WO2012015693A1 - Dérivés d'imidazole - Google Patents

Dérivés d'imidazole Download PDF

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Publication number
WO2012015693A1
WO2012015693A1 PCT/US2011/045022 US2011045022W WO2012015693A1 WO 2012015693 A1 WO2012015693 A1 WO 2012015693A1 US 2011045022 W US2011045022 W US 2011045022W WO 2012015693 A1 WO2012015693 A1 WO 2012015693A1
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alkyl
compound
pharmaceutically acceptable
acceptable salt
halogen
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PCT/US2011/045022
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English (en)
Inventor
Jian Liu
Deodial Guiadeen
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Merck Sharp & Dohme Corp.
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Priority to CA2805078A priority Critical patent/CA2805078A1/fr
Priority to AU2011282989A priority patent/AU2011282989A1/en
Publication of WO2012015693A1 publication Critical patent/WO2012015693A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

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, 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 antiobestic drugs having a 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 of 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
  • DGAT2 subtypes of DGATs
  • There is no significant homology at the generic or amino acid level between the DGAT1 and DGAT2 which are encoded by different genes (Proc.Natl.Acad.Sci.USA.,95,13018-13023,1998 and
  • 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 inhibitors are likely to be therapeutic drugs with efficacy for obesity, type 2 diabetes mellitus, lipidosis, hypertension, fatty liver, arteriosclerosis,
  • rings A and B are selected from the group consisting of benzene, pyridine, pyrazine and pryimidine; X, Y, Z, W, V, U, R 1 , R 2 and R 3 are defined herein.
  • the compounds of formula I act as DGATI inhibitors and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.
  • rings A and B are selected from the group consisting of benzene, pyridine, pyrazine and pryimidine;
  • X and Y are independently selected from the group consisting of-N- and -C H-;
  • Z is -N- or OO
  • W is -N-, -N(R 4 )-, -C (R 5 )- or -0-;
  • V and U are independently selected from the group consisting of-C(R 6 )- and -N-;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group ⁇ , C 3 -C 10 cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C 1 -C 6 alkylC 3 -C 10 cycloalkyl, C 1 -C 6 alky laryl, C 1 -C 6 alkylheteroaryl and C 1 - C.alkylcycloheteroaIkyl, wherein C 3 -C 10 cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C 1 -C 6 alkylC 3 - C 1 ocycloalkyl, C 1 -C 6 alkylaryl, C 1 -C 6 alkylheteroaryl and C 1 -C 6 alkylcycloheteroalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of ⁇
  • -NHCOOH -NHCOOC 1 -C 6 alkyl, -C ONH 2 , -C ONHC 1 -C 6 alkyl, -C ON(C 1 -C 6 alkyl) 2 , -NHS0 2 C 1 -C 6 alkyl, - SO 2 C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C 1 -C 6 alkylC 3 -C 10 cycloalkyl, C 1 -C 6 alkylaryl, C 1 -C 6 alkylheteroaiyl and C 1 -C 6 alkylcycloheteroalkyl.
  • ring A and ring B are individually selected from the group consisting of pyrazine or pyrimidine. In other embodiments, ring A and ring B are individually selected from the group consisting of benzene and pyridine, In one embodiment, ring A and ring B are both benzene. In one embodiment, ring A and ring B are both pyridine.
  • ring A is pyrazine. In another embodiment, ring A is pyrimidine. In yet another embodiment, ring A is pyridine. In still another embodiment, ring A is benzene.
  • ring B is pyrazine. In another embodiment, ring B is pyrimidine. In yet another embodiment, ring B is pyridine. In still another embodiment, ring B is benzene. In certain embodiments ring B is pyridine, pyrazine or pryimidine, wherein the pyridine, pyrazine or pryimidine e two bicyclic rings of formula I via a -C-C- bond. In other embodiments, ring B is pyridine wherein the pyridine is bonded to the two bicyclic rings of formula I via a -C-C - bond.
  • ring A is formula ⁇ :
  • X is independently selected from the group consisting of ⁇ N- and -C H-. In one embodiment, X is -C H-. In another embodiment, X is -N-.
