WO2013096093A1 - Composés en tant qu'inhibiteurs de dgat-1 - Google Patents

Composés en tant qu'inhibiteurs de dgat-1 Download PDF

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WO2013096093A1
WO2013096093A1 PCT/US2012/069616 US2012069616W WO2013096093A1 WO 2013096093 A1 WO2013096093 A1 WO 2013096093A1 US 2012069616 W US2012069616 W US 2012069616W WO 2013096093 A1 WO2013096093 A1 WO 2013096093A1
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mmol
phenyl
methyl
compound
pharmaceutically acceptable
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PCT/US2012/069616
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English (en)
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Robert J. Devita
Shuwen He
Jian Liu
Timothy A. Cernak
Arto D. Krikorian
Ginger XuQiang YANG
Zhicai Wu
Yang Yu
Dong-Ming Shen
Zhong LAI
Qingmei Hong
Ravi P. Nargund
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Merck Sharp & Dohme Corp.
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Publication of WO2013096093A1 publication Critical patent/WO2013096093A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

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 anti-obesity 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 aging.
  • 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).
  • DGATs There are two subtypes of DGATs, DGAT-1 and DGAT-2. There is no significant homology at the generic or amino acid level between the DGAT-1 and DGAT-2, which are encoded by different genes (Proc. Natl. Acad. Sci. USA., 95, 13018-13023, 1998 and JBC, 276, 38870-38876, 2001).
  • DGAT-1 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 DGAT-1 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.
  • DGAT-1 -knockout mice deficient in DGAT-1 at the genetic level was produced and analyzed.
  • the DGAT-1 -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).
  • DGAT-1 inhibitors are likely to be therapeutic drugs with efficacy for obesity, type 2 diabetes mellitus, lipidosis, hypertension, fatty liver, arteriosclerosis,
  • the compounds described herein are DGAT-1 inhibitors, which are useful in the treatment of obesity, type 2 diabetes mellitus, lipidosis, hypertension, fatty liver, arteriosclerosis, cerebrovascular disorder, coronary artery disease and metabolic syndrome, particularly, obesity and diabetes.
  • V is selected from the group consisting of -N- and -CH-;
  • X is selected from the group consisting of -N- and -CH-;
  • Y is selected from the group consisting of -N- and -CH- and -CR -;
  • Z is seleced from the group consisting of -N- and -CH- and -CR 2 -, wherein at least one of X, Y and Z must be -N-;
  • U is selected from the group consisting of phenyl, pyridine, pyrimidine, piperidine, azaspiroundecanyl and cyclohexane, wherein U is unsubstituted or substituted with - OH;
  • T is -O- or a bond
  • R 1 is selected from the group consisting hexahydrofurofuran, C ! -C 6 alkylCOOH, C C 6 alkylCOOC 1 -C 6 alkyl, CrQalkoxy, pyridine, Q-Qalkylpyridine, cyclohexane, C ⁇ - C 6 alkylcyclohexane, phenyl and C t -Cealkylphenyl, wherein the hexahydrofurofuran, pyridine, phenyl or cyclohexane can be unsubstituted or substituted with one or more substituents selected from the group consisting of COOH, C C 6 alkylCOOH, C 1 -C 6 alkylCOOC 1 -C 6 alkyl, -OH, d- C 6 alkyl and halogen;
  • R 2 is selected from the group consisting heterocycle, d-Cealkyl, phenyl, Q- C 6 alkylphenyl, halogen-substitutedCi-C 6 alkyl and C 3 -C 6 cycloalkyl, wherein the heterocycle, phenyl, or cycloalkyl can be unsubstituted or substituted with one or more substituents selected from the group consisting of C Cealkyl, halogen-substitutedC t -Qalkyl and halogen.
  • R 3 is optionally present at one of more at the ring carbons and is selected from the group consisting of halogen, -CN, Ci-Qalkyl and Q-Cealkoxy.
  • V is selected from the group conisisting of -island -CH-. In some embodiments, V is -N-. In other embodiments, V is -CH-.
