, C C6alkylOHCOOH, halogen-substitutedC C6alkylOH, -OCrC6alkyl, -Ohalogen- substitutedCi-Cealkyl, -COOH, -COCOOH, -COOCrC6alkyl, -CrC6alkylCOOCi-C6alkyl; -d- CealkylCOOH, -OCi-C6alkylCOOH, -CN, CrC6aIkylCN, -N02; NH2, NHCrC6alkyl, N(Cr C6alkyl)2, -NHCOOH, -NHCOOC C6alkyl, Ci-C6alkylCONH2, -CONH2, -CONHC3-C6alkyl, - NHCOC-CeaJkyl, -CON(CrC6alkyl)2, -NHS02CrC6alkyl, S02NH2, -S02CrC6alkyl; and
each occurrence of n independently selected from the list consisting of 1 or 2, DETAILED DESCRIPTION OF THE INVENTION
Compounds
A compound of formula (I):
Figure imgf000004_0001
I
or pharmaceutically acceptable salts thereof.
Of the compounds of formula I, X is -CH- or -N-. In certain embodiments, X is -
CH-. In other embodiments, X is -N-.
In any of the embodiments described above, each occurrence of n is independently selected from the list consisting of 1 or 2. In other embodiments, n is 1. In still other embodiments, n is 2.
Of the compounds of formula I, Z is selected from the group consisting of phenyl and nitrogen containing heterocycle, wherein the phenyl and nitrogen containing heterocycle can be unsubstituted or substituted with 1-3 substituents selected from a. In certain embodiments, Z is unsubstituted. In other embodiments Z is substituted with 1 substituent selected from a. In another embodiment, Z is substituted with 2 substituents selected from the group consisting of a. In yet another embodiment, Z is substituted with 3 substituents selected from the group consisting of a. In still yet another embodiment, Z is substituted with 1 or 2 substituents selected from the group consisting of a. In some embodiments, Z is substituted with 1-3 substituents independently selected from the group consisting of halogen, Ci-C6alk l, halogen-substitutedQ- Cealkyl, -OC C6alkyl, -COOH, -COOC Cealkyl, -d-CealkylCOOCrCealkyl, -Cr
C6alkylCOOH, -S02CrC6alkyls -CN, Ci-C6alkylCONH2 and ~-CONH2.
In certain embodiments of the compounds described herein Z is phenyl. In some embodiments, the phenyl Is unsubstituted. In other embodiments, the phenyl is substituted. In embodiments, Z is phenyl, wherein the phenyl is substituted with halogen, CrCsalkyl, halogen- substitutedCi-C6alkyl, -OCrQalkyl, -COOH, ~COOCi-C6alkyl, -CrC6alkylCOOCi-C6alkyl; - CrC6alkylCOOH, -S02CrC6alkyl, -CN, Ci-C6alkylCON¾ and -CON¾. From example, in certain embodiments of the compounds described herein, Z is phenyl, wherein the phenyl can be substituted with -COOH, -CH2COOH, -(CH2)2COOH, -C(CH3)2COOH, -COOMe, - C(CH3)2COOCH3, -OMe, -COOMe, -CH2COOCH2CH3, fluorine, methyl, -OH, triflouromethyl, -S02Me, -CH2CONH2, -C(CH3)2CONH25 CONH2 or -CN.
In certain embodiments of the compounds described herein Z is nitrogen- containing heterocycle. In some embodiments, the nitrogen-containing heterocycle is
unsubstituted. In other embodiments, the nitrogen-containing heterocycle is substituted.
Suitable examples of a nitrogen-containing heterocycle include, but are not limited to, benzimidazole, pyrimidine or pyridine. In embodiments, Z is nitrogen-containing heterocycle, wherein the nitrogen-containing heterocycle is substituted with substitutedCi-Cealkyl, -COOH, - COOCi-Cgalkyl, -CrQalkylCOOH, -CN and ~CONH2, From example, in certain embodiments of the compounds described herein, Z benzimidazole, pyrimidine or pyridine, wherein the benzimidazole, pyrimidine or pyridine can be substituted with -COOH, halogen-substitutedC]- C6alkyl or -C CealkylCOOH. In certain embodiments of the compounds described herein, Z is benzimidazole, pyrimidine or pyridine, wherein the benzimidazole, pyrimidine or pyridine can be unsubstituted
Of the compounds of formula I, R1 is selected from a. In certain embodiments, R1 is selected from the group consisting of halogen, -OCrC6alkyl, halogen-substitutedCi-Cealkyl. Suitable examples of R1 include, but are not limited to, chlorine, fluorine, methoxy and trifluromethyl.
in certain embodiments of the compounds described herein, R1 can be positioned as follows:
Figure imgf000005_0001
Of the compounds of formula I, R is selected from the group consisting of a. In some embodiments, Rz is selected from the group consisting of hydrogen, halogen and halogen- substitutedC]-C6alkyL In certain embodiments, R is hydrogen. In other embodiment, R is halogen. Suitable halogens include, but are not limited to, chlorine and fluorine. In still other embodiments, R2 is halogen-substitutedCi-C6alkyl. Suitable examples include, but are not limited to, trifluoromethyl.
Of the compounds of formula I, R is selected from the group consisting of hydrogen and -Cgalkyl. In certain embodiments, R2 is hydrogen. In yet other embodiments, R3 is C Cealkyl. Suitable examples include, but are not limited to, methyl.
Of the compounds of formula I, a is selected from the group consisting of halogen, Ci~C6alkyl, halogen-substitutedCrCealkyl, COCrCgalkyl, COhalogen-substitutedC C6alkyl, oxo, -OH, CrC6alkylOH, Cj-CealkylOHCOOH, halogen-substitutedC C6alkylOH, - OC C6alkyl, -Ohalogen-substitutedd-Cealkyl, -COOH, -COCOOH, -COOC C6alkyl, -Cr C6alkylCOOCi-C6aikyl, -C C6alkylCOOH, -OC C6alkylCOOH, -CN; d-CealkylCN, -NO¾ NH2, NHC,-C6alkyl, N(CrC6alkyl)2, -NHCOOH, -NHCOOQ-Csalkyl, -CON¾, -CONHCi- C6alkyl, ~NHCOC,-C6alkyi, ~CON(Ci-C6alkyl)2, -NHS02CrC6aUiyl, S02NH2; -S02C C6alkyl
Also described herein are compounds of formula la:
Figure imgf000006_0001
la
or pharmaceutically acceptable salts thereof, wherein R1 and Z are defined as above.
Also described herein are compounds of formula lb:
Figure imgf000006_0002
lb
or pharmaceutically acceptable salts thereof, wherein R1, R3 and Z are defined as above.
Examples of the compounds described herein include those shown in Table 1 :
Table 1
Figure imgf000006_0003
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
-8-
Figure imgf000010_0001
Figure imgf000011_0001
and pharmaceutically acceptable salts thereof.
Definitions
Examples of "halogen" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
The term "CpC galkyl" encompasses straight alk l having a carbon number of 1 to 6 and branched alkyl having a carbon number of 3 to 6. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1 ,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1 ,2-dimethylbutyl, 2,2- dimethylbutyl, 1-ethylbutyl, 1, ,2-trimethylpropyl, 1,2,2-trimethylpropyl, l-ethyl-2- methylpropyl, 1 -ethyl- 1-methylpropyl, and the like.
"Cycloalkyl" encompasses cycloalkyls having 3 to 10 carbons, forming one or more carbocyclic rings that are fused. "Cycloalkyl" also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. In one embodiment, the cycloalkyl can include 3-6 carbons, i.e. C3-C6cycloalkyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl,
decahydronaphthyl, indanyl and the like.
The term "-OCi -C 6alkyl" refers to an alkyl group having 1 to 6 carbons linked to oxygen, also known as an alkoxy group. Examples include methoxy, ethoxy, butoxy and propoxy.
The term "-OCi-C 6alkylCOOH" refers to an alkoxy group having 1 to 6 carbons substituted with a carboxylic acid (-COOH) group.
The term "halogen-substitutedCrC6 alkyl" encompasses CpC6 alkyl with the hydrogen atoms thereof being partially or completely substituted with halogen, examples thereof including fluoromethyl, difluoromethyl, trifiuoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl and the like.
The term "-Ohalogen-substitutedCpCealky means a -OCpCealkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different, and specifically includes, for example, a trifluoromethoxy group.
The term "-COCpC6arky means groups having CpC6alkyl bonded to carbonyl, and encompasses alkylcarbonyl having a carbon number of 1 to 6. Specific examples thereof include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and the like. The term "-COhalogen-substi ted -Cealkyl" means a -COCi~C6alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different.
The term "Ci-C6alkylOH" means a Q-Cealkyl substituted with an alcohol (-OH).
Examples include methanol, propanol, butanol and t-butanoL
The term "halogen-substitutedCrCealkylOH" means a halogen- substi tedQ-Qatkyl, as defined above, substituted with an alcohol (-OH).
The term rC6alkyIOHCOOH" means a C C6alkyl substituted with an alcohol (-OH) and a carboxylic acid group (-COOH).
The term "CrC6alkylCN" means a C|-C6alkyl substituted with an cyano group (-CN). The term "COOCi-Cealkyl" means a -COOH group wherein the -OH is replaced with an alkoxy group as defined above. Examples include methoxycarbonyl, eihoxycarbonyl and butoxycarbonyl.
The term
Figure imgf000012_0001
means a group having Ci-C6alkyl bonded to sulfonyl (-S02~). Specific examples thereof include methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl, tert-butanesulfonyl, and the like.
The term "oxo" means the functional group "=0", such as, for example, (1) "C=(0)' that is a carbonyl group; (2) "S~(0)", that is, a sulfoxide group; and (3) "N=(0)"s that is, an N-oxide group, such as pyridyl-N-oxide.
The term "NHQ-Cealkyl" means a group with one of the hydrogen atoms of amino (- N¾) being substituted with a C1-6 alkyl group. Specific examples thereof include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino, and the like.
The term "NCCi-Cealk iy means a group with the two amino hydrogen atoms each being substituted with a C1-6 alkyl group. Specific examples thereof include dimethylamino, diethylamino, ethylmethyiamino, di(n-propyl)amino, methyl(n-propyl)amino, diisopropylamino, and the like.
The term "NHCOiCrQalkyl" means a group with one of the amino hydrogen atoms being substituted with C1-6 alkoxycarbonyl and encompasses alkoxycarbonylamino having a carbon number of 1 to 6. Specific examples thereof include methoxycafbonylamino, ethoxycarbonylamino, n-propyloxycarbonylamino, isopropyloxycarbonylamino, n- butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, n- pentyloxycarbonylamino, and the like.
The term "NHCOCrC6alkyr means a group with one of the amino hydrogen atoms being substituted with Ci-6 alkylcarbonyl. Specific examples thereof include acetylamino, propionylamino, isobutyryl amino, valerylamino, isovalerylamino, pivaloylamino, and the like.
The term "CONHCrC6alkyl" means a group with one of the hydrogen atoms of carbamoyl (-CONH2) being substituted with Ci-6 alkyl. Specific examples thereof include methylcarbamoyl, ethylcarbarnoyl, n-propyl carbamoyl, isopropylcarbamoyl, n-butylcarbamoyl} sec-butylcarbamoyl, tert-butylcarbamoyl, and the like.
The term "CONtCi-Csalkyiy means a group with the two carbamoyl hydrogen atoms each being substituted with Ci-6 alkyt. Specific examples thereof include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl,, di(n-propyl)carbamoyl, methyl (n-propyl)carbamoyls diisopropylcarbamoyl, and the like.
The term "NHSChQ-Cgalkyl" means a group with one of the amino hydrogen atoms being substituted with C1-6 alkylsulfonyl. Specific examples thereof include
methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino,
isopropanesulfonylamino, n-butanesulfonylamino, sec-butanesulfonylamino, tert- butanesulfonylamino, and the like.