  • Y is independently selected from the group consisting of -N- and -C H-. In one embodiment, Y is -C H-. In another embodiment, Y is -N-.
  • Y is -N-. In another embodiment, Y is -OO.
  • W is -N(R 4 )-, -C(R 5 )- or -0-. In some embodiments, W is-N(R 4 )-. In other embodiments, W is -C (R 5 )-. In still other embodiments, W is -0-. In yet other embodiments, W is -N-.
  • V is independently selected from the group consisting of -C(R 6 )- and -N-. In one embodiment, V is -N-. In another embodiment, V is - C(R 6 )- In still other embodiments, V is -CH-.
  • U is independently selected from the group consisting of -C(R 6 )- and -N-. In one embodiment, U is -N-. In another embodiment, U is - C(R 6 )-. In still other embodiments, U is -CH-,
  • a is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, halogen-substitutedC 1 - C 6 alkyl, COC 1 -C 6 alkyl, oxo, -OH, C 1 -C 6 alkylOH, halogen-substitutedC 1 -C 6 alkylOH, -OC 1 -C 6 alkyl, - Ohalogen-substitutedC 1 -C 6 alkyl, -C OOH, -C OOC 1 -C 6 alkyl, -C 1 -C 6 alkylCOOC 1 -C 6 a]kyl, -C 1 - C 6 alkylCOOH, -OC 1 -C 6 alkylCOOH, -CN, C 1 -C 6 alkyiCN, -N0 2 , NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 ,
  • R 1 , R 2 , R 3 , R 4 , R 5 and R e are independently selected from the group a.
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, -CN, -OC 1 -C 6 alkyl, -Ohalogen-substitutedC 1 -C 6 alkyl, halogen and halogen-substitutedC 1 -C 6 alkyl.
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, -CN-, aryl, -OCp alkyl, -Ohalogen-substitutedC 1 -C 6 alkyI and halogen-substitutedC i -C 6 alkyl .
  • R 1 is independently selected from the group consisting of hydrogen, -CN, aryl, -OC 1 -Coalkyl, -Ohalogen-substitutedC 1 -Cgalkyl, halogen and halogen-substitutedC 1 -C 6 alkyl. In other embodiments, R 1 is independently selected from the group consisting of -CN, -OC 1 -C 6 alkyl, -Ohalogen-substitutedC 1 -C 6 alkyl, halogen and halogen-substitutedC r C 6 alkyl.
  • R 1 is selected from the group consisting of halogen and halogen- substitutedC 1 -C 6 alkyl.
  • R 1 is hydrogen.
  • R 1 is -CN.
  • R 1 is -OC 1 -C .alkyl.
  • R 1 is halogen. Suitable halogens include, but are not limited to, chlorine and fluorine.
  • R 1 is halogen- substitutedC 1 -C 6 alkyl. Suitable halogen-substitutedC 1 -C 6 alkyls include, but are not limited to, trifluoromethyl.
  • R 1 is -Ohalogen-substitutedC 1 -C 6 alkyl
  • Suitable -Ohalogen- substitutedC 1 -C 6 alkyls include, but are not limited to, trifluoromethoxy.
  • R 1 is phenyl
  • Suitable examples of an aryl substituent include but are not limited to, phenyl.
  • R 2 is selected from the group consisting of hydrogen and halogen. In one embodiment, R 2 is hydrogen. In another embodiment, R 2 is halogen. Suitable halogens include, but are not limited to, chlorine and fluorine.
  • R 2 is halogen or hydrogen and R 1 is selected from the group consisting of halogen, -CN-, aryl, -OC 1 -C6alkyl, -Ohalogen-substitutedC 1 -C 6 alkyl and halogen-substitutedC 1 -C 6 alkyl.
  • R 3 is selected from the group consisting of hydrogen, halogen, halogen- substitutedC 1 -Cialkyl and aryl.
  • R 3 is aryl, halogen and halogen- substitutedC 1 -C 6 alkyl wherein the aryl is substituted with -COOH, -OH or halogen-substitutedC r C 6 alkyl.
  • R 3 is hydrogen.