  • X is selected from the group conisisting of -N- and -CH-. In some embodiments, X is -N-. In other embodiments, X is -CH- . In certain embodiments, Y is selected from the group consisting of -N- and -CH- and -CR 2 -. In some embodiments, Y is -N-. In other embodiment, Y is -CH-. In still other embodiments, Y is -CR 2 -. In certain embodiments, Z is selected from the group consisting of-N- and -CH- and - CR 2 -. In some embodiments, Z is -N-. In other embodiment, Z is -CH-. In still other embodiments, Y is -CR -.
  • At least one of X, Y or Z is -N-. In other words in no
  • Y is selected from the group consisting of -N- and -CH- and -CR 2 -. In some embodiments, Y is -N-. In other embodiment, Y is -CH- or -CR 2 -.
  • U is selected from the group consisting of phenyl, pyridine, pyrimidine, piperidine, azaspiroundecanyl and cyclohexane.
  • U is phenyl.
  • U is pyridine.
  • U is pyrimidine.
  • U is piperidine.
  • other compounds described herein U is phenyl.
  • U is pyridine.
  • U is pyrimidine.
  • U is piperidine.
  • U is azaspiroundecanyl. In still other embodiments, U is cyclohexane. In certain embodiments U is selected from the group consisting of phenyl and pyridine.
  • U can be unsubstituted of substituted. In certain embodiments, U is substituted with -
  • U is piperidine subsitututed with -OH.
  • T is selected from the group consisting or -O- or a bond. In some embodiments of the compounds described herein, T is -0-. In other embodiments, T is a bond.
  • R 1 is selected from the group consisting hexahydrofurofuran, d- C 6 alkylCOOH, C 1 -C 6 alkylCOOC 1 -C 6 alkyl, d-C 6 alkoxy, pyridine, C 1 -C 6 alkylpyridine, cyclohexane, d-C 6 alkylcyclohexane, phenyl and d-C 6 alkylphenyl.
  • R 1 is d-C 6 alkylCOOH.
  • R 1 is d- C 6 alkylCOOd-C 6 alkyl.
  • R 1 is Ci-C 6 alkoxy.
  • Suitable alkoxys include, but are not limited to, methoxy, ethoxy, butoxy and propoxy.
  • R 1 is pyridine.
  • R 1 is d-Cgalkylpyridine.
  • R 1 is cyclohexane.
  • R 1 is phenyl.
  • R 1 is d-C 6 alkylphenyl.
  • R 1 is hexahydrofurofuran.
  • R 1 can be unsubstituted.
  • R 1 is hexahydrofurofuran, pyridine, phenyl or cyclohenxane
  • R 1 can substituted with one or more substituents selected from the group consisting of COOH, d-C 6 alkylCOOH, d-C 6 alkylCOOd-C 6 alkyl, -OH, Ci-C 6 alkyl and halogen.
  • R 1 is substituted with one substituent selected from the group consisting of COOH, d-C 6 alkylCOOH, d-C 6 alkylCOOd-C 6 alkyl, -OH, d-C 6 alkyl and halogen. In other embodiments, R 1 is substituted with two substituents selected from the group consisting of COOH, C C 6 alkylCOOH, d-CgalkylCOOd-dalkyl, -OH, C C 6 alkyl and halogen.
  • R 1 is substituted with three substituents selected from the group consisting of COOH, d-C 6 alkylCOOH, d-C 6 alkylCOOd-C 6 alkyl, -OH, Ci-C 6 alkyl and halogen. In other embodiments, R 1 is substituted with four substituents selected from the group consisting of COOH, d-C 6 alkylCOOH, d-dalkylCOOd-dalkyl, -OH, d-C 6 alkyl and halogen.
  • R 1 is substituted with COOH. In still other embodiments, R 1 is substituted with d-C 6 alkylCOOH. In other embodiments, R 1 is substituted with d- C 6 alkylCOOd-C 6 alkyl. In yet other embodiments, R 1 is substituted with -OH. In some embodiments, R 1 is substituted with d-C 6 alkyl. In yet other embodiments, R 1 is substituted with halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, and iodine.
