WO2013078413A1 - Modulateurs du stockage lipidique - Google Patents

Modulateurs du stockage lipidique Download PDF

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Publication number
WO2013078413A1
WO2013078413A1 PCT/US2012/066394 US2012066394W WO2013078413A1 WO 2013078413 A1 WO2013078413 A1 WO 2013078413A1 US 2012066394 W US2012066394 W US 2012066394W WO 2013078413 A1 WO2013078413 A1 WO 2013078413A1
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alkyl
compound
halo
alkoxy
mhz
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PCT/US2012/066394
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English (en)
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Matthew B. Boxer
Mathias BELLER
Kirsten TSCHAPALDA
Min Shen
Li Liu
Yaqin ZHANG
Zhuyin Li
Carole SZTALRYD
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The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V.
University Of Maryland, Baltimore
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Publication of WO2013078413A1 publication Critical patent/WO2013078413A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • LD lipid storage droplet
  • lipid storage diseases that are inherited metabolic disorders that result in harmful buildup of various lipids.
  • Most of these diseases termed lipidoses, are caused by various deficient enzymes such as: glucocerebrosidase (Gaucher disease), a- galactosidase-A (Fabry disease), ceramidase (Farber's disease), ⁇ -galactosidase (GM1 gangliosidoses), ⁇ -hexosaminidase (Tay-Sachs and Sandhoff disease), galactosylceramidase (Krabbe disease) and arylsulfatase A (metachromatic leukodystrophy) (Gieselmann, V.
  • Lipid droplets are established key components of cellular energy homeostasis that is often altered in obesity and its associated serious health consequences including increased risk for hypertension, insulin resistance, diabetes and coronary heart disease.
  • An important clue to the pathogenesis of these metabolic diseases is the presence of ectopic lipid droplets (LDs) in liver, skeletal, heart muscle of patients with "metabolic syndrome" and presence of LDs have been associated to tissue lipotoxicity and dysfunction.
  • LDs ectopic lipid droplets
  • R 1 is selected from alkyl, aryl, arylalkyl, and alkylaryl, each of which is optionally substituted with one or more substituents selected from halo, alkyl, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino, trialkylamino, guanidino, aminocarbonyl, aldehydo, and ureido;
  • R 2 is selected from heterocyclyl, heteroaryl, cycloalkyl, dimethylamino alkyl, and benzyl, each of which is optionally substituted with one or more substituents selected from halo, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino, trialkylamino, guanidino,
  • R 3 and R 4 are each independently a lower alkyl or, taken together with the carbon atom to which they are attached, form a 5- to 7-membered ring;
  • R 10 is selected from alkyl, dialkylaminoalkyl, heterocyclyl, heteroaryl, aryl, arylalkyl, arylcycloalkyl, and each of which is optionally substituted with one or more substituents selected from alkyl, halo, cycloalkyl, aryl, fused aryl, fused cyclic, arylalkyl, and
  • R are independently hydrogen or alkyl
  • R° and R' are independently hydrogen,lower alkyl, or arylalkyloxyalkyl, or, taken together with the carbon atom to which they are bonded, form a 5-7 membered ring;
  • R is H or a substituent selected from halo, alkyl, monohalo alkyl, dihaloalkyl, trihaloalkyl, monohalo alkoxy, dihalo alkoxy, trihalo alkoxy, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkoxy carbonyl, heterocyclyl, alkyl heterocyclyl, heterocyclylalkyl, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino,
  • R 9 is H, OR 15 , or NR I6 R 17 ; wherein R 15 , R 16 , and R 17 , are independently hydrogen or lower alkyl;
  • R is hydrogen or lower alkyl
  • R 19 is hydrogen or halo
  • A is NH(CH 2 ) m , CH 2 , or a bond; m is 0 or 1 ; n is 1 -5; and p is 0-3; a pharmaceutically acceptable salt thereof, or an enantiomer thereof; or a conjugate thereof wherein the conjugate comprises a marker group.
  • the invention also provides a method of preventing or treating a disease or disorder responsive to reduction of lipid storage droplets in an animal in need thereof comprising administering an effective amount of a compound of formula I, II, or III or a combination thereof:
  • R is selected from alkyl, aryl, arylalkyl, and alkylaryl, each of which is optionally substituted with one or more substituents selected from halo, alkyl, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino, trialkylamino, guanidino, aminocarbonyl, aldehydo, and ureido;
  • R 2 is selected from heterocyclyl, heteroaryl, cycloalkyl, dimethylamino alkyl, and benzyl, each of which is optionally substituted with one or more substituents selected from halo, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino, trialkylamino, guanidino,
  • R 3 and R 4 are each independently a lower alkyl or, taken together with the carbon atom to which they are attached, form a 5- to 7-membered ring;
  • R 10 is selected from alkyl, dialkylaminoalkyl, heterocyclyl, heteroaryl, aryl, arylalkyl, arylcycloalkyl, and each of which is optionally substituted with one or more substituents selected from alkyl, halo, cycloalkyl, aryl, fused aryl, fused cyclic, arylalkyl, and
  • R 1 1 , R 12 , R 13 , and R 14 are independently hydro gen or alkyl
  • R 6 and R 7 are independently hydrogen,lower alkyl, or arylalkyloxyalkyl, or, taken together with the carbon atom to which they are bonded, form a 5-7 membered ring;
  • R 8 is H or a substituent selected from halo, alkyl, monohalo alkyl, dihaloalkyl, trihaloalkyl, monohalo alkoxy, dihalo alkoxy, trihalo alkoxy, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkoxy carbonyl, heterocyclyl, alkyl heterocyclyl, heterocyclylalkyl, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino,
  • R 9 is H, OR 15 , or NR 16 R 17 ; wherein R 15 , R 16 , and R 17 , are independently hydrogen or lower alkyl;
  • R is hydrogen or lower alkyl
  • R 19 is hydrogen or halo
  • A is NH(CH 2 )m, CH 2 , or a bond
  • the invention additionally provides a method of identifying a molecular target involved in lipid storage in a cell, comprising contacting the cell with a compound of formula I, II, or III:
  • R 1 is selected from alkyl, aryl, arylalkyl, and alkylaryl, each of which is optionally substituted with one or more substituents selected from halo, alkyl, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino, trialkylamino, guanidino, aminocarbonyl, aldehydo, and ureido;
  • R 2 is selected from heterocyclyl, heteroaryl, cycloalkyl, dimethylamino alkyl, and benzyl, each of which is optionally substituted with one or more substituents selected from halo, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino, trialkylamino, guanidino,
  • R 3 and R 4 are each independently a lower alkyl or, taken together with the carbon atom to which they are attached, form a 5- to 7-membered ring;
  • R 10 is selected from alkyl, dialkylaminoalkyl, heterocyclyl, heteroaryl, aryl, arylalkyl, arylcycloalkyl, and each of which is optionally substituted with one or more substituents selected from alkyl, halo, cycloalkyl, aryl, fused aryl, fused cyclic, arylalkyl, and
  • R U , R 12 , R 13 , and R 14 are independently hydrogen or alkyl
  • R 6 and R 7 are independently hydrogen,lower alkyl, or arylalkyloxyalkyl, or, taken together with the carbon atom to which they are bonded, form a 5-7 membered ring;
  • R 8 is H or a substituent selected from halo, alkyl, monohalo alkyl, dihaloalkyl, trihaloalkyl, monohalo alkoxy, dihalo alkoxy, trihalo alkoxy, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkoxy carbonyl, heterocyclyl, alkyl heterocyclyl, heterocyclylalkyl, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino,
  • R 9 is H, OR 15 , or NR I 6 R 17 ; wherein R 15 , R 16 , and R 17 , are independently hydrogen or lower alkyl;
  • R is hydrogen or lower alkyl
  • R 19 is hydrogen or halo
  • A is NH(CH 2 )m, CH 2 , or a bond; m is 0 or 1 ; n is 1 -5; and p is 0-3; a pharmaceutically acceptable salt thereof, or an enantiomer thereof; or a conjugate thereof wherein the conjugate comprises a marker group; to form a complex of the target and the compound, pharmaceutically acceptable salt thereof, or an enantiomer thereof; and detecting the presence of complex of the target and the compound in the cell, wherein the presence of the complex indicates the presence of the molecular target in the cell.