  • R 3 is halogen. Suitable halogens include, but are not limited to, chlorine, bromine and fluorine.
  • R 3 is halogen- substitutedC 1 -C 6 alkyl.
  • Suitable halogen-substitutedC 1 -C 6 alkyls include but are not limited to, trifluoromethyl.
  • R 3 is aryl. Suitable aryl groups include, but are not limited to, phenyl.
  • the phenyl when R 3 is phenyl, the phenyl can be unsubstituted or substituted with at least one substituents selected from a .
  • the phenyl is substituted with -COOH.
  • R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkylaryl, aryl, -C 1 -C 6 alky!COOH, - C 1 - C 6 alkylCOOC
  • R 4 is hydrogen.
  • R 4 is CpC 6 alkyl, C 1 -C 6 alkylaryl, -C 1 - C 6 alkylCOOH, -C rC 6 alkylCOOC 1 -C 6 alkyl and -C OOC r Cfialkyl.
  • Suitable C,-C 6 alkyls include, but are not limited to, methyl, ethyl, propyl, f-butyl and butyl.
  • Suitable C 1 -C 6 alkylaryls include, but are not limited to, C ⁇ phenyl.
  • Suitable C 1 -C6alkylCOOC 1 -C 6 alkyls include, but are not limited to,
  • Suitable -C t -C 6 alkylCOOHs include, but are not limited to, C ⁇ COOH.
  • R 4 is aryl, wherein the aryl is substituted with -COOH, -C j-C 6 alkylCOOH, - C 1 - C 6 alkylCOOC 1 -C 6 alkyl and -C OOC 1 -C 6 alkyl.
  • R 4 is phenyl substituted with -COOH.
  • R 1 is halogen or halogen-substitutedC 1 -C 6 alkyl
  • R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C ialkylaryl, aryl, -C 1 -C 6 alkylCOOH, - C 1 -C 6 alkylCOOC 1 -C 6 alkyl and -C OOC 1 -C 6 alkyl wherein the C 1 -C 6 alkylaryl and aryl are unsubstituted or substituted with -COOH, -C 1 -C 6 alkylCOOH, - C 1 -C 6 alkylCOOC 1 -C 6 alkyl and -C OOC 1 -C 6 alkyl,
  • R 1 is selected from the group consisting of halogen and halogen- substitutedC 1 -C 6 alkyl
  • R 1 is hydrogen.
  • R 1 is halogen.
  • R 1 is halogen-subst.tutedC 1 -C «alkyl.
  • Suitable halogen-substitutedC 1 -C 6 alkyls include, but are not limited to, trifluoromethyl.
  • Suitable halogens include, but are not limited to, chlorine and fluorine.
  • R 4 is selected from the group consisting of hydrogen, C 1 -C ⁇ alkyl, C 1 - C s alkylaryl, aryl, -C 1 -C 6 alkylCOOH, - C 1 -C 6 alkylCOOC 1 -C 6 alkyl and -C OOC 1 -C 6 alkyl wherein the C,- C 6 alkylaryl and aryl are unsubstituted or substituted with -COOH, -C 1 -C 6 alkylCOOH, - C 1 - C 6 alkylCOOC 1 -C 6 alky 1 and -C OOC 1 -C 6 alkyl.
  • R 4 is hydrogen.
  • R 4 is C 1 -C 6 alkyl, C 1 -C 6 alkylaryl, -C
  • Suitable C ( -C jalkyls include, but are not limited to, methyl, ethyl, propyl, i-butyl and bulyl.
  • -C (salkylaryls include, but are not limited to, C ⁇ phenyl.
  • Suitable C 1 -C 6 alkylCOOCr C 6 alkyls include, but are not limited to, CH 2 COOCH 2 CH 3 .
  • Suitable -C 1 -QsalkylCOOHs include, but are not limited to, C ⁇ COOH.
  • R 4 is aryl, wherein the aryl is substituted with - COOH, -C 1 - salkylCOOH, - C 1 -C 6 alkylCOOCrC 1 ialkyl and -C OOC 1 -C 6 alkyl.
  • R 4 is phenyl substituted with -COOH.
