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WO2012024179A1 - Dérivés d'amide substitués en tant qu'inhibiteurs de dgat-1 - Google Patents

Dérivés d'amide substitués en tant qu'inhibiteurs de dgat-1 Download PDF

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WO2012024179A1
WO2012024179A1 PCT/US2011/047554 US2011047554W WO2012024179A1 WO 2012024179 A1 WO2012024179 A1 WO 2012024179A1 US 2011047554 W US2011047554 W US 2011047554W WO 2012024179 A1 WO2012024179 A1 WO 2012024179A1
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pharmaceutically acceptable
group
compound
alkyl
halogen
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PCT/US2011/047554
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Pauline C. Ting
Robert Aslanian
Jianhua Cao
David Kim
Nicolas Zorn
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Merck Sharp & Dohme Corp.
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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
    • C07D401/02—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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • 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

Definitions

  • the present invention is directed to novel substituted amide derivative compounds.
  • the compounds act as diacylglycerol O-acyltransferase type 1 inhibitors (hereinafter also referred to as "DGAT-1"), and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.
  • DGAT-1 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 l, 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, cerebrovascular disorder, coronary artery disease and metabolic syndrome, associated with the obesity.
  • each occurrence of U is independently selected from the group consisting of— N- and -CH-, wherein ring A is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, Cj-C 6 alkyl and halogen-substituted Ci-C galkyl;
  • ring B is piperidine, piperazine, piperazinone, pyridine or pyrrolidine, wherein ring B is unsubstituted or substituted with 1 -3 substituents selected from the group consisting of halogen, Cj-C 6 alkyl and halogen-substituted Q-C 6 alkyl;
  • W is -(CH 2 )n-C(0)NR 2 -(CH 2 )n- or -(CH 2 )n-NR 2 C(0)-(CH 2 )n-;
  • X is selected from the group consisting of -(C3 ⁇ 4)n-0-(CH 2 )n-; -(CH 2 )n ⁇
  • each occurrence of R 2 is independently selected from the group consisting of hydrogen and C
  • Y is C C 6 alkyl, phenyl or cycloalkyl, wherein the Ci ⁇ C 6 alkyl f phenyl or cycloalkyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, Cj-C 6 alkyl, halogen-substitutedCrCgalkyl, COCrCgalkyl, COhalogen-substitutedCj- C 6 alkyl, -OH, C r C 6 alkylOH, halogen-substitutedC r C 6 alkylOH, ⁇ OC r C 6 alkyl, -Ohalogen- substitutedCi-C 6 alk l, -COOH, -COCOOH, -COOC C 6 alkyl, -Ci-Cealk lCOOCi-Cealkyl, -C r QalkylCOOH and -Od-C 6 alkylCOOH;
  • Z is selected from the group consisting of phenyl, monocyclic cycloalkyl, monocyclic heterocycle, naphthalene, tetrahydronaphthalene,
  • Z is unsubsiituted or substituted with lor 2 substituents selected from the group consisting of halogen, C Ce lkyl, halogen-substitutedCi-Cgalkyl, COCi ⁇ C 6 alkyl, COhalogen- substitutedCrCealkyl, -OH, d-QaikylOH, halogen-substitutedC r C 6 alkylOH, -OCj -C 6 alkyl, - Ohalogen-substitutedC r C 6 alkyl, -COOH, -COCOOH, -COOC C 6 alkyl, -C r C 6 alkylCOOC C 6 alkyl, -C C 6 alkylCOOH and -Od-QalkyiCOOH; and
  • n 0, 1 or 2.
  • U is independently selected from the group consisting of -N- and -CH-. In certain embodiments, at both
  • U is -N-.
  • U is -CH-, i.e. phenyl.
  • one U is -CH- and the other is -N-.
  • ring A can be:
  • Ring A can be unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, Ci-C 6 alkyl and halogen-substituted C ⁇ -C 6 alkyl.
  • ring A is unsubstituted.
  • ring A can be an unsubstituted pyridine.
  • ring A is substituted.
  • Ring A can be substituted with one substituent.
  • Ring A can be substituted with two substituents.
  • Ring A can be substituted with three substituents.
  • ring A can be substituted with a halogen such as fluorine.
  • ring A is phenyl substituted with fluorine.
  • ring A is substituted with Ci-C ealkyl.
  • ring A is substituted with halogen- substituted Q-C 6 alkyl.
