WO2009026701A1 - Sirtuin inhibitors - Google Patents

Sirtuin inhibitors 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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alkyl
aryl
heteroaryl
heterocyclyl
optionally substituted
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PCT/CA2008/001520
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French (fr)
Inventor
Robert Deziel
Jubrail Rahil
Amal Wahhab
Martin Allan
Nathalie Nguyen
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Methylgene Inc.
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Publication of WO2009026701A1 publication Critical patent/WO2009026701A1/en

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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

This invention relates to compounds and methods for the inhibition of sirtuin enzymatic activity. More particularly, the invention provides for compounds of formula (I), Y__L__Z__D, and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers and enantiomers thereof, wherein Y, L, Z and D are as defined in the specification.

Description

SIRTUIN INHIBITORS
BACKGROUND OF THE INVENTION
Related Applications
This application claims the benefit of U.S. Provisional Application Serial Number 60/968,773 filed August 29, 2007. The entire teachings of the above-referenced application is incorporated herein by reference. Field of the Invention
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. Description of Related Art
Histone deacetylases are involved in the epigenetic regulation of gene expression through chromatin remodeling. As the name implies, HDACs deacetylate histone acetyl lysines. However, 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, PPARγ, 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. (Blander, G. and L. Guarante, 2004, The Sir2 Family of Protein Deacetylases, Annu. Rev. Biochem. 73:417-435; Dali-Youcef et al, 2007, Sirtuins: The ''magnificent seven" , Function, Metabolism and Longevity, Annals of Medicine 39:335-345; Jiang, 2008, Sirtuins: Novel Targets for Metabolic Disease in Drug Development, Biochemical and Biophysical Research Comm. 373:341-344). Functional validation data supports SIRTl as a candidate therapeutic target for cancer.
In cell culture, 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). In vivo, 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 1H363Y), and SIRT inhibitors (nicotinamide and splitomicin) have each been used to demonstrate that SIRT inhibition in MCF-7 and MDA-MB-231 breast cancer cells leads to reexpression of a panel of tumor suppressor genes and increased H4K16 and H3K9 acetylation at endogenous gene promoters (Pruitt, K., et. al., 2006, Inhibition of SIRTl Reactivates Silenced Cancer Genes without Loss of Promoter DNA Hypermethylation, PLoS Genetics 2(3):344-352).
SIRT2 is a NAD-dependent protein deacetylase that has been shown to deacetylase numerous substrates in vitro and in vivo such as α-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- lα and AceCS2 with a potential link to treating diseases and disorder such as, for example, those associated with adaptive thermogenesis and breast cancer. (Dali-Youcef et al., 2007, Sirtuins: The 'magnificent seven', Function, Metabolism and Longevity, Annals of Medicine 39:335-345). 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. (DaIi- Youcef et al, 2007, Sirtuins: The 'magnificent seven' , Function, Metabolism and Longevity, Annals of Medicine 39:335-345). 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. (DaIi- Youcef et al., 2007, Sirtuins: The 'magnificent seven' ', Function, Metabolism and Longevity, Annals of Medicine 39:335-345). 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 polβ 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.). (Dali-Youcef et al., 2007, Sirtuins: The 'magnificent seven', Function, Metabolism and Longevity, Annals of Medicine 39:335- 345). 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).
There is building evidence linking SIRTl to the FOXO family of forkhead transcription factors (Giannakou 2004). 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). In the context of a transfection assay, 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.
Currently known inhibitors of SIRTl deacetylase activity include 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. al., 2006, Comparative and Pharmacophore Model for Deacetylase SIRTl, J. Comput. Aided MoI. Des. 20:589-599; Heltweg et al., supra; and Blander et al., supra). With the exception of anilinobenzamide #7 (SIRTl IC50 = 17uM) and EX527 (SIRTl IC50 = 98nM), the other inhibitors are non-selective versus SIRT2 and very weak (SIRTl IC50S > 4OuM).
SUMMARY OF THE INVENTION
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.
In a first aspect, the present invention provides compounds that are useful as inhibitors of sirtuins and that have the formula (I):
Y— L— Z — D (I) and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers and enantiomers thereof, wherein Y, L, Z and D are as defined below, hi this first aspect, 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. In a second aspect, the invention provides a composition comprising a compound according to the present invention. In anotherembodiment, the composition further comprises an additional inhibitory agent.
In a third aspect, 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. Preferably the organism is a mammal, more preferably a human.
In a fourth aspect, 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 foregoing merely summarizes the above aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below. The patent and scientific literature referred to herein establishes knowledge that is available to those with skill in the art. Each issued patent, patent application, and other publication cited herein are hereby incorporated by reference in their entirety. In the case of inconsistencies, the teachings of the present disclosure will prevail.
DETAILED DESCRIPTION OF THE INVENTION 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.