  • the invention further provides a method of identifying a molecular target involved in lipid storage in a cell, comprising contacting the cell with a compound of formula I, II, or III:
  • R 1 is selected from alkyl, aryl, arylalkyl, and alkylaryl, each of which is optionally substituted with one or more substituents selected from halo, alkyl, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino, trialkylamino, guanidino, aminocarbonyl, aldehydo, and ureido;
  • R 2 is selected from heterocyclyl, heteroaryl, cycloalky], dimethylamino alkyl, and benzyl, each of which is optionally substituted with one or more substituents selected from halo, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino, trialkylamino, guanidino, aminocarbonyl, aldehydo, and ureido;
  • R 3 and R 4 are each independently a lower alkyl or, taken together with the carbon atom to which they are attached, form a 5- to 7-membered ring;
  • R 10 is selected from alkyl, dialkylaminoalkyl, heterocyclyl, heteroaryl, aryl, arylalkyl, arylcycloalkyl, and each of which is optionally substituted with one or more substituents selected from alkyl, halo, cycloalkyl, aryl, fused aryl, fused cyclic, arylalkyl, and
  • R H , R 12 , R 13 , and R 14 are independently hydrogen or alkyl
  • R 6 and R 7 are independently hydrogen,lower alkyl, or arylalkyloxyalkyl, or, taken together with the carbon atom to which they are bonded, form a 5-7 membered ring;
  • R 8 is H or a substituent selected from halo, alkyl, monohalo alkyl, dihaloalkyl, trihaloalkyl, monohalo alkoxy, dihalo alkoxy, trihalo alkoxy, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkoxy carbonyl, heterocyclyl, alkyl heterocyclyl, heterocyclylalkyl, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino,
  • R 9 is H, OR 15 , or NR 16 R 17 ; wherein R 15 , R 16 , and R 17 , are independently hydrogen or lower alkyl;
  • R is hydrogen or lower alkyl
  • R 19 is hydrogen or halo
  • A is NH(CH 2 ) m , CH 2 , or a bond; m is 0 or 1 ; n is 1 -5; and a pharmaceutically acceptable salt thereof, or an enantiomer thereof; or a conjugate thereof wherein the conjugate comprises a marker group; and determining a change in an activity of the molecular target, wherein the change in the activity of the molecular target indicates the activity of the molecular target in lipid storage in the cell.
  • the invention provides compound of formula I, II, or III:
  • R 1 is selected from alkyl, alkenyl, aryl, arylalkyl, and alkylaryl, each of which is optionally substituted with one or more substituents selected from halo, alkyl, hydroxy, hydroxyalkyl, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, trifluoroalkyl, trifluoroalkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino, trialkylamino, guanidino, aminocarbonyl, aldehydo, optionally protected aminopolyalkoxy, and ureido;
  • R is selected from heterocyclyl, heteroaryl, cycloalkyl, dimethylamino alkyl,
  • R 3 and R 4 are each independently a lower alkyl or, taken together with the carbon atom to which they are attached, form a 5- to 7-membered ring;
  • R 10 is selected from alkyl, dialkylaminoalkyl, heterocyclyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, (3-(trifluoromethyl)-3H-diazirin-3-yl), arylcycloalkyl, and each of which is optionally substituted with one or more substituents selected from alkyl, alkenyl, halo, cycloalkyl, aryl, fused aryl, fused cyclic, arylalkyl, heteroarylalkyl, and arylcarbonyl;
  • R 1 1 , R 12 , R 13 , and R 14 are independently hydrogen or alkyl
  • R 6 and R 7 are independently hydrogen,lower alkyl, or arylalkyloxyalkyl, or, taken together with the carbon atom to which they are bonded, form a 3-7 membered ring;
  • R 8 is H or a substituent selected from halo, alkyl, monohalo alkyl, dihaloalkyl, trihaloalkyl, monohalo alkoxy, dihalo alkoxy, trihalo alkoxy, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkoxy carbonyl, heterocyclyl, alkyl heterocyclyl, heterocyclylalkyl, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino,
  • R 9 is H, OR 15 , or NR 16 R 17 ; wherein R 15 , R 16 , and R 17 , are independently hydrogen or lower alkyl;
  • R 18 is hydrogen or lower alkyl
  • R 19 is hydrogen or halo
  • A is NH(CH 2 ) m , CH 2 , or a bond; m is 0 or 1 ; n is 1-5; and p is 0-1 ; a pharmaceutically acceptable salt thereof, or an enantiomer thereof; or a conjugate thereof wherein the conjugate comprises a marker group; with the proviso that, in the compound of formula I, when R 1 is 4-t-butyl phenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 3-trifiuoromethylphenyl, 4-trifluoromethylphenyl or 4-bromophenyl, then R 2 is not furazan-4-yl, 4-methylfurazan-5-yl, furazan-4-yl-N-oxide, isoxazol-5-yl, 3-methylisoxazol-4-yl, pyrazin-2-yl, or 3-hydroxypyridin-2-yl. [0011] In some embodiments, the compound is of formula I, wherein R 1
  • the compound is of formula I, wherein A is NH. In certain embodiments, the compound is of formula I, wherein A is a bond. In certain embodiments, the compound is of formula I, wherein A is CH 2 .
  • the compound is of formula I, wherein R 1 is phenyl, optionally substituted with one or more substituents selected from the group consisting of halo and alkyl.
  • the compound is of formula I, wherein R 1 is phenyl, optionally substituted with one or more substituents selected from the group consisting of fluoro, methyl, and t-butyl.
  • the compound is of formula I, wherein R 1 is phenyl substituted with one or more substituents selected from the group consisting of fluoro, methyl, and t-butyl.
  • R 2 is selected from the group consisting of heterocyclyl, heteroaryl, cycloalkyl, dimethylamino alkyl, and benzyl, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, carboxy, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino, and trialkylamino.
  • R 2 is selected from the group consisting of heterocyclyl, heteroaryl, cycloalkyl, dimethylamino alkyl, and benzyl, each of which is optionally substituted with hydroxy.
  • R 2 is selected from the group consisting of pyrazinyl, dioxinyl, thiadiazolyl, oxazolinylmethyl, pyridinyl, phenyl, benzyl, piperidinyl, cyclopropyl, thiopheneyl, cyclohexyl, pyrazolyl, dimethylaminomethyl, N-protected piperidinyl, and oxadiazolyl, each of which is optionally substituted with hydroxy.
