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WO2009026701A1 - Inhibiteurs de sirtuine - Google Patents

Inhibiteurs de sirtuine Download PDF

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Publication number
WO2009026701A1
WO2009026701A1 PCT/CA2008/001520 CA2008001520W WO2009026701A1 WO 2009026701 A1 WO2009026701 A1 WO 2009026701A1 CA 2008001520 W CA2008001520 W CA 2008001520W WO 2009026701 A1 WO2009026701 A1 WO 2009026701A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
heteroaryl
heterocyclyl
optionally substituted
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Ceased
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PCT/CA2008/001520
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English (en)
Inventor
Robert Deziel
Jubrail Rahil
Amal Wahhab
Martin Allan
Nathalie Nguyen
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Methylgene Inc
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Methylgene Inc
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Publication of WO2009026701A1 publication Critical patent/WO2009026701A1/fr
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Definitions

  • This invention relates to the inhibition of Class III histone deacetylases (HDAC), also known as sirtuins (SIRTs). More particularly, the invention relates to compounds and methods for inhibiting sirtuin enzymatic activity.
  • HDAC histone deacetylases
  • SIRTs sirtuins
  • Histone deacetylases are involved in the epigenetic regulation of gene expression through chromatin remodeling.
  • HDACs deacetylate histone acetyl lysines.
  • regulatory acetylation/deacetylation of proteins can affect proteins in addition to histones.
  • Class I and II HDACs remove acetyl groups by hydrolysis, while Class III HDACs, also known as sirtuins (SIRTs), employ a unique NAD-dependent mechanism.
  • Mammalian SIRT proteins comprise a family of seven homologs of yeast SIR2, an NAD-dependent deacetylase connecting metabolism with longevity. SIRT proteins contain a conserved SIRT core domain with varying lengths of N- or C-terminal sequences. Of the seven human SIRTs, SIRTl has been most extensively studied. Human SIRTl is the closest homolog of yeast SIR2, with roles in cell survival and metabolism. SIRTs 1-7 are localized to diverse cellular compartments, have varied enzymatic activities, target numerous histone and non-histone substrates, and therefore affect a broad range of cellular functions, including cell survival, metabolism and DNA repair (Haigis, M.C. and L. P. Guarente, 2006, Mammalian Sirtuins - Emerging Roles in Physiology, Aging, and Calorie Restriction, Genes & Development 20:2913-2921).
  • SIRTl is a nuclear, NAD-dependent protein deacetylase, and SIRTl has been shown to deacetylate numerous substrates in vitro and in vivo, including histones (H3, H4) and nonhistone proteins (p53, PML, hTERT, AR, Ku70, NFkB, BCL6, TAF68, CTIP2, FOXO, PGC- 1 alpha, PCAF/MyoD, HES-I, HEY-2, MEF2D, MyoD, PPAR ⁇ , p300, AceCSl and tat) with a potential link to treating diseases and disorders such as, for example, tumorigenesis (oncology applications), ageing, obesity, insulin resistance (type II diabetes) inflammation, heart failure, axonal degeneration and AIDS.
  • H3, H4 histones
  • nonhistone proteins p53, PML, hTERT, AR, Ku70, NFkB, BCL6, TAF68, CTIP2, FOXO, PGC- 1 alpha,
  • SIRTl RNAi induces growth arrest and/or apoptosis in human epithelial cancer cells (HCTl 16 colon epithelial cancer cells, HTB- 126 mammary epithelial cancer cells), but not normal human cells (ARPE- 19 normal pigmented retinal epithelial cells, HTB- 125 normal mammary epithelial cells, normal dermal fibroblasts) (Ford, J., et. al., 2005, Cancer-specific Functions of SIRTl Enable Human Epithelial Cancer Cell Growth and Survival, Cancer Research 65(22): 10457- 10463).
  • the SIRT inhibitor cambinol reduces growth of BCL6+ Daudi xenograft tumors (Heltweg, B., et. al., 2006, Antitumor Activity of a Small Molecule Inhibitor of Human Silent Information Regulator 2 Enzymes, Cancer Research 66(8):4368-4377).
  • Cambinol is a substrate competitive inhibitor of SIRTs 1 and 2 with weak potency (>50uM IC50).
  • SIRTl RNAi dominant negative SIRTl
  • SIRT inhibitors nicotinamide and splitomicin
  • SIRT2 is a NAD-dependent protein deacetylase that has been shown to deacetylase numerous substrates in vitro and in vivo such as ⁇ -tubulin (Dali-Youcef et al., 2007, Sirtuins: The 'magnificent seven ', Function, Metabolism and Longevity, Annals of Medicine 39:335- 345). Modulating SIRT2 expression levels has been shown to affect the cell cycle, with SIRT2 overexpression delaying mitosis and SIRT2 knockout MEFs having an extended Gl phase and a shortened S phase (Dryden 2003, Vaquero 2006). SIRT2 substrates also include histone H4K16 (North 2003, Vaquero 2006).
  • SIRT3 is a mitochondrial, NAD-dependent protein deacetylase that has been shown to deacetylase numerous substrates in vitro and in vivo such as PGC- l ⁇ and AceCS2 with a potential link to treating diseases and disorder such as, for example, those associated with adaptive thermogenesis and breast cancer.
  • SIRT3 is expressed in brown adipose tissue and overexpression increases mitochondrial respiration. SIRT3 deacetylates and activates mitochondrial acetyl-CoA-synthetase (Schwer 2006).
  • SIRT4 is a mitochondrial, NAD-dependent protein deacetylase that has been shown to deacetylase numerous substrates in vitro and in vivo such as glutamate dehydrogenase with a potential link to treating diseases and disorder such as, for example Type I and Type II diabetes.
  • SIRT4 has both ADP-ribosyltransferase activity and deacetylase activity and regulates insulin secretion by glucose response (Argmarmc and Auwerx Cell 2006).
  • SIRT5 is a mitochondrial, NAD-dependent protein deacetylase, having high expression levels in the brain, testicles, spleen, kidney, heart, liver, ovary, lung, thyroid, uterus and bone marrow.
  • SIRT5 can deacetylate cytochrome C and may regulate oxidative stress and apoptosis (Sclicker et al J MoI Biol 2008).
  • SIRT6 is a non-nuclear, NAD-dependent protein deacetylase that has been shown to deacetylase numerous substrates in vitro and in vivo such as DNA pol ⁇ with a potential link to treating diseases and disorder such as, for example, those associated with ageing (loss of subcutaneous fat, decreased bone mineral density, etc.).
  • SIRT6 has both ADP-ribosyltransferase and deacetylase activity. It can deacetylate H3K9 to modulate telometric chromatin (Michishita et al Nature 2008).
  • SIRT7 is a nuclear, NAD-dependent protein deacetylase that has been shown to deacetylate p53 in vitro. SIRT7 deficient mice have been shown to exhibit hyperacetylation of p53 in myocardium in vivo (Vakhrusheva et al Circ Res 2008). It has been shown also SIRT7 is an activator of RNA polymerase I transcription with a potential link to treating diseases and disorder such as, for example, thyroid cancer and breast cancer. (Dali-Youcef et al., 2007, Sirtuins: The 'magnificent seven', Function, Metabolism and Longevity, Annals of Medicine 39:335-345).
  • SIRT7 is localized to the nucleolus with high expression in proliferating tissues (liver, spleen, testes), and low expression in nonproliferating tissues (heart, brain, muscle). SIRT7 is expressed at high levels in thyroid carcinomas. Modulating SIRT7 expression affects rRNA transcription and SIRT7 RNAi induces apoptosis in U2OS cells (Ford et al., supra).
  • SIRTl has been shown to deacetylate FOXOl, FOXO3 and FOXO4, with varied effects on the localization and/or transactivation potential of these transcription factors.
  • Sirtuin activity affects FOXOl shuttling between the nucleus and cytoplasm, and increases FOXOl -mediated transactivation (Frescas 2005).
  • SIRTl deacetylates FOXO3, having a dual effect on FOXO3 functions, inhibiting cell death induction, but increasing cell cycle arrest and oxidative stress resistance mechanisms (Brunet 2004).
  • SIRTl has been shown to repress FOXO3a- mediated transactivation (Motta 2004). Also, SIRTl deacetylates FOXO4, enhancing FOXO4 transcriptional and biological activity (Van der Horst 2004). SIRTl function in shifting FOXO dependent responses away from cell death in favor of cell survival is clearly relevant to cancer cell biology.
  • SIRTl deacetylase activity includes nicotinamide, cambinol, sirtinol, splitomicin, anilinobenzamide #7 and EX527 (Suzuki, T., et. al., 2006, 2- Anilinobenzamides as SIRT Inhibitors, ChemMedChem 1:1059-1062; Napper, A.D., et. al., 2005, Discovery of Indoles as Potent and Selective Inhibitors of the Deacetylase SIRTl, Journal of Medicinal Chemistry 48(25):8045-8054; Huhtiniemi, T., et.
  • the present invention provides compounds and methods for the inhibition of sirtuin enzymatic activity.
  • the invention provides compounds and methods for treating cell proliferative diseases and conditions.
  • the present invention provides compounds that are useful as inhibitors of sirtuins and that have the formula (I):
  • the invention provides compounds of formula I that are useful as sirtuin inhibitors and, therefore, are useful research tools for the study of the role of sirtuins in both normal and disease states.
  • the invention provides a composition comprising a compound according to the present invention.
  • the composition further comprises an additional inhibitory agent.
  • the invention provides a method of inhibiting sirtuin activity, for example SIRTl, the method comprising contacting the sirtuin with a compound according to the present invention, or with a composition according to the present invention.
  • Inhibition of sirtuin can be in a cell or a multicellular organism. If in a cell, the method according to this aspect of the invention comprises contacting the cell with a compound according to the present invention, or with a composition according to the present invention. If in a multicellular organism, the method according to this aspect of the invention comprises administering to the organism a compound according to the present invention, or a composition according to the present invention.
  • the organism is a mammal, more preferably a human.
  • the invention provides a method for treating a SIRT protein mediated disease or disorder, comprising: administering to a patient in need of treatment a therapeutically effective amount of a compound according to the present invention or a composition thereof.
  • the present invention provides compounds and methods for the inhibition of sirtuin enzymatic activity.
  • the invention also provides compounds and methods for treating cell proliferative diseases and conditions.
  • the invention provides compounds of the formula (I), and racemic and scalemic mixtures, diastereomers and enantiomers thereof: Y— L— Z — D (I) and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein Y, L, Z and D are as defined herein.
  • the invention provides a composition comprising a compound according to the first aspect or anyembodiment thereof and a pharmaceutically acceptable carrier.
  • the invention provides a method of inhibiting sirtuin activity, the method comprising contacting the sirtuin, or a cell containing sirtuin activity with an inhibition effective amount of a compound according to the present invention, or with an inhibition effective amount of a composition according to the present invention.
  • Inhibition of sirtuin activity can be in a cell or a multicellular organism. If in a multicellular organism, the method according to this aspect of the invention comprises administering to the organism an inhibition effective amount of a compound according to the present invention, or an inhibition effective amount of a composition according to the present invention.
  • the organism is a mammal, more preferably a human.
  • the method further comprises concurrently or sequentially contacting the sirtuin, or the cell, with an effective amount of an additional sirtuin inhibitory agent, or if in a multicellular organism, concurrently or sequentially administering an inhibition effective amount of an additional sirutin inhibitory agent.
  • references to "a compound of the formula (I), formula (II), etc.,” (or equivalently, “a compound according to the first aspect", or “a compound of the present invention”, and the like), herein is understood to include reference to N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers, enantiomers and tautomers thereof and unless otherwise indicated.
  • a bivalent linking moiety can be "alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH 2 -CH 2 -), which is equivalent to the term “alkylene.”
  • alkyl in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH 2 -CH 2 -), which is equivalent to the term “alkylene.”
  • aryl refers to the corresponding divalent moiety, arylene.
  • AU atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).
  • a moiety may be defined, for example, as (A) 3 -B-, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B- and when a is 1 the moiety is A-B-. Also, a number of moietes disclosed here may exist in multiple tautomeric forms, all of which are intended to be encompassed by any given tautomeric structure.
  • C m -C n " cycloalkyl, “C 1n -C n “ heterocyclyl, “C m -C n “ heteroaryl or "m to n membered ring”, and the like means a cycloalkyl, heterocyclyl, hetero- aryl or ring having from “m” to "n” annular atoms, where “m” and “n” are integers.
  • a Cs-C ⁇ -heterocyclyl is a 5- or 6- membered ring having at least one heteroatom, and includes pyrrolidinyl (C 5 ) and piperidinyl (C 6 );
  • C 6 -heteroaryl includes, for example, pyridyl and pyrimidyl.
  • hydrocarbyl refers to a straight, branched, or cyclic alkyl, alkenyl, or alkynyl, each as defined herein.
  • a “C 0 " hydrocarbyl is used to refer to a covalent bond.
  • Co-C 3 -hydrocarbyl includes a covalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl, propynyl, and cyclopropyl.
  • aliphatic is intended to mean both saturated and unsaturated, straight chain or branched hydrocarbons. As will be appreciated by one of ordinary skill in the art, “aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl or alkynyl moieties.
  • alkyl and “alk”, are intended to mean a straight chain or branched hydrocarbon group having from 1 to 20 carbons, preferably 1 to 12 carbon atoms, alternatively 1-8 carbon atoms, and alternatively 1-6 carbon atoms.
  • Other alkyl groups have from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms and alternatively 2-6 carbon atoms.
  • alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like.
  • a "Co" alkyl (as in "Co-C 3 alkyl”) is a covalent bond.