In one aspect, 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. In the second aspect, the invention provides a composition comprising a compound according to the first aspect or anyembodiment thereof and a pharmaceutically acceptable carrier.
In a third aspect, 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. Preferably the organism is a mammal, more preferably a human. In anotherembodiment, 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.
For purposes of the present invention, the following definitions will be used (unless expressly stated otherwise).
Reference 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.
For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an "alkyl" moiety generally refers to a monovalent radical (e.g. CH3-CH2-), in certain circumstances 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., -CH2-CH2-), which is equivalent to the term "alkylene." (Similarly, in circumstances in which a divalent moiety is required and is stated as being "aryl," those skilled in the art will understand that the term "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). On occasion 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. For simplicity, reference to a "Cm-Cn" cycloalkyl, "C1n-Cn" heterocyclyl, "Cm-Cn" 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. Thus, for example, a Cs-Cδ-heterocyclyl is a 5- or 6- membered ring having at least one heteroatom, and includes pyrrolidinyl (C5) and piperidinyl (C6); C6-heteroaryl includes, for example, pyridyl and pyrimidyl.
The term "hydrocarbyl" refers to a straight, branched, or cyclic alkyl, alkenyl, or alkynyl, each as defined herein. A "C0" hydrocarbyl is used to refer to a covalent bond. Thus, "Co-C3-hydrocarbyl" includes a covalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl, propynyl, and cyclopropyl. The term "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.
The terms "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. Examples of 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-C3alkyl") is a covalent bond.
The term "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. Examples of 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. The term "alkenyl" as employed herein therefore encompasses cycloalkenyl groups. The term "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. Examples of 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. The term "alkenyl" as employed herein therefore encompasses cycloalkenyl groups..
The terms "alkylene," "alkenylene," or "alkynylene" as used herein are intended to mean an alkyl, alkenyl, or alkynyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Examples of alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Examples of alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene. Exampes of alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene. The term "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. In certain embodiments, the cycloalkyl group is fused to one or more aryl, heteroaryl or heterocyclic group (for example 1 or 2). Examples of 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.
The term "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)2NH-, or -NHS(O)2-.
The terms "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). Alternatively, the aryl group is a C6-Cioaryl group, alternatively a C6aryl group. Examples of aryl groups include, without limitation, phenyl, naphthyl (including 1-naphthyl and 2- naphthyl), anthracenyl, and fluorenyl. The terms "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. Alternatively, the aralkyl group is (C1-C6)alk(C6-C1o)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl. For simplicity, when written as "arylalkyl" this term, and terms related thereto, is intended to indicate the order of groups in a compound as "aryl - alkyl". Similarly, "alkyl-aryl" is intended to indicate the order of the groups in a compound as "alkyl-aryl".
The terms "heterocyclo", "heterocyclyl", "heterocyclic" or "heterocycle", and the like, are 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. In certain embodiments, the heterocyclic group is a bridged heterocyclic group (for example, a bicyclic moiety with a methylene, ethylene or propylene bridge). In a bicyclic or polycyclic structure, 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. Examples of 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, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl and other heterocycles described in Katritzky, A. R. and Rees, C. W., eds. Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Uses of Heterocyclic Compounds 1984, Pergamon Press, New York, N. Y.; and Katritzky, A. R., Rees, C. W., Scriven, E. F., eds. Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995 1996, Elsevier Science, Inc., Tarrytown, N.Y.; and references therein. In certain preferred, the heterocyclic group is fused to an aryl, heteroaryl, or cycloalkyl group. Examples of such 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.
In certain embodiments, the heterocyclic group is a heteroaryl group. As used herein, the term "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. The term "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. For example, a heteroaryl group may be pyrimidinyl, pyridinyl, benzimidazolyl, thienyl, benzothiazolyl, benzofuranyl and indolinyl. Examples of 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. Illustrative examples of 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. R., Rees, C. W., Scriven, E. F., eds. Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995 1996, Elsevier Science, Inc., Tarrytown, N.Y.; and references therein. The terms "cycloalkylene", "arylene," "heteroarylene," and "heterocyclylene" are intended to mean an cycloalkyl, aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
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. If a 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.
Examples of 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- dioxolane, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), furanyl, furopyridinyl (such as fuor[2,3-c]pyridinyl, furo[3,2-b]pyridinyl or furo[2,3-b]pyridinyl), fbryl, furazanyl, hexahydrodiazepinyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolinyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxetanyl, 2-oxoazepinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolopyridyl, 2H- pyrrolyl, pyrrolyl, quinazolinyl, quinolyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydro-l,l-dioxothienyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrazolyl, thiazolidinyl, 6H-l,2,5-thiadiazinyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1,2,5- thiadiazolyl, 1,3,4-thiadiazolyl), thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholuiyl sulfone, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, triazinylazepinyl, triazolyl (e.g., 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1,2,5- triazolyl, 1,3,4-triazolyl), and xanthenyl. A "halohydrocarbyl" as employed herein is a hydrocarbyl moiety, in which from one to all hydrogens have been replaced with an independently selected halo.