  • R 4 is C 1 -C 6 alkyl or aryl.
  • R 4 is CrC.alkyl. Suitable C 1 -C 6 alkyls include, but are not limited to, methyl, ethyl, propyl, /-butyl and butyl.
  • R 4 is aryl, wherein the aryl is phenyl.
  • the aryl group is substituted with -COOH, -C 1 -C 6 alkylCOOH, - C 1 -C 6 alkylCOOC 1 -C 6 alkyl and -COOC 1 -Cialkyl.
  • 4 is hydrogen.
  • halogen examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • C 1 -C ⁇ > 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, isobu ert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbulyl, 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-ethyl-2- methylpropy
  • C 3 -C6c cloalkyl 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, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like.
  • -OC 1 -C «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.
  • -OC 1 -C galkylCOOH refers to an alkoxy group having 1 to 6 carbons substituted with a carboxylic acid (-COOH) group.
  • halogen-substitutedC 1 -C f i alkyl encompasses C 1 -C 6 alkyl with the hydrogen atoms thereof being partially or completely substituted with halogen, examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl and the like.
  • -Ohalogen-substitutedC 1 -C 6 alkyl means a -OC 1 -C 6 alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different, and specifically includes, for example, a trifluoromethoxy group.
  • -COC 1 -C 6 alkyl 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-substitutedC 1 -C 6 alky 1 means a -COC 1 -C 6 alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different.
  • C 1 -C 6 alkylOH means a C 1 -Cgalkyl substituted with a hydroxyl group (-OH), also known as an alcohol. Examples include methanol, propanol, butanol and t-butanol.
  • C 1 -C 6 alkylCN means a C 1 -C 6 alkyl substituted with an cyano group (-CN).
  • halogen-substituted C 1 -CgalkylOH means a halogen-substituedCl -C6alkyl substituted with an alcohol (-OH).
  • COOC 1 -C 6 alkyl means a -COOH group wherein the -OH is replaced with an alkoxy group as defined above. Examples include methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.
  • SC ⁇ C 1 -C 6 alkyl means a group having C 1 -C 6 alk l bonded to sulfonyl (-SO2-). Specific examples thereof include methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl, tert-butanesulfonyl, and the like.
  • NHC 1 -C6alkyl means a group with one of the hydrogen atoms of amino (- N ⁇ ) being substituted with a C 1 .Cgalkyl group. Specific examples thereof include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-but lamino, tert-butylamino, and the like.
  • NiC 1 -Cealkyiy means a group with the two amino hydrogen atoms each being substituted with a C 1 .Csalkyl group. Specific examples thereof include dimethylamino, diethylamino, ethylmethylamino, di(n-propyl)amino, methyl(n-propyl)amino, diisopropylamino, and the like.
  • NHCC ⁇ C 1 -C 6 alkyl means a group with one of the amino hydrogen atoms being substituted with C 1 .C 6 alkoxycarbonyl and encompasses alkoxycarbonylamino having a carbon number of 1 to 6. Specific examples thereof include methoxycarbonylamino,
  • NRCOC 1 -C 6 alkyl means a group with one of the amino hydrogen atoms being substituted with C 1 .C 6 alkylcarbonyl. Specific examples thereof include acetylamino, propionylamino, isobutyryl amino, valerylamino, isovalerylamino, pivaloylamino, and the like.
  • CONHC 1 -C 6 alkyl means a group with one of the hydrogen atoms of carbamoyl (-CONH2) being substituted with C 1 .C 6 alkyl. Specific examples thereof include methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, and the like.
  • CON(C 1 -C(salkyl)2 means a group with the two carbamoyl hydrogen atoms each being substituted with C 1 -C 6 alkyl. Specific examples thereof include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, di(n-propyl)carbamoyl, methyl(n-propyl)carbamoyl, diisopropylcarbamoyl, and the like.
  • NHSChC 1 -C 6 alkyl means a group with one of the amino hydrogen atoms being substituted with C ⁇ .Ce alkylsulfonyl. Specific examples thereof include
  • aryl examples include phenyl, naphthyl, tolyl, and the like.