  • the compound is of formula II, wherein
  • R 3 and R 4 are each independently a lower alkyl or, taken together with the carbon atom to which they are attached, form a 5- to 7-membered ring;
  • R 10 is selected from alkyl, dialkylaminoalkyl, heterocyclyl, heteroaryl, aryl, arylalkyl, arylcycloalkyl, and each of which is optionally substituted with one or more substituents selected from alkyl, halo, cycloalkyl, aryl, fused aryl, fused cyclic, arylalkyl, and
  • R , R , R , and R are independently hydrogen or alkyl, and p is 0-3.
  • R is heteroaryl, optionally substituted with one or more substituents selected from alkyl, halo, cycloalkyl, aryl, fused aryl, fused cyclic, arylalkyl, and arylcarbonyl, wherein R 11 , R 12 , R 13 , and R 14 are independently hydrogen or alkyl, and wherein R 18 is hydrogen or lower alkyl.
  • R 10 is
  • R 5 is selected from lower alkyl, aryl, arylalkyl, dialkylaminoalkyl, heterocyclyl, heteroaryl, and benzyl, each of which is optionally substituted with one or more substituents selected from alkyl, arylalkyl, heteroaryl alkyl, alkenyl, and arylalkyl, wherein each of said optional substituents are further optionally substituted with one or more substituents selected from halo, alkyl, monohalo alkoxy, dihalo alkoxy, trihalo alkoxy, hydroxy, carboxy, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino, trialky
  • R 3 and R 4 are each independently ethyl or, taken together with the carbon atom to which they are attached, form a 5-membered ring.
  • R 5 is selected from the group consisting of thiophenopyrrolyl, phenyl, thiopheneyl, benzyl, dimethylamino alkyl, alkyl, benzodioxanyl, and cyclopenta[£>]thiopheneyl, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, phenylalkyl, dihalo alkoxy, and pyridyl alkyl.
  • R 5 is selected from the group consisting of thiophenopyrrolyl, phenyl, thiopheneyl, benzyl, dimethylamino alkyl, alkyl, benzodioxanyl, and cyclopenta[6]thiopheneyl, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, phenylalkyl, dihalo alkoxy, and pyridyl alkyl.
  • the compound is of formula III, wherein
  • R 6 and R 7 are independently lower alkyl or, taken together with the carbon atom to which they are bonded, form a 5-7 membered cycloalkyl ring;
  • R is H or a substituent selected from halo, alkyl, monohalo alkyl, dihaloalkyl, trihaloalkyl, cyano, nitro, alkoxy, heterocyclyl, alkyl heterocyclyl, heterocyclylalkyl, alkylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino, trialkylamino.
  • R 9 is H, OR 15 , or NR 16 R 17 ; and n is 1-5.
  • R 6 and R 7 are individually lower alkyl or, taken together with the carbon atom to which they are bonded, form a 5-7 membered cycloalkyl ring;
  • R 8 is H or a substituent selected from the group consisting of halo, cyano, alkoxy, monohalo alkyl, dihaloalkyl, trihaloalkyl, morpholino alkyl, benzo, fused thiopheno, alkyl thiazolyl, phenyl, aryloxy, alkoxycarbonyl, amino, aminoalkyl, alkylamino, dialkylamino, and trialkylamino;
  • R 9 is H, OR 15 , or NR I6 R 17 ; and n is 1 or 2.
  • R 6 and R 7 are individually lower alkyl or, taken together with the carbon atom to which they are bonded, form a 5-7 membered cycloalkyl ring;
  • R is H or a substituent selected from the group consisting of halo, cyano, alkoxy, monohalo alkyl, dihaloalkyl, trihaloalkyl, morpholino alkyl, benzo, fused thiopheno, alkyl thiazolyl, phenyl, aryloxy, alkoxycarbonyl, amino, aminoalkyl, alkylamino, dialkylamino, and trialkylamino;
  • R 9 is OR 15 ; and n is 1 or 2.
  • R 6 and R 7 are individually lower alkyl or, taken together with the carbon atom to which they are bonded, form a 5-7 membered cycloalkyl ring;
  • R 8 is H or a substituent selected from the group consisting of halo, cyano, alkoxy, monohalo alkyl, dihaloalkyl, trihaloalkyl, morpholino alkyl, benzo, fused thiopheno, alkyl thiazolyl, phenyl, aryloxy, alkoxycarbonyl, amino, aminoalkyl, alkylamino, dialkylamino, and trialkylamino;
  • R 9 is NR 16 R 17 ; and n is 1 or 2.
  • alkyl means a straight-chain or branched alkyl substituent containing from, for example, 1 to about 6 carbon atoms, preferably from 1 to about 4 carbon atoms, more preferably from 1 to 2 carbon atoms.
  • substituents include methyl, ethyl, propyl, isopropyl, M-butyl, sec- butyl, isobutyl, tert-bvXy ⁇ , pentyl, isoamyl, hexyl, and the like.
  • alkenyl means a straight-chain or branched unsaturated alkyl substituent containing from, for example, 2 to about 8 carbon atoms, preferably from 2 to about 6 carbon atoms, more preferably from 2 to 4 carbon atoms.
  • substituents include ethenyl, propeneyl, buteneyl, pendenyl, hexeneyl, hepteneyl, octeneyl, and the like.
  • cycloalkyl means a cyclic alkyl substituent containing from, for example, about 3 to about 8 carbon atoms, preferably from about 3 to about 7 carbon atoms, and more preferably from about 5 to about 6 carbon atoms.
  • substituents include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • the cyclic alkyl groups may be unsubstituted or further substituted with one or more alkyl groups such as methyl groups, ethyl groups, and the like.
  • fused cyclic refers to two or more rings fused together so as to form a bicyclic or polycyclic group wherein at least two of the rings are attached to each other by way of adjaceet carbons on each ring.
  • fused cyclic further includes bicyclic or polycyclic systems comprising one or more heteroatoms. Examples
  • heteroatom-containing fused cyclic systems include groups such
  • heteroaryl refers to a 5, 6, or 7-membered aromatic ring system containing one or more heteroatoms selected from the group consisting of O, N, S, and combinations thereof.
  • the heteroaryl group can be any suitable heteroaryl group.
  • the heteroaryl group can be a monocyclic heteroaryl group or a bicyclic heteroaryl group.
  • Suitable bicyclic heteroaryl groups include monocylic heteroaryl rings fused to a C 6 -Cio aryl ring. It is understood that a 6-membered heteroaryl group comprises 4n+2 ⁇ electrons, according to Huckel's Rule, and that a 5-, 7-, and 8-membered heteroaryl group has six electrons provided from a combination of p orbitals and an unshared pair of electrons provided by a heteroatom or heteroatoms which occupy bonding orbitals and constitute an aromatic sextet.
  • Non-limiting examples of suitable heteroaryl groups include furanyl, thiopheneyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiopheneyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolinyl, benzothiazolinyl, and quinazolinyl.
  • the heteroaryl group can be linked at any open position of the heteroaryl group.
  • the furanyl group can be a furan-2-yl group or a furan-3-yl group
  • the thiopheneyl group can be a thiophene-2-yl group or a
  • the heteroaryl group is optionally substituted with 1 , 2, 3, 4, or 5 substituents as recited herein, wherein the optional substituent can be present at any open position on the heteroaryl group.