"Heterocycle" unless otherwise specified, means an aromatic, partially aromatic or non- aromatic monocyclic or polycyclic (including bicyclic) ring having at least one ring heteroatom selected from O, S and N. Examples of heterocyclic groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazoJyl, pyridinyi, 2-oxo-(lH)~pyridinyl (2-hydroxy-pyridinyl), oxazolyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, ihienyl, pyrimidinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, d ydrobenzothienyl, indolizmyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indoiyl, isoquinolyl, dibenzofuranyl, imidazo[l,2- ajpyridinyl, [l,2,4-triazolo][4,3-a]pyridinyl, pyrazolo[l,5-a]pyridinyl, [l,2,4-triazolo][l,5- ajpyridinyl, 2-oxo- 1,3 -benzoxazolyl, 4-oxo-3H-quinazolinyl, 3-oxo-[i,2,4]-triazolo[4>3-ii]-2H'- pyridinyl, 5-oxo-[l,2,4]-4H-oxadiazolyl, 2-oxo-[l53,4]-3H-oxadiazolyl> 2-oxo- l,3-dihydro-2H- imidazolyl, 3-oxo-2,4-dihydro-3H-l,2,4-triazolyi, and the like. Examples of "heterocycle" also include tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2J3-dihydrofuro(2,3-£>)pyridyi, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2,l-&]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, 2- or 4-pyridones attached through the nitrogen or jV-substituted-(lH, 3H)-pyrimidine-2,4-diones (JV-substituted uracils). The term also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2~ azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 2- azabicyclo[2.2.2]octyl, and 3-azabicyclo[3.2.2]nonyl, and azabicyclo[2.2.1]heptanyl.
The term "pharmaceutically acceptable salt" refers to salts prepared from
pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term
"pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, trietbiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as argi ine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamme, N-ethylmorpholine, N-ethylpiperidme, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
The compounds of the present invention contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of these compounds.
Some of the compounds described herein contain olefmic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomericaliy pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racermc mixture of the compounds can also be separated directly by
chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
It will be understood that, as used herein, references to the compounds of the structural formulas described herein are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.
Solvates, and in particular, the hydrates of the compounds of the structural formulas described herein are included in the present invention as well.
Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of the present invention.
In the compounds of the formulas described herein, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the formulas described herein. For example, different isotopic forms of hydrogen (H) include protium (ΪΗ) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic formula can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
Methods of Treatment
Also encompassed by the present invention are methods of treating DGATl -related diseases. The compounds described herein are effective in preventing or treating various DGATl -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis. The compound of the invention is especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety.
One aspect of the invention described herein provides a method for the treatment and control of obesity or metabolic syndrome, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having the formulas described herein or a pharmaceutically acceptable salt thereof. For example, the compounds described herein are useful for treating or preventing obesity by administering to a subject in need thereof a composition comprising a compound of formula I, formula la or formula lb.
Methods of treating or preventing obesity and conditions associated with obesity refer to the administration of the pharmaceutical formulations described herein to reduce or maintain the body weight of an obese subject or to reduce or maintain the body weight of an individual at risk of becoming obese. 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 or combinations of the present invention. Another outcome of treatment may be preventing body weight gain, regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy and preventing weight gain from cessation of smoking. Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases. Yet another outcome of treatment may be decreasing the risk of developing diabetes in an overweight or obese subject. The treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof. The treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.
Prevention of obesity and obesity-related disorders refers to the administration of the pharmaceutical formulations described herein 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 or combinations 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. Moreover, if treatment is commenced in already obese subjects, such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, type 2 diabetes, polycystic ovary disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
Another aspect of the invention that is of interest relates to a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat hyperglycemia, diabetes or insulin resistance.
More particularly, another aspect of the invention that is of interest relates to a method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising
administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat type 2 diabetes.
Yet another aspect of the invention that is of interest relates to a method of treating non- insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat non-insulin dependent diabetes mellitus.
The present invention is also directed to the use of a compound of structural formula I, formula la or formula lb in the manufacture of a medicament for use in treating various DGAT1- related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congesti e cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis. The compounds described herein are especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety.
For example, the present invention is directed to the use of a compound of structural formula I, formula la or formula lb in the manufacture of a medicament for use in treating obesity, diabetes, hormone secretion disorder, hyperlipemia, gout and fatty liver.
Additionally, the present invention is directed to the use of a compound of structural formula I, formula la or formula lb in the manufacture of a medicament for use in treating obesity.
Pharmaceutical Compositions
Compounds of the invention may be administered orally or parenterally. As formulated into a dosage form suitable for the administration route, the compound of the invention can be used as a pharmaceutical composition for the prevention, treatment, or remedy of the above diseases.
In clinical use of the compound of the invention, usually, the compound is formulated into various preparations together with pharmaceutically acceptable additives according to the dosage form, and may then be administered. By "pharmaceutically acceptable" it is meant the additive, carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. As such additives, various additives ordinarily used in the field of pharmaceutical preparations are usable. Specific examples thereof include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, corn starch, macrocrystalline wax, white petrolatum, magnesium metasiiicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropyleellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, poiyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic acid anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, and the like.
Preparations to be formed with those additives include, for example, solid preparations such as tablets, capsules, granules, powders, suppositories; and liquid preparations such as syrups, elixirs, injections. These may be formulated according to conventional methods known in the field of pharmaceutical preparations. The liquid preparations may also be in such a form that may be dissolved or suspended in water or in any other suitable medium for their use.
Especially for injections, if desired, the preparations may be dissolved or suspended in physiological saline or glucose liquid, and a buffer or a preservative may be optionally added thereto. The pharmaceutical compositions may contain the compound of the invention in an amount of from 1 to 99.9 % by weight, preferably from 1 to 60 % by weight of the composition.
The compositions may further contain any other therapeutically-effective compounds.
In case where the compounds of the invention are used for prevention or treatment for the above-mentioned diseases, the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the patient and on the type and the range of the intended remedial effect. In general, when orally administered, the dose may be from 0.001 to 50 mg/kg of body weight/day, and it may be administered at one time or at several times. The dose is preferably from about 0.01 to about 25 mg kg/day, more preferably from
about 0.05 to about 10 mg/kg/day. For oral administration, the compositions are preferably
provided in the form of tablets or capsules containing from 0.01 mg to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 750, 850 and 1,000 milligrams of a compound described herein. This dosage regimen may be adjusted to provide the optimal therapeutic response.
Combination Therapy
The compounds of the present invention are further useful in methods for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other therapeui agents.
The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of formula I, formula la or formula lb or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of formula I, formula la or formula lb. When a compound of formula I, formula la or formula lb is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of formula I, formula . or formula lb is preferred. However, the combination therapy may also include therapies in which the compound of formula I, formula la or formula lb and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or mc other active ingredients, the compounds of the present invention and the other active ingredients may t used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions oft present invention include those that contain one or more other active ingredients, in addition to a compound of formula I, formula la or formula lb. Examples of other active ingredients that may be administered in combination with a compounc of formula I, formula la or formula lb, and either administered separately or in the same pharmaceutical composition, include, but are not limited to:
(I) dipeptidyl peptidase-TV (DPP-4) inhibitors;
(2) insulin sensitizers, including (i) PPARy agonists, such as the glitazones (e.g. pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligands, including (1) PPARa/γ dual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPA a agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), such as those disclosed in WO
2002/060388, WO 2002/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963, and (4) PPARy partial agonists; (ii) biguanides, such as metformin and its
pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and GlucophageXR®; (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;
(3) insulin or insulin analogs, such as insulin lispro, insulin detemir, insulin glargine, insulin glulisine, and inhalable formulations of each thereof;
(4) leptin and leptin derivatives and agonists;
(5) amylin and amylin analogs, such as pramlintide;
(6) sulfonylurea and non-sulfonylurea insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;
(7) α-glucosidase inhibitors (such as acarbose, voglibose and miglitol);
(8) glucagon receptor antagonists, such as those disclosed in WO 1998/04528, WO 1999/0142; WO 2000/39088, and WO 2000/69810;
(9) incretin mimetics, such as GLP-1, GLP- analogs, derivatives, and mimetics; and GLP-1 receptor agonists, such as exenatide, liraglutide, taspoglutide, AVE0010, CJC- 1131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof;
(10) LDL cholesterol lowering agents such as (i) H G-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fiuvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, coiesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl CoA:cholesterol acyltransferase inhibitors, such as avasimibe;
(I I) HDL-raising drugs, such as niacin or a salt thereof and extended-release versions thereof; MK-524A, which is a combination of niacin extended-release and the DP-1 antagonist MK-524; and nicotinic acid receptor agomsts;
(12) antiobesity compounds;
(13) agents intended for use in inflammatory conditions, such as aspirin, non-steroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors; (14) antihypertensive agents, such as ACE inhibitors (such as enalapril, iisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta
(15) glucokinase activators (GKAs), such as LY2599506;
(16) inhibitors of 1 Ιβ-hydroxysteroid dehydrogenase type 1, such as those disclosed in U.S.
Patent No. 6,730,690; WO 2003/104207; and WO 2004/058741;
(17) inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib and MK-0859;
(18) inhibitors of fructose 1,6-bisphosphatase, such as those disclosed in U.S. Patent Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476;
(19) inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2);
(20) AMP-activated Protein Kinase (AMPK) activators;
(21) agonists of the G-protein-coupIed receptors: GPR-109, GPR-119, and GPR-40;
(22) SSTR3 antagonists, such as those disclosed in WO 2009/011836;
(23) neuromedin U receptor agonists, such as those disclosed in WO 2009/042053, including, b not limited to, neuromedin S (NMS);
(24) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD);
(25) GPR-105 antagonists, such as those disclosed in WO 2009/000087;
(26) inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT) inhibitors and its various isoforrns, such as SGLT-1; SGLT-2, such as dapagliflozm and remogliflozin; and SGLT-3;
(27) inhibitors of acyi coenzyme A:diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGA1
2);
(28) inhibitors of fatty acid synthase;
(29) inhibitors of acetyl-CoA carboxylase-1 and 2 (ACC-1 and ACC-2);
(30) inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2);
(31) agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and h BAR); and
(32) bromocriptine mesylate and rapid-release formulations thereof.
Dipeptidyl peptidase-IY (DPP-4) inhibitors that can be used in combination with compounds c formula I, formula la or formula lb include, but are not limited to, sitagliptin (disclosed in US Patent IS 6,699,871), vildagliptin, saxagliptin, alogliptin, denagiiptin, carmegliptin, dutogliptin, melogliptin, linagliptin, and pharmaceutically acceptable salts thereof, and fixed-dose combinations of these compounds with metformin hydrochloride, pioglitazone, rosiglitazone, simvastatin, atorvastatin, or a sulfonylurea.
Other dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of formula I, formula la or formula lb include, but are not limited to: (2i?3^5J?)-5-(l-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)-2-(2I4,5- trifluorophenyl)tetrahydro-2H-pyran-3 -amine ;
(2i?,35s5i?)-5-(l-methyl-4J6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)-2-(2i4,5- trifluorophenyl)te1xahydro-2H-pyran-3-armne;
(2 53S,5i?)-2-(2,5-difluorophenyl)te^^
tetrahydro-2H-pyran-3 -amine ;
(3i?)-4-[(3i -3-amino-4-(2,4,5-trifluorophen^
2-one;
4-[(3i?)-3-amino-4-(2,5-difluorophenyl)butanoyl]hexah.ydro- 1 -methyl-2H- 1 ;4-diazepin-2-one hydrochloride; and
(3i?)-4-[(3i?)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-hexahydro-3-(2,2?2- fiuoro
diazepin-2-one; and
pharmaceutically acceptable salts thereof.
Antiobesity compounds that can be combined with compounds of formula I, formula la or formula lb include topiramate; zonisamide; naltrexone; phentermine; bupropion; the combination of bupropion and naltrexone; the combination of bupropion and zonisamide; the combination of topirama and phentermine; fenfluramine; dexfenfiuramine; sibutramine; lipase inhibitors, such as oriistat and cetilistat; melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists; CC -1 agonists; melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Y or Y5 antagonists (such as MK-0557); CBl receptor inverse agonists and antagonists (such as rimonabant am taranabant); β3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (such as bombesin receptor subtype-3 agonists); and 5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin. For a review of anti-obesity compounds that can be combined with compounds of the prese invention, see S. Chaki et al, "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity,1" Expert Opin. Ther. Patents, 11: 1677-1692 (2001); D. Spanswici and K. Lee, "Emerging antiobesity drugs," Expert Opin. Emerging Drugs, 8: 217-237 (2003); J. A. Fernandez-Lopez, et al., "Pharmacological Approaches for the Treatment of Obesity," Drugs, 62: 915- 944 (2002); and K.M. Gadde, et al., "Combination pharmaceutical therapies for obesity," Exp. Opin. Pharmacother., 10: 921-925 (2009).