  • R 1 is substituted with one or more substituents selected from the group consisting of COOH, d-C 6 alkylCOOH and d-C 6 alkylCOOd-C 6 alkyl.
  • R is cyclohexene substituted with d-CealkylCOOH.
  • R 1 includes an alkyl or any substituent of R 1 includes an alkyl
  • suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • R 2 is selected from the group consisting of heterocycle, Ci-Cealkyl, phenyl, CrCealkylphenyl, halogen-substitutedC ! -C 6 alkyl and C 3 -C 6 cycloalkyl.
  • R 2 is heterocycle. Suitable heterocycles include, but are not limited to, pyridine, pyrimidine, sulfolane, pyrrole, furan, thiene, imidazole, pyrazole, thiazole, oxazole, thiadiazole, pyrazine, and benzofuran.
  • R 2 is CrCealkyl.
  • Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • R 2 is phenyl.
  • R 2 is CrCealkylphenyl.
  • R 2 is halogen-substitutedd-Cealkyl.
  • Suitable halogen-substituted alkyls include, but are not limited to, mono-, di-, and trifluoromethyl.
  • R is C 3 -C 6 cycloalkyl.
  • Suitable cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 2 can be unsubstituted.
  • R 2 can be substituted with one or more substituents selected from the group consisting of Q-Qalkyl, halogen-substitutedCrQalkyl and halogen.
  • R is substituted with one substituent selected from the group consisting of Ci-Cealkyl, halogen- substitutedQ-Cealkyl and halogen.
  • R 2 is substituted with two substituents selected from the group consisting of Q-Cealkyl, halogen-substitutedCrCealkyl and halogen.
  • R 2 is substituted with three substituents selected from the group consisting of Q-Qalkyl, halogen-substitutedCrCealkyl and halogen. In some embodiments, R 2 is substituted with four substituents selected from the group consisting of Q-Cealkyl, halogen- substitutedQ-Qalkyl and halogen.
  • R 2 is substituted with Ci-C 6 alkyl.
  • Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • R 2 is substituted with halogen-substitutedd-Cealkyl.
  • Suitable halogen- substituted alkyls include, but are not limited to, mono-, di-, and trifluoromethyl.
  • R 2 is substituted with halogen.
  • Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, and iodine.
  • R 3 is optionally present at one of more at the ring carbons and is selected from the group consisting of halogen, -CN, C ! -C 6 alkyl and Ci-C 6 alkoxy.
  • R is -CN.
  • R is halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, and iodine.
  • R is Ci- C 6 alkyl.
  • R is Q-Cealkoxy.
  • halogen examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Ci-C 6 alkyl encompasses straight alkyl 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, 1,1,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, l-eth
  • C 3 -C 6 cycloalkyl encompasses cycloalkyls having 3 to 6 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. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • -Q-C 6 alkoxy 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.
  • halogen-substitutedCrCe alkyl encompasses Q-Q alkyl with the hydrogen atoms thereof being partially or completely substituted with halogen, examples thereof including fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1 ,2-difluoroethyl, 2,2-difluoroethyl and the like.
  • -halogen-substitutedQ-Cealkoxy means a -Q-Qalkoxy as defined above, which is substituted with 1-3 halogen atoms which are identical or different, and specifically includes, for example, a trifluoromethoxy group.
  • Q-CealkylOH means a d-Cealkyl substituted with an alcohol (-OH).
  • Examples include methanol, propanol, butanol and t-butanol.
  • heterocycle means mono- or bicyclic or bridged unsaturated, partially unsaturated and saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen.
  • Examples thereof include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalaziny
  • Examples also include tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-0)pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2,l- &]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, tetrahydropyran, and the like.
  • the term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-(lH, 3H)-pyrimidine-2,4-diones (TV-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 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,
  • 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 arginine, betaine, caffeine, choline, ⁇ , ⁇ -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, 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 arginine, betaine, caffeine, cho
  • a "subject” is a human or non-human mammal.