  • the heteroaryl group is optionally a fused cyclic system as described herein.
  • halo or halogen
  • aryl refers to an unsubstituted or substituted aromatic carbocyclic substituent, as commonly understood in the art, and the term “C 6 -Cio aryl” includes phenyl and naphthyl. It is understood that the term aryl applies to cyclic substituents that are planar and comprise 4n+2 ⁇ electrons, according to Huckel's Rule.
  • fused aryl refers to an unsubstituted or substituted aromatic carbocyclic substituent having fused thereto a 5- or 6-membered ring.
  • alkylaryl refers to an unsubstituted or substituted alkyl group bonded to an an unsubstituted or substituted aryl group.
  • the alkylaryl group is typically bonded to the core structure of the molecule by way of the alkyl portion of the alkylaryl group.
  • arylalkyl refers to an unsubstituted or substituted aryl group bonded to an an unsubstituted or substituted alkyl group.
  • the arylalkyl group is typically bonded to the core structure of the molecule by way of the aryl portion of the arylalkyl group
  • heterocycloalkyl means a non-aromatic cyclic alkyl substituent containing a heteroatom and further containing from, for example, about 3 to about 7 carbon atoms, preferably from about 3 to about 6 carbon atoms, and more preferably from about 3 to about 5 carbon atoms.
  • the heterocycloalkyl group can be monocyclic or can be fused to another ring, wherein the other ring can be a cycloalkyl ring, an aryl ring, or another heterocycloalkyl ring.
  • substituents include tetrahydrofuranyl, tetrahydrothiopheneyl, pyrrolidinyl, piperidinyl, tetrahydroazepinyl, and the like.
  • the heterocycloalkyl groups may be unsubstituted or further substituted with alkyl groups such as methyl groups, ethyl groups, and the like.
  • R 5 is selected from the group consisting of benzoxazol-2-yl, 5-bromo-benzoxazol-2-yl, 5-methyl-benzoxazol-2-yl, 6-methyl-benzoxazol-2-yl, 6-phenyl-benzoxazol-2-yl, benzoimidazol-2-yl, benzothiazol-2-yl, indol-l -yl, indol-2-yl, indol-3-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, imidazol-l-yl, imidazol-4-yl, thiazol-2-yl, thiazol-4-yl, pyrazol-3-yl, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4
  • R 5 is selected from the group consisting of
  • R 5 is benzoxazol-2-yl.
  • the compound or salt of formula (I), (II), or (III) can have at least one asymmetric carbon atom.
  • the compound or salt can exist in the racemic form, in the form of its pure optical isomers, or in the form of a mixture wherein one isomer is enriched relative to the other.
  • the inventive compounds when the inventive compounds have a single asymmetric carbon atom, the inventive compounds may exist as racemates, i.e., as mixtures of equal amounts of optical isomers, i.e., equal amounts of two enantiomers, or in the form of a single enantiomer.
  • single enantiomer is intended to include a compound that comprises more than 50% of a single enantiomer (i.e., enantiomeric excess up to 100% pure enantiomer).
  • the compound or salt can therefore exist as a mixture of diastereomers or in the form of a single diastereomer.
  • single diastereomer is intended to mean a compound that comprises more than 50% of a single diastereomer (i.e., diastereomeric excess to 100% pure diastereomer).
  • salts are intended to include nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977).
  • Suitable bases include inorganic bases such as alkali and alkaline earth metal bases, e.g., those containing metallic cations such as sodium, potassium, magnesium, calcium and the like.
  • suitable bases include sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.
  • Suitable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, maleic acid, tartaric acid, fatty acids, long chain fatty acids, and the like.
  • Preferred pharmaceutically acceptable salts of inventive compounds having an acidic moiety include sodium and potassium salts.
  • Preferred pharmaceutically acceptable salts of inventive compounds having a basic moiety include hydrochloride and hydrobromide salts.
  • the compounds of the present invention containing an acidic or basic moiety are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof.
  • solvates refers to a molecular complex wherein the solvent molecule, such as the crystallizing solvent, is incorporated into the crystal lattice.
  • the solvent incorporated in the solvate is water, the molecular complex is called a hydrate.
  • Pharmaceutically acceptable solvates include hydrates, alcoholates such as methanolates and ethanolates, acetonitrilates and the like. These compounds can also exist in polymorphic forms.
  • the present invention is further directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound, salt, enantiomer, or conjugate described herein.
  • the pharmaceutically acceptable carrier be one that is chemically inert to the active compounds and one that has no detrimental side effects or toxicity under the conditions of use.
  • compositions of the present invention are merely exemplary and are in no way limiting.
  • the pharmaceutical composition can be administered parenterally, e.g., intravenously, intraarterially, subcutaneously, intradermally, or intramuscularly.
  • the invention provides compositions for parenteral administration that comprise a solution or suspension of the inventive compound or salt dissolved or suspended in an acceptable carrier suitable for parenteral administration, including aqueous and non-aqueous isotonic sterile injection solutions.
  • an acceptable carrier suitable for parenteral administration including aqueous and non-aqueous isotonic sterile injection solutions.
  • the requirements for effective pharmaceutical carriers for parenteral compositions are well known to those of ordinary skill in the art. See, e.g., Banker and Chalmers, eds., Pharmaceutics and Pharmacy Practice, J. B. Lippincott Company,
  • Such solutions can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compound or salt of the present invention may be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose,
  • a pharmaceutically acceptable surfactant such
  • hydroxypropylmethylcellulose or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.
  • Oils useful in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations can contain preservatives and buffers.
  • such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17.
  • HLB hydrophile-lipophile balance
  • the quantity of surfactant in such formulations will typically range from about 5 to about 15% by weight.
  • Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • Topical formulations including those that are useful for transdermal drug release, are well-known to those of skill in the art and are suitable in the context of the invention for application to skin.
  • Topically applied compositions are generally in the form of liquids, creams, pastes, lotions and gels. Topical administration includes application to the oral mucosa, which includes the oral cavity, oral epithelium, palate, gingival, and the nasal mucosa.
  • the composition contains at least one active component and a suitable vehicle or carrier. It may also contain other components, such as an anti-irritant.
  • the carrier can be a liquid, solid or semi-solid.
  • the composition is an aqueous solution.
  • the composition can be a dispersion, emulsion, gel, lotion or cream vehicle for the various components.
  • the primary vehicle is water or a biocompatible solvent that is substantially neutral or that has been rendered substantially neutral.
  • the liquid vehicle can include other materials, such as buffers, alcohols, glycerin, and mineral oils with various emulsifiers or dispersing agents as known in the art to obtain the desired pH, consistency and viscosity.
  • the compositions can be produced as solids, such as powders or granules. The solids can be applied directly or dissolved in water or a biocompatible solvent prior to use to form a solution that is substantially neutral or that has been rendered substantially neutral and that can then be applied to the target site.
  • the vehicle for topical application to the skin can include water, buffered solutions, various alcohols, glycols such as glycerin, lipid materials such as fatty acids, mineral oils, phosphoglycerides, collagen, gelatin and silicone based materials.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as a therapeutically effective amount of the inventive compound dissolved in diluents, such as water, saline, or orange juice, (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules, (c) powders, (d) suspensions in an appropriate liquid, and (e) suitable emulsions.
  • Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.
  • the compound or salt of the present invention can be made into aerosol formulations to be administered via inhalation.