  • alkenyl is intended to mean an unsaturated straight chain, branched cyclic or bicylic hydrocarbon group with one or more carbon-carbon double bonds, having from 2 to 20 carbons, alternatively from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, and alternatively 2-6 carbon atoms.
  • alkenyl groups include, without limitation, vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, and 1-cyclohexenyl.
  • alkenyl as employed herein therefore encompasses cycloalkenyl groups.
  • alkynyl is intended to mean an unsaturated straight chain, branched, cyclic or bicylci hydrocarbon group with one or more carbon-carbon triple bonds, having from 2 to 20 carbons, alternatively from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, and alternatively 2-6 carbon atoms.
  • alkynyl groups include, without limitation, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2- heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, and 1 -cyclohexynyl.
  • alkenyl as employed herein therefore encompasses cycloalkenyl groups.
  • alkylene alkenylene
  • alkynylene alkynylene
  • alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.
  • alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene.
  • Exampes of alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.
  • cycloalkyl is intended to mean a saturated, partially unsaturated or unsaturated mono-, bi-, tri- or poly-cyclic hydrocarbon group having about 3 to 20 carbons, alternatively 3 to 15 carbons, alternatively having 3 to 12 carbons, alternatively 3 to 8 carbons, alternatively 3 to 6 carbons, and alternatively 5 or 6 carbons.
  • the cycloalkyl group is fused to one or more aryl, heteroaryl or heterocyclic group (for example 1 or 2).
  • cycloalkyl groups include, without limitation, cyclopenten-2-enone, cyclopenten-2-enol, cyclohex-2-enone, cyclohex-2-enol, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl etc.
  • heteroalkyl is intended to mean a saturated or unsaturated, straight chain or branched aliphatic group, wherein one or more carbon atoms in the group are independently replaced by a moiety selected from the group consisting of O, S, N, N-alkyl, -S(O)-, -S(O) 2 -, -S(O) 2 NH-, or -NHS(O) 2 -.
  • aryl or "ar”, are intended to mean a mono-, bi-, tri- or polycyclic aromatic moiety, for example a Ce-Cuaromatic moiety, for example comprising one to three aromatic rings.
  • An aryl group may optionally include an aromatic ring fused to a carbocyclic ring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings).
  • the aryl group is a C 6 -Cioaryl group, alternatively a C 6 aryl group.
  • aryl groups include, without limitation, phenyl, naphthyl (including 1-naphthyl and 2- naphthyl), anthracenyl, and fluorenyl.
  • aralkyl or arylalkyl are intended to mean a group comprising an aryl group covalently linked to an alkyl group. If an aralkyl group is described as “optionally substituted”, it is intended that either or both of the aryl and alkyl moieties may independently be optionally substituted or unsubstituted.
  • the aralkyl group is (C 1 -C 6 )alk(C 6 -C 1 o)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
  • arylalkyl this term, and terms related thereto, is intended to indicate the order of groups in a compound as “aryl - alkyl”.
  • alkyl-aryl is intended to indicate the order of the groups in a compound as "alkyl-aryl”.
  • heterocyclo is intended to mean a group which is a mono-, bi-, or polycyclic structure having from about 3 to about 20 ring atoms, alternatively about 3 to about 14 ring atoms, alternatively 3 to 10 ring atoms, wherein the ring atoms consist of carbon atoms, and one or more atoms independently selected from the group consisting of N, O, and S.
  • the ring structure may be saturated, unsaturated or partially unsaturated.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, hi certain embodiments, the heterocyclic group is non-aromatic, in which case the group is also known as a heterocycloalkyl.
  • the heterocyclic group is a bridged heterocyclic group (for example, a bicyclic moiety with a methylene, ethylene or propylene bridge).
  • one or more rings may be aromatic; for example one ring of a bicyclic heterocycle or one or two rings of a tricyclic heterocycle may be aromatic, as in indan and 9,10-dihydro anthracene.
  • heterocyclic groups include, without limitation, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, isothiazolyl, thiadiazolyl, t
  • the heterocyclic group is fused to an aryl, heteroaryl, or cycloalkyl group.
  • fused heterocycles include, without limitation, tetrahydroquinoline and dihydrobenzofuran. Specifically excluded from the scope of this term are compounds where an annular O or S atom is adjacent to another O or S atom.
  • the heterocyclic group is a heteroaryl group.
  • heteroaryl is intended to mean a mono-, bi-, tri- or polycyclic group having 5 to 18 ring atoms, alternatively 5 to 14 ring atoms, alternatively 5 to 10 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; preferably having 6, 10, or 14 pi electrons shared in a cyclic array; and having, in addition to carbon atoms, between one or more heteroatoms selected from the group consisting of N, O, and S.
  • heteroaryl is also intended to encompass the N- oxide derivative (or N-oxide derivatives, if the heteroaryl group contains more than one nitrogen such that more than one N-oxide derivative may be formed) of a nitrogen-containing heteroaryl group.
  • a heteroaryl group may be pyrimidinyl, pyridinyl, benzimidazolyl, thienyl, benzothiazolyl, benzofuranyl and indolinyl.
  • heteroaryl groups include, without limitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, benzo[b]thienyl, naphtha[2,3- b]thianthrenyl, zanthenyl, quinolyl, benzothiazolyl, benzimidazolyl, beta-carbolinyl and perimidinyl.
  • N-oxide derivatives of heteroaryl groups include, but are not limited to, pyridyl N-oxide, pyrazinyl N-opxide, pyrimidinyl N-oxide, pyridazinyl N- oxide, triazinyl N-oxide, isoquinolyl N-oxide, quinolyl N-oxide and other heteroaryl groups as described in Katritzky, A. R. and Rees, C. W., eds. Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Uses of Heterocyclic Compounds 1984, Pergamum Press, New York, N.Y.; and Katritzky, A.
  • cycloalkylene arylene
  • heteroarylene arylene
  • heterocyclylene arylene
  • a heteroalicyclic group refers specifically to a non-aromatic heterocyclyl radical.
  • a heteroalicyclic may contain unsaturation, but is not aromatic.
  • a heterocyclylalkyl group refers to a residue in which a heterocyclyl is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne radical.
  • Examples include (4-methylpiperazin-l-yl) methyl, (morpholin-4-yl) methyl, (pyridine-4-yl) methyl,2- (oxazolin-2-yl) ethyl,4- (4-methylpiperazin-l-yl)-2-butenyl, and the like.
  • hetero- cyclylalkyl is described as “optionally substituted” it is meant that both the heterocyclyl and the corresponding alkylene, alkylidene, or alkylidyne radical portion of a heterocyclylalkyl group may be optionally substituted.
  • a “lower heterocyclylalkyl” refers to a heterocyclylalkyl where the “alkyl” portion of the group has one to six carbons.
  • a heteroalicyclylalkyl group refers specifically to a heterocyclylalkyl where the heterocyclyl portion of the group is non-aromatic.
  • heterocyclyls and heteroaryls include, but are not limited to, azepinyl, azetidinyl, acridinyl, azocinyl, benzidolyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzofuryl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzothienyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, benzoxazolyl, benzoxadiazolyl, benzopyranyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, coumarinyl, decahydroquinolinyl, dibenzofuryl, 1,3- dioxo
  • Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular -CH- substituted with oxo is -C(O)-) nitro, halohydrocarbyl, hydrocarbyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups. Examples of substituents, which are themselves not further substituted (unless expressly stated otherwise) are:
  • R 32 and R 33 are each independently hydrogen, halo, hydroxyl or C)-C 4 alkyl
  • R 30 and R 31 are each independently hydrogen, cyano, oxo, hydroxyl, C 1 - Cgalkyl, d-Csheteroalkyl, Q-Cgalkenyl, carboxamido, C 1 -QaUCyI- carboxamido, carboxamido-d-C 3 alkyl, amidino, C 2 -C 8 hydroxyalkyl, d-dalkylaryl, aryl-d-C 3 alkyl, C 1 -C 3 alkylheteroaryl, heteroaryl-d- C 3 alkyl, d-Caalkylheterocyclyl, heterocyclyl-Crdalkyl Ci-
  • X 30 is selected from the group consisting of H, d-Cgalkyl, C 2 -Cgalkenyl-, C 2 -C 8 alkynyl-, -Co-C 3 alkyl-C 2 -C 8 alkenyl-C o -C 3 alkyl, C 0 -C 3 alkyl-C 2 - C 8 alkynyl-C 0 -C 3 alkyl, C 0 -C 3 alkyl-O-C 0 -C 3 alkyl-, HO-C 0 -C 3 alkyl-, C 0 - C 4 alkyl-N(R 30 )-C 0 -C 3 alkyl-, N(R 30 )(R 31 )-C 0 -C 3 alkyl-, N(R 30 )(R 31 )-C 0 -C 3 alkenyl-, N(R 3O )(R 31 )-C o -C 3 alkyny
  • Y 31 is selected from the group consisting of a direct bond, -O-, -N(R 30 )-, -C(O)-, -O-C(O)-, -C(O)-O-, -N(R 30 )-C(O)-, -C(O)-N(R 30 )-, -N(R 30 )- C(S)-, -C(S)-N(R 30 )-, -N(R 30 )-C(O)-N(R 31 )-, -N(R 3O )-C(NR 3O )-N(R 31 )-,
  • a moiety that is substituted is one in which one or more (alternatively one to four, alternatively from one to three or alternatively one or two), hydrogens have been independently replaced with another chemical substituent.
  • substituted phenyls include 2-flurophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2- fluoro-3-propylphenyl.
  • substituted n-octyls include 2,4- dimethyl-5-ethyl-octyl and 3-cyclo ⁇ entyl-octyl. Included within this definition are methylenes (-CH 2 -) substituted with oxygen to form carbonyl -CO-.
  • substituents When there are two optional substituents bonded to adjacent atoms of a ring structure, such as for example a phenyl, thiophenyl, or pyridinyl, the substituents, together with the atoms to which they are bonded, optionally form a 5- or 6- membered cycloalkyl or hetero- cycle having 1, 2, or 3 annular heteroatoms.
  • a group such as a hydrocarbyl, heteroalkyl, heterocyclic and/or aryl group is unsubstituted.
  • a group such as a hydrocarbyl, heteroalkyl, heterocyclic and/or aryl group is substituted with from 1 to 4 (alternatively from one to three, or alternatively one or two) independently selected substituents.
  • substituents on alkyl groups include, but are not limited to, hydroxyl, halogen (e.g., a single halogen substituent or multiple halo substituents; in the latter case, groups such as -CF 3 or an alkyl group bearing Cl 3 ), oxo, cyano, nitro, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, cycloalkylalkyl, cycloalkylalkyloxy, hydroxyalkyl, acyl, alkanoyl, heteroaryl, heteroaryloxy, cycloheteroalkyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, hetero- arylalkoxy, aryloxyalkyl, aryloxyary
  • substituents on alkenyl and alkynyl groups include, but are not limited to, alkyl or substituted alkyl, as well as those groups recited as examples of alkyl substituents.
  • substituents on cycloalkyl groups include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as those groups recited about as examples of alkyl substituents.
  • substituents include, but are not limited to, spiro-attached or fused cyclic substituents, for example spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
  • cycloalkyl groups when a cycloalkyl is substituted by two C 1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, for example a C 1-3 alkylene chain.
  • Cycloalkyl groups having this crosslinked structure include bicyclo[2.2.2]octanyl and norbornanyl.
  • substituents on cycloalkenyl groups include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as those groups recited as examples of alkyl substituents.
  • substituents include, but are not limited to, spiro-attached or fused cyclic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
  • a cycloalkenyl when a cycloalkenyl is substituted by two C 1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, for example a C 1-3 alkylene chain.
  • substituents on aryl groups include, but are not limited to, nitro, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, cyano, alkyl or substituted alkyl, as well as those groups recited above as examples of alkyl substituents.
  • substituents include, but are not limited to, fused cyclic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalky, cylcoalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
  • substituents on aryl groups include, but are not limited to, haloalkyl and those groups recited as examples of alkyl substituents.
  • the two alkyl groups may combine together to form an alkylene chain, for example a C 1 . 3 alkylene chain.
  • substituents on heterocyclic groups include, but are not limited to, spiro-attached or fused cylic substituents at any available point or points of attachement, for example spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro- attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloakenyl, fused heterocycle and fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
  • the two alkyl groups may combine together to form an alkylene chain, for example a C 1-3 alkylene chain.
  • a heterocyclic group is substituted on carbon, nitrogen and/or sulfur at one or more positions.
  • substituents on carbon include those groups recited as examples of alkyl substituents.
  • substituents on nitrogen include, but are not limited to alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl.
  • substituents on sulfur include, but are not limited to, oxo and C 1-6 alkyl.
  • nitrogen and sulfur heteroatoms may independently be optionally oxidized and nitrogen heteroatoms may independently be optionally quaternized.
  • substituents on ring groups include halogen, alkoxy and alkyl.
  • substituents on alkyl groups include halogen and hydroxy.
  • substituents on aromatic polycycles including, but not limited to, naphthyl and quinoline, include CrQalkyl, cycloalkylalkyl (e.g.
  • R ⁇ is selected from the group consisting of H, Ci-Cealkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and -(CH 2 ) 0-6 Z a R bb , wherein Z a is selected from the group consisting of O, NR CC , S and S(O), and R bb is selected from the group consisting of H, C 1 - C 6 alkyl, C 4 -Cc>cycloalkyl, C 4 -C 9 heterocycloal
  • R cc is selected from the group consisting of H, C ! -C 6 alkyl, C 4 - Cgcycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g. benzyl), heteroarylalkyl (e.g. pyridylmethyl) and amino acyl.