  • ring B is piperidine, piperazine,
  • ring B is piperidine. In other embodiments ring B is piperazine. In still other embodiments, ring B is pyridine. In yet other embodiments, ring B is pyrrolidine. In still other embodiments, ring B is piperazinone.
  • Ring B can be unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, Cj -C 6 alkyl and halogen-substituted Cj-C 6 alkyl.
  • ring B is unsubstituted.
  • ring B can an unsubstituted piperazine or piperazinone.
  • Ring B is an unsubstituted pyridine.
  • ring B is an unsubstituted pyrrolidine.
  • ring B is an unsubstituted. piperidine.
  • ring B is substituted with. 1-3 substituents selected from the group consisting of halogen, Ci-C 6 alkyl and halogen-substituted C ⁇ ⁇ C 6 alkyl. Ring B can be substituted with one substituent. Ring B can be substituted with two substituents. Ring B can be substituted with three substituents. For example ring B can be substituted with a halogen such as fluorine, in certain embodiments ring B is piperidine substituted with fluorine. In other embodiments, ring B is substituted with Ci-C ⁇ alkyl. In still other embodiments, ring B is substituted with halogen-substituted Ci-C 6 alkyl.
  • each occurrence of U is independently selected from the group consisting of -CH- and -N-. In certain embodiments, at both
  • U is -N-.
  • U is -CH-, i.e. phenyl.
  • one U is -CH- and the other is -N-.
  • ring A
  • V is -CR or -N-. In certain embodiments V is -N-. In other embodiments, V is -CR 4 -, wherein R 4 is selected from, the group consisting of hydrogen, halogen, Cr-Cealkyl and halogen-substitutedCi-Cealkyl. In certain embodiments, R 4 is hydrogen. In other embodiments, R 4 is halogen. In still other embodiments, R 4 is C C 6 alkyl. In yet other embodiments, R 4 is halogen substituted C f -Cealkyl.
  • R is selected from the group consisting of hydrogen, halogen, Cj-C 6 alkyl and halogen-substitutedCi-Cealkyl.
  • R 3 is hydrogen.
  • R 3 is halogen.
  • R 3 is Cj-Qalkyi
  • R 3 is halogen substituted Cs-C 6 alkyl.
  • W is -(CH 2 )n-C(0)NR 2 -(CH 2 )n ⁇ or -(CH 2 )n- NR 2 C(0)-(CH 2 )n ⁇ .
  • W is -(CH 2 )n-C(0)NR 2 -(CH 2 )n ⁇ .
  • W is -(CH 2 )n-NR 2 C(0)-(CH 2 )n-.
  • Each occurence of n can be 0, 1 , or 2.
  • W is -C(0)NR 2 -.
  • W is -NR 2 C(0)-.
  • described herein are compounds of formula Ic:
  • X is selected from the group consisting of - (CH 2 )n-0-(CH 2 )ns -(C3 ⁇ 4)n-C(0)NR 2 -(C3 ⁇ 4)n-; -(C3 ⁇ 4)n-C(0)CR1H-(CH 2 )ns -(CH 2 )n-C(R 1 ) 2 - (CH 2 )ns -(CH 2 )n-NR 2 C(0)-(CH 2 )n-; -(CH 2 )n-OC(0)-(CH 2 )n-; -(CH 2 )n-C(0)0-(CH 2 )n-; - (CH 2 )n ⁇ NR 2 S0 2 -(CH 2 )n-; -(CH 2 )n-S0 2 NR 2 -(CH 2 )n-; -(CH 2 )n-C(0)n-(CH 2 )n-; -(CH 2 )n- NR 2 C(0)CR1H-(CH 2 )n-
  • R 1 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl. In certain embodiments, R 1 is hydrogen. In other embodiments, R 1 is Ci-QalkyL
  • R 2 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyL In certain embodiments, R 2 is hydrogen. In other embodiments, R " is Ci-C 6 alkyl.
  • X is -C3 ⁇ 40-, -C(O)-,
  • X is - CH 2 0-, -C(0)-, -C(0) H- 9 - NHC(O)-, -CH 2 C(0)NH-, -(CH 2 ) 2 C(0)NH- or -0-. In still another embodiment, X is -C3 ⁇ 40-.