  • the compounds are preferably supplied in finely divided form along with a surfactant and propellant. Typical percentages of active compound are 0.01%-20% by weight, preferably 1 %- 10%.
  • the surfactant must, of course, be nontoxic, and preferably soluble in the propellant.
  • Such surfactants are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride.
  • Mixed esters such as mixed or natural glycerides may be employed.
  • the surfactant may constitute 0.1 %-20% by weight of the composition, preferably 0.25%-5%. The balance of the composition is ordinarily propellant.
  • a carrier can also be included as desired, e.g., lecithin for intranasal delivery.
  • aerosol formulations can be placed into acceptable pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer. Such spray formulations may be used to spray mucosa.
  • the compound or salt of the present invention may be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • the compound or salt of the present invention may be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.
  • inclusion complexes such as cyclodextrin inclusion complexes, or liposomes.
  • Liposomes serve to target the compounds to a particular tissue, such as lymphoid tissue or cancerous hepatic cells. Liposomes can also be used to increase the half-life of the inventive compound.
  • Liposomes useful in the present invention include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like.
  • the active agent to be delivered is incorporated as part of a liposome, alone or in conjunction with a suitable chemotherapeutic agent.
  • liposomes filled with a desired inventive compound or salt thereof can be directed to the site of a specific tissue type, hepatic cells, for example, where the liposomes then deliver the selected compositions.
  • Liposomes for use in the invention are formed from standard vesicle-forming lipids, which generally include neutral and negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally guided by consideration of, for example, liposome size and stability of the liposomes in the blood stream.
  • a liposome suspension containing a compound or salt of the present invention may be administered intravenously, locally, topically, etc. in a dose that varies according to the mode of administration, the agent being delivered, and the stage of disease being treated.
  • the invention further provides a method for treating or preventing a disease or disorder responsive to reduction of lipid storage droplets in an animal in need thereof comprising administering an effective amount of a compound of formula I, II, or III or a combination thereof:
  • R ! is selected from alkyl, aryl, arylalkyl, and alkylaryl, each of which is optionally substituted with one or more substituents selected from halo, alkyl, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino, trialkylamino, guanidino, aminocarbonyl, aldehydo, and ureido;
  • R 2 is selected from heterocyclyl, heteroaryl, cycloalkyl, dimethylamino alkyl, and benzyl, each of which is optionally substituted with one or more substituents selected from halo, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino, trialkylamino, guanidino,
  • R 3 and R 4 are each independently a lower alkyl or, taken together with the carbon atom to which they are attached, form a 5- to 7-membered ring;
  • R 10 is selected from alkyl, dialkylaminoalkyl, heterocyclyl, heteroaryl, aryl, arylalkyl, arylcycloalkyl, and each of which is optionally substituted with one or more substituents selected from alkyl, halo, cycloalkyl, aryl, fused aryl, fused cyclic, arylalkyl, and
  • R 1 1 , R 12 , R 13 , and R 14 are independently hydrogen or alkyl
  • R 6 and R 7 are independently hydrogen,lower alkyl, or aryl alkyl oxyalkyl, or, taken together with the carbon atom to which they are bonded, form a 5-7 membered ring;
  • R 8 is H or a substituent selected from halo, alkyl, monohalo alkyl, dihaloalkyl, trihaloalkyl, monohalo alkoxy, dihalo alkoxy, trihalo alkoxy, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono alkyl, carboxy alkyl, dicarboxy alkyl, dicarboxy haloalkyl, sulfonyl, cyano, nitro, alkoxy, alkoxy carbonyl, heterocyclyl, alkyl heterocyclyl, heterocyclylalkyl, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, aminoalkyl, alkylamino, dialkylamino,
  • R 9 is H, OR 15 , or NR 16 R 17 ; wherein R 15 , R 16 , and R 17 , are independently hydrogen or lower alkyl;
  • R is hydrogen or lower alkyl
  • R 19 is hydrogen or halo
  • A is NH(CH 2 ) m , CH 2 , or a bond; m is 0 or 1 ; n is 1 -5; and p is 0-1 ; a pharmaceutically acceptable salt thereof, or an enantiomer thereof; or a conjugate thereof wherein the conjugate comprises a marker group.
  • the disease or disorder can be any suitable disease or disorder and can be, for example, selected from the group consisting of Gaucher disease, Fabry disease, Farber's disease, GM1 gangliosidoses, Tay-Sachs disease, Sandhoff disease, Krabbe disease, metachromatic leukodystrophy, obesity, atherosclerosis, and ectopic fat deposition.
  • Gaucher's disease is a genetic disease in which a fatty substance (lipid) accumulates in cells and certain organs. Gaucher's disease is the most common of the lysosomal storage diseases. It is caused by a hereditary deficiency of the enzyme
  • glucocerebrosidase also known as acid ⁇ -glucosidase.
  • the enzyme acts on a fatty substance glucocerebroside (also known as glucosylceramide).
  • glucocerebroside accumulates, particularly in white blood cells (mononuclear leukocytes). Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain and bone marrow.
  • Symptoms may include enlarged spleen and liver, liver malfunction, skeletal disorders and bone lesions that may be painful, severe neurologic complications, swelling of lymph nodes and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelets and yellow fatty deposits on the white of the eye (sclera). Persons affected most seriously may also be more susceptible to infection. Some forms of Gaucher's disease may be treated with enzyme replacement therapy.
  • Fabry disease also known as Fabry's disease, Anderson-Fabry disease, angiokeratoma corporis diffusum and alpha-galactosidase A deficiency
  • Fabry disease is a rare X-linked recessive (inherited) lysosomal storage disease, which can cause a wide range of systemic symptoms.
  • Fabry disease results from a deficiency of the enzyme alpha galactosidase A (a- GAL A, encoded by GLA) due to mutation which causes a glycolipid known as
  • Gb3, GL-3, or ceramide trihexoside globotriaosylceramide
  • Farber disease also known as Farber's lipogranulomatosis, ceramidase deficiency, "Fibrocytic dysmucopolysaccharidosis,” and “Lipogranulomatosis” is a rare autosomal recessive lysosomal storage disease that cause an accumulation of fatty material lipids leading to abnormalities in the joints, liver, throat, tissues and central nervous system.
  • the enzyme ceramidase breaks down fatty material in the body's cells.
  • Farber Disease the gene responsible for making this enzyme is mutated. Hence, the fatty material is never broken down and, instead, accumulates in various parts of the body, leading to the signs and symptoms of the disorder.
  • the GM1 gangliosidoses are caused by a deficiency of beta- galactosidase, with resulting abnormal storage of acidic lipid materials in cells of the central and peripheral nervous systems, but particularly in the nerve cells.
  • Tay-Sachs disease is caused by insufficient activity of an enzyme called hexosaminidase A that catalyzes the biodegradation of fatty acid derivatives known as gangliosides.
  • Hexosaminidase A is a vital hydrolytic enzyme, found in the lysosomes, that breaks down phospholipids. When Hexosaminidase A no longer functions properly, the lipids accumulate in the brain and interfere with normal biological processes. Gangliosides are made and biodegraded rapidly in early life as the brain develops. Patients and carriers of Tay-Sachs disease can be identified by a simple blood test that measures hexosaminidase A activity.