  • non-aromatic polycycles include, but are not limited to, bicyclic and tricyclic fused ring systems where each ring can be 4-9 membered and each ring can contain zero, 1 or more double and/or triple bonds.
  • Suitable examples of non-aromatic polycycles include, but are not limited to, decalin, octahydroindene, perhydrobenzocycloheptene and perhydrobenzo-[/]-azulene.
  • Such groups are optionally substituted with for example, but not limited to, CrCgcycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • non-aromatic polycycles include both unsubstituted cycloalkyl groups and cycloalkyl groups that are substituted by one or more suitable substituents, including but not limited to, C ! -C 6 alkyl, halo, hydroxy, aminoalkyl, oxyalkyl, alkylamino and OR aa , such as alkoxy.
  • suitable substituents including but not limited to, C ! -C 6 alkyl, halo, hydroxy, aminoalkyl, oxyalkyl, alkylamino and OR aa , such as alkoxy.
  • substituents for such cycloalkyl groups include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.
  • mixed aryl and non-aryl polycycles include bicyclic and tricylic fused ring systems where each ring can be 4-9 membered and at least one ring is aromatic.
  • Suitable examples of mixed aryl and non-aryl polycycles include methylenedioxyphenyl, bis- methylenedioxyphenyl, 1,2,3,4-tetrahydronaphthalene, dibenzosuberane dihydroanthracene and 9H-fluorene. Such groups are unsubstituted or substituted by nitro or as described above for non-aromatic polycycles.
  • Polyheteroaryls include bicyclic and tricyclic fused rings systems where each ring can independently be 5 or 6 membered and contain one or more heteroatom, for example, 1, 2, 3 or 4 heteroatoms, chosen from O, N or S such that the fused ring system is aromatic.
  • Suitable examples of polyheteroaryl ring systems include quinoline, isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridine, indole, benzofuran, benzothiofuran, benzindole, benzoxazole, pyrroloquinoline, and the like.
  • suitable substituents including but not limited to, straight and branched optionally substituted C 1 -QaIlCyI, unsaturation (i.e., there are one or more double or triple C-C bonds), acyl, cycloalky, halo, oxyalkyl, alkylamino, aminoalkyl, acylamino and
  • Examples of suitable straight and branched Q-Cealkyl substituents include but are not limited to methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec- butyl, t-butyl and the like.
  • substituents include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.
  • Nitrogen atoms are unsubstituted or substituted, for example by R cc .
  • Examples of substituents on such nitrogen atoms include H, CrQalkyl, acyl, aminoacyl and sulfonyl.
  • non-aromatic polyheterocyclics include but are not limited to bicyclic and tricyclic ring systems where each ring can be 4-9 membered, contain one or more heteroatom, for example 1, 2, 3 or 4 heteroatoms, chosen from O, N or S and contain zero, or one or more C-C double or triple bonds.
  • non-aromatic polyheterocycles include but are not limited to, hexitol, cis-perhydro-cyclohepta[b]pyridinyl, decahydro- benzo[fj[l,4]oxazepinyl, 2,8-dioxabicyclo[3.3.0]octane, hexahydro-thieno[3,2-b]thiophene, perhydropyrrolo[3,2-b]pyrrole, perhydronaphthyridine, perhydrop-lH- dicyclopenta[b,e]pyran.
  • non-aromatic polyheterocyclics are unsubstituted or substituted on a carbon atom by one or more substituents, including but not limited to straight and branched optionally substituted CrC ⁇ alkyl, unsaturation (i.e., there are one or more double or triple C-C bonds), acyl, cycloalky, halo, oxyalkyl, alkylamino, aminoalkyl, acylamino and OR ⁇ , for example alkoxy.
  • substituents including but not limited to straight and branched optionally substituted CrC ⁇ alkyl, unsaturation (i.e., there are one or more double or triple C-C bonds), acyl, cycloalky, halo, oxyalkyl, alkylamino, aminoalkyl, acylamino and OR ⁇ , for example alkoxy.
  • Examples of suitable straight and branched C!-C 6 alkyl substituents include but are not limited to methyl, ethyl, n-propyl, 2- propyl, n-butyl, sec-butyl, t-butyl and the like.
  • substituents include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl. Nitrogen atoms are unsubstituted are substituted, for example, by R cc .
  • Examples of N substituents include H, C 1 -C 4 alkyl, acyl, aminoacyl and sulfonyl.
  • Exampels of mixed aryl and non-aryl polyheterocycles include but are not limited to bicyclic and tricyclic fused ring systems where each ring can be 4-9 membered, contain one or more heteroatom chosen from O, N or S and at least one of the rings must be aromatic.
  • Suitable examples of mixed aryl and non-aryl polyheteorcycles include 2,3-dihydroindole, 1,2,3,4-tetrahydroquinoline, 5,1 l-dihydro-10H-dibenz[b,e][l,4]diazepine, 5H- dibenzo[b,e][l,4]diazepine, l,2-dihydropyrrolo[3,4-b][l,5]benzodiazepine, 1,5- dihydropyrido[2,3-b] [ 1 ,4]diazepin-4-one, 1 ,2,3,4,6, 11 -hexhydro-benzo[b]pyrido[2,3- e][l,4]diazepine-5-one.
  • Nitrogen atoms are unsubstituted or substituted, for example, by R cc .
  • Examples of N substituents include H, C 1 - 4 alkyl, acyl aminoacyl and sulfonyl.
  • halogen refers to chlorine, bromine, fluorine, or iodine.
  • acyl refers to an alkylcarbonyl or arylcarbonyl substituent.
  • acylamino refers to an amide group attached at the nitrogen atom (i.e., R-CO-NH-).
  • carbamoyl refers to an amide group attached at the carbonyl carbon atom (i.e., NH 2 -CO-).
  • the nitrogen atom of an acylamino or carbamoyl substituent is additionally optionally substituted.
  • sulfonamido refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom.
  • amino is meant to include NH 2 , alkylamino, di-alkyl-amino (wherein the alkyl groups are the same or different), arylamino, and cyclic amino groups.
  • ureido refers to a substituted or unsubstituted urea moiety.
  • radical means a chemical moiety comprising one or more unpaired electrons.
  • substituents of a moiety are chosen from “one or more" groups it is to be understood that the moiety optionally has, unless otherwise stated, from one up to the maximum number of substitutable hydrogens on the moiety replaced with a substituent independently chosen from among the specified groups.
  • substituents on cyclic moieties include 5- to 6-membered mono- and 9- to 14-membered bi-cyclic moieties fused to the parent cyclic moiety to form a bi- or tri-cyclic fused ring system.
  • cyclic moieties also include 5- to 6-membered mono- and 9- to 14-membered bi-cyclic moieties attached to the parent cyclic moiety by a covalent bond to form a bi- or tri-cyclic bi-ring system.
  • an optionally substituted phenyl includes, but is not limited to, the following:
  • a saturated or unsaturated three- to eight-membered carbocyclic ring is for example a four- to seven-membered, alternatively a five- or six-membered, saturated or unsaturated carbocyclic ring.
  • saturated or unsaturated three- to eight-membered carbocyclic rings include phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • a saturated or unsaturated three- to eight-membered heterocyclic ring contains at least one heteroatom selected from oxygen, nitrogen, and sulfur atoms.
  • the saturated or unsaturated three- to eight-membered heterocyclic ring for example contains one or two heteroatoms with the remaining ring-constituting atoms being carbon atoms.
  • the saturated or unsaturated three- to eight-membered heterocyclic ring is for example a saturated or unsaturated four- to seven-membered heterocyclic ring, alternatively a saturated or unsaturated five- or six-membered heterocyclic ring.
  • saturated or unsaturated three- to eight-membered heterocyclic groups include thienyl, pyridyl, 1,2,3-triazolyl, imidazolyl, isoxazolyl, pyrazolyl, piperazinyl, piperazino, piperidyl, piperidino, morpholinyl, morpholino, homopiperazinyl, homopiperazino, thiomorpholinyl, thiomorpholino, tetrahydropyrrolyl, and azepanyl.
  • sirtuin As used herein, the terms "Sirtuin”, “Class III histone deaceytlase”, or “Sirtuin protein” refers to a member of the sirtuin deacetylase protein family, for example to the sir2 family, which include yeast Sir2, C. elegans Sir-2.1 and human SIRTl and SIRT2 proteins. Other family members include the four additional yeast Sir2-like genes termed "HST genes” (homologies of Sir two) HSTl, HST2, HST3 and HST4, and the five other human homologues hSIRT3, hSIRT4, hSIRT5, hSIRT ⁇ and hSIRT7 (Brachmann et al. (1995) Genes Dev.
  • HST genes homologues of Sir two
  • sirtuins are those that share more similarities with SIRTl, i.e., hSIRTl, and/or Sir2 than with SIRT2, such as those members having at least part of the N- terminal sequence present in SIRTl and absent in SIRT2 such as SIRT3 has.
  • Other sirtuins are those that share more similarities with SIRT7.
  • the sirtuin is a human sirtuin.
  • the sirtuin is derived from a protozoal or fungal source.
  • sirutin inhibitor and “inhibitor of sirutin” and the like, are intended to mean a compound having a structure as defined herein, which is capable of directly or indirectly interacting with a sirutin and inhibiting its enzymatic activity.
  • inhibitorting sirutin enzymatic activity is intended to mean reducing the a functional property or biological ability of a sirtuin.
  • the inhibition of sirtuin activity may be at least about 10%.
  • such inhibition of sirtuin activity is at least about 50%, alternatively at least about 75%, and alternatively at least about 90%.
  • inhibition of sirtuin activity is at least 95% alternatively at least 99%.
  • the concentration of inhibitor which reduces the activity of a sirtuin to 50% of that of the uninhibited enzyme is determined as the IC 50 value.
  • inhibitor effective amount is meant to denote a dosage sufficient to cause inhibition of sirtuin activity in a cell, which cell can be in a multicellular organism.
  • the multicellular organism can be, for example, a plant, a fungus, or an animal, preferably a mammal, more preferably a human.
  • the fungus may be infecting a plant or a mammal, preferably a human, and could therefore be located in and/or on the plant or mammal.
  • the method according to this aspect of the invention comprises administering to the organism a compound or composition according to the present invention.
  • Administration may be by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, intravenous or intrarectal.
  • compounds of the invention are administered intravenously in a hospital setting.
  • administration may for example be by the oral route.
  • sirtuin inhibition is specific, i.e., the sirtuin inhibitor reduces a functional property or biological ability of a sirtuin at a concentration that is lower than the concentration of the inhibitor that is required to produce another, unrelated biological effect.
  • the concentration of the inhibitor required for sirtuin inhibitory activity is at least 2-fold lower, alternatively at least 5-fold lower, alternativelyat least 10- fold lower, and alternatively at least 20-fold lower than the concentration required to produce an unrelated biological effect.
  • therapeutically effective amount is an amount of a compound of the invention, that when administered to a patient, elicits the desired therapeutic effect.
  • the therapeutic effect is dependent upon the disease being treated and the results desired.
  • the therapeutic effect can be treatment of a disease-state.
  • the therapeutic effect can be inhibition of sirtuin activity.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art.
  • patient as employed herein for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the compounds, compositions and methods of the present invention are applicable to both human therapy and veterinary applications. In another embodiment the patient is a mammal, and in another embodiment the patient is human.
  • treating covers the treatment of a disease-state in an animal and includes at least one of: (i) preventing the disease-state from occurring, in particular, when such animal is predisposed to the disease-state but has not yet been diagnosed as having it; (ii) inhibiting the disease-state, i.e., partially or completely arresting its development; (iii) relieving the disease-state, i.e., causing regression of symptoms of the disease-state, or ameliorating a symptom of the disease; and (iv) reversal or regression of the disease-state, preferably eliminating or curing of the disease, hi another embodiment of the present invention the animal is a mammal, for example a primate, for example a human, hi certain embodiments, the terms “treating", “treatment”, or the like, as used herein covers the treatment of a disease-state in an organism and includes at least one of (ii), (iii) and (iv) above.
  • a SIRT protein mediated disease or disorder is for example a disease or disorder selected from the group consisting of brain cancer, breast cancer, colon cancer, liver cancer, spleenic cancer testicular cancer and thyroid cancer.
  • a SIRT protein mediated disease or disorder is for example a disease or disorder selected from the group consisting of age related disorders, loss of subcutaneous fat and decreased bone mineral density.
  • a SIRT protein mediated disease or disorder is for example a disease or disorder selected from the group consisting of Type I and Type II diabetes. In another embodiment, a SIRT protein mediated disease or disorder is for example obesity.
  • a SIRT protein mediated disease or disorder is for example a disease or disorder selected from the group consisting of inflammation, heart failure, axonal degeneration, AIDS and adaptive thermogenesis.
  • the compounds of the present invention form salts which are also within the scope of this invention.
  • Reference to a compound of the invention, for example a compound of Formula (I), herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)" denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
  • a compound of Formula (I) contains both a basic moiety, such as but not limited to a pyridine or imidazole, and an acidic moiety such as but not limited to a carboxylic acid
  • zwitterions inner salts
  • Pharmaceutically acceptable salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation.
  • Salts of the compounds of the invention may be formed, for example, by reacting a compound of the present invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salts precipitates or in an aqueous medium followed by lyophilization.
  • the compounds of the present invention which contain a basic moiety may form salts with a variety of organic and inorganic acids.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanethanethane, acetatesulfates, adipates, algina
  • the compounds of the present invention which contain an acidic moiety may form salts with a variety of organic and inorganic bases.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D- glucamines, N-methyl-D-glycamides, f-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibuty and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g. methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g. dimethyl, diethyl, dibuty and diamyl sulfates
  • long chain halides e.g.