  • a subject is a human.
  • a subject is a non-human mammal, including, but not limited to, a monkey, dog, baboon, rhesus, mouse, rat, horse, cat or rabbit.
  • a subject is a companion animal, including but not limited to a dog, cat, rabbit, horse or ferret.
  • a subject is a dog.
  • a subject is a cat.
  • 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 enantiomerically 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 racemic 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 (lH) and deuterium ( ⁇ H).
  • 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.
  • DGAT1 -related diseases are also encompassed by the present invention.
  • 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 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 subject 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 any of the formulas described herein.
  • 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, 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 subjects 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 ahd/dr 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.
  • the following diseases, disorders and conditions are related to Type 2 diabetes, and therefore may be treated, controlled or in some cases prevented, by treatment with the
  • Another aspect of the invention that is of interest relates to a method of treating hyperglycemia, hypertriglyceridemia, diabetes or insulin resistance in a mammalian subject in need of such treatment which comprises administering to said subject 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 subject in need of such treatment comprising administering to the subject 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 subject in need of such treatment comprising administering to the subject 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 any of the formulas described herein in the manufacture of a medicament for use in treating various DGATl -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liter, 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 chromat
  • the present invention is directed to the use of a compound of any of the formulas described herein 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 any of the formulas described herein in the manufacture of a medicament for use in treating obesity.
  • DGAT-1 inhibitors may also serve as antiviral therapeutics that selectively suppresses HCV's (Hepatitis C virus) interation with lipid droplets without compromising the overall formation of lipid droplets in liver cells Nature Medicine, vol. 16, no. 11 pages 1295-1298, November 2010.
  • HCV's Hepatitis C virus
  • 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 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, microcrystalline wax, white petrolatum, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, 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 in 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.
  • 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.
  • the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the subject 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 a time or in 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.
  • 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 therapeutic 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 any of the formulas described herein 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 any of the formulas described herein.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of any of the formulas described herein is preferred.
  • the combination therapy may also include therapies in which the compound of any of the formulas described herein and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of any of the formulas described herein.
  • composition include, but are not limited to:
  • DPP -4 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 PPAR ligands, including (1) PPARa/ ⁇ dual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPARa agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), such as those disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963, and (4)
  • 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; (7) ⁇ -glucosidase inhibitors (such as acarbose, voglibose and miglitol);
  • glucagon receptor antagonists such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;
  • incretin mimetics such as GLP-1, GLP-1 analogs, derivatives, and mimetics
  • GLP-1 receptor agonists such as exenatide, liraglutide, lixisnatide, taspoglutide, AVE0010, CJC-1131, and
  • BIM-51077 including intranasal, transdermal, and once- weekly formulations thereof;
  • LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelam 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, 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; and nicotinic acid receptor agonists;
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • NSAIDs non-steroidal antiinflammatory 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 blockers (such as and calcium channel blockers (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
  • GKAs glucokinase activators
  • inhibitors of 11 ⁇ -hydroxysteroid dehydrogenase type 1 such as those disclosed in U.S. Patent No. 6,730,690; WO 03/104207; and WO 04/058741;
  • 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 WO2009/042053, including, bu1 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 isoforms, such as SGLT-1;
  • SGLT-2 such as PF-04971729, dapagliflozin and remogliflozin; and SGLT-3;
  • agonists of the TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR131, and M- BAR.