  • Sandhoff disease also known as Sandhoff-Jatzkewitz disease, variant 0 of GM2- Gangliosidosis or Hexosaminidase A and B deficiency, is a lysosomal genetic, lipid storage disorder caused by the inherited deficiency to create functional beta-hexosaminidases A and B.
  • These catabolic enzymes are needed to degrade the neuronal membrane components, ganglioside GM2, its derivative GA2, the glycolipid globoside in visceral tissues, and some oligosaccharides. Acccumulation of these metabolites leads to a progressive destruction of the central nervous system and eventually to death.
  • neurodegenerative disorder is clinically almost indistinguishable from Tay-Sachs disease, another genetic disorder that disrupts beta-hexosaminidases A and S.
  • Krabbe disease is caused by mutations in the GALC gene located on chromosome 14 (14q31), which causes a deficiency of an enzyme called galactocerebrosidase.
  • the build up of unmetabolized lipids affects the growth of the nerve's protective myelin sheath (the covering that insulates many nerves) and causes severe degeneration of motor skills.
  • myelin sheath the covering that insulates many nerves
  • Metachromatic leukodystrophy (MLD, also called Arylsulfatase A deficiency) is a lysosomal storage disease which is commonly listed in the family of leukodystrophies.
  • Leukodystrophies affect the growth and/or development of myelin, the fatty covering which acts as an insulator around nerve fibers throughout the central and peripheral nervous systems.
  • Obesity, atherosclerosis, and ectopic fat deposition all relate to the accumulation of fat within mammals.
  • Obesity is characterized by the excessive presence of tissues containing lipids, which are contained within lipid droplets within the cells.
  • Atherosclerosis is at least partially characterized by the presence of fibro-lipid plaques, wherein the accumulation of lipid-laden cells underneath the intima of the arteries results in the formation of such plaques.
  • Ectopic fat deposition results from deposition of fat in internal organs, arteries, and muscle. Thus, reduction of lipid storage droplets within cells is expected to mitigate and/or ameliorate the detrimental effects of fat deposition within mammals.
  • the term "animal” includes mammal.
  • the term “mammal” includes, but is not limited to, the order Rodentia, such as mice, and the order Logomorpha, such as rabbits. It is preferred that the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs). It is more preferred that the mammals are from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order Perssodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Ceboids, or Simioids (monkeys) or of the order Anthropoids (humans and apes). An especially preferred mammal is the human.
  • the subject can be the unborn offspring of any of the forgoing hosts, especially mammals (e.g., humans), in which case any screening of the subject or cells of the subject, or administration of compounds to the subject or cells of the subject, can be performed in utero.
  • mammals e.g., humans
  • any screening of the subject or cells of the subject, or administration of compounds to the subject or cells of the subject can be performed in utero.
  • Treating within the context of the present invention, means an alleviation of symptoms associated with a disorder or disease, or halt of further progression or worsening of those symptoms.
  • successful treatment may be used in conjunction with dietary restrictions aimed at reducing lipids in the diet.
  • successful treatment may include a reduction in clinical markers such as levels of lipids in blood or urine, and/or changes in clinical symptoms. Treatment may also include
  • the compounds and pharmaceutical formulations of the present invention may be administered on a chronic basis.
  • the compounds of the invention can also be administered in conjunction with dietary restrictions.
  • Preventing refers to a prophylactic treatment of an animal - an individual prone or subject to development of a condition, in particular, a disease or disorder responsive to reduction of lipid storage droplets.
  • a condition in particular, a disease or disorder responsive to reduction of lipid storage droplets.
  • those of skill in the medical arts may be able to determine, based on clinical symptoms and patient history, a statistical predisposition of a particular individual to the development of the aforesaid disease or disorder.
  • a family history of a disease or disorder responsive to reduction of lipid storage droplets can be used to assess the predisposition of a particular individual to the development of such disorders and thus inform the individual as to the desirability of preventative treatment with a compound or salt of the invention or a medicament formed therefrom.
  • an individual predisposed to the development of a disease or disorder responsive to reduction of lipid storage droplets may be treated with a compound or a composition of the present invention in order to prevent, inhibit, reduce the effect of a development of, or slow the development of the disease or disorder or ameliorate the condition.
  • the dose administered to a mammal, particularly, a human, in accordance with the present invention should be sufficient to effect the desired response.
  • Such responses include reversal or prevention of the adverse effects of the disease for which treatment is desired or to elicit the desired benefit.
  • dosage will depend upon a variety of factors, including the age, condition, and body weight of the human, as well as the source, particular type of the disease, and extent of the disease in the human.
  • the size of the dose will also be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states may require prolonged treatment involving multiple administrations.
  • Suitable doses and dosage regimens can be determined by conventional range- finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound.
  • the present inventive method typically will involve the administration of about 0.1 to about 300 mg of one or more of the compounds described above per kg body weight of the mammal.
  • the dose of the pharmaceutically active agent(s) described herein for methods of preventing diseases or disorders responsive to reduction can be about 0.001 to about 1 mg/kg body weight of the subject being treated per day, for example, about 0.001 mg, 0.002 mg, 0.005 mg, 0.010 mg, 0.015 mg, 0.020 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg/kg body weight per day.
  • the dose of the pharmaceutically active agent(s) described herein for methods of treating diseases or disorders, e.g., diseases responsive to reduction of lipid storage droplets, can be about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000 mg/kg body weight per day.
  • the invention provides a method of identifying a molecular target involved in lipid storage in a cell, comprising contacting the cell with a compound of formula I, II, or III as described herein to form a complex of the target and the compound, pharmaceutically acceptable salt thereof, or an enantiomer thereof; and detecting the presence of complex of the target and the compound in the cell, wherein the presence of the complex indicates the presence of the molecular target in the cell.
  • the compound can be a compound as described herein or can be a conjugate thereof wherein the conjugate comprises a marker group.
  • Suitable conjugates can be, for example, conjugates wherein the compound further comprises a biotinylated moiety, a fluorescent moiety (e.g., a dye moiety), and the like.
  • the conjugates can be formed for example by attaching a biotinylated moiety or a fluorescent moiety to the compound using any suitable chemistry.
  • Detection of the complex and the compound in the cell can be accomplished using any suitable means.
  • Non-limiting means to detection of the complex and the compound in the cell include determining a change in a spectral property such as adsorption of UV light, by use of affinity chromatography wherein a biotinylated moiety interacts with a suitable component of a chromatography column, and the like.
  • the method further comprises isolating the complex.
  • isolating the complex For example, use of affinity chromatography in conjunction with a biotinylated derivative of the compound can allow for isolation of the complex.
  • the invention provides a method of identifying a molecular target involved in lipid storage in a cell, comprising contacting the cell with a compound of formula I, II, or III, determining a change in an activity of the molecular target, wherein the change in the activity of the molecular target indicates the activity of the molecular target in lipid storage in the cell.
  • the activity of the molecular target can be determined while the molecular target is present in the cell, for example, by determining a change in the production one or more downstream products resulting from activity of the molecular target.
  • the molecular target can be isolated from other components of the cell and the change of its activity can be determined via assay of the isolated molecular target.
  • the compounds of the invention can be synthesized by any suitable method, for example, via the methods depicted in Schemes I-III set forth in Examples 3-5.