  • pharmaceutically acceptable salts is intended to mean salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects.
  • compositions including a compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug of a compound according to the present invention as described herein, or a racemic mixture, diastereomer, enantiomer or tautomer thereof.
  • a composition comprises a compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug of a compound according to the present invention as described herein present in at least about 30% enantiomeric or diastereomeric excess, hi certain desirable embodiments of the invention, the compound, N-oxide, hydrates, solvate, pharmaceutically acceptable salt, complex or prodrug is present in at least about 50%, at least about 80%, or even at least about 90% enantiomeric or diastereomeric excess, hi certain other desirable embodiments of the invention, the compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug is present in at least about 95%, alternatively at least about 98% and alternatively at least about 99% enantiomeric or diastereomeric excess.
  • a compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug is present as a substantially racemic mixture
  • Some compounds of the invention may have chiral centers and/or geometric isomeric centers (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, enantiomeric, diastereoisomeric and geometric isomers.
  • the invention also comprises all tautomeric forms of the compounds disclosed herein. Where compounds of the invention include chiral centers, the invention encompasses the enantiomerically and/or diasteromerically pure isomers of such compounds, the enantiomerically and/or diastereomerically enriched mixtures of such compounds, and the racemic and scalemic mixtures of such compounds.
  • a composition may include a mixture of enantiomers or diastereomers of a compound of Formula (I) in at least about 30% diastereomeric or enantiomeric excess, hi certain embodiments of the invention, the compound is present in at least about 50% enantiomeric or diastereomeric excess, in at least about 80% enantiomeric or diastereomeric excess, or even in at least about 90% enantiomeric or diastereomeric excess, hi certain embodiments of the invention, the compound is present in at least about 95%, alternataively in at least about 98% enantiomeric or diastereomeric excess, and alternatively in at least about 99% enantiomeric or diastereomeric excess.
  • the chiral centers of the present invention may have the S or R configuration.
  • the racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivates or separation by chiral column chromatography.
  • the individual optical isomers can be obtained either starting from chiral precursors/intermediates or from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
  • the present invention also includes prodrugs of compounds of the invention. The term
  • prodrug is intended to mean a derivative of a compound of the present invention that requires a transformation, for example, within the body, to release the active compound. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the parent compound.
  • a hydroxyl containing compound may be converted to, for example, a sulfonate, ester or carbonate prodrug, which may be hydrolyzed in vivo to provide the hydroxyl compound.
  • An amino containing compound may be converted, for example, to a carbamate, amide, enamine, imine, N-phosphonyl, N-phosphoryl or N-sulfenyl prodrug, which may be hydrolyzed in vivo to provide the amino compound.
  • a carboxylic acid compound may be converted to an ester (including silyl esters and thioesters), amide or hydrazide prodrug, which be hydrolyzed in vivo to provide the carboxylic acid compound.
  • Prodrugs for drugs which have functional groups different than those listed above are well known to the skilled artisan.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs of compounds of the invention include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified.
  • Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N 5 N- dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like.
  • the compounds of the invention may be administered as is or as a prodrug, for example in the form of an in vivo hydrolyzable ester or in vivo hydrolyzable amide.
  • An in vivo hydrolyzable ester of a compound of the invention containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include Ci-C 6 alkoxymethyl esters (e.g., methoxymethyl), Q-C ⁇ alkanoyloxymethyl esters (e.g., for example pivaloyloxymethyl), phthalidyl esters, C 3 - Qcycloalkoxycarbonyloxy-CrCealkyl esters (e.g., l-cyclohexylcarbonyloxyethyl); 1,3- dioxolen-2-onylmethyl esters (e.g., 5-methyl-l,3-dioxolen-2-onylmethyl; and C 1 - C 6 alkoxycarbonyloxyethyl esters (e.g., 1-methoxycarbonyloxyethyl) and may be formed at any appropriate carboxy group in the compounds of this invention.
  • Ci-C 6 alkoxymethyl esters e.g., methoxymethyl
  • An in vivo hydrolyzable ester of a compound of the invention containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy.
  • a selection of in vivo hydrolyzable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(N 1 N- dialkylaminoethyl)-iV-alkylcarbamoyl (to give carbamates), /V,/V-dialkylaminoacetyl and carboxy acetyl.
  • substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4- position of the benzoyl ring.
  • a suitable value for an in vivo hydrolyzable amide of a compound of the invention containing a carboxy group is, for example, a /V-Ci-C 6 alkyl or N,N-di-d-C 6 alkyl amide such as TV-methyl, TV-ethyl, /V-propyl, /V,7V-dimethyl, JV-ethyl-N-methyl or TV.iV-diethyl amide.
  • the prodrug Upon administration to a subject, the prodrug undergoes chemical conversion by metabolic or chemical processes to yield a compound of the present invention, or a salt and/or solvate thereof.
  • Solvates of the compounds of the present invention include, for example, hydrates.
  • a polar functional group e.g., a carboxylic acid, an amino group, a hydroxyl group, etc.
  • a promoiety which is labile under physiological conditions.
  • ""Promoiety” refers to a form of protecting group that when used to mask a functional group within a compound molecule converts the drug into a prodrug.
  • the promoiety will be attached to the compound via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.
  • protecting are intended to refer to a process in which a functional group in a chemical compound is selectively masked by a non-reactive functional group in order to allow a selective reaction(s) to occur elsewhere on said chemical compound.
  • non-reactive functional groups are herein termed "protecting groups”.
  • nitrogen protecting group is intended to mean a group capable of selectively masking the reactivity of a nitrogen (N) group.
  • suitable protecting group is intended to mean a protecting group useful in the preparation of the compounds of the present invention. Such groups are generally able to be selectively introduced and removed using mild reaction conditions that do not interfere with other portions of the subject compounds.
  • the invention provides compounds of the formula (I):
  • X is O or S
  • M is nitrogen, oxygen, or sulfur; wherein when M is oxygen or sulfur, R b is absent and W is nitrogen;
  • W is nitrogen, oxygen, or sulfur; wherein when W is oxygen or sulfur, R c is absent and M is nitrogen; each R a is independently selected from the group consisting of -H, -Ci-C 6 alkyl, a protecting group, -Ci-C ⁇ alkyl-aryl, aryl, -CrC ⁇ alkyl-heteroaryl, heteroaryl, -CrC ⁇ alkyl-cycloalkyl, cycloalkyl, -d-Cealkyl-heterocyclyl, heterocyclyl, -C(O)-O-C j-C 6 alkyl, -C(O)-O-C 1 - C 6 alkyl-heterocyclyl, -C(O)-O-C i-C 6 alkyl-alkenyl, -C(O)-O-C 1 -C 6 alkyl-aryl, -CO-CF 3
  • R b and R c when present, are independently selected from the group consisting of -H, -OH, -CN, -O-alkyl, -O-alkyl-aryl, -O-alkyl-heteroaryl, -d-Cealkyl, -C(O)-alkyl, -NH 2 , -NH- alkyl, -C(O)-H, a protecting group, -d-C 6 alkyl-aryl, aryl, -d-C ⁇ alkyl-heteroaryl, -hetero- aryl, -Ci-C ⁇ alkyl-cycloalkyl, cycloalkyl, -Ci-C ⁇ alkyl-heterocyclyl, heterocyclyl, -C(O)-Co- C 3 alkyl-aryl, -C(O)-C 0 -C 3 alkyl-heteroaryl, -C(O)
  • R h is selected from the group consisting of H, -OH, -CN, -C r C 6 alkyl, -C 0 -C 6 alkyl-O-C 0 - C 6 alkyl-aryl, -Co-C ⁇ alkyl-O-Co-C ⁇ alkyl-heteroaryl, wherein each of said alkyl, aryl, and heteroaryl is optionally substituted; or, R h and R c , together with the atoms to which they are attached, optionally form a 3 to 9-membered heterocyclyl, heteroaryl, heterocyclyl-aryl or heterocyclyl-heteroaryl, each of which is optionally substituted;
  • HA is optionally substituted heterocyclyl, heteroaryl, heterocyclyl-aryl or heterocyclyl- heteroaryl;
  • Z is selected from the group consisting of a covalent bond, -C 3 -Csalkyl-, -C 0 -C 3 alkyl-Ci- C 8 heteroalkyl-C 0 -C 3 alkyl-, -C 0 -C 3 alkyl-C 2 -C 8 alkenyl-C 0 -C 3 alkyl-, -C 0 -C 3 alkyl-C 2 - C 8 alkynyl-C 0 -C 3 alkyl-, -Co-Cealkyl-aryl-Co-C ⁇ alkyl-, -C 0 -C 6 alkyl-aryl-C 2 -C 6 heteroalkyl-,
  • each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocyclyl, aryl and heteroaryl moiety of the aforementioned L are optionally substituted; wherein each Y is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryl-heteroaryl, aryl-heteroarylalkyl, heteroaryl-alkylaryl, aryl-aryl, aryl- arylalkyl, aryl-alkylaryl, aryl-C 0 -C 3 alkyl-O-C 0 -C 3 alkyl-aryl, aryl-Co-C 3 alkyl-S(0) 0-2
  • a 2a and A 2b together are a covalent bond and are attached to form a ring;
  • B , B and B are each independently a natural or synthetic amino acid and when any of B ,
  • each R 3 and R 3a are independently selected from the group consisting of -H, -OH, -C(O)H, heterocyclyl, Q-Qalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C 2 -C 4 alkyl-OR a , -C(O)-O-C 2 - C 4 alkyl-NR a R a , heteroalkyl, C 0 -C 6 alkylheteroaryl, C(O)CF 3 , -C(O)-NH 2 , -C(O)-NH-Cr C 6 alkyl, -NH 2 , C 3 -C 6 cycloalkyl, -d-C 6 alkylaryl, heteroaryl-aryl, aryl and alkylheteroaryl, wherein each alkyl, alkenyl, alkynyl, heterocyclyl, Q-Qalkyl, C 2 -C 6
  • each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl moiety of Y, L, Z, R a , R b , R c , R 3 and R 3a is independently optionally substituted with one or more groups independently selected from R 4 .
  • each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl moiety of Y, L, Z, R a , R b , R c , R 3 and R 3a is independently optionally substituted with one or more groups independently selected from oxo, -OH, -CN, Ci-C ⁇ alkyl, d-C 6 alkoxy, -NO 2 , -N(R a ) 2 , -N(R 7 )(R 7a ), halo, -SH, -S-C 1 - C 6 alkyl, -S(O)-C 1 -C O aIlCyI, -S-C(O)-C ! -C 6 alkyl and mono- to per-halogenated Ci-C 6 alkyl.
  • a CrC 6 alkyl moiety of an R 4 is optionally substituted with a substituent selected from the group consisting of -OH, -NO 2 and C 0 -C 6 alkyl-C(O)-N(R 3 )(R 3a ).
  • each alkyl, alkenyl, alkynyl, hetero- alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl moiety of Z is independently optionally substituted with one or more substituents independently selected from the group consisting of oxo, -OH, -CN, d-C 6 alkyl, Ci-C 6 alkoxy, -NO 2 , -N(R 3 )(R 3a ), halo, -SH and mono- to per- halogenated C i -C 6 alkyl .
  • L is selected from the group consisting of
  • -Co-C 6 alkyl-C(S)-Co-C 3 alkyl- wherein when the -Co-C 6 alkyl is C 1 -C 3 alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R 3 )-C(O)-C 0 - C 3 alkyl-Y, -N(R 3 )-C(S)-C 0 -C 3 alkyl-Y, -C(O)-N(R 3 )(R 3a ), -C(S)-N(R 3 )(R 3a ), -C(O)-N(R 3 )-
  • -C 3 alkyl it is optionally substituted with a substituent selected from the group consisting of -C(O)-N(R 3 )-C 0 -C 3 alkyl-Y, -C(O)-heterocyclyl, -C(O)-N(R 3 )(R 3a ), aryl-aryl, aryl-heteroaryl, -heteroaryl-aryl, heteraryl-heteroaryl, heteroaryl, heterocyclyl-heteroaryl and heterocyclyl; -Co-C 6 alkyl-C(0)-N(R 3 )-C 0 -C 3 alkyl-, wherein when the -C 0 -C 6 alkyl is Q-Qalkyl it is optionally substituted with a substituent selected from the group consisting of -N(R 7 )(R 7a ), -N(R 3 )(R 3a ), -N(R 3 )
  • d-C 3 alkyl is optionally substituted with -C(O)N(R 3 )-C 1 -C 3 alkyl-A la and the Q-G / alkyl is optionally substituted with a substituent selected from the group consisting of -N(R 3 )-C(O)-O-C r C 3 alkyl-A lb , -N(R 3 )-C(O)-C r
  • a la and A lb are independently selected from the group consisting of alkyl, alkenyl and a protecting group; or
  • L is selected from the group consisting of -C 1 -C 6 alkyl-N(R 3 )-C 0 -C 3 alkyl-, wherein the Ci-C 6 alkyl is optionally substituted with a substituted selected from the group consisting of -C 1 -C 4 alkyl-OR a , -Cj-C 6 alkyl- N(R 3 )(R 3a )-, -C 0 -C 4 alkyl-C(O)OR 3 and -C 0 -C 3 alkyl-C(O)-N(R 3 )(R 3a ); -Co-C 6 alkyl-N(R 3 )-C(0)-C 0 -C 3 alkyl-, wherein the C r C 6 alkyl is optionally substituted with a substituent selected from the group consisting of -C !