  • Y is Q-C ealkyl, phenyl or cycloalkyl, wherein the Ci-C galkyl, phenyl or cycloalkyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, CrC 6 aIkyl, halogen-substitutedCt-Cealkyl, COQ- C 6 alkyl, COhalogen-substitutedCi-Qalkyl, -OH, CrC 6 alkylOH, halogen-substitutedQ- C 6 alkylOH, -OC C 6 alkyl, -Ohalogen-substitutedCi-C 6 alkyl, -COOH, -COCOOH, -COOC r C 6 alkyl, -Cj-CealkylCOOCi-Cealk l, -C C 6 alkylCOOH and -OC C 6 alkylCO
  • Y is phenyl. In other embodiments of the compounds described herein, Y is cycloalkyl. Suitable examples of cycloalkyl, include but are not limited to cyclohexane. In still other embodiments, Y is Ci-C 6 alkyl. Suitable examples of Ci-C 6 alkyl include, but are not limited to isobutane.
  • Y is substituted with
  • Y is substituted with one substituent selected from the group consisting of halogen, -COOH, ⁇ COOCi-C 6 alkyl and Ci-Cealkyl, In still other embodiments, Y is substituted with 2 substituents selected from the group consisting of halogen, -COOH, -
  • Y is phenyl wherein the phenyl is substituted with -COOH.
  • Z is selected from the group consisting of phenyl, monocyclic cycloalkyl, monocyclic heterocycle, naphthalene, tetrahydronaphthalene,
  • Z is unsubstituted or substituted with lor 2 substituents selected from the group consisting of halogen, Ci-C 6 alkyl, halogen ⁇ substitutedCrC 6 alkyl, COCrCealkyl, COhalogen- substitutedC r C 6 alkyl, -OH, C[-C 6 alkylOH, haiogen-substitutedCi-QalkylOH, -OCi-C 6 alkyl, - Ohalogen-substitutedC C 6 alkyl 5 -COOH, -COCOOH, -COOd-C f ialkyl, -Ci-C 6 alkylCOOCi- C 6 alkyl, -C C 6 alkylCOOH and -OC C 6 alkylCOOH.
  • substituents selected from the group consisting of halogen, Ci-C 6 alkyl, halogen ⁇ substitutedCrC 6 alkyl, COCrCeal
  • Z is phenyl.
  • Z is monocyclic cycloalkyl. Suitable examples of monocyclic cycloalkyl include cyclohexane and cyclopentane.
  • Z is monocyclic heterocycle. Suitable examples of monocyclic heterocycle includes, pyridine, pyrimidine and pyridazine.
  • Z is selected from the group consisting of:
  • Z is naphthalene. In still other embodiments of the compounds described herein, Z is tetrahydronaphthalene. In otiier embodiments, Z is a bicyclic heterocycle, containing nitrogen, selected from the group consisting of :
  • Z is a bicyclic heterocycle, containing oxygen, selected from the group consisting of :
  • Z is selected from the group consisting of:
  • Z is a phenyl group and a five-membered heterocycle separated by a linker group, such as,
  • Z is selected from the group consisting of:
  • Z is selected from the group consisting of:
  • Z is selected from the group consisting of:
  • Z is substituted with nts selected from the group consisting of halogen, -COOH, -OCi-Cealkyl, - Ohalogen-substitutedCj-Cealkyl, halogen-substitutedCj-Qalkyl, d-C 6 alkyl and -NH-phenyL
  • Z is substituted with 1 substituent selected from the group consisting of halogen, -COOH, -OCj-Cgalkyl, -Ohalogen-substitutedCi-C 6 alkyl 5 halogen-substitutedCj- Cgalkyl, C]-C 6 alkyl and -NH-phenyL
  • Z is substituted with 2 substituents selected from the group consisting of halogen, -COOH, -OCi-C 6 alkyl, -Ohalogen-substitutedCi- Cgalkyl, halogen
  • Z is substituted with -COOH, In other embodiments, Z is substituted with -OCj-Qalkyl, such as, but not limited to, methoxy. In still other embodiments, Z is substituted with -Ohal.ogen-substitutedCrC 6 alkyi, such as, but not limited to,
  • Z is substituted with -Ct-C$alkyl 5 such as, but not limited to, methyl.
  • Z is substituted with -halogen-substitutedCj- C 6 alkyl, such as, but not limited to, trifluoromethyl.
  • Z is substituted with -NH-phenyl.