  • heteroaryl means 5-membered or 6-membered monocyclic heteroaryl containing one or more, preferably one to three, same or different heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, or otherwise means condensed-ring heteroaryl formed by condensation of such monocyclic heteroaryl and the above- mentioned heteroaryl or alternatively by mutual condensation of the same or different monocyclic heteroaryl groups.
  • 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, phthalazinyl, naphthyridinyl 5 quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, pyrido [3 ,2-b] pyridyl, and the like.
  • CycloheteroalkyP means mono- or bicyclic or bridged saturated rings containing at least one heteroatom selected from N, S and 0, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen.
  • the term also includes monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non- aromatic portion.
  • cycloheteroalkyl examples include tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-i))pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6- dihydroimidazo[2 9 l-_j]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, 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)-pyrirnidine-2,4-diones (N-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 cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogens.
  • cycloheteroalkylCOOH refers to a cycloheteroalkyl, as defined above, substituted with a carboxylic group (-COOH).
  • C 1 -C6alkylC 3 -C 1 ocycloalkyl, C 1 -C6alkylaryl, C 1 -C 6 alkylheteroaryl and C 1 - C 6 alkylcycloheteroalkyl refer to a C 1 -C 6 alkylgroup substituted with a C 3 - C 1 ocycloalkyl, aryl, heteroaryl and cycloheteroalkyl, as defined above.
  • 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, methylbromid
  • 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
  • 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 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 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 ( H) 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.
  • DGAT1 -related diseases are also encompassed by the present invention.
  • the compounds described herein are effective in preventing or 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/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 or formula la.
  • 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 ah 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 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 formula I or formula la 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/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 present invention is directed to the use of a compound of formula I or formula la 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 formula I or formula la in the manufacture of a medicament for use in treating obesity.
  • 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.
  • 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 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 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 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 formula I or formula la 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 therefor, contemporaneously or sequentially with a compound of formula I or formula la.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of formula I or formula la is preferred.
  • the combination therapy may also include therapies in which the compound of formula I or formula la and one or more other drugs are administered on different overlapping schedules.
  • compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of formula I or formula la.
  • Examples of other active ingredients that may be administered in combination with a compound of formula I or formula la, and either administered separately or in the same pharmaceutical composition include, but are not limited to:
  • DPP-4 dipeptidyl peptidase-IV
  • 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 ⁇
  • 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
  • PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate)
  • SPPARy 's selective PPARy modulators
  • PPARy partial agonists such as those disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963
  • PPARy partial agonists such as those disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963
  • PPARy partial agonists such as those disclosed in WO 02/060388,
  • insulin or insulin analogs such as insulin lispro, insulin detemir, insulin glargine, insulin glulisine, and inhalable formulations of each thereof;
  • amy 1 in and amy 1 in analogs such as pramlintide
  • 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
  • glucagon receptor antagonists such as those disclosed in WO 98/04528, WO 99/01423, WO
  • incretin mimetics such as GLP-1, GLP-1 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) HMG-C oA 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-C oA reductase inhibitors lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin
  • HDL ⁇ rais ⁇ ng 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 agonists such as niacin or a salt thereof and extended-release versions thereof