  • L is selected from the group consisting of -Co-C 6 alkyl-N(R 3 )-C(0)-C 1 -C 7 alkyl-, wherein the d-C 7 alkyl is optionally substituted with a substituent selected from the group consisting of -N(R 7 )(R 7a ), -N(R 3 )C(O)-C 0 -C 3 alkyl- heterocyclyl, -N(R 3 )-C(O)-C 0 -C 6 alkylaryl-R a , -N(R 3 )-C(O)-C 1 -C 6 alkyl-R a and -N(R 3 )-
  • -C 3 alkyl-A la and the d-C 7 alkyl is optionally substituted with a substituent selected from the group consisting of -N(R 3 )-C(O)O-C 1 -C 3 alkyl-A lb , -N(R 3 )-C(O)-C r C 3 alkyl-A lb , -N(R 3 )-S(O) 2 -C 1 -C 3 alkyl-A lb , -N(R 3 )-C(O)-N(R 3 )-C 1 -C 3 alkyl-A lb and - N(R 3 )-S(O) 2 -N(R 3 )-d-C 3 alkyl-A lb , wherein A la and Au, are independently selected from the group consisting of alkyl, alkenyl and a protecting group; or
  • L is a selected from the group consisting of -C 0 -C 7 alkyl-N(R 3 )-C(O)-heterocyclyl-C 0 -C 6 alkyl-, wherein a Ci-C 7 alkyl is optionally substituted with -C 0 -C 3 alkyl-C(O)OR a or -d-C 3 alkyl-OR a ; and
  • B 1 , B 2 and B 3 are independently selected from the group consisting of D-GIy, L-GIy, D-Pro, L-Pro, D-Tyr, L-Tyr, D- Tyr(OR a ), L-Tyr(OR a ), D-Phe, L-Phe, D-PhCR 4 , L-PlIeR 4 , D-Aib, L-Aib, D-AIa, L-AIa, D- ProR 3 , L-ProR 3 , D-IIe, L-IIe, D-Leu, L-Leu D-PheR 3 , L-PheR 3 , D-Pip and L-Pip.
  • each alkyl, alkenyl, alkynyl, hetero- alkyl, benzyl and heterocyclyl moiety of R 7 and R 7a is independently optionally substituted with one or more substituents selected from the group consisting of oxo, -OH, -CN, C 1 -
  • each Y is independently selected from the group consisting of aromatic polycycle, non-aromatic polycycle, mixed aryl and non-aryl polycycle, polyheteroaryl, non-aromatic polyheterocycle, mixed aryl and non-aryl polyheterocycle, each of which is optionally substituted.
  • each Y is independently selected from the group consisting of aryl, aryl-aryl, heteroaryl, aryl-heteroaryl, heteroaryl-aryl, cycloalkyl, heterocyclyl and heterocyclyl -heteroaryl, each of which is optionally substituted.
  • D is , or
  • D is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • D is X In another embodiment of the present invention, D is , for example
  • X is O. In another embodiment of the present invention, X is S. In another embodiment of the present invention, R a , R and R c are independently selected from the group consisting of -H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, aryl, heteroaryl, and aryl-Ci-Csalkyl-.
  • R a and R b together with the nitrogen atom to which they are attached form a 3 to 9-membered heterocyclyl, heteroaryl, or hetero- cyclyl-aryl, wherein each of the heterocyclyl, heteroaryl and heterocyclyl-aryl is optionally substituted.
  • R 3 and R 3a are independently selected from the group consisting of -H, OH, d-C 6 alkyl, C 3 -C 6 cycloalkyl, -C(O)CF 3 , -C(O)H, -C 1 -
  • C 4 alkyl-C(O)OR a heterocyclyl, -C 2 -C 4 alkyl-OR a , C 2 -C 4 alkylene; C 2 -C 6 alkenyl, C 2 -C 6 hydroxyalkyl -Ci-C 6 alkylaryl, aryl, -Co-Qalkylheteroaryl, and -C 1 -C 3 alkyl-C(O)N(R 3 )- heteroaryl.
  • R 3 and R 3a are independently selected from the group consisting of -Q-Qalkylaryl, t-butyl, benzyl and aryl.
  • R 3 and R 3a are independently selected from the group consisting of ethanol, tetrahydro-2H-pyran, phenyl and benzyl.
  • R 3 and R 3a are independently Cj-C 4 alkyl.
  • the R 3 and the R a together with the nitrogen atom to which they are attached optionally form a ring selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, pyrrolydinyl, and azetidinyl.
  • R 4 is selected from the group consisting of -H, -CH 3 , -S(O) 2 -N(R 3 )(R 3a ), -SO 3 H, -O-C 2 -C 4 alkyl-heterocyclyl, -0-C 0 -
  • R h is -CH 3 .
  • R h is -CF 3 .
  • L is selected from the group consisting of
  • a la and An are independently selected from the group consisting of alkyl, alkenyl and protecting group, and each A is independently selected from N, CH or C (when A is attached to Y or Z), wherein there may be 0, 1 , 2 or 3 nitrogen.
  • Z is selected from the group consisting of
  • each Y is independently selected from the group consisting of
  • B ⁇ B 2 and B 3 are each independently a natural or synthetic amino acid;
  • M 3 is selected from the group consisting of M 4 is selected from the group consisting of and ⁇ ys ⁇ &ni bonc
  • M 4 is ⁇ ⁇ - ⁇ * ⁇ - ⁇
  • D 1 -D 2 is selected from the group consisting of a
  • D 3 is selected from the group consisting of a covalent bond, ⁇ wherein the are optionally substituted
  • D 4 is selected from the group consisting of ;
  • E 1 -E 2 is selected from the group consisting of
  • R 6 is selected from the group consisting of -H, -CrCgalkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -CrC ⁇ heteroalkyl, heterocyclyl-Co-C ⁇ alkyl-, aryl-Co-C 6 alkyl-, heteroaryl-C 0 -C 6 alkyl-, C 3 - C 6 cycloalkyl-C 0 -C 6 alkyl-, N(R 3 )(R 3a )-C 1 -C 6 alkyl-, N(R 3 )(R 3a )-C(O)-C r C 6 alkyl- and N(R 3 )(R 3a )-C(S)-C 1 -C 6 alkyl-, wherein each alkyl, alkenyl, alkynyl, heteoralkyl, cycloalkyl, aryl, heteroaryl, or
  • each alkyl, alkenyl, alkynyl, heteoralkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl moiety of R 6 is independently optionally substituted with one or more groups independently selected from R 4 .
  • R 6 is selected from the group consisting of
  • R 7 is selected from the group consisting of -H, optionally substituted C 1 -C 6 alkyl, -(CH 2 ) 2-4 OR a , -OMe, -(CH 2 ) 2- 4 N(R 3 )(R 3a ), -C(O)Ot-butyl, -C(O)O-benzyl, -(CH 2 ) 2 -morpholinyl and -(CH 2 ) 2 - ⁇ iperazynnyl.
  • R a and R c are -H;
  • R b is -O-alkyl-aryl or -O-alkyl-heteroaryl, wherein said alkyl, aryl and heteroaryl moieties are optionally substituted;
  • Z is -C 1 -C 8 alkyl-;
  • L is covalent bond, -C 0 -C 6 alkyl-N(R 3 )C(O)-C 0 -C 3 alkyl-, -C 0 -C 6 alkyl-N(R 3 )C(S)-C 0 -C 3 alkyl-, -C 0 -C 6 alkyl-C(O)N(R 3 )-C 0 -C 3 alkyl- or -C 0 -C 6 alkyl-C(S)N(R 3 )-C 0 -C 3 alkyl-,; and
  • Y is selected from the group consisting of alkyl, aryl, heteroaryl, aryl-aryl, heteroaryl-aryl-, aryl-heteroaryl- and polycycle, wherein each alkyl, aryl, heteroaryl and polycycle group is optionally substituted.
  • the alkyl, aryl, heteroaryl and polycycle groups are optionally substituted with aryl-C 0 -C 6 alkyl-O-, heteroaryl-Co- C 6 alkyl-O-, heteroaryl-O- or aryl-, said aryl-Co-C ⁇ alkyl-O, heteroaryl-Co-C ⁇ alkyl-O-, heteroaryl-O- or aryl- groups being further optionally substituted, for example with a substituent selected from the group consisting of halo, hydroxy, xyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, C ! -C 6 alkyl and alkoxy.
  • L is -C 0 -C 6 alkyl-N(R 3 )C(O)-C 0 -C 3 alkyl- or -C 0 -C 6 alkyl-N(R 3 )C(S)-C 0 -C 3 alkyl-.
  • W is nitrogen
  • R c is -H;
  • R h is -Co-Cealkyl-O-Co-Cealkyl-aryl or -Co-Cealkyl-O-Co-Cealkyl-heteroaryl, wherein the alkyl, aryl and heteroaryl moieties are optionally substituted;
  • Z is -Ci-C 8 alkyl-
  • L is covalent bond, -C 0 -C 6 alkyl-N(R 3 )C(O)-C 0 -C 3 alkyl or -C 0 -C 6 alkyl-C(O)N(R 3 )-C 0 -C 3 alkyl; and Y is selected from the group consisting of alkyl, aryl, heteroaryl, aryl-aryl, heteroaryl-aryl-, aryl-heteroaryl- and polycycle, wherein each alkyl, aryl, heteroaryl and polycycle group is optionally substituted.
  • the alkyl, aryl, heteroaryl and polycycle groups are optionally substituted with aryl-Co-C 6 alkyl-0-, heteroaryl-C 0 - C 6 alkyl-O, heteroaryl-O- or aryl-, said aryl-C 0 -C 6 alkyl-O-, heteroaryl-C 0 -C 6 alkyl-O-, heteroaryl-O- or aryl- groups being further optionally substituted, for example with a substituent selected from the group consisting of halo, hydroxy, xyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, Ci-C ⁇ alkyl and alkoxy.
  • L is -C 0 -C 6 alkyl-N(R 3 )C(O)-C 0 -C 3 alkyl.
  • the compounds are represented by the formula (II): or an N-oxide, hydrate, solvate, pharmaceutically acceptable salt, prodrug or complex thereof, and racemic and scalemic mixtures, diastereomers and enantiomers thereof, wherein R is selected from the group consisting of:
  • D is selected from the group consisting of
  • R 1 is an optional substituent and nl is 0-4.
  • D is ; W is nitrogen or oxygen; M is nitrogen; R a , R b and R c are -H; Z is -Ci-C 8 alkyl- or -C 1 -C 8 alkyl-C(O)-; L is -C 0 -C 6 alkyl-N(R 3 )C(O)-C 0 -C 3 alkyl; and Y is alkyl, aryl, heteroaryl, heteroaryl-aryl or aryl-heteroaryl, wherein the alkyl, aryl and heteroaryl groups are optionally substituted.
  • the alkyl, aryl and heteroaryl groups are optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, aryl, -O-alkyl-heteroaryl and -O-alkyl-aryl.
  • a substituent selected from the group consisting of alkoxy, alkyl, aryl, -O-alkyl-heteroaryl and -O-alkyl-aryl.
  • W is nitrogen or oxygen; R c is -H;
  • R h is H or -C ! -C 6 alkyl, wherein said alkyl is optionally substituted;
  • Z is -Cj-C 8 alkyl- or -C 1 -C 8 alkyl-C(O)-;
  • L is -C 0 -C 6 alkyl-N(R 3 )C(O)-C 0 -C 3 alkyl;
  • Y is alkyl, aryl, heteroaryl, heteroaryl-aryl or aryl-heteroaryl, wherein the alkyl, aryl and heteroaryl groups are optionally substituted.
  • the alkyl, aryl and heteroaryl groups are optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, aryl, -O-alkyl-heteroaryl and -O-alkyl-aryl.
  • R a , R b and R c are -H
  • R 3 is -H or Ci-C ⁇ alkyl; Z is optionally substituted -C 1 -C 8 alkyl-;
  • L is selected from the group consisting of
  • B 1 , B and B are independently
  • R h is H or -CrC 6 alkyl, wherein said alkyl is optionally substituted;
  • R 3 is -H or Ci-C ⁇ alkyl;
  • Z is optionally substituted -Ci-C 8 alkyl-
  • L is selected from the group consisting of
  • each heteroaryl or aryl moiety is optionally substituted; -C 0 -C 6 alkyl-heteroalkyl-C 0 -C 6 alkyl-C(O)-N(R 3 )-C 0 -C 3 alkyl-, wherein when the C 0 -C 3 alkyl is C 1 -C 3 alkyl, the C 1 -C 3 alkyl is optionally substituted with heteroaryl, -N(R 3 )(R 3a ) or -N(R 3 )- Y; and
  • each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-O-, aryl-N(R 3 )-C(O)-hetero- aryl, heteroaryl-N(R 3 )-C(O)-heteroaryl, aryl-N(R 3 )-C(O)-aryl, heterocyclyl-C 0 -C 6 alkyl-
  • B , B 2 and B 3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe-
  • R a , R b and R c are -H
  • R 3 is -H or C 1 -QaIkVl; Z is optionally substituted -C 1 -C 8 alkyl-;
  • L is selected from the group consisting of
  • B 1 , B 2 and B 3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe- 4-CF 3 .
  • R h is H or -d-Qalkyl, wherein said alkyl is optionally substituted;
  • R 3 is -H or d-Cealkyl;
  • Z is optionally substituted -C 1 -C 8 alkyl-;
  • L is selected from the group consisting of
  • W and M are nitrogen;
  • R a , R b and R c are -H;
  • R 3 is -H or Ci-C 6 alkyl;
  • Z is optionally substituted -C 1 -C 8 alkyl-;
  • L is
  • each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, ary
  • B , B and B are independently selected from the group consisting of D-Pro, L-ile and D-Phe- 4-CF 3 .