Glucagon receptor antagonists that can be used in combination with the compounds of formula formula la or formula lb include, but are not limited to:
7Y-[4-((15)-l - {3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-l H-pyrazol-1 - yl } ethyl)benzoyl]- -aIanine;
N-[4-(( 1 R)- 1 - { 3 -(3 ,5-dichlorophenyl)- 5 - [6-(trifluoromethoxy)-2-naphthyl]- 1 H-pyrazol- 1 - yl } ethyl)benzoyl] -β-alanine;
N-(4- { 1 - [3 -(2 , 5 -dichlorophenyl)-5-(6-methoxy-2-naphthyl)- 1 H-pyrazol- 1 -yl] ethyl } benzoyl)- β- alanine; N-(4-{(lS)-l-[3-(3,5-dicMorophenyl)-5-(6-methoxy-2-naphthyl)-lH-pyrazol-l- yl] ethyl } benzoyl)- -alanine ;
N-(4-{(lS)-l-[(R)-(4-cWorophenyl)(7-flu^
alanine; and
N-(4-{(l S)-l-[(4-chlorophenyl)(6-chloro-8-methylquinolin-4-yl)methyl]butyl}benzoyl)- - alanine; and
pharmaceutically acceptable salts thereof.
Inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
[5-(5 - {4-[2-(trifluoromethyl)phenoxy]piperidin- 1 -yl } - 1 ,3 ,4-thiadiazol-2 -yI)-2H-tetrazol-2- yl] acetic acid;
(2'-{4-[2-(trifluoromethyl)phenoxy]piperidin-l-y]}-2,5'-bi-l,3-thiazol-4-yl)acetic acid;
(5-{3-{4-(2-bromo-5-fluorophenoxy)piperidin-l-yl]isGxazol-5-yl}-2H-tetrazol-2-yl)acetic acid; (3 - { 3 - [4-(2-bromo-5 -fluorophenoxy)piperidin- 1 -yl] - 1 ,2,4-oxadiazol~5 -yl } - 1 H-pyrrol- 1 -yl )acetic acid;
(5- {5-[4-(2~bromo-5-fluorophenoxy)piperidin- 1 -yl]pyrazm-2-yl} -2H-tetrazol-2»yl)acetic acid; and
(5-{2-[4-(5-bromo-2-chlorophenoxy)piperidin-l-yl]pyrimidin-5-yl}-2H-tetrazol-2-yl)acetic acid; and pharmaceutically acceptable salts thereof.
Glucokinase activators that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
3 -(6-ethanesulfonylpyridin-3 -yloxy)-5-(2-hydroxy- 1 -methyl-ethoxy)-N-( 1 -methyl- 1 H-pyrazol-3 - yl)benzamide;
5-(2~hydroxy- 1 -methyI~ethoxy)-3 -(6-methanesulfonyIpyridin-3-yloxy)-N-( 1 -methyl- 1 H-pyrazol- 3-yl)benzamide;
5-( 1 -hydroxymethyl-propoxy)- 3 -(6-methanesulfonylpyridin-3 -yl oxy)-N-( 1 -methyl- 1 H-pyrazol-3 - yi)benzamide;
3-(6-methanesulfonylpyridin-3-yioxy)-5-(I-methoxymethyl-propoxy)-N-(l-methyl-lH-pyrazol- 3-yl)benzamide;
5-isopropoxy-3-(6-memanesulfonylpyridin-3-yloxy)-N-(l-memyl-lH-pyra2;oI-3-yi)benzamide; 5 -(2-fhioro- 1 -fluoromethyl-ethoxy)-3 -(6-methanesulfonylpyridin-3 -yloxy)-N-( 1 -methyl- 1 H- pyrazol-3 -yl)benzarnide;
3 -( {4-[2~(dimethylamino)ethoxy]phenyl }thio)-N-(3 -methyl- 1 ,2,4-thiadiazol-5 -yI)-6-[(4-methyl- 4H- 1 ,2,4-triazol-3-yl)thio]pyridine-2~carboxamide;
3-({4-[(l -methylazetidin-3-yl)oxy]phenyl}thio)-N-(3-methyl- 1 ,2,4-thiadiazol-5-yl)-6-[(4-methyl- 4H-l,2?4-triazol-3-yl)thio]pyridine-2-carboxamide; N-(3-memyl-l
Figure imgf000024_0001
1- ylethoxy)phenyl]tbio}pyridine-2-carboxamide; and
3-[(4-{2-[(2R)-2-me lpyn:olidin-l-yl]eta
methyl-4H~l,2,4-triazol-3-yl)thio]pyridine-2-carboxamide; and pharmaceutically acceptable salts thereof.
Agonists of the GPR-119 receptor that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
rac-c is 5 -chloro-2- { 4- [2-(2- { [5-(methylsulfonyl)pyridin-2-yl] oxy } ethyl)cyclopropyl] piperidin- 1 - yl}pyrimidine;
5-chloro~2- {4-[(lR,2S)-2-(2-{ [5-(methylsulfonyl)pyridin-2-yl]oxy} ethyl)cyclopropyl]piperidin- 1 -yl}pyrimidine;
rac cis-5 -chloro-2 - [4~(2- { 2- [4-(methylsulfonyl)phenoxy]ethyl } cyclopropyl)piperidin- - yl]pyrimidine;
5-chloro-2-[4-((l S,2R)-2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl) piperidin-1 - yljpyrimidine;
5-chloro-2-[4~((lRs2S)-2- {2-[4-(methylsulfonyl)phenoxy]ethyl} cyclopropyl) piperidin- 1- yl]pyrimidine;
rac cw-5-chloro-2-[4~(2- {2- [3-(methylsulfonyl)phenoxy]ethyl } cyclopropyl)piperidin- 1 - yljpyrimidine; and
rac cis -5 -chloro-2- [4-(2-{ 2- [3 -(5 -methyl- 1 s3,4-oxadiazol~2-yl)phenoxy]ethyl} cyclopropyl) piperidin- 1 ~yl]pyrimidine; and pharmaceutically acceptable salts thereof.
Selective PPARy modulators (SPPARyM's) that can be used in combination with the compoun of formula I, formula la or formula lb include, but are not limited to:
(2S)-2-( {6-chloro~3 - [6-(4-chlorophenoxy)-2-propylpyridin-3 -yl] - 1 ,2-benzisoxazol-5 - yl}oxy)propanoic acid;
(2iS)-2-( { 6-chloro~3 -[6-(4-fluorophenoxy)-2-propylpyridin-3 -yl]- 1 ,2-benzisoxazol- 5 - yl}oxy)propanoic acid;
(2S)-2-{ [6~chloro-3-(6-phenoxy-2-propylpyridin-3-yl)- 1 ,2-benzisoxazol-5-yl]oxy} propanoic acid;
(2Z?)-2-({ 6-chloro- 3 - [6-(4-chlorophenoxy)-2-propylpyridin-3 -yl] - 1 ,2-benzisoxazol-5- yl}oxy)propanoic acid;
(2R)-2- { 3 - [3 -(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)- 1 H-indol- 1 - yl]phenoxy}butanoic acid;
(2S)-2- {3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)- lH-indol-1 - yl]phenoxy}butanoic acid;
2- { 3 - [3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)- 1 H-indol- 1 -yl]phenoxy} -2- methylpropanoic acid; and (2R)-2- { 3 - [3 -(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)- 1 H-indol - 1 - yl]phenoxy}propanoic acid; and pharmaceutically acceptable salts thereof.
Inhibitors of 1 Ιβ-hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
3-[l-(4-chloropherayl)-fra«s-3^
cWorophenyl)-fraiF¾5'-3-fluorocycloburyl]-4-cyclopropyl-5-(l-methylcyclopropyl)-r-4H-l,2!4- triazole;
3- [ 1 -(4-chlorophenyl)-;ra/ii'-3 -fluorocyclobutyl] -4-methyl-5- [2-(trifluoromethoxy)phenyl] -r-4H~ 1 ,2,4-triazole;
3- [ 1 -(4-chlorophenyl)cyclobutyl]-4-rnethyl-5- [2-(trifluoromethyl)phenyl] -4H- 1 ,2,4-triazole;
3- {4-[3-(emylsulfonyl)propyl]bicyclo[2.2 ]oct-l-yl}-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H -1 ,2,4-triazole;
4- methyl-3-{4-[4-(methylsuIfonyl)phenyl]bicyclo[2.2.2]oct-l-yl}-5-f2-(trifluoromethyl)phenyl]- 4H ,2,4-triazole;
3-(4-{4-methyl-5-[2-(trifluorom
(3,3 ,3-trifluoropropyl)- 1 ,2,4-oxadiazole;
3(4.{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-l -yl)-5- (3 ,3,3-trifluoroemyl)-l ,2,4-oxadiazole;
5- (3,3-difluorocyclobutyl)-3-(4-{4-me
yl}bicyclo[2.2.2]oct-l -yl)- 1 ,2,4-oxadiazole;
5-(I-fluoro-l-memylethyl)-3~(4-{4-met^
yl}bicyclo[2.2.2]oct- 1 -yl)-l ,2,4-oxadiazole;
2-(l , 1 -difiuoroethyl)-5-(4- {4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-l ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-l-yl)-l,3,4-oxadiazole;
2-(3,3-difluorocyclobutyl)-5-(4-{4-methyl-5-[2-(triiluoromemyl)phenyl]-4H-l,2,4-triazol-3- yl } bicyclo [2.2.2]oct- 1 -yl)- 1 ,3 ,4-oxadiazole; and
5-(l , 1 -difluoroethyl)-3-(4- {4-methyl-5-[2-(trifluoromethyl)phenyi]-4H-l ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-l-yl)-l,2,4-oxadiazole; and pharmaceutically acceptable salts thereof.
Somatostatin subtype receptor 3 (SSTR3) antagonists that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
Figure imgf000025_0001
Figure imgf000026_0001
and pharmaceutically acceptable salts thereof.
AMP-activated Protein Kinase (AMPK) activators that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
Figure imgf000026_0002
Figure imgf000027_0001
and pharmaceutically acceptable salts thereof.
Inhibitors of acetyl-CoA carboxylase- 1 and 2 (ACC-1 and ACC-2) that can be used in combination with the compounds of formula 1, formula la or formula lb include, but are not limited to: 3-{r-[(l-cyclopropyl-4-methoxy-lH-indol-6-yl)carbonyi]-4-oxospiro[chroman- 2,4'-piperidm]- 6-yl} benzoic acid;
5-{r-[(l-cycIopropyl-4-methoxy-lH-ii^
yl} nicotinic acid;
- [( 1 -cyclopropyl-4-methoxy- 1 H-indol-6-yl)carbonyl] -6-( 1 H-tetrazol-5 -yi)spiro [chroman-2 ,4'- piperidin]-4-one;
Γ- [( 1 -cyclopropyl-4-ethoxy-3 -methyl- 1 H-indol-6-yl)carbonyl]-6-( 1 H-tetrazol-5- yl)spiro [chroman-2,4 -piperidin] -4-one ; and 5 - { Γ- [( 1 -cyclopropyl ~4-methoxy-3 -m^
piperidin]-6-yl} nicotinic acid; and
pharmaceutically acceptable salts thereof.