  • the mobile phase consisted of acetonitrile and water (each containing 0.1 % trifluoroacetic acid). A gradient of 10% to 50% acetonitrile over 8 minutes was used during the purification. Fraction collection was triggered by UV detection (220 nM). Analytical analysis was performed on an Agilent LC/MS (Agilent Technologies, Santa Clara, CA).
  • Method 1 A 7 minute gradient of 4% to 100% Acetonitrile (containing 0.025% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) was used with an 8 minute run time at a flow rate of 1 mL/min. A Phenomenex Luna CI 8 column (3 micron, 3 x 75 mm) was used at a temperature of 50°C.
  • Method 2 A 3 minute gradient of 4% to 100% Acetonitrile (containing 0.025%
  • trifluoroacetic acid in water (containing 0.05% trifluoroacetic acid) was used with a 4.5 minute run time at a flow rate of 1 mL/min.
  • a Phenomenex Gemini Phenyl column (3 micron, 3 x 100 mm) was used at a temperature of 50° C.
  • Purity determination was performed using an Agilent Diode Array Detector on both Method 1 and Method 2.
  • Mass determination was performed using an Agilent 6130 mass spectrometer with electrospray ionization in the positive mode. 1H NMR spectra were recorded on Varian 400 MHz spectrometers.
  • This example demonstrates a primary qHTS assay for lipid storage modulators. Almost all mammalian components were identified and characterized in the fruit fly
  • Drosophila melanogaster (Bohni, R. et al., Cell 1999, 97, 865-75; Gronke, S. et al. Curr Biol 2003, 13, 603-6; Gronke, S. et al., Cell Metab 2005, 1 , 323-30; Gronke, S. et al. PLoS Biol 2007, 5, el 37; Teixeira, L. et al. Mech Dev 2003, 120, 1071-81). Additionally, LDs of Drosophila and mammals are coated with a similar set of proteins (Bartz, R. et al., J
  • Drosophila is a prime model organism for lipid storage focused research due to the evolutionary conservation of key components, as well as certain advantages, including minimized redundancy of pathway components.
  • Drosophila melanogaster encodes for orthologs of >60% of the human disease-associated genes, making it a prime in vivo system to study disease pathways (Chien, S. et al. Nucleic Acids Res.lQQl, 30, 149-151).
  • the qHTS was performed with embryonic Drosophila S3 cells (Bloomington Drosophila Stock Center [DGRC]), that showed excellent oleic acid feeding characteristics and good performance during automated liquid handling in 1 ,536-well format (Table 2). 4 ⁇ of cells at 1.25 x 10 6 cells/ml were dispensed into LoBase Aurora COC 1,536-well plates (black walled, clear bottom) with a bottle-valve solenoid-based dispenser (Kalypsys) to obtain 5,000 cells/well.
  • DGRC Bombington Drosophila Stock Center
  • the total intensity in channel 1 (500-530 nm) reflected lipid droplet accumulation.
  • Cells were detected using channel 3 (575-640 nm) with 5 ⁇ width and 100 ⁇ depth filters.
  • the ratio of the total intensity in PMT channel 1 over total intensity of channel 3 was also calculated. Percent activity was computed relative to an internal control (100% inhibited lipid droplet deposition due to the presence of 20 ⁇
  • Triacsin C which was added to 32 wells/plate.
  • This example demonstrates a cytotoxicity assay for lipid storage modulators.
  • Cytotoxicity was tested using CellTiter-Glo to measure ATP levels using a final compound concentration of 46.2 ⁇ to 0.3 nM and a 24 hr time point with the following protocol: Cytotoxicity test after compound treatment was measured using a luciferase- coupled ATP quantitation assay (CellTiter-Glo, Promega) for lipid storage modulators in Drosophila S3 Cells. The change of intracellular ATP content indicates the number of metabolically competent cells after compound treatment. S3cells were harvested from T225 flask and resuspended in Schneider's Drosophila medium with 5% FCS and.
  • Tetraoctylammonium bromide in DMSO was transferred to each well of the assay plate using a pintool (Kalypsys, San Diego, CA), One microliter of oleic acid (400 ⁇ ) was added, and the plate was lidded with stainless steel rubber gasket-lined lids containing pinholes. After 24 hours incubation at 24 °C and 95% humidity, 4 ⁇ 1 of CellTilter-GloTM luminescent substrate mix (Promega) was added to each well. The plate was incubated at room
  • NCGC00238537 (LLI01-002)
  • NCGC00238560 (LLIOl -01 1)
  • NCGC00238547 (LLI01-012) N-(l-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-lH-indazol-4-yl)cyclopropanecarboxamide
  • NCGC00238548 (LLI01-013)
  • NCGC00238559 (LLI01-014)
  • NCGC00238557 (LLI01-015)
  • NCGC00238558 (LLI01-016) tert-Butyl 2-(l-(2,4-difluorophenyI)-4,5,6,7-tetrahydro-lH-indazol-4- ylcarbamoyl)piperidine-l-carboxylate
  • NCGC00238556 (LLI01-018)
  • NCGC00238550 (LLI01-020)
  • NCGC00238551 (LLI01-022)
  • NCGC00238552 (LLI01-025)
  • NCGC00238553 (LLI01-026)
  • NCGC00238539 (LLI01-030)
  • NCGC00238554 (LLI01-046_2 ,ul )
  • NCGC00238541 (LLI01-050) N-(l-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-lH-indazol-4-yl)pyrazine-2-carboxamide
  • NCGC00241413 (LLI01-091)
  • NCGC00241414 (LLI01-094)
  • NCGC00241415 (LLI01-095)
  • NCGC00241416 (LLI01-096)
  • NCGC00241417 (LLIOl-097)
  • NCGC00241418 (LLI01-098)
  • NCGC00241420 (LLI02-001)
  • NCGC00241421 (LLI02-002) N-(3,4-diethoxyphenethyl)-l-phenylcyclopropanecarboxamide
  • NCGC00241422 (LLI02-003)
  • NCGC00251423 (LLI02-004)
  • NCGC00241424 (LLI02-005)
  • NCGC00241425 (LLI02-006) N-(3,4-diethoxyphenethyl)-4-(pyridin-3-ylmethyl)-4H-thieno[3,2-b]pyrrole-5- carboxamide
  • NCGC00241426 (LLI02-007)
  • NCGC00241428 (LLI02-009)
  • NCGC00241430 (LLI02-011)