  • halogen examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Cj-C galkyl 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, l-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-meihyIpentyl, 1 , 1 -dimethylbutyl, 1 ,2-dimethylbutyI, 2,2- dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylprop
  • Cycloalkyl encompasses cycloalkyls having 3 to 10 carbons, forming one or more carbocyclic rings that are fused. “Cycloalkyl” also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. In one embodiment, the cycloalkyl can include 3-6 carbons, i.e. Cs-Cgcycloalkyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl,
  • -OC C ealkyl refers to an alkyl group having 1 to 6 carbons linked to oxygen, also known as an alkoxy group. Examples include methoxy, ethoxy, butoxy and propoxy.
  • -OCi-C ealkylCOOH refers to an alkoxy group having 1 to 6 carbons substituted with a carboxylic acid (-COOH) group.
  • halogen- substitutedCi-C 6 alkyl encompasses Q-Q alkyl with the hydrogen atoms thereof being partially or completely substituted with halogen, examples thereof include fluoromethyl, difluoromethyl, trifluoromethyi, 2-fluoroethyl, 1 ,2-difluoroethyl, 2,2-difluoroethyl and the like.
  • -Ohalogen-substitutedCi-Cgalkyl means a -OCrC 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.
  • -COCrCealkyl means groups having Ci-C 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 Cealkyl means a -COCi-C 6 alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different.
  • Ci-C 6 alkylOH means a C Ce lkyl substituted with an alcohol (-OH).
  • Examples include methanol, propanol, butanol and t-butanol.
  • halogen-substitutedCi ⁇ C 6 alkylOH means a halogen-substitutedCi-C 6 alkyl, as defined above, substituted with an alcohol (-OH).
  • halogen-substituted Ci-C 6 alkyIOH means a halogen-substituted CrC 6 alkyl substituted with an alcohol (-OH).
  • COOCi-Cealkyl means a -COOH group wherein the -OH is replaced with an alkoxy grou as defined above. Examples include methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.
  • aryl examples include phenyl, naphthyl, tolyl, and the like.
  • Heterocycle unless otherwise specified, means an aromatic, partially aromatic or non- aromatic monocyclic or polycyclic (including bicyclic) ring having at least one ring heteroatom selected from O, S and N.
  • heterocyclic groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, 2-oxo-(lH)-pyridinyl (2-hydroxy-pyridinyl), oxazolyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidinyl, pyrazinyl, benzisoxazolyl, benzoxazolyi, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl,
  • heterocycle also include tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2 ?
  • 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-a2abicyclo[3.2.2]nonyl, and azabicyclo[2.2.1jheptanyl.
  • 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, glycollyiarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbro
  • suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N s N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethyienediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethyl amine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion-exchange resins such as arginine, betaine,
  • 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 chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • 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 (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.
  • DGAT- 1 -related diseases are also encompassed by the present invention.
  • the compounds described herein are effective in preventing or treating various DGAT- 1 -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 chromat
  • 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 any one 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 gain, regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy and preventing weight gain from cessation of smoking.
  • Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases.
  • Yet another outcome of treatment may be decreasing the risk of developing diabetes in an overweight or obese subject.
  • the treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof.
  • the treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.
  • Prevention of obesity and obesity-related disorders refers to the administration of the pharmaceutical formulations described herein to reduce or maintain the body weight of a subject at risk of obesity.
  • One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds or combinations of the present invention.
  • Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy.
  • Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity.
  • Another outcome of prevention may be decreasing the occurrence and/or severity of obesity-related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity.
  • such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, type 2 diabetes, polycystic ovary disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
  • arteriosclerosis such as, but not limited to, arteriosclerosis, type 2 diabetes, polycystic ovary disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
  • Another aspect of the invention that is of interest relates to a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat hyperglycemia, diabetes or insulin resistance.
  • Another aspect of the invention that is of interest relates to a method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising
  • Yet another aspect of the invention that is of interest relates to a method of treating non- insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat non-insulin dependent diabetes mellitus.
  • the present invention is also directed to the use of a compound of structural formula I, la or lb in the manufacture of a medicament for use in treating various DGAT-1 -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,
  • 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 compounds described herein are especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety.
  • the present invention is directed to the use of a compound of structural formula I, la or lb in the manufacture of a medicament for use in treating obesity, diabetes, hormone secretion disorder, hyperlipemia, gout and fatty liver.
  • the present invention is directed to the use of a compound of structural formula I, la or lb in the manufacture of a medicament for use in treating obesity.
  • Compounds of the invention may be administered orally or parenterally.