In another aspect of the invention, a pharmaceutical composition is disclosed which comprises one or more of the following agents:
(a) a compound of structural formula I, formula la or formula lb;
(b) one or more compounds selected from the group consisting of:
(1) dipeptidyl peptidase-IV (DPP-4) inhibitors;
(2) insulin sensitizers, including (i) PPARy agonists, such as the glitazones (e.g.
pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PP AR ligands, including (1) PPARa/γ dual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPARa agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrat and bezaflbrate), (3) selective PPARy modulators (SPPARyM's), and (4) PPARy partial agonists; (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and GlucophageXR®; (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;
(3) sulfonylurea and non-sulfonylurea insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;
(4) a-glucosidase inhibitors (such as acarbose, voglibose and miglitol);
(5) glucagon receptor antagonists;
(6) LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pravastatin, and rosuvastatir (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelara hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl CoA:cholesterol acyltransferase inhibitors, such as avasimibe;
(7) HDL-raising drugs, such as niacin or a salt thereof and extended-release versions thereof; MK.-524A, which is a combination of niacin extended-release and the DP-1 antagonist MK-52 and nicotinic acid receptor agonists;
(8) antiobesity compounds;
(9) agents intended for use in inflammatory conditions, such as aspirin, non-steroidal an inflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
(10) antihypertensive agents, such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta;
(11) glucokmase activators (GKAs), such as LY2599506; (12) inhibitors of 1 Ιβ-hydroxysteroid dehydrogenase type 1;
(13) inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib and MK-
0859;
(14) inhibitors of fructose 1,6-bisphosphatase;
(15) inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2);
(16) AMP-activated Protein Kinase (AMPK) activators;
(17) agonists of the G-protein-coupled receptors: GPR-109, GPR-1 19, and GPR-40;
( 8) SSTR3 antagonists;
(19) neuromedin U receptor agonists, including, but not limited to, neuromedin S (NMS
(20) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD);
(21 ) GPR- 105 antagonists;
(22) inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2, such as dapagliflozin and remogliflozin; and SGLl 3;
(23) inhibitors of acyl coenzyme Ardiacylglycerol acyltransferase 1 and 2 (DGAT-1 and
DGAT-2);
(24) inhibitors of fatty acid synthase;
(25) inhibitors of acetyl-CoA carboxylase-1 and 2 (ACC-1 and ACC-2);
(26) inhibitors of acyl coenzyme Armonoacylglyceroi acyltransferase 1 and 2 (MGAT-1 and MGAT-2);
(27) agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPRI31 and M-BAR); and
(28) bromocriptine mesylate and rapid-release formulations thereof; and (c) a pharmaceutically acceptable carrier.
When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
The weight ratio of the compound of the present invention to the second active ingredient may varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of eacl will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1 : 1000, preferably about 200:1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s). General Schemes and Examples
The following is a list of abbreviations used in the description of the Schemes and synthesis of the Intermediates and Examples shown below.
List of Abbreviations:
DMF = dimethylformamide
EtOAc = ethyl acetate
HATU 2-( 1 H-7 - Azabenzotriazol- 1 -y 1)~ 1 , 1 ,3 , 3 - tetramethyl
uronium hexafiuorophosphate Methanaminium
LiOH = lithium hydroxide
Na2S04 = sodium sulfate
r or RT room temperature
tetrahydrofuran
Scheme 1
Figure imgf000030_0001
Figure imgf000031_0001
Step 1 : methyl 6-fpiperazin-l-yl pyrazine-2-carboxylate
To methyl 6-(4-(tert-butoxycarbonyl)piperazin-l-yl)pyrazine-2-carboxyiate (193 mg, 0.60 mmol) in 1, 4-dioxane (5mL) was added 4 N hydrogen chloride in dioxane (0.5 mL). The reaction mixture was stirred at RT overnight then concentrated to give ethyl 6-(4-(5-(5-(trifluoromethyl)- lH-benzo[d]imidazol-2-yl)pyridin-2-yl)piperazin-l-yl)pyrazine-2-carboxyIate as a white solid. LC/MS = 223 [U+l].
Step 2: ethyl 6-(4-(5-(5-(trifluoromethvI -lH-berizofd]imidazol-2-yl)pyridin-2-yl)piperazin-l- yl)pyrazine-2-carboxyiate
To ethyl 6-(4-(5-(5-(trifluoromethyl)- 1 H-benzo[d]imidazol-2-yl)pyridin-2-yl)piperazin- 1 - yl)pyrazine-2-carboxylate (89 mg, 0.40 mmol) in DMF (4.0 mL) was added 2-(6-fluoropyridin-3- yl)-5-(trifluoromethyl)-lH-benzo[d]imidazole (112 mg, 0.40 mmol) and N, N- diisopropylethylamine (0.035 mL, 0.20 mmol). The reaction mixture was heated at 100 °C for 5 h then cooled to RT and concentrated. Water (1 0 mL) was added, and the aqueous solution was extracted with CH2CI2 (3 x 50 mL). The combined organic extract was dried (MgS0 ), filtered, and concentrated. Purification by silica gel chromatography (eluant: 3: 1 CH2C12 : methanol) to obtain ethyl 6-(4-(5-(5-(trifluoromemyl)-lH-benzo[d]irnidazol-2-yl)pyridin-2-yl)p
yl)pyrazine-2-carboxylate as a brown solid. LC/MS = 484 [M+l].
Step 3: 6-(4-(5 -(5 -f trifluororoethvO- 1 H-benzo [dl imidazol-2- yl)pyridin-2-yl)piperazin- 1 - yl)pyrazine-2-carboxylic acid To a solution of 5-((l-(5-(5-chloro-lH-benzo[d]imidazol-2-yl)pyridin-2-yl)piperidi yl)methoxy)isophthalate (48 mg, 0.10 mmol) in MeOH (3.0 mL), THF (3.0 mL), and water (2.0 mL) was added 1 N aq. sodium hydroxide (2.0 mL). The reaction mixture was stirred at RT for 5 h then 1 N HCl (2.5 mL) was added, and the solution was concentrated. The title compound 6-(4- (5-(5-(trifluoromethyl)-lH-berizo^
carboxylic acid was obtained after purification by reverse phase Gilson HPLC (eluant: H20 : C¾CN) as a white solid. LC/MS - 470 [M+l].
EXAMPLE 2
Figure imgf000032_0001
Step 1 : 5-chloro-2-(6-fluoropyridin-3 -ylV 1 H-benzo [d] imidazole
4-Ch]orobenzene-l,2-diamine (5.0 g, 35.2 mmol) was dissolved in DMF (40 mL) with water (1 mL), and oxone (14.1 g, 22.9 mmol) was added. 6-Fluoronicotinaldehyde (4.62 g, 37.0 mmol) dissolved in DMF (20 mL) was added dropwise over 20 mins via addition funnel. The reaction mixture was stirred at RT for 3 h then poured onto water (1000 mL). Solid potassium carbonate was added to adjust pH to 7. The precipitate was filtered and washed with water. The solid was then dissolved in CH2Q2 and washed with water. The organic layer was dried (MgS04), filtered, and concentrated. Purification by silica gel chromatography (eluant: 0 - 25% EtOAc - CH2C12) to yield 5-chloro-2-(6-fluoropyridin-3-yi)-lH-benzo[d]imidazole as a yellow solid. LC/MS = 249 [M+l].
Step 2: 5-chloro-2-[6-[4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin- 1 -yl]pyridin-3-yl"|- IH- benzo [(flimidazole
A mixture of 5-chloro-2-f 6-fluoropyridin-3-yl)~ 1 H-benzo Fd] imidazole (270 mg, 0.1 Ϊ mmol), 2- (piperazin-l-yl)-4-(trifluoromethyl)pyrimidine (30 mg, 0.13 mmol) and triethylamine (33 mg, 45 uL, 0.33 mmol) in DMF (1.0 mL) was heated at 130 °C for 3 h then cooled to RT. The product was purified by reverse phase Gilson HPLC to yield the title compound as a pale yellow solid. LC/MS = 460.3 [M+l]. EXAMPLE 3
Figure imgf000033_0001
5-chloro-2- 6-f 4-phenylpiperazin- 1 -yl )pyridin- 3 -yl J - 1 H-benzimidazole
Step 1 : To a solution of 6-ch!oro-3-pyridinecarboxaldehyde (1.02g, 7.2mmol) and 4-chloro-lf2- phenylenediamine (1.03g, 7.2mmol) in DMF (8mL) was added water (lmL). Oxone ® (2.88g, 4.68rnmol) was added in one portion and the mixture was stirred at RT for 2 hours. 120mL of saturated 2C03 solution was added and the mixture was stirred for 1 hour. The precipitate was filtered and dried. The solid was dissolved in ethyl acetate and passed through a plug of silica gel using 50% ethyl acetate/ hexanes as eluent. The solvent was evaporated to give a tan solid. LC- MS (M+H) = 265
Step 2: To a solution of 5-chloro-2- (6-chloropyridin-3-yl)- lH-benzimidaole, (105mg, 0.4mmol) in DMA (400uL) was added N,N diisopropylethylamine (103mg; O.Smmol). To this mixture was added l~phenylpiperazine (65mg, 0.4mmol). The mixture was heated to 120° C for 3 hours and cooled to RT. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and dried over Na2S04. The solvent was evaporated and the solids were washed with ethyl acetate to give a yellow solid. LC-MS (M+H) = 390
The following examples were made in an analogous manner:
Figure imgf000033_0002
Figure imgf000034_0001
EXAMPLE 10
Figure imgf000034_0002
2- f 6-(4-phenylpiperazin- 1 - yl)pyridin-3 -yll -5 -(trifluoromethyl - 1H-benzimidazole
Stepl: To a solution of 4-trifluoromet yl-l}2-phenylenediamine (l.Og, 5.68mmoI) in THF (lOmL) was added 6-chloro-3-pyridinecarboxaldehyde (800mg, 5.68mmol). The mixture was stirred at T for 2 hours and the solvent was evaporated. The solids were washed with a minimum of methylene chloride and filtered to give 2-(6-chloropyridin-3-yl)-5-(trifiuoromethyl)- lH-benzimidazole as a yellow solid. LC-MS (M+H) =298 Step 2: To a solution of 2-(6-cliloropyridin-3-yl)-5-(trifluoromethyl) H-beri2irnidazole (50mg, 0.168mmol) in DMA (840uL) was added polymer bound rnorpholine (200mgs 2.75mmol/g). 1- Phenylpiperazine (54.5mg, 0,336mmol) was added and the mixture was heated to 120° C for 2 hours. The cooled mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2S04 and concentrated. The residue was chromatographed over silica gel using 5-10% MeOH/C¾Cl2 as gradient to give 2-[6-(4-phenylpiperazin-l-yl)pyridin-3-yl]-5- (trifluoromethyl)-lH-benzimidazole as a foam. LC-MS (M+H) = 424
The following examples were made in an analogous manner:
Figure imgf000035_0002
Figure imgf000035_0001
3-{4-[5-(5-chloro-lH-benzimidazol-2-yl)pyridin-2-yl]piperazm- 1 -yl}benzoic acid
Step 1 : To a solution of tert- butyl 3-aminobenzoate (500mg9 2.59mmol) in 2,6-lutidine (lmL) was added 2-chloro-N-(2-chloroethyl)ethanamine (462mg, 2.59mmol). The mixture was heated to 100° C for 16 hours. The cooled mixture was diluted with acetone (20mL) and filtered. The solvents were evaporated and the residue was chromatographed over silica gel using 10% MeOH/CH2Cl2 as eluent to give tert-butyl 3-(piperazin-l-yl)benzoate. LC-MS (M+H) = 263 Step 2: To a solution of 5-chloro-2- (6-chloropyridin-3-yl)- IH-benzimidaole (54mg,
0.204mmol) and teri-butyl 3-(piperazin-l-yl)benzoate (54mg, 0.204mmol) in DMA (0.5mL) under argon was added Ν,Ν-diisopropylethylamine (79mg, 0.613mmol). The mixture was heated to 100° C for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2S04 and concentrated. The residue was chromatographed over silica gel using 20- 00% ethyl acetate/hexanes as gradient to give tert-butyl 3-{4-[5-(5-chloro-lH- benzimidazol-2-yl)pyridin-2-yl]piperazin-l-yl} benzoate. LC-MS (M+H) = 491 Step 3: feri-butyl 3-{4-[5-(5-c oro-lH-benzirmdazol-2-yl)p^
(22mg, 0.045mmol) was dissolved in C¾C12 (lmL) and TFA (ImL) was added. The mixture, was stirred at T for 16 hours. The solvent was evaporated and the residue was purified by Reverse Phase HPLC using 30-100% CH3CN/H2O/0.1%TFA as gradient to give -{4-[5-(5- cMoro-lH-berizimidazol-2-yl)p^ acid as the TFA salt. LC-MS (M+H) = 434.