  • W is nitrogen
  • R c is -H
  • R h is H or -Q-Qalkyl, wherein said alkyl is optionally substituted;
  • R 3 is -H or Q-C 6 alkyl;
  • Z is optionally substituted -C 1 -C 8 alkyl-
  • each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-O-, aryl-N(R 3 )-C(O)-heteroaryl, heteroaryl-N(R 3 )-C(O)-heteroaryl, aryl-N(R 3 )-C(O)-aryl, heterocyclyl-C 0 -C 6 alkyl-N(R 3 )- C(O)-heteroaryl and B 2 -B 1 -N(R 3 )-C(O)-C 1 -C 7 alkyl-, wherein the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl groups are optionally substituted and the C 1 -C 7 alkyl-, wherein the cycloalkyl, aryl, heteroaryl, heterocyclyl and
  • Z and L are covalent bonds; wherein when any of B 1 , B 2 and B 3 are attached together, they are attached by a peptide bond, and B 1 ,
  • B and B are independently selected from the group consisting of D-Pro, L-ile and D-Phe- 4-CF 3 .
  • R a , R b and R c are -H
  • R 3 is -H or Cj-C 6 alkyl
  • Z is optionally substituted -C 1 -C 8 alkyl-;
  • L is -C 0 -C 6 alkyl-N(R 3 )C(O)-C 0 -C 3 alkyl-, wherein when the C 0 -C 3 alkyl is d-C 3 alkyl, the C 1 -C 3 alkyl is optionally substituted with -N(R 3 )-C(O)-O-C 0 -C 3 alkyl-Y, -NH 2 , -NH-S(O) 2 -Y, -NH-C(O)-NH-C 0 -C 3 alkyl-Y, -NH-heteroaryl-aryl, -N(R 3 )C(O)-C 0 -C 3 alkyl-Y.
  • each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-O-, aryl-N(R 3 )-C(O)-heteroaryl, heteroaryl-N(R 3 )-C(O)-heteroaryl, aryl-N(R 3 )-C(O)-aryl, heterocyclyl-C 0 -C 6 alkyl-N(R 3 )- C(O)-heteroaryl and B 2 -B !
  • cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl groups are optionally substituted with one, two or three (alternatively one or two, alternatively one) substituents selected from the group consisting of halo, alkoxy, optionally substituted CrC 6 alkyl, alkoxycarbonyl-, -OH, -CN, -C(O)-OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-Q-C ⁇ alkyl-aryl, optionally substitued -C(O)-O-Ci-C 6 alkyl, -NH 2 , optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C 1 -C 7 alkyl is optionally substituted with -NR 3 -
  • W is nitrogen
  • R c is -H;
  • R h is H or -C ! -C 6 alkyl, wherein said alkyl is optionally substituted;
  • R 3 is -H or Ci-C 6 alkyl
  • Z is optionally substituted -C 1 -C 8 alkyl-
  • Ci-C 3 alkyl is optionally substituted with -N(R 3 )-C(O)-O-C 0 -C 3 alkyl-Y, -NH 2 , -NH-S(O) 2 -Y,
  • each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-O-, aryl-N(R 3 )-C(O)-heteroaryl, heteroaryl-N(R 3 )-C(O)-heteroaryl, aryl-N(R 3 )-C(O)-aryl, heterocyclyl-C 0 -C 6 alkyl-N(R 3 )- C(O)-heteroaryl and B 2 -B 1 -N(
  • substituents selected from the group consisting of halo, alkoxy, optionally substituted Ci-C ⁇ alkyl, alkoxycarbonyl-, -OH, -CN, -C(O)-OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-Q-Qalkyl-aryl, optionally substitued -C(O)-O-C i-C ⁇ alkyl, -NH 2 , optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C 1 -C 7 alkyl is optionally substituted with -NR 3 -B 3 and the amine of B 3 is conected with the acid of B 2 to form a peptide bond, and wherein when Y is B 2 -B 1 -N(R 3 )-C(O)-C 1 - C 7 alkyl
  • D is ; W and M are nitrogen; R a , R b and R c are -H; R 3 is -H; R 4 is H or F;
  • Z is optionally substituted -Ci-C 8 alkyl-;
  • L is selected from the group consisting of
  • each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, hetero- aryl-aryl, aryl-heteroaryl and B 2 -B 1 -N(R 3 )-C(O)-C 1 -C 7 alkyl-, wherein the aryl and heteroaryl are optionally substituted, and the C 1 -C 7 alkyl is optionally substituted with -NR 3 -B 3
  • R h is H or -Ci-C ⁇ alkyl, wherein said alkyl is optionally substituted;
  • R 3 is -H
  • R 4 is H or F
  • Z is optionally substituted -C 1 -C 8 alkyl-;
  • L is selected from the group consisting of
  • each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl and B 2 -B 1 -N(R 3 )-C(O)-C 1 -C 7 alkyl-, wherein the aryl and heteroaryl are optionally substituted, and the C 1 -C 7 alkyl is optionally substituted with -NR 3 -B 3 and the amine of B is conected with the acid of
  • W and M are nitrogen; R a , R b and R° are -H;
  • R 3 is -H
  • R 4 is H or F
  • Z is optionally substituted -C 1 -C 8 alkyl-
  • L is selected from the group consisting of -C 0 -C 6 alkyl-C(O)-N(R 3 )-C 0 -C 3 alkyl-, wherein when the C 0 -C 3 alkyl is d-C 3 alkyl, the C 1 -C 3 alkyl is optionally substituted with -C(0)-N(R 3 )-Co-C 3 alkyl-Y, -heteroaryl-aryl, hetero- aryl, -N(R 3 )(R 3a ) or -N(R 3 )-Y;
  • each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, hetero- aryl-aryl, aryl-heteroaryl and B 2 -B 1 -N(R 3 )-C(O)-C 1 -C 7 alkyl-, wherein the aryl and heteroaryl groups are optionally substituted with one, two or three (alternatively one or two, alternatively one) substituents selected from the group consisting of halo, alkoxy, optional
  • W is nitrogen
  • R c is -H;
  • R h is H or -Ci-C 6 alkyl, wherein said alkyl is optionally substituted;
  • R 3 is -H
  • R 4 is H or F
  • Z is optionally substituted -C 1 -C 8 alkyl-
  • L is selected from the group consisting of -C 0 -C 6 alkyl-C(O)-N(R 3 )-C 0 -C 3 alkyl-, wherein when the C 0 -C 3 alkyl is d-C 3 alkyl, the C 1 -C 3 alkyl is optionally substituted with -C(O)-N(R 3 )-C 0 -C 3 alkyl-Y, -heteroaryl-aryl, hetero- aryl, -N(R 3 )(R 3a ) or -N(R 3 )-Y;
  • each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, hetero- aryl-aryl, aryl-heteroaryl and B 2 -B 1 -N(R 3 )-C(O)-Ci-C 7 alkyl-, wherein the aryl and heteroaryl groups are optionally substituted with one, two or three (alternatively one or two, alternatively one) substituents selected from the group consisting of halo, alkoxy, optionally
  • Ci-C 7 alkyl is optionally substituted with -NR 3 -B 3 and the amine of B 3 is conected with the acid of B 2 to form a peptide bond
  • Y is B 2 -B 1 -N(R 3 )-C(O)-C 1 - C 7 alkyl-
  • Z and L are covalent bonds; wherein when any of B 1 , B 2 and B 3 are attached together, they are attached by a peptide bond, and B 1 , B 2 and B 3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe- 4-CF 3 .
  • R a , R b and R c are -H; R 3 is -H;
  • R 4 is H or F
  • Z is optionally substituted -C 1 -C 8 alkyl-
  • each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, hetero- aryl-aryl, aryl -heteroaryl and B 2 -B 1 -N(R 3 )-C(O)-C 1 -C 7 alkyl-, wherein the aryl and heteroaryl groups are optionally substituted, and the C 1 -C 7 alkyl is optionally substituted with - NR 3 -B 3 and the amine of B 3 is
  • B , B and B are independently selected from the group consisting of D-Pro, L-ile and D- Phe-4-CF 3 .
  • W is nitrogen;
  • R c is -H;
  • R h is H or -Q-Qalkyl, wherein said alkyl is optionally substituted;
  • R 3 is -H;
  • R 4 is H or F;
  • Z is optionally substituted -C 1 -C 8 alkyl-;
  • L is -C 0 -C 6 alkyl-N(R 3 )C(O)-C 0 -C 3 alkyl-, wherein when the C 0 -C 3 alkyl is Ci-C 3 alkyl, the C 1 -C 3 alkyl is optionally substituted with -N(R 3 )C(O)-C 0 -C 3 alkyl-Y, -N(R 3 )(R 3a ) or -N(R 3 )-Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, hetero-
  • NR 3 -B 3 and the amine of B is conected with the acid of B 2 to form a peptide bond, and wherein when Y is B ⁇ B 1 -N(R 3 ⁇ C(O)-C 1 -C 7 alkyl-, then Z and L are covalent bonds; wherein when any of B 1 , B 2 and B 3 are attached together, they are attached by a peptide bond, and B 1 , B and B 3 are independently selected from the group consisting of D-Pro, L-ile and D- Phe-4-CF 3 .
  • W and M are nitrogen;
  • R a , R b and R c are -H;
  • R 3 is -H;
  • R 4 is H or F;
  • Z is optionally substituted -C 1 -C 8 alkyl-;
  • L is -C 0 -C 6 alkyl-N(R 3 )C(O)-C 0 -C 3 alkyl-, wherein when the C 0 -C 3 alkyl is d-C 3 alkyl, the C 1 -C 3 alkyl is optionally substituted with -N(R 3 )C(O)-C 0 -C 3 alkyl-Y, -N(R 3 )(R 3a ) or -N(R 3 )-Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, hetero- aryl-aryl, aryl-heteroaryl and B 2 -B 1 -N(R 3 )-C(O)-C 1 -C 7 alkyl-, wherein the aryl and hetero- aryl groups are optionally substituted with one, two or three (alternative
  • B 1 , B 2 and B 3 are independently selected from the group consisting of D-Pro, L-ile and D-
  • W is nitrogen
  • R c is -H
  • R h is H or -CrC ⁇ alkyl, wherein said alkyl is optionally substituted;
  • R 3 is -H;
  • R 4 is H or F
  • Z is optionally substituted -C 1 -C 8 alkyl-
  • each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, hetero- aryl-aryl, aryl -heteroaryl and B 2 -B 1 -N(R 3 )-C(O)-C 1 -C 7 alkyl-, wherein the aryl and heteroaryl groups are optionally substituted with one, two or three (alternatively one or two, alternatively one) substituents selected from the group consisting of halo, al
  • a substituent selected from the group consisting of optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-Q-C ⁇ alkyl-aryl, optionally substituted -C(O)-O-C i-C ⁇ alkyl, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle is itself further optionally substituted on an alkyl, aryl, heteroaryl or heterocylclyl moiety with a substituent selected from the group consisting of -0-C 1 - Qalkyl-alkoxy, -CF 3 , -O-aryl, alkoxy, -NH-C(O)-C i-C 6 alkyl, halogen, C r C 6 alkyl, -O-(halo substituted alkyl) and -O-alkyl-N(alkyl) 2 .
  • each Y is independently selected from the group consisting of alkyl, aryl, aryl-aryl, heteroaryl, aryl-heteroaryl, heteroaryl-aryl, cycloalkyl, heterocyclyl and heterocyclyl-heteroaryl, each of which is optionally substituted;
  • L is selected from the group consisting of
  • W is nitrogen
  • R c is -H; X is S;
  • R h is -d-C 6 alkyl or -d-C ⁇ alkyl-phenyl, wherein said alkyl and phenyl are optionally independently substituted;
  • Z is optionally substituted -C 3 -C 8 alkyl- (for example -C 4 alkyl-);
  • L is -N(H)-C(O)-C 1 alkyl-, wherein the dalkyl is substituted with -N(H)-C(O)- 0-C 1 -C 6 alkyl-phenyl or -N(H)-C(O)-O-C 1 -C 6 alkyl;
  • Y is aryl-heteroaryl- or heteroaryl-, each of which is optionally substituted.
  • Y is phenyl-thiazolyl, thiazole or imidazole.
  • Z is -C 4 alkyl-.
  • R is -d-C 6 alkyl or -C i-C ⁇ alkyl -phenyl, wherein said alkyl and phenyl are optionally independently substituted;
  • Z is optionally substituted -C 3 -C 8 alkyl- (for example -C 4 alkyl-);
  • L is -dalkyl-, substituted with a substituent selected from the group consisting of -N(H)-C(O)-O-C 1 -C 6 alkyl-phenyl, -N(H)-C(O)-O-C 1 -C 6 alkyl, -NH-C(O)-hetero- cyclyl-d-Cealkyl and -NH-C(O)-C 1 -C 6 alkyl-SO 2 -C 1 -C 6 alkyl; and Y is heteroaryl-, which is optionally substituted.
  • Y is optionally substituted benzimidazole. In certain other embodiments, Y is benzimidazole substituted with -NO 2 or -C(O)-NH 2 . In certain other embodiments, Z is -C 4 alkyl-.
  • R a is H
  • R b is phenyl or Ci-C 6 alkyl
  • Z is optionally substituted -C 3 -C 8 alkyl- (for example -C 4 alkyl-);
  • L is -N(H)-C(O)-C ⁇ IlCyI-, wherein the Qalkyl is substituted with -N(H)-C(O)- O-d-Cealkyl-phenyl;
  • Y is aryl-heteroaryl-, which is optionally substituted, hi certain other embodiments, Y is optionally substituted phenyl-thiazolyl-.