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • NSAIDs non-steroidal anti-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, oimesartan medoxomii, 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, oimesartan medoxomii, valsartan, telmisartan, and eprosart
  • GKAs glucokinase activators
  • inhibitors of 11 ⁇ -hydroxy steroid dehydrogenase type 1 such as those disclosed in U.S, Patent No. 6,730,690; WO 03/104207; and WO 04/0587 1;
  • inhibitors of cholesteryl ester transfer protein such as torcetrapib and M -0859;
  • 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, but 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- ; SGLT-2, such as dapagliflozin and remogliflozin; and SGLT-3;
  • SGLT sodium-glucose transporter
  • MGAT-1 and MGAT-2 inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2
  • MGAT-2 acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2
  • agonists of the TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR] 31, and M-BAR
  • TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR] 31, and M-BAR
  • Dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of formula I or formula la 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 formula I or formula la include topiramate; zonisamide; naltrexone; phentermine; bupropion; the combination of bupropion and naltrexone; the combination of bupropion and zonisamide; the combination of topiramate and phentermine; fenfluramine;
  • melanocortin receptor agonists in particular, melanocortin-4 receptor agonists
  • CCK-1 agonists melanin-concentrating hormone (MCH) receptor antagonists
  • neuropeptide Yi or Y5 antagonists such
  • Glucagon receptor antagonists that can be used in combination with the compounds of formula I or formula la include, but are not limited to: N-[4-((lS l- ⁇ 3-(3,5-dichlorophenyl>5-[6 ⁇
  • Inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) that can be used in combination with the compounds of formula I or formula la include, but are not limited to:
  • Glucokinase activators that can be used in combination with the compounds of formula I or formula la include, but are not limited to:
  • Agonists of the GPR-119 receptor that can be used in combination with the compounds of formula I or formula la include, but are not limited to:
  • SPPARyM's Selective PPARy modulators that can be used in combination with the compounds of formula I or formula la 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 or formula la include, but are not limited to:
  • Somatostatin subtype receptor 3 (SST 3) antagonists that can be used in combination with the compounds of formula I or formula la 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 I or formula la include, but are not limited to:
  • composition which comprises one or more of the following agents:
  • insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g. pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPA 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), and (4) ⁇ partial agonists; (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®
  • sulfonylurea and non-sulfonylurea insulin secretagogues such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateg!inide and repaglinide;
  • ct-glucosidase inhibitors such as acai'bose, voglibose and miglitol
  • LDL cholesterol lowering agents such as (i) HMG-C oA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pravastatin, 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 holesterol acyltransferase inhibitors, such as avasi ibe;
  • HDL-raising drugs such as niacin or a salt thereof and extended-release versions thereof
  • M -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 (NSAEDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • antihypertensive agents such as ACE inhibitors (such as enalapril, lisiuopril, 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 anc calcium channel blockers;
  • ACE inhibitors such as enalapril, lisiuopril, 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 (MS); (20) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD);
  • (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;
  • SGLT sodium-glucose transporter
  • TGR5 receptor also known as GPBARl, BG37, GPCR19, GPR131, 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 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).
  • Step A ethyl 4-(3-nitropyri&n-2 ⁇ amino)benzoate
  • Step B ethyl 4-(3-aminopyridin-2-ylamino benzoate
  • ethyl 4-(3-nitropyridin-2-ylamino)benzoate 5 g, 17.42 mmol, 1.00 equiv
  • Palladium carbon 10%, 1 g
  • methanol 500 mL
  • THF 100 mL
  • the solid was filtered out.
  • the filtrate was concentrated under vacuum, which resulted in product ethyl 4-(3-aminopyridin-2- ylamino)benzoate as a gray solid.
  • Step D ethyl 4-(2-oxo-l .2- ⁇ 3 ⁇ 4.5- ⁇ -3- ⁇ 1 ⁇ 6 ⁇ - ⁇ 3 ⁇ 4 ⁇ 6
  • Step E 4-C2-oxo-l .2-dihvdroimidazo(-4.S-b]pyridin-3-vnbenzoic acid
  • Step A 2-nitropyridin-3 -yl trifluoromethanesulfonate
  • Step B ethyl 4- [( 2-nitrop yridin-3 -vDaminol benzoate
  • Step C ethyl 4-r(2-aminopyridin-3-yl)amino '
  • Step D ethyl 4-(2-oxo-2.3-dihvdroimidazor4.5-blpyridin-l -yPbenzoate
  • Step E 4-(2-oxo-2.3-dihvdroimidazo
  • CDCI3 ⁇ : 10.9 (1H, br), 8.17 (3H, m), 7.64 (2H, d, 8.5 Hz), 7.37 (1H, d, 7.5 Hz), 7.07 (1H, dd, 5.5, 2.0 Hz), 1.62 (9H, s) ppm.