EXAMPLE 14
Figure imgf000036_0001
(4-{4-[5-(5-chloro-lH-benzimidazol-2-yl)pyridin-2-yl]piperazin-l-yl}phenyl)acetic acid
Step 1 : To a solution of ethyl (4-bromophenylacetate)(1.02g, 4.20mmol), 1- benzylpiperazine(740mg, 4.20Γητηο1), palladium acetate (47mg, 0.21mmol)s
dicyclohexlphosphino-2,,4's6,-triiisopropylbiphenyl (200mg, 0.42mmol) in dry DMA(5mL) was added cesium carbonate (2.73g, 8.39mmol). The mixture was degassed with argon gas and heated to 150° C in a microwave for 1 hour. The cooled mixture was partitioned between ethyl acetate and ammonium chloride solution. The organic layer was dried over Na2S04 and concentrated. The residue was chromatographed over silica gel using 20-100% ethyl acetate/ hexanes as eluent to give ethyl [4-(4-benzylpiperazin-l-yl)phenyl]acetate. LC-MS (M+H) = 339
Step 2: A solution of ethyl [4-(4-benzylpiperazin-l-yl)phenyl] acetate (445mg, 1.31mmol) in ethanol (lOmL) was added 20% Pd(OH)2 on carbon (lOOmg). The mixture was stirred under 1 atm of hydrogen for 16 hours. The catalyst was filtered and the solvent was evaporated to give ethyl [4-(piperazin-l-yl)phenyl]acetate. LC-MS (M+H)= 249 Step 3: To a solution of 5-chloro-2- (6-chloropyridin-3-yl)- lH-benzimidaole (80mg,
0.303mmol) in dry DMA(600uL) was added ethyl [4-(piperazin-l-yl)phenyl] acetate (75mg, O.303mmol) and Ν,Ν-diisopropylethylamine (78mg5 0.606mmol). The mixture was heated to 110° C for 16 hours. The cooled mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, dried over Na2S04 and concentrated. The residue was chromatographed over silica gel using 20-100% ethyl acetate/ hexanes as eluent to give ethyl (4- {4-[5-(5-cWoro-lH-benzimidazol-2-yl)^^
(M+H) = 476 Step 4: To a solution of ethyl (4-{4-[5-(5-chloro-lH-benzimidazol-2-yl)pyridin-2-yl}piperazin- l-yl}phenyl)acetate (24mg, 0.050mml) in THF (2mL) was added IN NaOH (200uL,
0.202mmol). The mixture was heated to 50° C for 6 hours and stirred at RT for 16 hours. The solvent was evaporated and the residue was taken up in water (2mL). IN HCL (200uL) was added and the precipitate was filtered to give (4-{4-[5-(5-chloro-lH-benzimidazol-2-yl)pyridin- 2-yl]piperazin-l -yl}phenyl)acetic acid as a tan solid LC-MS (M+H) = 448
The following examples were prepared in an analogous manner:
Figure imgf000037_0002
Figure imgf000037_0001
2-(4- { 4- [5 -(5-chloro- 1 H-benzimidazol-2-yl)pyridin-2-yl] piperazin- 1 -yl } phenyl)acetamide To a solution of (4-{4-[5-(5-chloro-lH-beri2imida2ol-2-yl)pyridm-2-yl]piperazin- l-yl}phenyl)acetic acid (24mg. 0.054mmol) in dry DMF (lmL) was added carbonyl diimidazole (17mg, 0.107mmoi). The mixture was stirred for 2 hours and 0.5M ammonia in dioxane (3mL) was added. The mixture was stirred in a sealed tube for 16 hours. The solvents were evaporated and the residue was dissolved in DMF (lmL). The mixture was purified by reverse phase Prep HPLC using 30-100% C¾CN/H2O/0.1%TFA as gradient to give 2-(4-{4-[5-(5-chloro-lH- benzimidazol-2-yl)pyridin-2-yl]piperazin-l-yl}phenyl)acetamide as the TFA salt. LC-MS (M+H) = 447
Figure imgf000038_0001
4- { 4- [5 -(5-chloro- 1 H-benzimidazol-2-yl)pyridin-2-yl]piperazin- 1 -yl } benzamide
To a suspension of 4-{4-[5~(5-chloro-lH-benzimidazol-2-yl)pyridin-2- yl]piperazin-l-yl}benzonitrile (8mg, 0.019inrnol) in ethanol (lmL) was added 5N NaOH (7uL, 0.039rnmol)5 followed by 30% hydrogen peroxide solution (4uL. 0.039mmol). The mixture was heated to 55° C overnight. 5 more equivalents of 30% hydrogen peroxide solution were added and the mixture was heated overnight. 10 more equivalents of 30% hydrogen peroxide solution were added and the mixture was heated overnight. The cooled mixture was purified by reverse phase Prep HPLC using 30-100% CH3CN/H2O/0.1%TFA as gradient to give -{4-[5~(5-chloro- lH-benzimidazol-2-yl)pyridin-2-yl]piperazin-i-yl} benzamide as the TFA salt . LC-MS (M+H)= 433
Figure imgf000038_0002
6- {4- 5-(5-cMoro-lH-benzimidazoI-2-yl)pyridin-2-yl]piperazin-l -yl}pyridine-3-carboxamide
Step 1 : A solution of 6-chloropyridme-3-carboxamide (lOOmg, 0.639mmol), /ert-butyl piperazine-1-car.boxylate (119mg, 0.639mmol) and Ν,Ν-diisopropylethylamine (248mg, 1.91mmol) in dry DMA (3mL) was heated to 150° C in a microwave for 2 hours. The cooled mixture was partitioned between ethyl acetate and water. The organic layer was twice washed with water and dried over Na2S04 . The solvent was evaporated to give /eri-butyl 4-(5- carbamoylpyridin-2-yl)piperazine-l-carboxylate as a tan solid. LC-MS (M+H) = 307
Step 2; To a suspension of fert-butyl 4-(5-carbamoylpyridin-2"yl)piperazine-l-carboxylate (120mg, 0.392mmol) was added 4M HCl in dioxane (4mL). The mixture was stirred at RT for 3 hours and evaporated to dryness to give a tan solid. The solid was dissolved in DMA (2mL) and 5-chloro-2- (6-chloropyridin-3-yl)- lH-benzimidaole (55mg, 0.208mmol) was added followed by Ν,Ν-diisopropylethylamine (27mg, 0.208mmol). The mixture was heated to 110° C overnight. The solvent was evaporated and the residue was purified by reverse phase Prep HPLC using 30- 100% CH3CN/H2O/0.1%TFA as gradient to give 6-{4-[5-(5-chloro-lH-benzimidazol-2- yl)pyridin-2-yl]piperazin-l-yl}pyridine-3-carboxamide as the TFA salt. LC-MS (M+H) =434
EXAMPLE 20
Figure imgf000039_0001
6- {4- [5 -(5 -chloro- 1 H-benzimidazol-2-yl)pyridin-2-yl3piperazin- 1 -yl } pyridine- 3 -carbonitrile Step 1: To a solution of 6-chloropyridine-3 -carbonitrile (300mg, 2.16mmol) and tert-butyl piperazine-l-carboxylate (403 mg, 2.16mmol) in DMA (3mL) was added N,N- diisopropylethylamine (840mg, 6.50mmol). The mixture was heated to 150° C in a microwave for 2 hours. The cooled mixture was partitioned between ethyl acetate and water. The organic layer was twice washed with water and dried over Na2S04 to give fert-butyl 4-(5-cyanopyridin- 2-yl)piperazine-l~carboxylate. LC-MS (M-BOC) =189. To a solution of fert-butyl 4-(5- cyanopyridin-2-yl)piperazine-l-carboxylate (560mg, 1.94mol) was stirred in 4M HCl in dioxane overnight. The solvent was evaporated to give 6-(piperazin-l-yl)pyridine-3 -carbonitrile as a tan solid. LC-MS (M+H) = 189 Step 2: A mixture of 6-(piperazin-l-yl)pyridine-3 -carbonitrile (73mg, 0.324mmol), 2-(6- bromopyridin-3~yl)-5-chloro-lH-benzimidazole (lOOmg, 0.324mmol) and potassium carbonate (134mg, 0.972mmol) was heated to 1 10° C in DMA (2mL) overnight. The solvent was evaporated and the residue was taken up in methanol and filtered. The mixture was purified by reverse phase Prep HPLC using 30-100% CH3CN/H2O/0.1%TFA as gradient to give 6-{4- 5-(5- cWoro-lH-beixzimidazol-2-yl)pyridin-2-yl]piperazin-l-yl}pyridi as the TFA salt.
LC-MS (M+H)= 416
Figure imgf000040_0001
6- {4-[5 -(5 -chloro- 1 H-benzimidazol-2-yl)pyridin-2-y 1] piperazin- 1 -yl } pyridine- 3 -carboxylic acid A solution of 6-{4-[5-(5-cMoro-lH-benzimidazol-2-yl)pyridin-2-yl]piperazin-l- yl}pyridine-3-carbonitrile (l Omg, 0.024mmol) and 5N NaOH (150uL, 0.720mmol) in ethanol was heated to 80° C overnight. The cooled mixture was purified by reverse phase Prep HPLC using 10-50% CH3CN/H2O/0.1%TFA as gradient to give 6-{4-[5-(5-chloro-lH-benzimidazol-2- t. LC-MS (M+H)= 435
Figure imgf000040_0002
2-(4- { 4- [5 -(5-chloro- 1 H-benzimidazol-2-yl)pyridin-2-yl] piperazin- 1 -yl } phenyl)-2- methylpropanoic acid
Step 1 : A solution of 2-methyl-2-(4-nitrophenyl)propanoic acid (1.02g, 4.88mrnol) in 1.25M methanolic HCL (lOmL) was stirred at RT overnight. The mixture was partitioned between ethyl acetate and sodium bicarbonate soln. The organic layer was dried over Na2S04 and concentrated to give methyl 2-methyl-2-(4-nitrophenyl)propanoate which was dissolved in methanol (lOmL). The solution was treated with 10% palladium on carbon (lOOmg) and stirred under latm of hydrogen for 3 hours. The catalyst was filtered and the solvent was evaporated to give methyl 2- (4-aminophenyl)-2-methylpropanoate as a clear oil, LC-MS (M+H)= 194 Step 2: To a solution of N-benzyl-2-cUoro-N-(2-chloroethyl)ethanamine (180mg, 0.776mmol) and methyl 2-(4-aminophenyl)-2-methylpropanoate (150mg, 0.776mmol) in DMA (3mL) was added sodium iodide (233mg, 1.55mmol) and potassium carbonate (215mg, 1.55mmol). The mixture was heated to 110° C overnight. The cooled mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2S04 and concentrated. The residue was chromatographed over silica gel using 15-60% ethyl acetate/ hexanes as eluent to give methyl 2- [4-(4~benzylpiperazin-l-yl)phenyl]-2-methylpropanoate. LC-MS (M+H)= 353 Step 3 : A solution of methyl 2-[4-(4-beri2ylpiperazin-l-yl)phenyl]-2-methyipropanoate (115mg, 0.326mmol) in methanol (5mL) and 20% Pd(OH)2 on carbon (50mg) was stirred under 1 atm of hydrogen for 3 hours. The catalyst was filtered and the solvent was evaporated to give methyl 2- methyl-2-[4-(piperazin-l-yl)phenyl]propanoate as a clear oil. LC-MS (M+H)= 263 Step 4; To a solution of 5-chloro-2- (6-chloropyridin-3-yl)- lH-benzimidaole (80mg,
0.303mmol) and methyl 2-methyl-2-[4-(piperazin-l-yl)phenyl]propanoate (79mg, 0.303mmol) in dry DMA (2mL) was added Ν,Ν-diisopropylethylamine (78mg, 0.606mmol). The mixture was heated to 1 10° C overnight. The cooled mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2S04 and concentrated. The residue was chromatographed over silica gel using 20-80% ethyl acetate/ hexanes as eluent to give methyl 2-(4-{4-[5-(5-chloro- lH-benzimidazol-2-yl)pyridin-2-yl]piperazin-l -yl}phenyl)-2-methylpropanoate. LC-MS (M+H)= 490
Step 5: A solution of methyl 2-(4-{4-[5-(5-cWoro~lH-benzimidazol-2-yl)pyridin-2-yl]piperazin- l-yl}phenyl)-2-methylpropanoate (30mg, 0.061mmol) in methanol (2mL) was treated with 5N NaOH (122uL, 0. 1rnmol) and the mixture was heated to 50° C overnight. An additional lOOuL of 5N NaOH solution was added and the mixture was heated to reflux for 2 hours. The solvent was evaporated and the residue was taken up in water (2mL). The pH was adjusted to 7 by addition of IN HC1. The precipitate was filtered and dried to give 2-(4-{4-[5-(5-chloro-lH- benzimidazol-2-yl)pyridin-2-yI]piperazin-l-yl}phenyl)-2-methylpropanoic acid. LC-MS (M+H) - 476