  • Dipeptidyl peptidase-IV (DPP -4) inhibitors that can be used in combination with compounds of any of the formulas described herein include, but are not limited to, sitagliptin (disclosed in US Patent No. 6,699,871), vildagliptin, saxagliptin, alogliptin, denagliptin, 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
  • DPP-4 dipeptidyl peptidase-IV
  • Antiobesity compounds that can be combined with compounds of any of the formulas described herein include topiramate; zonisamide; naltrexone; phentermine; bupropion; the combination of bupropion and naltrexone; the combination of bupropion and zonisamide; the combination of topiramati and phentermine; fenfluramine; dexfenfluramine; sibutramine; lipase inhibitors, such as orlistat and cetilistat; melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists; CCK-1 agonists; melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Yi or Y5 antagonists (such as MK-0557); CBl receptor inverse agonists and antagonists (such as rimonabant and taranabant); ⁇ 3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (such as bombe
  • 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 any of the formulas described herein include, but are not limited to:
  • SCD stearoyl-coenzyme A delta-9 desaturase
  • Glucokinase activators that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:
  • Agonists of the GPR-119 receptor that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:
  • SPPARyM's Selective PPARy modulators
  • Inhibitors of 1 ⁇ -hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:
  • Somatostatin subtype receptor 3 (SSTR3) antagonists that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:
  • AMPK activators that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:
  • Inhibitors of acetyl-CoA carboxylase- 1 and 2 that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to: 3 - ⁇ ⁇ -[( 1 -cyclopropyl-4-methoxy- 1 H-indol-6-yl)carbonyl] -4-oxospiro [chroman- 2,4'-piperidin] - 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, aleghtazar, sodelglitazar, and naveglitazar
  • PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate)
  • SPPARyM's selective PPARy modulators
  • PPARy partial agonists PPARy partial agonists
  • 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;
  • 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, pitavastatin, and rosuvastatin
  • bile acid sequestering agents such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran
  • inhibitors of cholesterol absorption such as ezetimibe
  • acyl CoA holesterol acyltransferase inhibitors such as avasimibe
  • 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 agonists;
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • NSAIDs non-steroidal antiinflammatory drugs
  • COX-2 selective cyclooxygenase-2
  • antihypertensive agents such as ACE inhibitors (such as enalapril, Hsinopril, 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 blockers (such as and calcium channel blockers (such as;
  • ACE inhibitors such as enalapril, Hsinopril, ramipril, captopril, quinapril, and tandolapril
  • A-II receptor blockers such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan
  • GKAs glucokinase activators
  • 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 SGLT- 3; (23) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase 1 and 2 (DGAT-1 and
  • TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR.
  • the compounds described herein can be combined with a DPP-IV inhibitor, such as sitagliptin.
  • DPP 4 is responsible on the inactivation of incretin hormones GLP- l(glucagon-like peptide- 1) and GIP (glucose-dependent insulinotropic polypeptide).
  • GLP- l(glucagon-like peptide- 1) and GIP glucose-dependent insulinotropic polypeptide.
  • sitagliptin would inhitbit the inactivation of incretin hormones while DGAT-1 would inhibit tryglicride synthesis.
  • 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 be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each 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.
  • the compound of the present invention and other active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • Benzimidic acid methyl ester hydrochloride (2 g, 11.65 mmol) was treated with EtOH ( 10 mL) and cooled in ice- water bath. Sodium ethoxide (0.793 g, 11.7 mmol) was added at 0°C, and then stirred for 20 min at RT. 4-iodobenzhydrazide (3.05 g, 11.65 mmol) was added and the mixture was heated at reflux for lh. The mixture was then concentrated to dryness. After the residue was azetroped with toluene once, it was treated with xylene (50 ml) and heated at 160°C for lh, and then cooled to RT.
  • Methyl (trans&cis-4-hvdroxycvclohexyi)acetate Methyl (trans&cis-4-hydroxycyclohexyl)acetate was prepared from methyl 2-(4- hydroxyphenyl) acetate according to a known procedure (Birch, Alan Martin et. al. PCT Int. Appl, 2009024821, 26 Feb 2009).
  • the first peak was determined to be cis-Methyl 2-(4-((5- bromopyridin-2-yl)oxy)cyclohexyl)acetate.
  • LC-MS (ES, m/z) C 14 H 18 BrN0 3 : 327; Found: 328 [M+H] + .
  • the second peak was determined to be trans-Methyl 2-(4-((5-bromopyridin-2- yl)oxy)cyclohexyl)acetate.