  • the compound of the invention can be used as a pharmaceutical composition for the prevention, treatment, or remedy of the above diseases.
  • the compound of the invention In clinical use of the compound of the invention, usually, the compound is formulated into various preparations together with pharmaceutically acceptable additives according to the dosage form, and may then be administered.
  • pharmaceutically acceptable it is meant the additive, carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • additives various additives ordinarily used in the field of pharmaceutical preparations are usable.
  • gelatin lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, corn starch, 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 for their use.
  • the preparations may be dissolved or suspended in physiological saline or glucose liquid, and a buffer or a preservative may be optionally added thereto.
  • 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 one time or at several times.
  • the dose is preferably from about 0.01 to about 25 mg/kg/day, more preferably from
  • compositions are preferably
  • 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,
  • This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • 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 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 formula I, la or lb is preferred.
  • the combination therapy may also include therapies in which the compound of formula I, la or lb and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or 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 formula I, la or lb.
  • composition include, but are not limited to:
  • DPP-4 dipeptidyl peptidase-IV
  • (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 2002/060388, WO 2002/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963, and (4)
  • salts in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortarnet®, and GlucophageXR®;
  • PTP - IB protein tyrosine phosphatase- 1 B inhibitors ;
  • 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;
  • a-glucosidase inhibitors such as acarbose, voglibose and miglitol
  • glucagon receptor antagonists such as those disclosed in WO 1998/04528, WO 1999/01423, WO 2000/39088, and WO 2000/69810;
  • incretin mimetics such as GLP-1, GLP-1 analogs, derivatives, and mimetics
  • GLP-1 receptor agonists such as exenatide, liraglutide, taspoglutide, AVEOOIO, CJC-1 131, 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
  • M -524A which is a combination of niacin extended-release and the DP-1 antagonist M .-524
  • 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, teimisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers.
  • ACE inhibitors such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril
  • A-II receptor blockers such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, teimisartan, and eprosartan
  • renin inhibitors such as
  • GKAs glucokinase activators
  • inhibitors of 1 ⁇ -hydroxy steroid dehydrogenase type 1 such as those disclosed in U.S. Patent No. 6,730,690; WO 2003/104207; and WO 2004/058741 ;
  • inhibitors of cholesteryl ester transfer protein such as torcetrapib and M -0859
  • inhibitors of fructose 1,6-bisphosphatase such as those disclosed in U.S. Patent Nos.
  • inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2);
  • AMPK AMP-activated Protein Kinase
  • neuromedin U receptor agonists such as those disclosed in WO 2009/042053, including, 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-1; SGLT-2, such as dapagliflozin and remogliflozin; and SGLT-3;
  • SGLT sodium-glucose transporter
  • TGR5 receptor also known as GPBAR1, BG37, GPC 19, GPR131, and M- BAR
  • Dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds 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, rosiglitazbne, simvastatin, atorvastatin, or a . sulfonylurea.
  • DPP-4 dipeptidyl peptidase-IV
  • DPP-4 dipeptidyl peptidase-IV
  • Antiobesity compounds that can be combined with compounds 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 topiramate and phentermine; fenfluramine; dexfenfluramine; sibutramine; lipase inhibitors, such as orlistat and cetilistat; melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists; CC -1 agonists; melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Y ⁇ or Y5 antagonists (such as MK-0557); CBl receptor inverse agonists and antagonists (such as rimonabant and taranabant); ⁇ 3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (such as bomb
  • 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.
  • Glucagon receptor antagonists that can be used in combination with the compounds of the formulas described herein include, but are not limited to:
  • Inhibitors of stearoyl-coenzyme A delta-9 desatu ase (SCD) that can be used in combination with the compounds of the formulas described herein include, but are not limited to:
  • Glucokinase activators that can be used in combination with the compounds of the formulas described herein include, but are not limited to:
  • Agonists of the GPR-1 19 receptor that can be used in combination with the compounds of the formulas described herein include, but are not limited to: rac-cis 5-chloro-2- ⁇ 4-[2-(2- ⁇ [5-(methylsulfonyl)pyridin-2-yl]oxy ⁇ ethyl)cyclopropyl] piperidin-1 - yl ⁇ pyrimidine;
  • SPPARyM's Selective PPARy modulators that can be used in combination with the compounds of the formulas described herein include, but are not limited to:
  • Inhibitors of 11 ⁇ -hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds 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 the formulas described herein include, but are not limited to:
  • AMP-activated Protein Kinase (AMPK) activators that can be used in combination with the compounds 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 the formulas described herein include, but are not limited to; 3 - ⁇ 1 '- [( 1 -cy clopropyl-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:
  • insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g.