Figure imgf000041_0001
2-(4-{4-[5-(5-cWoro-lH-bei zimidazol-2-yl)pyridin-2-yl]piperazin-l-yl}phenyl)- 2-methylpropanamide was prepared in the same manner as Example 22 using 2-methyl-2-[4- (piperazin-l-yl)phenyl]propanamide as the intermediate. LC-MS (M+H)= 477 EXAMPLE 24
Figure imgf000042_0001
(4- { 4- [5-(5 -chloro- 1 H-benzimidazol-2-yl)-3-fluoropyriclin-2-yl] piperazin- 1 -yl } phenyl)acetic acid
Step L To a solution of 6-chloro-5-fluoropyridine-3-carbaldehyde (188mg, LI 18mmol) in DMF (4mL) and water (lmL) was added 4-chloro~l,2-phenylenediamine (185mg, L30mmol). Oxone ® (471mgJ 0.766mmol) was added and the mixture was stirred at RT for 1 hour. The mixture was diluted with water (20mL) and stirred for 30 min. The solids were filtered and dried to give 5- c loro-2-(6-chloro-5-fiuoropyridin-3-yl)-lH-benzimidazole. LC-MS (M+H)= 283
Step 2: To a solution of 5-chloro-2-(6-cWoro-5-fluoropyridin-3-yl)-lH-beri2imidazole (60mg, 0.213mmol) in dry DMA (2mL) was added ethyl [4-(piperazin-l-yl)phenyl] acetate (53π¾, 0.213mmol) and Ν,Ν-diisopropyletliylamine (82mg, 0.638mmol). The mixture was heated to 150° C for 90 min. The cooled mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2S04 and concentrated. The residue was chromatographed over silica gel using 20-100% ethyl acetate/ hexanes as eluent to give ethyl (4-{4~[5-(5-chloro-lif- benzimidazol-2-yl)-3-fiuoropyridin-2-yl]piperazin-l-yl}phenyl)acetate. LC-MS (M+H)= 494
Step 3: A solution of ethyl (4-{4-[5-(5-cUoro-lH-benzimidazol-2-yl)-3-fluoropyridin-2- yljpiperazin-l-yl}phenyl)acetate (40mg5 0.081mmol) in ethanol (4mL) was treated with 5N NaOH (O.SlOmmol). The mixture was heated to 60° C for 2 hours. The solvent was evaporated and the residue was taken up in water (5mL). The solution was neutralized with I N HC1 and extracted with ethyl acetate containing 10% ethanol. The organic layer was dried over Na2S04 and concentrated to give (4-{4-[5-(5-chloro-lH-benzimidazol-2-yl)-3-fluoropyridin-2- yl] piperazin- l-yl}phenyl)acetic acid as a tan solid. LC-MS (M+H)^ 466
Figure imgf000042_0002
5-cWoro-2-(6-{4-[4-(methylsulfonyl)pte Step 1 : To a solution of 1-benzylpiperazine (200mg, l .Hmmol) and 1-bromo- 4(methylsulfonyl)benzene (267mg,T .14mmol) in DMA (4mL) was added palladium acetate (12.7mg, 0.057mrnol)s dicyclohexlphosphino-2'54',6'-triiisopropylbiphenyl (54mgf 0.113mmoi) and cesium carbonate (739mg, 2.27mmol). The mixture was heated to 150° C under argon in a microwave for 1 hour. The cooled mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2S04 and concentrated. The residue was chromatographed over silica gel using 40-100% ethyl acetate/ hexanes as eluent to give l~benzyl-4-[4- (methylsulfonyl)phenyl]piperazine. LC-MS (M+H)= 331 Step 2: A solution of l-benzyl-4-[4-(methylsulfonyl)phenyl]piperazine (143mg, 0.433mol) in methanol (5mL) was treated with 20% Pd(OH)2 on carbon. The mixture was stirred under 1 atm of hydrogen for 3 hours and the catalyst was filtered. The solvent was evaporated to give l-[4- (methylsulfonyl)phenyl]piperazine as a yellow solid. LC-MS (M+H)= 241 Step 3: To a solution of 2-(6-bromopyridin-3-yl)-5-chloro-lH-berizimidazole (70mgs
0.227mmol) and l-[4-(meraylsulfonyl)phenyl]piperazine (54.5mgf 0.227mmol) in dry DMA (3mL) was added N,N-diisopropylethylamine (59mg, 0.454mmol). The mixture was heated to 110° C under argon for 16 hours. The mixture was filtered and was purified by reverse phase Prep HPLC using 30-60% C¾CN/H2O/0.1%TFA as gradient to give 5-cMoro-2-(6-{4-(4- (methylsulfonyl)phenyl]piperazin-l-yl}pyridin-3-yl)-lH-benzimidazole as the TFA salt. LC-MS (M+H)= 468
Figure imgf000043_0001
2-(6- {4-[4-(methylsulfonyl)phenyl]piperazin- 1 -yl }pyridin-3 -yl)-5- (trifluoromethyl)-lH-benzimidazole was prepared in the same manner as Example 25 using 2-(6- fluorop5Tidin-3-yl)-5-(trifluoromethyl)-lH-benzimidazole as the intermediate. LC-MS (M+H)~ 502
EXAMPLE 27
H
Figure imgf000043_0002
3-(4-{4-[5-(5~cMoro-lH-berizimidazol-2-yl)^ acid
Step 1: To a solution of 1 -benzylpiperazine (500mg, 2.84mmol) and methyl 3-(4- bromophenyl)propanoate (690mg, 2.84mmol) in dry DMA (5mL) was added
dicyclohexlphosphino-2',4',6'-triiisopropylbiphenyl (135mg, 0.284mmol)5 palladium acetate (32mg, 0.142rnmol) and cesium carbonate (1.85g, 5.67mmol). The mixture was heated to 100° C for 16 hours. The cooled mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2S04 and concentrated. The residue was chromatographed over silica gel using 20-100% ethyl acetate/ hexanes as eluent to give methyl 3-[4-(4-benzylpiperazin-l- yl)phenyl]propanoate. LC-MS (M+H)= 339
Step 2: A solution of methyl 3-[4-(4-benzylpiperazin-l-yl)phenyl]propanoate (720mg>
2.13mmol) in methanol (50mL) was treated with 20% Pd(OH)2 on carbon (400mg). The mixture was stirred under 1 atm of hydrogen for 2 hours and the catalyst was filtered. The solvent was evaporated to give methyl 3-[4-(p5perazin-l-yl)phenyl]propanoate. LC-MS (M+H)= 249
Step 3: To a solution of 2-(6-chloropyridin-3-yl)-5-chloro-lH-benzimidazole (60mg,
0.227mmol) and methyl 3-[4-(piperazin-l-yl)phenyl]propanoate (56mg, 0.227mmol) was added N,N-diisopropylethylamine (59mg, 0.454mmol). The mixture was heated to 100° C under argon for 16 hours. The cooled mixture was purified by reverse phase Prep HPLC using 30- 100% CH3CN/H2O /0.1%TFA as gradient to give methyl 3-(4-{4-[5-(5-chloro-IH~berrzimidazol-2- yl)pyridin-2-yl]piperazin-l-yl}phenyl)propanoate as the TFA salt. LC-MS (M+H)= 476
Step 4: A suspension of methyl 3-(4-{4-[5~(5-chloro-lH-benzimidazol-2-yl)pyridin-2- yl]piperazin-l-yl}phenyl)propanoate TFA salt (12mg, 0.025mmol) in methanol and treated with 5N NaOH (200uL). The mixture was heated to 50° C for 4 hours. The mixture was evaporated to dryness and the residue was taken up in hot acetone, filtered and concentrated to dryness, The residue was taken up in methanol and was chromatographed over silica gel using 10% methanol/CH2CL2 as eluent to give 3-(4-{4-[5-(5-chloro-lH-benzimidazol-2-yl)pyridin-2- yl]piperazin-l-yl}phenyl)propanoic acid. LC-MS (M+H)= 462
EXAMPLE 28
Figure imgf000044_0001
3-(4-{4-[5-(5<Moro H-berizimi^
yl}phenyl)propanoic acid was prepared in the same manner as Example 27 using 5-chloro-2-(6- chloro-5-fluoropyridin-3-yl)-lH-benzimidazole as the intermediate. LC-MS (M+H)= 480
EXAMPLE 29
Figure imgf000045_0001
methyl 6-(4-{5-[5-(trifluoromemyl)-lH-benzimidazol-2-yl]pyridin-2-yl}piperazin-l-yl)pyridin 3-carboxylate Step, 1 : To a solution of 2-(6-bromopyridin-3-yl)-5-(trifluoromemyi)-lH-benzimidazoie, prepared in the same manner as Example 4, (300mg, 0.877mmol) in dry DMA (3mL) was added 1-benzylpiperazine (155mg, 0.877mmol) and NsN-diisopropylethylamine (227mg, 1.75mmoI). The mixture was heated to 150° C in a microwave for 30 min. The cooled mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2S0 and concentrated. The residue was chromatographed over silica gel using 20-100% ethyl acetate/ hexanes as eluent to give 2-[6-(4-benzyipiperazin-l-yl)pyridin-3-yl]~5-(trifiuoromethyl)-lH- benzimidazole. LC-MS (M+H)= 438
Step 2: A solution of 2-[6-(4-benzylpiperazin- 1 -yl)pyridin-3 -yl] -5 -(trifluoromethyl)- 1 H- benzimidazole (200mg, 0.457mmol) in methanol (5mL) was treated with 20% Pd(OH)2 on carbon (80mg). The mixture was stirred under 1 aim of hydrogen for 16 hours. The catalyst was filtered and the solvent evaporated to give 2-[6-(piperazin-l-yl)pyridin-3-yl]-5-(trifluoromethyl)- lH-benzimidazole. LC-MS ( +H)= 348 Step 3: To a solution of 2-[6-(piperazin-l -yl)pyridin-3-yl] -5 -(trifluoromethyl)- 1 J-benzimidazole (19mg, 0.055mmol) in dry DMA (2mL) under argon was added methyl 6-chloropyridine-3- carboxylate (lOmg, 0.066mmol), cesium fluoride (8mg, 0.055mmol) and sodium bicarbonate (23mg, 0.274mmol). The mixture was heated to 150° C in a microwave for 30 min. and the cooled mixture was purified by reverse phase Prep HPLC using 30-100% CH3CN H2O/0.1%TFA as gradient to give methyl 6-(4-{5-[5-(trifluoromemyl)-lH-benzimidazol-2-yl]pyridin-2-- yl}piperazin-l-yl)pyridine-3-carboxylate as the TFA salt. LC-MS (M+H)^ 483 EXAMPLE 30
Figure imgf000046_0001
6-(4- { 5 - [5-(trifluoromethyl)- 1 H-benzimidazol-2-yl]pyridin-2-yl } piperazin- 1 -yl)pyridine-3 - carboxylic acid
A solution of methyl 6-(4-{5-[5-(1xifluoromethyl)-lH-benzirnidazol-2-yl]pyridin- 2-yl} piperazin- l-yl)pyridine-3-carboxylate (lOmg, 0.021mmol) in methanol was treated with 5N NaOH (83uL, 0.415mmol). The mixture was heated to 50° C for 16 hours. The cooled mixture was acidified to pH 5 by addition of IN HC1 and purified by reverse phase Prep HPLC using 30- 100% CH3CN H2O/0.1%TFA as gradient to give 6-(4-{5-[5-(trifluoromethyl)-lH-benzimidazol- 2-yl]pyridm-2-yl}piperazin-l-yl)pyridine-3-carboxylic acid as the TFA salt. LC-MS (M+H)= 469
Figure imgf000046_0002
(6- {4- [5-(5-chIoro- 1 H-benzimidazol-2-yl)pyridin-2-yl]piperazin- 1 -yl } -5-fiuoropyridin-3 - yl)acetic acid
Step 1 : To a solution of 6-fluoro-3-pyridinecarboxaldehyde (1.76g, 14.0mmol) and 4-chloro~l,2- phenylenediamine (2.0g, 14.0mmol) in DMF (20mL) was added water (2mL). Oxone ®
(5.60g,9.12mmol) was added in portions over 10 min and the mixture was stirred for 1 hour. The mixture was diluted with water (200mL) and stirred for 30 min. and the solids filtered. The solids were taken up in hot ethyl acetate and filtered. The solids were suspended in toluene and the mixture evaporated to dryness to give 5-chloro-2-(6-fluoropyridin-3-yl)-lH-benzimidazole. LC- MS (M+H)= 248