  • D is ; W is nitrogen;
  • R c is -H; X is S;
  • M is nitrogen;
  • R a is H;
  • R b is phenyl or C i -C 6 alkyl ;
  • Z is optionally substituted -C 3 -C 8 alkyl- (for example -C 4 alkyl-);
  • L is -Cialkyl- substituted with -N(H)-C(O)-O-CrC 6 alkyl-phenyl, -N(H)-C(O)- O-d-C ⁇ alkyl and -NH-C(O)-C 1 -C 3 alkyl-SO 2 -C 1 -C 3 alkyl;
  • Y is optionally substituted benimidazole.
  • Z is -C 4 alkyl-.
  • Y is substituted with -C(O)-NH 2 .
  • Y is further selected from optionally substituted aryl-heteroaryl, for example naphthylene-triazole.
  • the invention provides compounds of the formula (III):
  • D is selected from the group consisting of
  • R b and R h are independently selected from the group consisting of -C 1-6 alkyl, -C 6-10 aryl and -Ci.Cealkyl-Q.Cearyl;
  • L is selected from the group consisting of -C 0-6 alkylene-, -C 0-3 alkylene-N(H)- C(O)-C 0-6 alkylene-, optionally substituted with 0-3 R 4 ;
  • Y is selected from the group consisting of optionally substituted -C 6-1O aryl and optionally substituted -5-10 membered heteroaryl;
  • R 4 is selected from the group consisting of -N(H)-C(O)-R 3 and -N(H)-C(O)-O-R 3 ;
  • R 3 is selected from the group consisting of optionally substituted -C 1-6 alkyl, -C 1-6 heteroalkyl, -3-10 membered heterocyclyl and -C 7-16 alkylaryl.
  • a substituent selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl is itself further optionally substituted with a substituent selected from the group consisting of -O-d-Cealkyl-alkoxy, -CF 3 , -O-aryl, alkoxy, -NH-C(O)-C 1 -C 6 alkyl, halogen, C r C 6 alkyl, -O- (halo substituted alkyl) and -O-alkyl-N(alkyl) 2 .
  • Y is further selected from heterocyclyl. In another embodiment according to the present invention, Y is further selected from heterocyclyl.
  • L is -C 0 -C 6 alkyl-C(O)-N(R 3 )-C 0 -C 3 alkyl-, wherein when the C 0 -C 3 alkyl is Q-Qalkyl, the C 1 -C 3 alkyl is optionally substituted with aryl, heteroaryl, -heteroaryl-aryl, -aryl-hetero- aryl, -aryl-aryl or heteroaryl-heteroaryl, wherein each heteroaryl or aryl moeity is optionally substituted; and Y is aryl or heteroaryl, each of which is optionally substituted.
  • L is -C 0 -C 6 alkyl-0-C 0 -C 1 alkyl-C(0)-N(R 3 )-Co-C 3 alkyl-, wherein when the C 0 -C 3 alkyl is C 1 - C 3 alkyl, the C 1 -C 3 alkyl is optionally substituted with -heteroaryl-aryl, -heteroaryl-heteroaryl, heteroaryl, -heteroaryl-heterocylcyl, wherein each heteroaryl and aryl moeity is optionally substituted; and
  • Y is optionally substituted aryl.
  • the C 1 -C 3 alkyl is optionally substituted with -heteroaryl-aryl, -heteroaryl-heteroaryl, heteroaryl, -heteroaryl-heterocylcyl, wherein each heteroaryl and aryl moeity is further optionally substituted with 1 to 3 of optionally substituted aryl, alkoxy, -N(alkyl) 2 , halogen, alkyl, fused heterocyclyl, -CF 3 , optionally substituted heterocyclyl, -0-C 1 - C 6 alkyl-N(alkyl) 2 , -O-C r C 6 alkyl-NH2 and -NH-aryl.
  • L is -C 0 -C 6 alkyl-C(O)-N(R 3 )-C 0 -C 3 alkyl-, wherein when the C 0 -C 3 alkyl is C r C 3 alkyl, the C 1 -C 3 alkyl is optionally substituted with -C(O)-N(R 3 )-C 0 -C 3 alkyl-heteroaryl, -C(O)-
  • Y is H, optionally substituted aryl or optionally substituted heterocyclyl.
  • Y is optionally substituted heteroaryl.
  • Y is optionally substituted aryl or optionally substituted heteroaryl, wherein each heteroaryl or aryl moeity is optionally substituted with 1 or 2 independently selected halogen, alkyl or alkoxy.
  • L is -Co-C 6 alkyl-0-C 0 -C 1 alkyl-C(0)-N(R 3 )-Co-C 3 alkyl-, wherein when the C 0 -C 3 alkyl is C 1 - C 3 alkyl, the C 1 -C 3 alkyl is optionally substituted with -C(O)-N(R 3 )-C 0 -C 3 alkyl-hetero- cyclyl or -C(O)-N(R 3 )-C 0 -C 3 alkyl-aryl, wherein each heterocyclyl or aryl moeity is optionally substituted; and Y is optionally substituted aryl or optionally substituted heteroaryl.
  • Y is optionally substituted aryl.
  • -C(0)-N(R 3 )-Co-C 3 alkyl- heterocyclyl is -C(O)-N(R 3 )-C 0 -C 3 alkyl-heteroaryl.
  • Y-L- is phenyl-CH 2 -O-
  • L is -C 0 -C 6 alkyl-O-C 0 -C 1 alkyl-C(O)-N(R 3 )-C 0 -C 3 alkyl-, wherein when the C 0 -C 3 alkyl is C 1 -
  • the C 1 -C 3 alkyl is optionally substituted with -C(O)-N(R 3 )-C 0 -C 3 alkyl-heteroaryl or -C(O)-N(R 3 )-C 0 -C 3 alkyl-aryl, wherein each heteroaryl or aryl moeity is optionally substituted with 1 to 3 independent substituents selected from the group consisting of halogen, -OH, -NH 2 , alkyl, -C(O)-OH, -C(O)-O-alkyl, -C(O)-NH-optionally substituted aryl, -C(O)-NH-o ⁇ tionally substituted heteroaryl, -C(O)-NH-alkyl-O-alkyl, -C(O)-NH- alkyl-heterocyclyl, -alkyl-optionally substituted aryl, alkoxy, optionally substituted aryl,
  • substituents selected from the group consisting of -C(O)-NH-optionally substituted aryl, -C(O)-NH- optionally substituted heteroaryl, -alkyl-optionally substituted aryl, optionally substituted aryl and optionally substituted heteroaryl are optionally substituted with 1 or 2 independently selected substituents selected from the group consisting of halogen, alkoxy, alkyl, -O-aryl,
  • L is phenyl-CH 2 -O-C(O)-
  • L is phenyl-CH 2 -O-C(O)-NH-C 1 -C 3 alkyl-, wherein the C 1 -C 3 alkyl is substituted with -C(O)- NH-thiazolyl, wherein the thiazolyl is optionally substituted with 1 or 2 independently selected substituents selected from the group consisting of optionally substituted aryl, alkyl, -C(O)-O-alkyl, -C(O)-OH, -C(O)-NH-optionally substituted aryl, -C(O)-NH- optionally substituted heteroaryl, -C(O)-NH-alkyl-O-alkyl, -C(O)-NH-alkyl-heterocyclyl, fused optionally substituted cycloalkyl, fused optionally substituted heterocyclyl and fused optionally substituted aryl.
  • L is -Co-C 6 alkyl-N(R 3 )-C(0)-N(R 3 )-C 0 -C 3 alkyl-, wherein when the C 0 -C 3 alkyl is d-C 3 alkyl, the C 1 -C 3 alkyl is optionally substituted with -C(O)-N(R 3 )-C 0 -C 3 alkyl-heteroaryl-aryl, -C(O)-N(R 3 )-C 0 -C 3 alkyl-heteroaryl, or -C(O)-N(R 3 )-C 0 -C 3 alkyl-aryl, wherein each heteroaryl or aryl moeity is optionally substituted; and
  • Y is optionally substituted aryl, optionally substituted heterocyclyl or optionally substituted cycloalkyl.
  • Y is an optionally substituted heteroaryl.
  • L is -C 0 -C 6 alkyl-0-C 0 -C 3 alkyl-C(0)-N(R 3 )-Co-C 3 alkyl-, wherein when a C 0 -C 3 alkyl is C 1 - C 3 alkyl, the C 1 -C 3 alkyl is optionally substituted with -C(O)-N(R 3 )-C 0 -C 3 alkyl-heteroaryl,
  • W is further selected from O.
  • the compounds of the invention can be prepared according to the reaction schemes for the examples illustrated below utilizing methods known to one of ordinary skill in the art. These schemes serve to exemplify some procedures that can be used to make the compounds of the invention. One skilled in the art will recognize that other general synthetic procedures may be used.
  • the compounds of the invention can be prepared from starting components that are commercially available. Any kind of substitutions can be made to the starting components to obtain the compounds of the invention according to procedures that are well known to those skilled in the art.
  • Step 1 (S)-2-(benzyloxycarbonylamino)-6-(tert-butoxycarbonylamino)hexanoic acid N-(4- phenylthiazol-2-yl)amide (1)
  • Step 3 (S)-benzyl l-oxo-l-(4-phenylthiazol-2-ylamino)-6-thioureidohexan-2-ylcarbamate (3)
  • dichloromethane 1.0 mL
  • thiophosgene 23 uL, 0.30 mmol
  • the mixture was stirred at 0°C for Ih.
  • a solution of ammonia in methanol 0.2 mL of 7N solution, 1.4 mmol was added dropwise. The mixture was stirred at room temperature for 2 days.
  • Step 1 (S)-benzyl 6-acetamido-l-oxo-l-(4-phenylthiazol-2-ylamino)hexan-2-ylcarbamate (4) To amine 2 (88 mg, 0.20 mmol) in tetrahydrofuran (2 mL) at 0°C was added triethylamine (84 uL, 0.60 mmol) followed by acetyl chloride (15 uL, 0.20 mmol) and the mixture was stirred at 0°C for Ih.
  • Step 1 (S)-2-(benzyloxycarbonylamino)-6-(tert-butoxycarbonylamino)hexanoic acid N-
  • Step 2 (S)-benzyl 6-amino-l-oxo-l-(phenylamino)hexan-2-yl carbamate (7)
  • Step 3 (S)-benzyl 6-ethanethioamido-l-oxo-l-(phenylamino)hexan-2-yl carbamate (8)
  • Step 1 (S)-6-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-(tert- butoxycarbonylamino)hexanoic acid N-(4-phenylthiazol-2-yl)amide (16)
  • Step 3 (S)-tert-butyl 6-ethanethioamido-l-oxo-l-(4-phenylthiazol-2-ylamino)hexan-2- ylcarbamate (18)
  • Title compound 18 (34 mg, 54%) was obtained as a white solid by following the general procedure G except using 17 (55 mg, 0.14 mmol) as starting material.
  • Step 1 (S)-tert-butyl l-oxo-l-(4-phenylthiazol-2-ylamino)-6-thioureidohexan-2-ylcarbamate (19)
  • Step 1 (S)-tert-butyl 7-bromo-6-oxo-5-(benzyloxycarbonylaniino)heptylcarbamate (34) Ethyl chloro formate (0.505 mL, 5.26 mmol) was added to a solution of Z-lys(Boc)-
  • Step 2 (S)-benzyl 5-(t-butoxycarbonylamino)-l-(2-(phenylamino)thiazol-4- yl)pentylcarbamate (35)
  • a solution of 34 (0.200 g, 0.437 mmol) and phenyl thiourea (73.2 mg, 0.481 mmol) in ethanol (1.74 mL) was stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by silica gel chromatography with EtOAc (20-50%) in hexane to afford 35 (0.106 g, 47%) as a white solid.
  • Triethylamine (58.4 ⁇ l, 0.419 mmol) and ethyl dithioacetate (36.1 ⁇ L, 0.314 mmol) were added to a solution of 36 (86.0 mg, 0.209 mmol) in THF (838 ⁇ L) at 0 °C and the reaction was stirred for 16 h.
  • the mixture was diluted with 10% HCl in water and extracted with EtOAc (3x), and the organic extracts were dried (Na 2 SO 4 ), filtered and evaporated and the residue was purified by silica gel chromatography with EtOAc (40-80%) in hexane to afford 37 (24.5 mg, 25%) as a white solid.
  • Step 1 (S)-benzyl 5-(t-butoxycarbonylamino)l-(2-phenyl-lH-imidazol-4-yl)pentylcarbamate
  • Step 2 (S)-benzyl 5-ethanethioamido- 1 -(2 -phenyl- lH-imidazol-4-yl)pentylcarbamate (39)
  • Compound 38 (0.107 g, 0.224 mmol) was treated with a 25% solution of TFA/ DCM (1 mL) as described in the general procedure B, and the crude amine was obtained as a yellow foam (51 mg, 60%).
  • Step 1 (S)-methyl 2-(benzyloxycarbonylamino)-6-ethanethioamidohexanoate (40)
  • Step 4 (S)-benzyl 5-ethanethioamido-l-(5-phenyl-lH-imidazol-2-yl)pentylcarbamate (43)
  • ammonium acetate 787 mg, 10.21 mmol
  • Saturated Na 2 CO 3 solution was added and the mixture was extracted with EtOAc and the extracts were dried over MgSO 4 , filtrated and concentrated and the residue was purified by prep-HPLC (Aquasil C 18, 5-95%MeOH/H 2 O) to afford 43 as white solid (29 mg, 16.3%).