  • PPARa/ ⁇ dual agonists such as muraglitazar, aleglitazar, sodelglitazar, and navegtitazar
  • 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-giucosidase inhibitors such as acarbose, voglibose and miglitol
  • LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors
  • lovastatin simvastatin, pravastatin, cerivastatin, fiuvastatin, atorvastatin, pravastatin, 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:cholesterol 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-l 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-Il receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers.
  • ACE inhibitors such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril
  • A-Il receptor blockers such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan
  • renin inhibitors such as aliski
  • GKAs glucokinase activators
  • CETP cholesteryl ester transfer protein
  • 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;
  • SGLT sodium-glucose transporter
  • TGR5 receptor also known as GPBAR1, 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 d -(5 -mtropwidin ⁇ 2-yl)piperidin-4- ypmethanol
  • Step B ( 1 -f 5-mtropyridin-2-vi)piperidin-4-yl )methyl methanesulfonate
  • Step D methyl 3-f(l-(5-aminopyiidin-2-yl)piperidin-4-yl methoxy)benzoate
  • Step A t-butyl 4-(5-nitropyridin-2-yl)piperazine- -carboxylate
  • Step B N-(5 -nitropyridin-2-yl)piperazine
  • Step C 4-(5-Nitropyridin-2-yl)-N-(2-fiuorophenyl)piperazine- 1 -carboxamide
  • Step D 4-(5-Aminopyridin-2-yl)-N ⁇ (2-fluorophenyl)piperazine- 1 -carboxamide
  • Step A tert-butyl 4-fluoro-4-f hydroxymethyDpiperidine- 1 -carboxylate
  • Step C i4-fluoro-l-(5-nitropyridin-2-yDpiperidin-4-yl)methanol
  • Step A f 4-fluoro- 1 -(5-nitropyridin-2-yl)piperidin-4-yi)methyl methanesulfonate This compound was made by following the same method described in Intermediate 1 ,
  • Step E methyl 3 -((4-fluoro- 1 -(5 ⁇ mtropyridin-2-yl)piperidin-4- yl)methoxy benzoate
  • Step F methyl 3-(( 1 -(5-aminopyridin-2-yl)-4-fluoropiperidin-4- yl)methoxy)benzoate
  • Step A fert-butyl 4-(3-(methoxycarbonyl benzyl -3-oxopiperazine- 1 -carboxylate
  • Step B methyl 3-(Y2-oxopiperazm- -yl)methyl)benzoate
  • Step C methyl 3-((4-f 5-nitropyridin-2-yl)-2-oxopiperazin- 1 -yl)methyl)benzoate
  • Step A ethyl 4-(5 -bromopyridin-2-yloxy)cycl ohexanecarboxylate
  • Step B ethyl 4-( 5-(4 A5 -tetramethyl- 1.3.2-dioxaboroian-2-yl pyridin-2- vioxy)cyclohexanecarboxylate
  • Step C ethyl 4-(5 -amino-2,3 '-bipyridin-6'-yloxy cyclohexanecarboxylate
  • Step D ethyl 4-(5-(3-phenoxybenzamido)-2 3'-bipyridin-6'-yloxy cyciohexanecarboxylate
  • ethyl 4-(5-amino-2 ; 3'-bipyridin-6'-yloxy)cyclohexanecarboxylate 100 mg, 0.293 mmol
  • 3-phenoxy benzoic acid 69 mg, 0.322 rnmol
  • CH2CI2 10 mL
  • HATU 167 mg, 0.440 mmol
  • Hunig's base 153 pL, 0.879 mmol
  • Step E 4-(5-(3-phenoxybenzamido)-2 ⁇ 3'-bipyridin-6'-yloxy cyclohexanecarboxylic acid
  • Step A methyl 2-(phenylamino)pyrimidine-4 -carbox ylate
  • Methyl 2-chloropyrimidine-4-carboxylate 250 mg, 1.45 mmol
  • aniline 0.132 mL, 1.45 mmol
  • NaHC0 3 18.2 mg, 2.17 mmol
  • Step A methyl 3 -(5-bromopyridin-2-yloxyV2,2-dimethylpropanoate
  • the suspension was cooled to RT and filtered over a thin celite pad.