As employed herein, and unless stated otherwise, when a moiety (e.g., alkyl, hetero- alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, etc.) is described as "optionally substituted" it is meant that the group optionally has from one to four, alternatively from one to three, alternatively one or two, independently selected non-hydrogen substituents. 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:
(a) halo, hydroxy, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, (b) Q-Csalkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, Cj-Cgalkyl, C1-
C8alkenyl, Q-Cgalkoxy, CrCgalkyamino, d-Csalkoxycarbonyl, aryloxycarbonyl, C2-C8acyl, -C(O)-N(R30)-alkyl-cycloalkyl, -C(O)-N(R30)- alkyl-heterocyclyl, -C(O)-N(R30)-alkyl-aryl, -C(O)-N(R30)-alkyl-heteroaryl, -C(O)-cycloalkyl, -C(O)-heterocyclyl, -C(O)-aryl, -C(O)-heteroaryl, C2-
Cgacylamino, Q-Cgalkylthio, arylalkylthio, arylthio, CrCsalkylsulfϊnyl, arylalkylsulfinyl, arylsulfinyl, d-Qalkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, Co-CόN-alkyl carbamoyl, C2-C i5N,7V-dialkyl carbamoyl, C3-C7 cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C3-C7heterocycle, Cs-C^heteroaryl or any of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above; and
(c) -(CR32R33VNR30R31, wherein s is from 0 (in which case the nitrogen is directly bonded to the moiety that is substituted) to 6,
R32 and R33 are each independently hydrogen, halo, hydroxyl or C)-C4alkyl, and R30 and R31 are each independently hydrogen, cyano, oxo, hydroxyl, C1- Cgalkyl, d-Csheteroalkyl, Q-Cgalkenyl, carboxamido, C1-QaUCyI- carboxamido, carboxamido-d-C3alkyl, amidino, C2-C8hydroxyalkyl, d-dalkylaryl, aryl-d-C3alkyl, C1-C3alkylheteroaryl, heteroaryl-d- C3alkyl, d-Caalkylheterocyclyl, heterocyclyl-Crdalkyl Ci-
C3alkylcycloalkyl, cycloalkyl-Ci-dalkyl, C2-Csalkoxy, C2-Cgalkoxy-d- C4alkyl, d-Cgalkoxycarbonyl, aryloxycarbonyl, aryl-d- C3alkoxycarbonyl, heteroaryloxycarbonyl, heteroaryl-Ci-
C3alkoxycarbonyl, d-Cgacyl, Co-Cgalkyl-carbonyl, aryl-C0-C8alkyl- carbonyl, heteroaryl-Co-Cgalkyl-carbonyl, cycloalkyl-Co-C8alkyl- carbonyl, heterocyclyl-Co-Cgalkyl-carbonyl, Co-Cgalkyl-NH-carbonyl, aryl-Co-Cgalkyl-NH-carbonyl, heteroaryl-Co-Cgalkyl-NH-carbonyl, cycloalkyl-Co-Cgalkyl-NH-carbonyl, heterocylclyl-Co-C8alkyl-NH- carbonyl, cycloalkyl-S(O)2-, heterocyclyl-S(O)2-, aryl-S(O)2-, hetero- aryl-S(O)2-, Co-Cgalkyl-O-carbonyl, aryl-Co-Cgalkyl-O-carbonyl, hetero- aryl-Co-C8alkyl-0-carbonyl, cycloalkyl-Co-Cgalkyl-O-carbonyl, hetero- cyclyl-Co-Cgalkyl-O-carbonyl, d-Cgalkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, d-Cgalkyl- NH-sulfonyl, arylalkyl-NH-sulfonyl, aryl-NH-sulfonyl, heteroarylalkyl- NH-sulfonyl, heteroaryl-NH-sulfonyl aroyl, aryl, cycloalkyl, hetero- cyclyl, heteroaryl, aryl-d-C3alkyl-, cycloalkyl-d-Csalkyl-, hetero- CyCIyI-C1 -C3alkyl-, heteroaryl-CrCsalkyl-, or a protecting group, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above; or R30 and R31 taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents selected from the group consisting of (a) above, a protecting group, and (X30- Y3 *-), wherein said heterocyclyl may also be bridged (forming a bicyclic moiety with a methylene, ethylene or propylene bridge); wherein
X30 is selected from the group consisting of H, d-Cgalkyl, C2-Cgalkenyl-, C2-C8alkynyl-, -Co-C3alkyl-C2-C8alkenyl-Co-C3alkyl, C0-C3alkyl-C2- C8alkynyl-C0-C3alkyl, C0-C3alkyl-O-C0-C3alkyl-, HO-C0-C3alkyl-, C0- C4alkyl-N(R30)-C0-C3alkyl-, N(R30)(R31)-C0-C3alkyl-, N(R30)(R31)-C0- C3alkenyl-, N(R3O)(R31)-Co-C3alkynyl-, (N(R3O)(R3 ^)2-C=N-, C0- C3alkyl-S(O)0-2-C0-C3alkyl-, CF3-C0-C3alkyl-, d-Qheteroalkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-Q-Caalkyl-, cycloalkyl-Q- C3alkyl-, heterocyclyl-C1-C3alkyl-, heteroaryl-d-Qsalkyl-, N(R30)(R31)- heterocyclyl-C1-C3alkyl-, wherein the aryl, cycloalkyl, heteroaryl and heterocycyl are optionally substituted with from 1 to 3 substituents from (a); and
Y31 is selected from the group consisting of a direct bond, -O-, -N(R30)-, -C(O)-, -O-C(O)-, -C(O)-O-, -N(R30)-C(O)-, -C(O)-N(R30)-, -N(R30)- C(S)-, -C(S)-N(R30)-, -N(R30)-C(O)-N(R31)-, -N(R3O)-C(NR3O)-N(R31)-,