  • tert-butyl 4-(3-(ethoxycarbonyl)cyclohexyl)-4-hydroxypiperidine-l-carboxylate (2.6 g, 7.31 mmol, 1 equiv) was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (5 mL) and aged at room temperature for 2.5 hours at which time NMR indicated complete removal of the Boc group. Volatiles were removed in vacuo and to the residue was added 2-chloro-5- cyanopyridine (1.01 g, 7.31 g, 1 equiv), sodium bicarbonate (3.07 g, 36.6 mmol, 5.0 equiv), and NMP (8 mL) then the mixture stirred at 60 °C overnight.
  • trans-ethyl 4-hydroxycyclohexanecarboxylate To a solution of 1.427 L of water was added 9.7 g of mono potassium phosphate and 12.4 grams of dipotassium phosphate. To this was added 5.71 g of MIF-20 and 1.43 g of NAPD to give a pH of 7. To the mixture was added 256.78 g (1.509 mol) of ethyl 4- oxocyclohexanecarboxylate in 1.427 L of 2-propanol. The pH of the mixture was controled at 7 by the addition of 1 M HCl. Stirred the mixture at 30 °C for 20 h. The reaction mixture was then extracted with 1.5 L of MTBE.
  • aqueous layer was back extracted with a 3:1 mixture of MTBE/2-propanol (2 X 600 mL).
  • the organic layer was then concentrated under reduced pressure and re-dissolved in 1.5 L of MTBE.
  • the organic layer was washed with brine (2 X 300 mL), dried over sodium sulfate, concentrated and flushed with 1 L of MTBE to give ethyl trans- 4-hydroxycyclohexanecarboxylate as colorless oil with > 99:1 trans/cis selectivity.
  • Methyl 2-(trans-4-hydroxycyclohexyl)acetate (8 g, 46.5 mmol) was dissolved in anhydrous THF (100 ml) at 0°C, TEA (7.12 ml, 51.1 mmol) added, followed by drop wise addition of TMS-C1 (6.23 ml, 48.8 mmol). The reaction mixture aged for 30 min then diluted with hexane (100 ml) and filtered through a small pad of celite eluting with hexane and concentrated.
  • the active catalyst was then added to the first solution and was warmed to 60 °C for 30 min.
  • the reaction mixture was cooled to rt and diluted with EtOAc and filtered to remove insoluble materials.
  • the layers were separated the organic layer was washed with brine, dried over MgS0 4 , filtered and concentrated under reduced pressure.
  • the resulting solid was slurred in 2:1 hexane MTBE and filtered to provide 9.1 g (90%) of 6'-fluoro-2,3'-bipyridine-5- carbonitrile that was sufficiently pure for subsequent transformations.
  • the active catalyst was then added to the first solution and was warmed at reflux for 1 h.
  • the reaction mixture was cooled to rt and diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried over MgS0 4 and concentrated under reduced pressure.
  • the crude solid was slurred in MTBE and then filtered to give 15.0 g (90%) of 2- fluoro-4-(6-fluoropyridin-3-yl)benzonitrile that was sufficiently pure for subsequent transformations.
  • Step 2 To a mixture of methyl 2-((lr,4r)-4-(4*-(5-phenyl-4H-l,2,4-triazol-3-yl)-[l,r-biphenyl]-4- yl)cyclohexyl) acetate (165 mg, 0.365 mmol) in THF (1.5 ml) /water (1 ml)/MeOH (1.5 ml) was added LiOH monohydrate (92 mg, 2.192 mmol). The reaction mixture was stirred at 40°C over night. The mixture was cooled to RT and neutralized by HC1 (2N, aq).
  • Step 2 2-((lr,4r)-4-(4'-(5-phenyl-4H-l,2,4- triazol-3-yl)-[l, -biphenyl]-4-yl)cyclohexyl)acetic acid (Step 2), starting from Methyl 2-(4'-(5- phenyl-4H-l,2,4-triazol-3-yl)-2,3,4,5-tetrahydro-[l,r-biphenyl]-4-yl)acetate.