  • the celite pad was rinsed with Et 2 0 (150 mL).
  • the filtrate was concentrated to a volume of ca. 5 mL, then diluted with Et 2 0 (150 mL), quenched with water (90 mL) and decanted.
  • the aqueous layer was extracted with Et 2 0; the combined organic extract was successively washed with water then brine, dried (MgSC ⁇ ), filtered and concentrated. Purification by silica gel chromatography (eluant: 0-20%
  • Step B methyl 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin ⁇ 2- yloxy propanoate [lJ'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (217 mg, 0.27 mmol), potassium acetate (1.57 g, 16.0 mmol), bis(pinacolato)diboron (1.62 g, 6.39 mmol) and methyl 3- (5-bromopyridm-2-yloxy)-2,2-dimethylpropanoate (1.53 g, 5.32 mmol) were mixed at RT in anhydrous 1,4-dioxane (27 mL).
  • Step C potassium trifluoro(6-r3-methoxy-2,2-dimethvi-3-oxopropoxy pyridin-3-yl ' )borate
  • Potassium hydrogen difluoride (525 mg, 6.72 mmol) was added at RT to a solution of methyl 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yloxy)propanoate (750 mg, 2.24 mmol) in a 2:1 mixture of water and methanol (11 mL). The reaction was stirred at RT in a polypropylene reactor for 4 h.
  • Step D methyl 2,2-dimethyl-3 -( 5-( 4-nitrophenyl)pyridin-2-yIoxy)propanoate
  • Step E methyl 3-(5-f4-aminophenyl pyridin-2-yloxy)-2,2-dimethylpropanoate
  • Step A fert-butyl 4-(( memylsulfonyloxy methyl)piperidine- 1 -carboxylate
  • Step B f erf-butyl 4-(Y3 -(methoxycarbonyl phenoxy)methYl)piperidine- 1 -carboxylate
  • Step D methyl 3-((l-( ' 5-nitropyrimidin-2-yl)piperidin-4-yl)methoxy)benzoate
  • Step E methyl 3-((l-(5-ai inop imidin-'2-yl)piperidin-4-yl)methoxy)berLzoate
  • the in vitro assay to identify DGAT1 inhibitors uses human DGAT1 enzyme expressed in Sf9 insect cells prepared as microsomes.
  • the reaction is initiated by the addition of the combined substrates 1,2-dioleoyl-sn-glycerol and [ 14 C] ⁇ palmitoyl-Co A and incubated with test compounds and microsomal membranes for 2 hours at room temperature.
  • the assay is stopped by adding 0.5 mg wheat germ agglutinin beads in assay buffer with 1% Brij-35 and 1% 3 -cholamidopropyldimethyl-ammonio-1 -propane sulfonate. Plates are sealed with TopSeal and incubated for 18 hours to allow the radioactive triglyceride product to come into proximity with the bead. Plates are read on a TopCount instrument.
  • Percent inhibition was calculated as the percent of (test compound inhibition minus non-specific binding) relative to (total binding minus non-specific binding). IC 5 o values were determined by curve fitting the data to a Sigmoidal dose-response in GrapbPad Prism utilizing the following equation;
  • a and B are the bottom and top of the curve (highest and lowest inhibition), respectively, and X is the logarithm of concentration.
  • the solution is incubated at room temperature for 1 hour after which 20 ⁇ , of a 90 ⁇ 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin solution in 90% ethanol was added. After incubation in the dark for 30 minutes at room temperature, fluorescence was measured on a Perkin Elmer Envision multilabel reader.
  • the IC50 is determined from a 4 parameter fit of the plot of %Inhibition vs. Concentration of Test Compound in the reaction and is defined as the concentration at which the curve crosses the 50% inhibition line.
  • % inhibition [1 -(fluorescence counts from test compound- average fluorescence counts from LC)/(average fluorescence counts from HC-average fluorescence counts from LC)] x 100%

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Abstract

L'invention concerne des composés de formule I. Les composés de formule I agissent en tant qu'inhibiteurs de DGAT-1 et peuvent être utiles pour prévenir et traiter l'hyperlipidémie, le diabète sucré et l'obésité, ou pour agir comme remède pour ces maladies.