  • Step A N-[4-(lH-indol-2-yl)phenyl1-2-iiitropyridin-3 -amine
  • Step B N-r4-QH-indol-2-yl)phenyl1pyridine-2 > 3-diamine
  • Step A fe -butyl 4- ( 1 - ⁇ 4- ⁇ 2-ethoxy-2-oxoethvttphenvn -2-oxo- 1.2-dihvdro-3H- imi dazo ⁇ 4.5 - >lpyridin-3 -yl I benzoate
  • Step B 4- ( 3 - ⁇ 4- ⁇ 2-ethoxy-2-oxoethvDphenyl] -2-oxo-2.3 -dihvdro- 1 H-imidazo ⁇ 4.5 - 6]pyridin-l -yl ) benzoic acid
  • Step C ethyl [4-(2-oxo- 1 -f 4- [5 -( trifluoromethyl)-2.3 -dihvdro- 1 H-benzimidazol-2 - vllpheiiyl)-1.2-dihvdro-3H-imidazo[4.5- ⁇ lpyridin-3-yl ' )phenyl1acetate
  • Step D ⁇ -(2- ⁇ - 1 - 4- ⁇ 6-( trifluoromethyl)- 1 H-benzimidazol-2-yll phenyl ) - 1.2-dihvdro- SH ⁇ rddazo ⁇ .S- ⁇ lpyridin-S-ynphenyllacetic acid
  • Step B fert-butyl 4- [2- (3 -bromopyr idin-2-yl')hydrazinyl1 carbonyl I benzoate
  • Step C 4-f 8-bromof l .2.41triazolor4.3-alpyridin-3-vDbenzoic acid
  • Step D 8-bromo-3-(4-f6-(trifluoromemyl l/- r -benzimidazol-2- yl]phenyll [1.2.4)triazoloi 4.3 pyridine
  • Step A 4-( ' 6-iodo-2-oxo-2.3-dihvdro- 1 H midazor4.5 -6]pyridin- 1 -yPbenzoic acid
  • StepB 6-iodo- 1 - ⁇ 4- f 5 -( trifluoromethylV 1 H-benzimidazol-2-vH henyl -1.3 -dihvdro-2H- imidazor4.5-3 ⁇ 41pyridin-2-one
  • Step C ethyl 3-(2-oxo- 1 - ⁇ 4-[ -(trifluoromethyl )- lH-beiizimidazol-2-ylfohenyl -2.3- d ydroAH idszc ⁇ .5-b ⁇ ddm'6-y ⁇ )b xa.oai
  • Step D 3-f2-oxo-1-i4-r5-ftrifluoromemylVlH-ber ⁇
  • StepB lithium 4-f3-benzyl-2-oxo-2 > 3-dihvdro-1H-imidazof4.5-blpyridin-1-yl benzoate
  • Step C 4-benzyl- 1 - ⁇ 4- [6-f trifluoromethvD- 1 H-benzimidazol-2-yl] phenyl ) - 1.4-dihvdro- 2H-imidazo[4.5-61pyridin-2-one
  • Step A benzyl 4-f3-(2-ethoxy-2-oxoethylV2-oxo-2-3-dihvdro-lH-inudazo[4.5-3 ⁇ 4 yllbenzoate and benzyl 4-i4-f2-ethoxy-2-oxoelJ ylV2-oxo-2.4-dihydro-lH-unidazof4.5- 61pyridin-l -yllbenzoate
  • Step B 4-r3-( -emoxy-2-oxoemylV2-oxo-2 -d vdro-l#-i ⁇
  • Step C ethyl ⁇ 2- ⁇ - 1 - ( A- ⁇ 6-f trifluoromethyl)- 1 H-benzimidazoI-2-ylfohenyl ) - 1.2- dihvdro H-imidazoi4.S-&1pyridin-3-yl ' )acetate and (2-oxo-l - f 4-f 6-ftrifluoromethyl ' )- 1H- benzimidazol-2- ⁇ phenyl ) - 1.2-dihvdro-3H-imidazo ⁇ 4.5-3 ⁇ 41 ⁇ ( ⁇ -3 -vDacetic acid
  • a 5 ml seal tube was treated with 6-fluoro-1 -dihydro-2H-pyrrolo[3,2-&]pyridin-2-one (100 mg, 0.657 mmol), intermediate 5 (253 mg, 0.651 mmol), copper(I) iodide (25.04 rag, 0.131 mmol) and potassium carbonate (182 mg, 1.315 mmol), capped and evacuated and backfilled with N2- Dioxane (6.0 ml) followed by trans-(lR,2R)-N > N'-bismethyl-1,2-cyclohexanediamme (0.021 ml, 0.131 mmol) was then added under N2 and the mixture stirred at 85 °C for 20 hr.