  • LC-MS (ES, m/z) C 22 H 21 N 3 0 2 : 359; Found: 360 [M+H] + .
  • the cooled mixture was directly purified by preparative reverse phase HPLC (20% to 80% acetonitrile in water with 0.05% TFA) to obtain the TFA salt of methyl 2-(3-(5-(5- (trifluoromethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-3-azaspiro[5.5]undecan-9-yl)acetate as a white solid (1.9 mg): [MH] + calculated m/z 438; found m/z 438.
  • the ester was dissolved in 1 mL each of THF, water and methanol.
  • reaction mixture was purged with N 2 for 10 min followed by microwave at 120°C for 20 min.
  • the reaction mixture was filtered and concentrated in vacuo.
  • Residue purified by eluting through a silica gel column with a 0-60% Hexane/EtOAc solvent system to provide product methyl 2- ((1 r,4r)-4-((5-(5-(5-(3 ,4-difluorophenyl)-4H- 1 ,2,4-triazol-3-yl)pyridin-2-yl)pyrimidin-2- yl)oxy)cyclohexyl)acetate.
  • LC-MS (ES, m/z) C 26 H 24 F 2 N 6 0 3 : 507; Found: 506[M+H] + .
  • trans-ethyl 4-(5-(3-fluoro-4-(5-phenyl-4H- l,2,4-triazol-3-yl)phenyl)pyridin-2-yloxy)-l-methylcyclohexanecarboxylate was used as the starting material. This resulted in 12 mg (27%) of trans-4-(5-(3-fluoro-4-(5-phenyl-4H-l,2,4- triazol-3-yl)phenyl)pyridin-2-yloxy)l -methylcyclohexanecarboxylic acid as a white solid.
  • Examples 81 to 90 Prepared according the procedure described for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H-l,2,4- triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, starting from 2-(cis-4-(l-(5- cyanopyridin-2-yl)piperidin-4-yloxy)cyclohexyl)acetic acid and appropriate hydrazides, but omitting the hydrolysis step.
  • Examples 91 to 105 Prepared according the procedure described for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H-l,2,4- triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, starting from 2-(trans-4-(l-(5- cyanopyridin-2-yl)piperidin-4-yloxy)cyclohexyl)acetic acid and appropriate hydrazides, but omitting the hydrolysis step.
  • Examples 106 to 112 Prepared following the procedure described above for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, but starting with methyl 2-((ls,4s)- 4-(l-(5-cyanopyridin-2-yl)piperidin-4-yl)cyclohexyl)acetate and appropriate hydrazides.
  • Examples 113 to 121 Prepared following the procedure described above for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, but starting with 2-(4-(l-(5- cyanopyridin-2-yl)piperidin-4-yl)phenyl)acetic acid and appropriate hydrazides. The saponification step was omitted since the starting material was an acid.
  • Examples were assayed as follows: 20uL substrate mixture of 300uM diolein, 40uM oleoyl-CoA, 10% ethanol and luL of the compound with different concentrations were delivered to a 384 well assay plate (Corning 3573) using a Tecan with TeMO module. Later 19uL of enzyme mixture of 1.05ug/ml human DGAT1 in buffer (200mM Tris, pH7, 200mM sucrose, 200mM MgC12 + 20ug/ml NEM-treated BSA) was added via a Multidrop Combi using a microcassette. 20uL of 90uM CPM reagent in 90% ethanol was added after 1 hour incubation at room temperature. After 30 minutes at room temperature in dark, fluorescence measurement on Envision was carried out and IC50 values were calculated.
  • Example hDGATl Example hDGATl
  • Example hDGATl Example hDGATl

Abstract

L'invention concerne des composés de formule I. Les composés de formule I agissent comme inhibiteurs de DGAT1 et peuvent être utiles dans la prévention, le traitement ou l'action comme agent réparateur pour l'hyperlipidémie, le diabète sucré et l'obésité.