Step 2: To a solution of 5-chloro-2~(6-fluoropyridin-3-yl)-lH-benzimidazole (2.0g, 8.08mmol) in DMSO (lOmL) was added piperazine (1.39g, 16.5mmol). The mixture was heated to 160° C in a microwave for 1 hour. The cooled mixture was poured into water and the solids were filtered and air dried to give 5-ch]oro-2-[6-{piperazin-l-yl)pyridin-3-yl]-lH-benzimidazole. LC-MS (M+H)= 314
Step 3: To a solution of 5-cMoro-2-[6-^iperazin-l-yl)pyridin-3-yl]-lH-benzimidazole (200mg, 0.637mraol) in dry NMP (2mL) under argon was added ethyl (5,6-difiuoropyridin-3-yl)acetate, prepared in the same manner as in patent WO 2007/120729, (128mg, 0.637mmol). Sodium bicarbonate (268mg, 3.19mmol) was added and the mixture was heated to 150° C for 90 min. in a microwave. The cooled mixture was purified by reverse phase Prep HPLC using 30-100% CH3CN/H2O/0.1%TFA as gradient to give ethyl (6-{4-[5-(5-chloro-lH-benzimidazol-2- yl)pyridin~2-yi]piperazm-l -yl}-5-fluoropyridin-3-yl)acetate as a TFA salt. LC-MS (M+H)= 495
Step 4: A solution of ethyl (6-{4-[5-(5-cMoro-lH-benzimidazol-2-yl)pyridin-2-yl]piperazin-l- yl}-5-fluoropyridin-3-yl)acetate TFA salt (lOOmg, 0.202mmol) in ethanol (5mL) was treated with 5N NaOH (404uL, 2.02mmol) and the mixture was heated to 50° C for 2 hours. Acetic acid ( 16uL, 2.02mmol) was added and the mixture was purified by reverse phase Prep HPLC using 10-100% C¾CN/H2O/0.1%TFA as gradient to give (6-{4-[5-(5-chloro-lH-benzimidazol-2- yl)pyridin-2-yl]piperazin-l-yl}-5-fluoropyridin-3-yl)acetic acid as the TFA salt. LC-MS (M+H)= 467
Figure imgf000047_0001
[5-fluoro~6-(4-{5-[5-(trifluoromemyl)-lH-benzimidazol-2-yl]pyridin-2- yl}piperazin-l-yl)pyridin-3-yl]acetic acid was prepared in the same manner as Example 32. LC- MS (M+H)= 501
Figure imgf000047_0002
(4-{4-[5-(5-memoxy-3H-imidazo[4,5-6]pyridm^
acid Step 1 : To a solution of 6-methoxypyridine-2,3 -diamine ( 1.71g, 12.3mmol) in DMF (20mL) was added 6-fluoropyridine-3-carbaldehyde (1.54g, 12.3mmol) and water (2mL), Oxone φ ( 4.91g, 7.99mmol) was added and the mixture was stirred for 1 hour. Dilute potassium carbonate solution was added to pH 7 (200mL) and the solids were filtered and air dried to give 2-(6- fiuoropyridin-3-yl)-5-methoxy-3H-imidazo[4s5-&]pyridine. LC-MS (M+H)= 245
Step 2: To a solution of 2-(6-fluoropyridin-3-yl)-5-methoxy-3H-imidazo[4,5-&]pyridine (44mg, O.lSlmmol) in dry DMA (2mL) under argon was added ethyl [4-(piperazin-l-yl)phenyl]acetate (45mg, O.lSlmmol). Sodium bicarbonate (46mg, 0.543mmol) was added and the mixture was heated to 150° C for 90 min. in a microwave. The cooled mixture was purified by reverse phase Prep HPLC using 30-100% CH3CN/¾O/0.1%TFA as gradient to give ethyl (4-{4-[5-(5- methoxy-3H-midazo[4,5-&]pyridin-2- as the TFA salt. LC-MS (M+H)= 473 Step 3: A solution of ethyl (4-{4-[5-(5-methoxy-3H-imidazo[4,5-&]pyridm-2-yl)pyridin~2- yl]piperazin-l-yl}phenyl)acetate TFA salt (25mg, O,053mmol) in ethanol was added 5N NaOH (300uL). The mixture was heated to 50° C for 2 hours and the solvent was evaporated. The residue was taken up in water (3mL) and acidified to pH 4 with IN HCL The precipitate was filtered and dried to give (4-{4-[5-(5-methoxy-3H-imidazo[4,5- ?]pyridin-2-yl)pyridin-i2- yl]piperazin-l-yl}phenyl)acetic acid. LC-MS (M+H)= 445
EXAMPLE 34
Figure imgf000048_0001
methyl 5-fluoro-6- {4-[5-(5-methoxy-3H-imidazo[4,5-5]pyridin-2-yl)pyridin-2-yl]piperazin- 1 - yl } pyridine- 3 -carboxylate
Step 1 : To a solution of 2-(6-fluoropyridm-3-yl)-5-methoxy-3H-imidazo[4,5-&]pyridine (400mg, 1.64mmol) in dry DMA (1 OmL) under argon was added 1 -benzylpiperazine (289mg> 1.64mmol) and sodium bicarbonate (688mg, 8.19mmol). The mixture was heated to 150° C for 60 min. in a microwave. The mixture was partitioned between ethyl acetate and water and the organic layer was dried over Na2S04. The solvent was evaporated and the residue was chromatographed over silica gel using 20-100% acetone/ hexanes as eluent to give 2-[6-(4-benzylpiperazin-l-yl)pyridin- 3-yl]-5-methoxy~3H-imidazo[4f5-%yridme. LC-MS (M+H) = 401 Step 2: A solution of 2-[6-(4-benzylpiperazin-l-yl)pyridin-3~yl]-5-raethoxy-3H-imidazo[4f5- £]pyridine (345mg, 0.86mmol) in methanol (20mL) was treated with 20% Pd(OH)2 on carbon (150mg). The mixture was stirred under latm of hydrogen for 16 hours. The catalyst was filtered and the solvent was evaporated to give 5-methoxy-2-[6-(piperazin-l-yl)pyridin-3-yl]-3H- imidazo [4, 5 -b] yridine as a waxy solid. LC-MS (M+H) = 311
Step 3: To a solution of 5-methoxy-2-[6-(piperazin-l-yl)pyridin-3-yl]-3H-imidazo[4,5- £>]pyridine (54mg? 0.174mmol) in dry DMA(2mL) degassed with argon was added methyl 5,6- difluoropyridine-3-carboxylate (30mg, 0.174mmol) and sodium bicarbonate (73mg, 0.87mmol). The mixture was heated to 150° C for 60 min. in a microwave. The mixture was purified by reverse phase Prep HPLC using 10-100% CH3CN/H2O/0.1%TFA as gradient to give methyl 5- fluoro-6-{4-[5-(5-memoxy-3H-imidazo[4,5-&]pyridin-2-yl)pyridin-2-yl]piperazin^
3-carboxylate. LC-MS (M+H) = 464
EXAMPLE 35
Figure imgf000049_0001
5-fluoro-6-{4-[5-(5-methoxy-3H-irm^
yl}pyridine-3-carboxylic acid
A solution of methyl 5-fluoro-6-{4-[5-(5~memoxy-3H-imidazo[4,5-&]pyridm-2- yl)pyridin-2-yl]piperazin-l-yl}pyridine-3-carboxylate (52mg, O.l lmmol) in methanol (5mL) was treated with sodium hydroxide 5N (300uL) and the mixture was heated to 50° C for 3 hours. The cooled mixture was concentrated to 2mL and purified by reverse phase Prep HPLC using 10- 100% CH3CN/¾O/0.1%TFA as gradient to give -fluoro-6-{4-[5-(5-methoxy-3H-imidazo[4i5- 6]pyridin-2-yl)pyridin-2-yl]piperazin-l-yl}pyridine-3~carboxylic acid. LC-MS (M+H) = 450
Figure imgf000049_0002
[4-(4-{3-fluoro-5-[5-(trifluoromethyl)-3H-imidazo[4,5-&]pyridin-2-yl]pyridin-2-yl}pipe] yl)phenyl]acetic acid Step 1 : To a solution of concentrated sulfuric acid (30mL) cooled to 0° C was carefully added 30% hydrogen peroxide (15mL). 2-chloro-6-(trifluoromethyl)pyridin-3-amine (1.96g, 9.97mmol) was added as a solid over 5 minutes. The ice bath was removed and the mixture was allowed to warm to RT and stir for 16 hours. The mixture was poured over ice and the solution was neutralized with concentrated ammonium hydroxide solution. The solution was extracted with ethyl acetate and the combined extracts were dried over Na2S04 . The solvent was evaporated to give a yellow solid which was dissolved in methanolic ammonia 7M and stirred in a sealed flask for 16 hours. The mixture was filtered and the solvent evaporated. The residue was
chromatographed over silica gel using 20-100% ethyl acetate/ hexanes as eluent to give 3-nitro- 6-(trifluoromethyl)pyridin-2-amine as a white solid. LC-MS (M+H) = 208
Step 2: To a solution of 3-nitro-6-(trifLuoromethyl)pyridin-2-amine (838mg, 4.05mmol) in methanol (30mL) was added 10% palladium on carbon (400mg). The mixture was hydrogenated on a Parr shaker at 40 psi for 90 min. The catalyst was filtered and the solvent was evaporated to give 6~(trifluoromethyl)pyridine-2,3-diamine as a yellow solid. LC-MS (M+H) = 178
Step 3: To a solution of 5,6-difluoropyridine-3-carboxylic acid (348mg, 2.19mmol) in dry NMP(3mL) was added l-hydroxybenzotriazole (335mg, 2.19mmol),and iV-[3- (dimethylamino)propyl3-N'-ethyicarbodiimide hydrochloride (420mg> 2.19mmol). The mixture was stirred for 10 min. and 6-(trifluoromethyl)pyridine-2, 3 -diamine (388mg, 2.19mmol) was added. The mixture was stirred at RT for 16 hours. Acetic acid (2mL) was added and the mixture was heated to 120° C for 60 min. in a microwave. The cooled mixture was partitioned between ethyl acetate and sodium bicarbonate solution. The organic layer was dried over Na2S04 and concentrated. The mixture was purified by phase Prep HPLC using 10-100%
CH3CN H2O/0.1 %TFA as gradient. The resulting mixture was treated with acetic acid at 120° C for 30 min. in a microwave. The acetic acid was evaporated and the residue was washed with toluene twice to give 2-(5,6-difluoropyridin-3-yl)-5-(trifluoromethyl)-3H-imidazo[4,5-¾]pyridine. LC-MS (M+H) = 301 Step 4: To a solution of 2-(5,6-difluoropyridin-3-yl)-5-(trifluoromethyl)-3H-imidazo[4?5- >]pyridine (45mg, 0.15mmol) in dry NMP(2mL) was added ethyl [4-(piperazin-l- yl)phenyl] acetate (37mg, O.lSmmol) and sodium bicarbonate (38mg, 0.45mmol). The mixture was heated to 120° C in a sealed tube for 4 hours. The cooled mixture was purified by phase Prep HPLC using 10-100% C¾CN/H2O/0.1%TFA as gradient to give ethyl [4-(4-{3-fiuoro-5-[5- (trifluoromethyl)-3H-imidazo[4,5-53pyr^ as the TFA salt. LC-MS (M+H) = 529 Step 5: A solution of ethyl [4-(4-{3-fluoro-5-[5-(trifluoromethyl)-3H-imidazo[4,5-6]pyridin-2-- yl]pyridin-2-yl}piperazin-l-yl)phenyl]acetate,TFA salt (6mg, 0.009mmol) in ethanol (3mL) was added IN sodium hydroxide (28uL). The mixture was heated to 50° C for 8 hours and stirred at RT for 16 hours. The mixture was concentrated to dryness and the residue was taken up in water (lrnL). The solution was passed through an ion exchange resin BioRad AG 50W8X using water as eluent to give 4-(4-{3-fluoro-5-[5-(trifluorome ^^
yl}piperazin-l-yl)phenyl]acetic acid, sodium salt. LC-MS (M+H) ^ 501
The following compounds can also be made using the methods described above:
Figure imgf000051_0001
Assay 1
The in vitro assay to identify DGAT1 inhibitors uses human DGAT1 enzyme expressed in Sf9 insect cells prepared as microsomes. The reaction is initiated by the addition of the combined substrates 1,2-dioleoyl-sn-glycerol and [1 C]-palmitoyl-Co A and incubated with test compounds and microsomal membranes for 2 hours at room temperature. The assay is stopped by adding 0.5 mg wheat germ agglutinin beads in assay buffer with 1% Brij-35 and 1% 3 -cholamidopropyldimemyl-ammomo-1 -propane sulfonate. Plates are sealed with TopSeal and incubated for 18 hours to allow the radioactive triglyceride product to come into proximity with the bead. Plates are read on a TopCount instrument.