  • NCGC00241431 (LLI02-012)
  • NCGC00241433 (LLI02-014)
  • NCGC00241434 (LLI02-017)
  • NCGC00241436 (LLI02-019) 3-Benzoyl-N-(3,4-diethoxyphenethyl)benzamide
  • NCGC00241436 (LLI02-024)
  • NCGC00241436 (LLI02-025)
  • NCGC00241436 (LLI02-029)
  • NCGC00034917 (LLI02-042)
  • NCGC00241447 (LLI02-045)
  • NCGC00241448 (LLI02-047)
  • NCGC241449 (LLI02-051)
  • NCGC00241450 (LLI02-054)
  • NCGC00241451 (LLI02-055)
  • NCGC00241452 (LLI02-056)
  • NCGC00241453 (LLI02-063)
  • NCGC00189556 (LLI02-071_2 nd _NEG)
  • NCGC00242548 (LLI02-073)
  • NCGC00242550 (LLI02-085) l-(2-(3-(2-Chlorophenyl)ureido)-2-methylpropanoyl)piperidine-4-carboxylic acid
  • NCGC00242551 (LLI02-091) te -Butyl 2-(2-(2-(4-(4-(picolinamido)-4,5,6,7-tetrahydro-lH-indazol-l- yl)phenoxy)ethoxy)ethykarbamate
  • NCGC00242552 (LLI02-098)
  • NCGC00242553 (LLI03-001)
  • NCGC00242554 (LLI03-002)
  • NCGC00242555 (LLI03-003)
  • NCGC00242556 (LLI03-004)
  • NCGC00242559 (LLI03-008)
  • NCGC00242560 (LLI03-009)
  • NCGC00242565 (LLI03-019)
  • NCGC00242566 (LLI03-021)
  • NCGC00242567 (LLI03-022)
  • NCGC00242568 (LLI03-023)
  • NCGC00242571 (LLI03-036)
  • NCGC00242572 (LLI03-037) tert-Butyl 2-(2-(2-(2-(4-(picolinamido)-4,5,6,7-tetrahydro-lH-indazoI-l- yl)ethoxy)ethoxy)ethylcarbamate
  • NCGC00242573 (LLI03-044)
  • NCGC00242574 (LLI03-047)
  • NCGC00242575 (LLI03-050) tert-Butyl 2-(2-(2-(3-(4-(picolinamido)-4,5,6,7-tetrahydro-lH-indazol-l- yl)phenoxy)ethoxy)ethoxy)ethylcarbamate
  • NCGC00242563 (LLI03-065) l-(2-(3-(2-Chlorophenyl)ureido)-2-methylpropanoyl)-N-ethylpiperidine-4-carboxamide
  • NCGC00242564 (LLI03-066) l-(2-(3-(2-Chlorophenyl)ureido)-2-methylpropanoyl)-N,N-diethylpiperidine-4- carboxamide
  • NCGC00244462 (LLI03-089)
  • NCGC00244960 (LLI04-001)
  • NCGC00244961 (LLI04-002)
  • NCGC00244965 (LLI04-051)
  • NCGC00244966 (LLI04-052) N-(l-(4-(2-(2-(2-(2-(2-(2-(2-(2-(l-(7-hydroxy-2-oxo-2H-chromen-3-yl)-lH-l,2,3-triazol-4- yl)ethylamino)ethoxy)ethoxy)ethoxy)phenyl)-4,5,6,7-tetrahydro-lH-indazol-4- yl)picolinamide
  • This example provides S3 lipid droplet data, S3 cytotoxicity data, and Cos-7 lipid droplet data exhibited by various embodiments of the invention. The results are set forth in Table 4.
  • NCGC00238539- 01 0.1254 -106.4422 4.4488 -56.1755 A NCGC00238541 - 01 3.5338 -103.9098 15.785 -83.7849 A
  • NCGC00238544- 01 null 5.2709 >57 ⁇ -10 NE
  • NCGC00244964- 01 0.01 -104.104 6.2841 -85.9431 A NCGC00244964- 02 0.01 12 -103.1464 12.5385 -88.279 A
  • NCGC00241439- 01 null 1.6541 15.785 -42.3881 NE
  • NCGC00238537 (LLI01-002)
  • NCGC00238560 (LLIOl-01 1)
  • NCGC00238548 (LLIOl-013)
  • NCGC00238559 (LLI01 -014)
  • NCGC00238557 (LL101 -015)
  • NCGC00238556 (LLI01-018)
  • NCGC00238550 (LLI01-020)
  • NCGC00238551 (LLI01-022)
  • NCGC00238549 (LLI01 -023)
  • NCGC00238552 (LLIO 1-025)
  • NCGC00238553 (LLIO 1-026)
  • NCGC00238554 (LLI01-046_2 nd )
  • NCGC00241413 (LLI01-091)
  • NCGC00241414 (LLI01-094)
  • NCGC00241415 (LLI01-095)
  • NCGC00241416 (LLI01-096)
  • NCGC00241417 (LLI01 -097)
  • NCGC00241418 (LLI01 -098)
  • NCGC00241419 (LLI01-099)
  • NCGC00241420 (LLI02-001)
  • NCGC00241421 (LLI02-002)
  • NCGC00241422 (LLI02-003)
  • NCGC00251423 (LLI02-004)
  • NCGC00241424 (LLI02-005)
  • NCGC00241425 (LLI02-006)
  • NCGC00241426 (LLI02-007)
  • NCGC00241427 (LLI02-008)
  • NCGC00241428 (LLI02-009)
  • NCGC00241429 (LLI02-010)
  • NCGC00241431 (LLI02-012)
  • NCGC00241433 (LLI02-014)
  • NCGC00241434 (LLI02-017)
  • NCGC00241436 (LLI02-019)
  • NCGC00241437 (LLI02-020)
  • NCGC00241441 (LLI02-025)
  • NCGC00241445 (LLI02-029)
  • NCGC00034917 (LLI02-042)
  • NCGC00241447 (LLI02-045)
  • NCGC00241448 (LLI02-047)
  • NCGC00241449 (LLI02-051)
  • NCGC00241450 (LLI02-054)
  • NCGC00241451 (LLI02-055)
  • NCGC00241452 (LLI02-056)
  • NCGC00241453 (LLI02-063)
  • NCGC00189556 (LLI02-071_2 nd _NEG)
  • NCGC00242548 (LLI02-073)
  • NCGC00242550 (LLI02-085) l-(2-(3-(2-Chlorophenyl)ureido)-2-methylpropanoyl)piperidine-4-carboxylic acid
  • NCGC00242551 (LLI02-091)
  • NCGC00242552 (LLI02-098)
  • NCGC00242553 (LLI03-001)

Abstract

Cette invention concerne des composés de formules I, II, et III : Formules I, II, et III, R1-R19 et n dans les Formules étant tels que définis dans la description, ou des sels pharmaceutiquement acceptables de ceux-ci ou un énantiomère ou conjugué de ceux-ci, le conjugué comprenant un groupe marqueur, pouvant être utilisés pour traiter ou prévenir une maladie ou un trouble réagissant à la réduction des gouttelettes de stockage lipidique chez un animal en ayant besoin. Des compositions pharmaceutiques contenant ces composés ou des sels pharmaceutiquement acceptables de ceux-ci et un véhicule pharmaceutiquement acceptable et des méthodes pour traiter ou prévenir les maladies et les troubles neurodégénératifs sont également décrites.
PCT/US2012/066394 2011-11-22 2012-11-21 Modulateurs du stockage lipidique WO2013078413A1 (fr)

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AU2014254392B2 (en) * 2013-03-15 2018-05-24 Epizyme, Inc. Substituted benzene compounds
CN108191764A (zh) * 2018-01-12 2018-06-22 扬州大学 1,3-二芳基-1,5,6,7-四氢吲唑衍生物的合成方法
WO2021105906A1 (fr) * 2019-11-25 2021-06-03 Gain Therapeutics Sa Composés aryle et hétéroaryle, leurs utilisations thérapeutiques dans des conditions associées à l'altération de l'activité de la galactocérébrosidase
WO2022060764A1 (fr) * 2020-09-18 2022-03-24 Merck Sharp & Dohme Corp. Benzofuran-carboxamides modifiés comme inhibiteurs du glucosylcéramide synthase
CN115304544A (zh) * 2022-08-01 2022-11-08 童航 一种5-溴-2-(甲基氨基)吡啶的合成方法

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