PCT/US2012/069616 2011-12-21 2012-12-14 Composés en tant qu'inhibiteurs de dgat-1 WO2013096093A1 (fr)

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US20150274672A1 (en) * 2012-10-11 2015-10-01 Merck Sharp & Dohme Corp. Substituted spiropiperidinyl compounds useful as gpr120 agonists
US9815813B2 (en) 2014-01-17 2017-11-14 Novartis Ag 1-(triazin-3-yl/pyridazin-3-yl)-piper(-azine)idine derivatives and compositions therefor for inhibiting the activity of SHP2
US10077276B2 (en) 2014-01-17 2018-09-18 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US10093646B2 (en) 2014-01-17 2018-10-09 Novartis Ag 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
CN108727345A (zh) * 2017-04-25 2018-11-02 广东东阳光药业有限公司 一种咪唑环中间体的制备方法
US10287266B2 (en) 2015-06-19 2019-05-14 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10308660B2 (en) 2015-06-19 2019-06-04 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
CN112125891A (zh) * 2019-06-24 2020-12-25 华东师范大学 一种n2选择性的四氢呋喃/四氢噻吩取代的三氮唑衍生物及其合成方法和应用
US10934285B2 (en) 2016-06-14 2021-03-02 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10975080B2 (en) 2015-06-19 2021-04-13 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2

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US20150274672A1 (en) * 2012-10-11 2015-10-01 Merck Sharp & Dohme Corp. Substituted spiropiperidinyl compounds useful as gpr120 agonists
CN105073111A (zh) * 2012-10-11 2015-11-18 默沙东公司 用作gpr120激动剂的取代的螺哌啶基化合物
EP2906542A4 (fr) * 2012-10-11 2016-07-20 Merck Sharp & Dohme Composés spiropipéridinyliques substitués utiles comme agonistes de gpr120
US9708270B2 (en) * 2012-10-11 2017-07-18 Merck Sharp & Dohme Corp. Substituted spiropiperidinyl compounds useful as GPR120 agonists
US10968235B2 (en) 2014-01-17 2021-04-06 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US10077276B2 (en) 2014-01-17 2018-09-18 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US10093646B2 (en) 2014-01-17 2018-10-09 Novartis Ag 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
US11401259B2 (en) 2014-01-17 2022-08-02 Novartis Ag 1-Pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
US11952386B2 (en) 2014-01-17 2024-04-09 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US10301278B2 (en) 2014-01-17 2019-05-28 Novartis Ag 1-(triazin-3-yl/pyridazin-3-yl)-piper(-azine)idine derivatives and compositions therefor for inhibiting the activity of SHP2
US9815813B2 (en) 2014-01-17 2017-11-14 Novartis Ag 1-(triazin-3-yl/pyridazin-3-yl)-piper(-azine)idine derivatives and compositions therefor for inhibiting the activity of SHP2
US10336774B2 (en) 2014-01-17 2019-07-02 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US10774065B2 (en) 2014-01-17 2020-09-15 Novartis Ag 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
US10287266B2 (en) 2015-06-19 2019-05-14 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10308660B2 (en) 2015-06-19 2019-06-04 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10975080B2 (en) 2015-06-19 2021-04-13 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10934285B2 (en) 2016-06-14 2021-03-02 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US11905283B2 (en) 2016-06-14 2024-02-20 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
CN108727345A (zh) * 2017-04-25 2018-11-02 广东东阳光药业有限公司 一种咪唑环中间体的制备方法
CN108727345B (zh) * 2017-04-25 2023-06-27 广东东阳光药业有限公司 一种咪唑环中间体的制备方法
CN112125891A (zh) * 2019-06-24 2020-12-25 华东师范大学 一种n2选择性的四氢呋喃/四氢噻吩取代的三氮唑衍生物及其合成方法和应用
CN112125891B (zh) * 2019-06-24 2022-06-07 华东师范大学 一种n2选择性的四氢呋喃/四氢噻吩取代的三氮唑衍生物及其合成方法和应用

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