PCT/US2011/047554 2010-08-18 2011-08-12 Dérivés d'amide substitués en tant qu'inhibiteurs de dgat-1 WO2012024179A1 (fr)

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WO2015140658A1 (fr) * 2014-03-17 2015-09-24 Pfizer Inc. Inhibiteurs de diacylglycérol acyltransférase pour le traitement de troubles métaboliques ou analogues
JP2016513112A (ja) * 2013-02-18 2016-05-12 ザ スクリプス リサーチ インスティテュート 治療的潜在能力を有するバソプレッシン受容体のモジュレーター
CN108250194A (zh) * 2018-02-12 2018-07-06 李化绪 一种二氟苯并噻唑类化合物及其在降血脂药物中的应用
WO2018172852A1 (fr) * 2017-03-21 2018-09-27 Arbutus Biopharma Corporation Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant
CN110545817A (zh) * 2016-11-28 2019-12-06 百时美施贵宝公司 Gsk-3抑制剂
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
WO2021133038A1 (fr) * 2019-12-23 2021-07-01 주식회사 엘지화학 Nouveau dérivé d'amide utile en tant qu'inhibiteur de la diacylglycérol acyltransférase 2, et son utilisation
RU2810064C1 (ru) * 2019-12-23 2023-12-21 ЭлДжи КЕМ, ЛТД. Новое амидное производное, используемое в качестве ингибитора диацилглицерол o-ацилтрансферазы 2, и его применение

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JP2016513112A (ja) * 2013-02-18 2016-05-12 ザ スクリプス リサーチ インスティテュート 治療的潜在能力を有するバソプレッシン受容体のモジュレーター
US9440949B2 (en) 2014-03-17 2016-09-13 Pfizer Inc. Diacylglycerol acyltransferase 2 inhibitors
TWI551596B (zh) * 2014-03-17 2016-10-01 輝瑞大藥廠 二醯甘油醯基轉移酶２抑制劑
CN106103425A (zh) * 2014-03-17 2016-11-09 辉瑞公司 用于治疗代谢及相关病症的二酰甘油酰基转移酶2抑制剂
JP2017507979A (ja) * 2014-03-17 2017-03-23 ファイザー・インク 代謝性および関連障害の処置において使用するためのジアシルグリセロールアシルトランスフェラーゼ２阻害剤
US9789110B2 (en) 2014-03-17 2017-10-17 Pfizer Inc. Diacylglycerol acyltransferase 2 inhibitors
WO2015140658A1 (fr) * 2014-03-17 2015-09-24 Pfizer Inc. Inhibiteurs de diacylglycérol acyltransférase pour le traitement de troubles métaboliques ou analogues
US10188653B2 (en) 2014-03-17 2019-01-29 Pfizer Inc. Diacylglycerol acyltransferase 2 inhibitors
EA032356B1 (ru) * 2014-03-17 2019-05-31 Пфайзер Инк. Ингибиторы диацилглицеринацилтрансферазы 2 для применения в лечении метаболических и связанных с метаболизмом расстройств
CN110545817A (zh) * 2016-11-28 2019-12-06 百时美施贵宝公司 Gsk-3抑制剂
CN110545817B (zh) * 2016-11-28 2022-11-15 百时美施贵宝公司 Gsk-3抑制剂
WO2018172852A1 (fr) * 2017-03-21 2018-09-27 Arbutus Biopharma Corporation Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant
US11098010B2 (en) 2017-03-21 2021-08-24 Arbutus Biopharma Corporation Substituted dihydroindene-4-carboxamides and analogs thereof, and methods using same
CN108250194A (zh) * 2018-02-12 2018-07-06 李化绪 一种二氟苯并噻唑类化合物及其在降血脂药物中的应用
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
WO2021133038A1 (fr) * 2019-12-23 2021-07-01 주식회사 엘지화학 Nouveau dérivé d'amide utile en tant qu'inhibiteur de la diacylglycérol acyltransférase 2, et son utilisation
KR20210081285A (ko) * 2019-12-23 2021-07-01 주식회사 엘지화학 디아실글리세롤 아실트랜스퍼라제 2 억제제로서 유용한 신규 아미드 유도체 및 이의 용도
KR102557329B1 (ko) 2019-12-23 2023-07-19 주식회사 엘지화학 디아실글리세롤 아실트랜스퍼라제 2 억제제로서 유용한 신규 아미드 유도체 및 이의 용도
RU2810064C1 (ru) * 2019-12-23 2023-12-21 ЭлДжи КЕМ, ЛТД. Новое амидное производное, используемое в качестве ингибитора диацилглицерол o-ацилтрансферазы 2, и его применение

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