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Abstract

L'invention concerne des composés de formule (I) : Les composés de formule I agissent en tant qu'inhibiteurs de DGAT1 et peuvent être utiles pour la prévention, le traitement ou pour agir en tant qu'agent correctif pour l'hyperlipidémie, le diabète sucré et l'obésité.
PCT/US2011/045022 2010-07-28 2011-07-22 Dérivés d'imidazole WO2012015693A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013187496A1 (fr) 2012-06-15 2013-12-19 田辺三菱製薬株式会社 Composé hétérocyclique aromatique
US20140088124A1 (en) * 2011-06-02 2014-03-27 Robert J. DeVita Imidazole derivatives
WO2014140241A1 (fr) * 2013-03-15 2014-09-18 Intervet International B.V. Dérivés de pyridine en tant qu'inhibiteurs de dgat-1
WO2014181813A1 (fr) * 2013-05-10 2014-11-13 武田薬品工業株式会社 Composé hétérocyclique
CN105175414A (zh) * 2015-09-30 2015-12-23 山东大学 咪唑[4,5-b]吡啶巯乙酰胺类衍生物及其制备方法与应用
US9302996B2 (en) 2010-12-17 2016-04-05 Mitsubishi Tanabe Pharma Corporation Continuous arycyclic compound

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3985891A (en) * 1973-02-03 1976-10-12 Boehringer Ingelheim Gmbh 2-Phenyl-imidazo (4,5-b)pyridines and salts thereof
US5942532A (en) * 1997-09-05 1999-08-24 Ortho Pharmaceutical Corporation 2-substituted phenyl-benzimidazole antibacterial agents
US6582351B1 (en) * 1999-07-21 2003-06-24 Fujisawa Pharmaceutical Co., Ltd. Imidazopyridinone derivatives and their use as phosphodiesterase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3985891A (en) * 1973-02-03 1976-10-12 Boehringer Ingelheim Gmbh 2-Phenyl-imidazo (4,5-b)pyridines and salts thereof
US5942532A (en) * 1997-09-05 1999-08-24 Ortho Pharmaceutical Corporation 2-substituted phenyl-benzimidazole antibacterial agents
US6582351B1 (en) * 1999-07-21 2003-06-24 Fujisawa Pharmaceutical Co., Ltd. Imidazopyridinone derivatives and their use as phosphodiesterase inhibitors

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9302996B2 (en) 2010-12-17 2016-04-05 Mitsubishi Tanabe Pharma Corporation Continuous arycyclic compound
US9975871B2 (en) 2010-12-17 2018-05-22 Mitsubishi Tanabe Pharma Corporation Continuous arycyclic compound
US20140088124A1 (en) * 2011-06-02 2014-03-27 Robert J. DeVita Imidazole derivatives
WO2013187496A1 (fr) 2012-06-15 2013-12-19 田辺三菱製薬株式会社 Composé hétérocyclique aromatique
US9546155B2 (en) 2012-06-15 2017-01-17 Mitsubishi Tanabe Pharma Corporation Aromatic heterocyclic compound
US10308636B2 (en) 2012-06-15 2019-06-04 Mitsubishi Tanabe Pharma Corporation Aromatic heterocyclic compound
WO2014140241A1 (fr) * 2013-03-15 2014-09-18 Intervet International B.V. Dérivés de pyridine en tant qu'inhibiteurs de dgat-1
WO2014181813A1 (fr) * 2013-05-10 2014-11-13 武田薬品工業株式会社 Composé hétérocyclique
CN105175414A (zh) * 2015-09-30 2015-12-23 山东大学 咪唑[4,5-b]吡啶巯乙酰胺类衍生物及其制备方法与应用

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CA2805078A1 (fr) 2012-02-02

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