  • Step 3 (S)-benzyl 5-(t-butoxycarbonylamino)-l-(5-(trifluoromethyl)-lH-imidazol-2- yl)pentylcarbamate (54)
  • Step 2 (S)-benzyl 5-(t-butoxycarbonylamino)-l-(4,5-dibromo-lH-imidazol-2- yl)pentylcarbamate (57)
  • NBS 56.9 mg, 0.320 mmol
  • the resulting solution was allowed to warp up to room temperature and was stirred for 16h, the mixture was cooled to 0 °C and more NBS (56.9 mg, 0.320 mmol) was added and after 30 minutes at 0 °C the reaction was complete.
  • Step 3 (S)-benzyl 5-(t-butoxycarbonylamino)-l-(4-bromo-lH-imidazol-2- yl)pentylcarbamate (58) To a stirred solution of 57 (150 mg, 0.268 mmol) in dioxane (2.142 mL) and
  • Step 2 (S)-tert-butyl l-(5-(lH-indol-3-yl)-lH-imidazol-2-yl)-5-aminopentylcarbamate (61) To 60 (147 mg, 0.284 mmol) in MeOH (1.9 mL) at room temperature was added Pd/C
  • Triphosgene (0.036 mL, 0.469 mmol) was added to a solution of 61 (120 mg, 0.313 mmol) in THF (1.565 mL) and Et3N (0.065 mL, 0.469 mmol) at 0 °C. The mixture was stirred for Ih, then methylamine 33% in EtOH (0.390 mL, 3.13 mmol) was added, and the reaction was allowed to warp up to room temperature and stirred for 2h.
  • Step 1 (S)-benzyl 6-(t-butoxycarbonylamino)-l-(2-aminophenylamino)-l-oxohexan-2- ylcarbamate (66)
  • Step 2 (S)-benzyl 5-(t-butoxycarbonylamino)-l-(lH-benzo[d]imidazol-2-yl)pentylcarbamate
  • Step 3 (S)-benzyl 5-amino-l-(lH-benzo[d]imidazol-2-yl)pentylcarbamate (68) To a stirred solution of 67 (322 mg, 0.712 mmol) in CH2C12 (2.372 mL) at room temperature was added TFA (1.096 mL, 14.23 mmol) as described in general procedure B.
  • Step 4 (S)-benzyl l-(lH-benzo[d]imidazol-2-yl)-5-(3-methylthioureido)pentylcarbamate (69)
  • Step3 (S)-N-(5-amino-5-(6-(4-fluorophenyl)- 1 H-benzo[d]imidazol-2- yl)pentyl)ethanethioamide (72)
  • Amide 71 (5.315 g, 10.88 mmol) in AcOH (27.2 ml) was heated at 60 °C for Ih as described in general procedure X.
  • the benzimidazole was obtained as a light brown solid (4.442g, 87%).
  • Step 4 (S)-N-(5-ethanethioamido- 1 -(6-(4-fluorophenyl)- 1 H-benzo[d]imidazol-2-yl)pentyl)- 2,2,2-trifluoroacetamide (73)
  • Trifluoroacetic anhydride (0.056 mL, 0.4 mmol) was added dropwise to a solution of 72 (148 mg, 0.4 mmol) and Et3N (0.139 mL, 1.0 mmol) in THF (1.6 mL) at 0 °C and the resulting solution was allowed to stir for 16h at room temperature. A solution of saturated NaHCO 3 was added and the mixture was extracted with EtOAc and the extracts were dried over MgSO 4 , filtrated and concentrated and the residue was purified by chromatography with EtOAc (20% to 100%) in hexane to afford 73 (53 mg, 28.4%) as a yellow solid.
  • Step 1 (S)-pyridin-2-ylmethyl 5-ethanethioamido-l-(6-(4-fluorophenyl)-lH- benzo[d]imidazol-2-yl)pentylcarbamate (74)
  • Step 1 (S)-N-(5-(3-benzylureido)-5-(6-(4-fluorophenyl)-lH-benzo[d]imidazol-2- yl)pentyl)ethanethioamide(75)
  • Step 2 (S)-benzyl l-(7-chloro-lH-benzo[d]imidazol-2-yl)-5- ethanethioamidopentylcarbamate (77)
  • Step 1 (S)-benzyl 5-ethanethioamido-l-(7-nitro-lH-benzo[d]imidazol-2-yl)pentylcarbainate (78)
  • Step 2 (S)-benzyl 1 -(7-amino- lH-benzo[d]imidazol-2-yl)-5- ethanethioamidopentyl carbamate (79)
  • Step 1 (S)-benzyl 5-ethanethioamido- 1 -(7-(4-fiuorobenzamido)- 1 H-benzo[d]imidazol-2- yl)pentylcarbamate (80)
  • Step 1 (S)-benzyl l-oxo-l-(4-phenylthiazol-2-ylamino)-6-(3,3,3- trifluoropropanamido)hexan-2-ylcarbamate (151)
  • Step 2 (S)-benzyl l-oxo-l-(4-phenylthiazol-2-ylamino)-6-(3,3,3- trifluoropropanethioamido)hexan-2-ylcarbamate (152)
  • Step 1 (S)-benzyl 6-(hydrazinecarbothioamido)-l-oxo-l-(4-phenylthiazol-2-ylamino)hexan- 2-ylcarbamate (153)
  • Step 1 (S)-benzyl 6-(methylthiocarbonothioylamino)-l-oxo-l-(4-phenylthiazol-2- ylamino)hexan-2-ylcarbamate (154)
  • Step 1 (S)-benzyl 6-(2-hydroxyethanethioamido)-l-oxo-l-(4-phenylthiazol-2- ylamino)hexan-2-ylcarbamate (155) To a solution of 149 (125.1 mg, 0.226 mmol) in MeOH (2255 ⁇ l) at 0 °C was added K 2 CO 3 (94 mg, 0.677 mmol) and the mixture was stirred for 30 min., then stirring, EtOAc and a saturated solution of NaCl were added, and the organic extracts were dried over Na 2 SO 4 and concentrated and the residue was purified by chromatography with EtOAc (10 to 100%) in hexane afford 155 (87.1 mg, 75 % yield) as a white solid.
  • Step 1 benzyl (S)-6-t-butoxycarbonylamino-l-((R)-2-hydroxy-l-phenylethylamino)-l- oxohexan-2-ylcarbamate (156)
  • Step 2 benzyl (lS)-5-t-butoxycarbonylamino-l-(4-phenyl-4,5-dihydrooxazol-2- yl)pentylcarbamate (157)
  • Step 3 benzyl (lS)-5-ethanethioamido-l-(4-phenyl-4,5-dihydrooxazol-2-yl)pentylcarbamate
  • Step 2 (S)-benzyl 5-t-butoxycarbonylamino-l-(5-phenyl-lH-l,2,4-triazol-3- yl)pentylcarbamate (160)
  • Step 4 (S)-benzyl 5-(3-methylthioureido)-l-(5-phenyl-lH-l,2,4-triazol-3-yl)pentylcarbamate (162)
  • Step 1 (S)-benzyl 6-t-butoxycarbonylamino-l-(2-(l-iminoethyl)hydrazinyl)-l-oxohexan-2- ylcarbamate (165)
  • Step 2 (S)-benzyl 5-t-butoxycarbonylamino-l-(5-methyl-lH-l,2,4-triazol-3- yl)pentylcarbamate (166)
  • Step 1 (S)-benzyl 8-t-butoxycarbonylamino-l-(naphthalen-2-yl)-l,3-dioxooctan-4- ylcarbamate (185)
  • Step 2 (S)-benzyl 5-t-butoxycarbonylamino-l-(5-(naphthalen-2-yl)-lH-pyrazol-3- yl)pentylcarbamate (186)
  • the invention provides compositions comprising a compound according to the invention or an N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug thereof, or a racemic or scalemic mixture, diastereomer, enantiomer or tautomer thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
  • Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, intravenous or intrarectal. In certain embodiments, compounds of the invention are administered intravenously in a hospital setting.
  • compositions may be in the form of liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets or capsules; and for intranasal formulations, in the form of powders, nasal dropsa or aerosols.
  • the compositions of the invention may be administered systemically or locally.
  • the characteristics of the carrier will depend on the route of administration.
  • pharmaceutically acceptable means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s).
  • compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • diluents such as, butyl alcohol, glycerol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mann
  • the composition comprises a compound, N- oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug of a compound according to the present invention as described herein present in at least about 30% enantiomeric or diastereomeric excess.
  • the compound, N-oxide, hydrates, solvate, pharmaceutically acceptable salt, complex or prodrug is present in at least about 50%, at least about 80%, or even at least about 90% enantiomeric or diastereomeric excess.
  • the compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug is present in at least about 95%, alternatively at least about 98% or alternatively at least about 99% enantiomeric or diastereomeric excess.
  • a compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug is present as a substantially racemic mixture.
  • the composition further comprises an additional therapeutic or inhibitory agent.
  • salts are intended to mean salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects.
  • examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for Example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid.
  • the compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR + Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
  • salt is also meant to encompass complexes, such as with an alkaline metal or an alkaline earth metal.
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver an inhibition effective amount without causing serious toxic effects.
  • Dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg/kg, alternatively 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day.
  • a typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier.
  • the effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
  • the composition further comprises an agent, such as an antisense oligonucleotide, that inhibits the expression of a sirtuin gene.
  • an agent such as an antisense oligonucleotide
  • a nucleic acid level inhibitor e.g., antisense oligonucleotide
  • a protein level inhibitor i.e., inhibitor of sirtuin enzyme activity
  • results in an improved inhibitory effect thereby reducing the amounts of the inhibitors required to obtain a given inhibitory effect as compared to the amounts necessary when either is used individually.
  • the antisense oligonucleotides according to this aspect of the invention are complementary to regions of RNA or double-stranded DNA that encode a sirtuin gene.
  • Additional inhibitory agents may also be present in the compositions of this invention, where the combination causes no unacceptable adverse effects.
  • the invention provides a method of inhibiting sirtuin activity the method comprising contacting the sirtuin with an inhibition effective amount of a compound according to the present invention, or with an inhibition effective amount of a composition according to the present invention.
  • Inhibition of sirtuin activity can be in a cell or a multicellular organism. If in a cell, the method according to this aspect comprises contacting the cell with an inhibition effective amount of a compound according to the present invention, or with an inhibition effective amount of a composition according to the present invention. If in a multicellular organism, the method according to this aspect of the invention comprises administering to the organism an inhibition effective amount of a compound according to the present invention, or an inhibition effective amount of a composition according to the present invention.
  • the organism is a mammal, more preferably a human.
  • the method further comprises contacting the sirtuin or the cell, with an effective amount of an additional inhibitory agent, or if in a multicellular organism, concurrently or sequentially administering an inhibition effective amount of an additional inhibitory agent.
  • the method is a method of treating a disease responsive to an inhibitor of sirtuin activity and comprises administering to an individual in need thereof an effective amount of a compound or composition thereof according to the present invention.
  • the method of treatment further comprises administering an effective amount of an additional therapeutic agent, wherein the additional therapeutic agent is a therapeutic agent appropriate for treating the disease.
  • Measurement of the enzymatic activity of a sirtuin can be achieved using known methodologies.
  • the sirutin inhibitor interacts with and reduces the activity of all sirtuins in a cell. In some other embodiments according to this aspect of the invention, the sirtuin inhibitor interacts with and reduces the activity of fewer than all sirtuins in the cell. In certain embodiments, the inhibitor interacts with and reduces the activity of one sirtuin (e.g., SIRTl but does not interact with or reduce the activities of other sirtuins (e.g., SIRT3)
  • the sirtuin inhibitor of the present invention may be administered together with another sirtuin or HDAC inhibitor known in the art or which will be discovered. Administration of such sirtuin or HDAC inhibitors may be done sequentially or concurrently.
  • the compositions comprise an sirtuin inhibitor of the present invention and/or an antisense oligonucleotide and/or another sirutin inhibitor known in the art or which will be discovered.
  • the active ingredients of such compositions act synergistically to produce a therapeutic effect.
  • sirtuin inhibitors include, but are not limited to, nicotinamide, cambinol, sirtinol, splitomicin, anilinobenzamide #7 and EX527.
  • SIRT1-2-3 Enzymatic Assay Protocol Buffer; 5OmM HEPES, pH 8.0, 137mM NaCl, 2.7mM KCl, ImM MgCl 2
  • Nicotinamide Sigma Cat#N-3376

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Abstract

L'invention concerne des composés et procédés pour l'inhibition de l'activité enzimatique de la sirtuine et, en particulier, des composés de la formule (I), Y__L__Z__D, et leurs N-oxydes, hydrates, solvates, sels pharmaceutiquement acceptables, pro-médicaments et complexes, et leurs mélanges racémiques et scalémiques, diastéréo-isomères et énantiomères, Y, L, Z et D étant tels que définis dans la description.
PCT/CA2008/001520 2007-08-29 2008-08-29 Inhibiteurs de sirtuine Ceased WO2009026701A1 (fr)

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US11998553B2 (en) 2018-07-17 2024-06-04 Insmed Incorporated Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides for treating lupus nephritis
US12059424B2 (en) 2018-03-01 2024-08-13 Astrazeneca Ab Pharmaceutical compositions comprising (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide
US12226418B2 (en) 2018-06-01 2025-02-18 Incyte Corporation Dosing regimen for the treatment of PI3K related disorders
US12479837B2 (en) 2023-01-06 2025-11-25 Insmed Incorporated Reversible DPP1 inhibitors and uses thereof

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