Percent inhibition was calculated as the percent of (test compound inhibition minus non-specific binding) relative to (total binding minus non-specific binding). IC50 values were determined by curve fitting the data to a Sigmoidal dose-response in GraphPad Prism utilizing the following equation:
Y - A + (B-A)/(l+10^((LogIC50-X))), where A and B are the bottom and top of the curve (highest and lowest inhibition), respectively, and X is the logarithm of concentration.
Assay 2
To a 384 well assay plate was added 1 μΐ, of a 400 μΜ solution of the test compound in DMSO and 20 μΐ, of a substrate mix that is 300 μΜ in diolein and 40 μ in oleoyl- CoA in 10% ethanol. To this was added 19 Ε of 1.05 μg/mL human DGAT1 -expressed yeast membrane fraction in a buffer of the following composition: 200 rnM Tris, pH 7, 200 mM sucrose, 200 mM magnesium chloride, and 20 μg mL N-ethylmaleimide-treated bovine serum albumin. The solution is incubated at room temperature for 1 hour after which 20 μΐ, of a 90 μΜ 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin solution in 90% ethanol was added. After incubation in the dark for 30 minutes at room temperature, fluorescence was measured on a Perkin Elmer Envision multilabel reader. The IC50 is determined from a 4 parameter fit of the plot of %Inhibition vs.
Concentration of Test Compound in the reaction and is defined as the concentration at which the curve crosses the 50% inhibition line.
The inhibitory activity was calculated from the following formula:
% inhibition = [1 -(fluorescence counts from test compound- average fluorescence counts from LC)/(average fluorescence counts from HC-average fluorescence counts from LC)] x 100%
LC = low control = maximal inhibition by excess amount of a Merck DGAT1 inhibitor
HC = high control = DMSO = uninhibited control
Examples 1 -2 were assayed, the compounds were assayed using Assay 1. If Examples 3-36 were assayed, the compounds were assayed using Assay 2.
Potency of DGAT-1 Inhibitors
Figure imgf000052_0001
7 155 26 17
8 80 27 11
9 25 28 5.7
10 374 29 54
12 64 30 6.2
13 78 31 6.3
14 4.8 32 76
15 84 33 49
16 15 34 620
17 12 35 150
18 11 36 4.7
19 30

Claims

WHAT IS CLAIMED IS:
Figure imgf000054_0001
or pharmaceutically acceptable salts thereof, wherein X is selected from the group consisting of - CH- or -Ns
Z is selected from the group consisting of phenyl and nitrogen containing heterocycle, wherein the phenyl and nitrogen containing heterocycle can be unsubstituted or substituted with 1-3 substituents selected from a;
R1, R2 and R3 are independently selected from the group consisting of a;
a is selected from the group consisting of halogen, Cj-Cealkyl, halogen- substitutedCi-Cealkyl, COC Cealkyl, COhalogen-substitutedCi-C6alkyl, oxo, -OH, - C6alkylOH, Q-QalkyiOHCOOH, halogen-substitutedCi-C6alky!OH, -OQ-QalkyL -Ohalogen- substitutedCrC6alkyl, -COOH, -COCOOH, -COOC C6alkyl, -Ci-CealkylCOOd-Qalkyl, -C CgalkylCOOH, -OCrC6aikylCOOa -CN, Ci-C6aIkylCN, -N02, NH2, NHCi-Cealk l, N(C C6alkyl)2, -NHCOOH, -NHCOOCrC6alkyl, Ci-C6alkylCONH2, -CONH2, -CONHCi-C6alkyl, - NHCOCi-Cealkyl, -CON(Ci-C6alkyl)2, -NHSOsCrCealkyi, S02NH2> -S02Ci-C6alk I; and
each occurrence of n independently selected from the list consisting of 1 or 2.
2. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein X is -N-.
3. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein X is -CH-.
4. A compound of any one of claims 1-3 or pharmaceutically acceptable salt thereof wherein R1 is selected from the group consisting of halogen, C Cealk l, -OCi-C6alk l, halogen-substitutedCrCealkyl.
5. A compound of any one of claims 1-3 or pharmaceutically acceptable salt thereof wherein R1 is selected from the group consisting of chlorine, fluorine and triiluromethyl,
6. A compound of any one of claims 1 -5 or pharmaceutically acceptable salt thereof wherein R2 is C)-C6alkyl halogen-substituted Ci-Cealkyl or halogen.
7. A compound of any one of claims 1-5 or pharmaceutically acceptable salt thereof wherein R is methyl or fluorine.
8. A compound of any one of claims 1 -7 or pharmaceutically acceptable salt thereof wherein R is halogen-substitutedC1-C6alkyl or halogen.
9. A compound of any one of claims 1 -7 or pharmaceutically acceptable salt thereof wherein R is fluorine
10. A compound of any one of claims 1 -9 or pharmaceutically acceptable salt thereof wherein Z is phenyl.
1 1. A compound of any one of claims 1-9 or pharmaceutically acceptable salt thereof wherein Z is a heterocycle, wherein the heterocycle is benzimidazole, pyrimidine or pyridine.
12. A compound of any one of claims 1-11 or pharmaceutically acceptable salt thereof wherein Z is unsubstituted.
13. A compound of any one of claims 1-1 1 or pharmaceutically acceptable salt thereof wherem Z is substituted with 1 -3 substituents independently selected from the group consisting of halogen, d-Qalkyl, halogen-substitutedC[-C6alkyl, -OCj-Cealkyl, -COOH, - COOCrC6alkyl, -Ci-CealkylCOOCrQalkyl, -Q-CealkylCOOH, -S02C1-C6alkyli -CN, Cr C6alkylCON¾ and -CONH2.
14. A compound or pharmaceutically acceptable salt thereof selected from the group consisting of:
Figure imgf000056_0001
-55-
Figure imgf000057_0001
Figure imgf000058_0001
-57-
Figure imgf000059_0001
Figure imgf000060_0001
15. A pharmaceutical composition comprising a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. Use of a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating a condition selected from the group consisting of obesity and diabetes.
17. A method for the treatment of a condition selected from the group consisting of obesity and diabetes comprising administering to an individual a pharmaceutical composition comprising the compound of any one of claims 1-14.
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* Cited by examiner, † Cited by third party
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US20130143876A1 (en) * 2011-12-02 2013-06-06 Gerald Juergen Roth New piperidine derivatives, pharmaceutical compositions and uses thereof
US20140088124A1 (en) * 2011-06-02 2014-03-27 Robert J. DeVita Imidazole derivatives
WO2014175330A1 (en) * 2013-04-24 2014-10-30 塩野義製薬株式会社 5-oxybenzimidazole and 5-oxyaza benzimidazole derivative having ampk activation effect
JP2019517563A (en) * 2016-06-09 2019-06-24 プラマーナ ファーマシューティカルズ インコーポレイテッド Compounds and G proteins containing benzo [d] [1,3] oxathiol, benzo [d] [1,3] oxathiol 3-oxide or benzo [d] [1,3] oxathiol 3,3-dioxide Method / use thereof as an agonist of conjugated receptor 119
WO2023203161A1 (en) * 2022-04-22 2023-10-26 Universite Paris Cite Compounds inducing production of proteins by immune cells

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080096895A1 (en) * 2004-09-20 2008-04-24 Xenon Pharmaceuticals Inc. Heterocyclic Derivatives and Their Use as Stearoyl-Coa Desaturase Inhibitors
WO2009040410A1 (en) * 2007-09-28 2009-04-02 Novartis Ag Oxadiazole- and oxazole-substituted benzimidazole- and indole-derivatives as dgat1 inhibitors
US20090270468A1 (en) * 2003-05-09 2009-10-29 Roger Smith Preparation and use of aryl alkyl acid derivatives for the treatment of obesity
US20090298853A1 (en) * 2007-12-20 2009-12-03 Astrazeneca Ab Carbamoyl Compounds as DGAT1 Inhibitors 190
US20100081643A1 (en) * 2008-09-26 2010-04-01 Bookser Brett C Novel cyclic benzimidazole derivatives useful as anti-diabetic agents

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090270468A1 (en) * 2003-05-09 2009-10-29 Roger Smith Preparation and use of aryl alkyl acid derivatives for the treatment of obesity
US20080096895A1 (en) * 2004-09-20 2008-04-24 Xenon Pharmaceuticals Inc. Heterocyclic Derivatives and Their Use as Stearoyl-Coa Desaturase Inhibitors
WO2009040410A1 (en) * 2007-09-28 2009-04-02 Novartis Ag Oxadiazole- and oxazole-substituted benzimidazole- and indole-derivatives as dgat1 inhibitors
US20090298853A1 (en) * 2007-12-20 2009-12-03 Astrazeneca Ab Carbamoyl Compounds as DGAT1 Inhibitors 190
US20100081643A1 (en) * 2008-09-26 2010-04-01 Bookser Brett C Novel cyclic benzimidazole derivatives useful as anti-diabetic agents

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140088124A1 (en) * 2011-06-02 2014-03-27 Robert J. DeVita Imidazole derivatives
US20130143876A1 (en) * 2011-12-02 2013-06-06 Gerald Juergen Roth New piperidine derivatives, pharmaceutical compositions and uses thereof
US8759528B2 (en) * 2011-12-02 2014-06-24 Boehringer Ingelheim International Gmbh Piperidine derivatives, pharmaceutical compositions and uses thereof
WO2014175330A1 (en) * 2013-04-24 2014-10-30 塩野義製薬株式会社 5-oxybenzimidazole and 5-oxyaza benzimidazole derivative having ampk activation effect
JPWO2014175330A1 (en) * 2013-04-24 2017-02-23 塩野義製薬株式会社 5-oxybenzimidazole and 5-oxyazabenzimidazole derivatives having AMPK activating action
JP2019517563A (en) * 2016-06-09 2019-06-24 プラマーナ ファーマシューティカルズ インコーポレイテッド Compounds and G proteins containing benzo [d] [1,3] oxathiol, benzo [d] [1,3] oxathiol 3-oxide or benzo [d] [1,3] oxathiol 3,3-dioxide Method / use thereof as an agonist of conjugated receptor 119
JP2022022216A (en) * 2016-06-09 2022-02-03 プラマーナ ファーマシューティカルズ インコーポレイテッド COMPOUNDS CONTAINING BENZO[d][1,3]OXATHIOLE, BENZO[d][1,3]OXATHIOLE 3-OXIDE OR BENZO[d][1,3]OXATHIOLE 3,3-DIOXIDE AND METHODS/USES THEREOF AS AGONISTS OF G PROTEIN-COUPLED RECEPTOR 119
WO2023203161A1 (en) * 2022-04-22 2023-10-26 Universite Paris Cite Compounds inducing production of proteins by immune cells

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