-N(R30)-C(NR31)-, -C(NR31)-N(R30)-, -N(R30)-C(S)-N(R31)-, -N(R30)- C(O)-O-, -0-C(O)-N(R31)-, -N(R30)-C(S)-O-, -0-C(S)-N(R31)-, -S(O)0- 2-, -SO2N(R31)-, -N(R31)-SO2- and -N(R30)-SO2N(R31)-.
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. As a non-limiting example, substituted phenyls include 2-flurophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2- fluoro-3-propylphenyl. As another non-limiting example, substituted n-octyls include 2,4- dimethyl-5-ethyl-octyl and 3-cycloρentyl-octyl. Included within this definition are methylenes (-CH2-) substituted with oxygen to form carbonyl -CO-.
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. hi certain embodiments, a group, such as a hydrocarbyl, heteroalkyl, heterocyclic and/or aryl group is unsubstituted.
In other embodiments, 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. Examples of 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 -CF3 or an alkyl group bearing Cl3), 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, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, thiol, haloalkyl, trihaloalkyl, alkylthio, -ORa, -SRa, -S(=O)Re, -S(=O)2R6, -P(=O)2Re, -S(=O)2OR6, -P(=O)2ORe, -NR13R0, -NRbS(=O)2Re, -NR15PC=O)2R6, -SC=O)2NR6R0, -P(=O)2NRbR°, -C(=O)ORe, -C(=O)Ra, -C(=0)NRbRc, -OC(=O)Ra, -OCC=O)NR1Tl0, -NRbC(=O)ORe, -NR41CC=O)NR11R0, -NR11SC=O)2NR1Tl0, -NR^C=O)2NR15R0, -NRbC(=O)Ra or -NR15PC=O)2R6, wherein Ra is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; Rb, R° and Rd are independently hydrogen, alkyl, cycloalkyl, heterocycle or aryl, or said Rb and R° together with the N to which they are bonded optionally form a heterocycle; and R6 is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. In the aforementioned exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl can themselves be optionally substituted.
Examples of 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. Examples of 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. Other examples of 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. In anotherembodiment, when a cycloalkyl is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, for example a C1-3 alkylene chain. Cycloalkyl groups having this crosslinked structure include bicyclo[2.2.2]octanyl and norbornanyl. Examples of 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. Other examples of 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. In anotherembodiment, when a cycloalkenyl is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, for example a C1-3 alkylene chain. Examples of 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. Other examples of 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. Still other examples of substituents on aryl groups (phenyl, as a non-limiting example) include, but are not limited to, haloalkyl and those groups recited as examples of alkyl substituents. In anotherembodiment, when an aryl group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, for example a C1.3 alkylene chain.
Examples of substituents on heterocyclic groups include, but are not limited to, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, nitro, oxo (i.e., =O), cyano, alkyl, substituted alkyl, as well as those groups recited as examples of alkyl substituents. Other examples of 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. In anotherembodiment, when a heterocyclic is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, for example a C1-3 alkylene chain.
In certain embodiments, a heterocyclic group is substituted on carbon, nitrogen and/or sulfur at one or more positions. Examples of substituents on carbon include those groups recited as examples of alkyl substituents. Examples of substituents on nitrogen include, but are not limited to alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl. Examples of substituents on sulfur include, but are not limited to, oxo and C1-6alkyl. In certain embodiments, nitrogen and sulfur heteroatoms may independently be optionally oxidized and nitrogen heteroatoms may independently be optionally quaternized.
Exemplary substituents on ring groups, such as aryl, heteroaryl, cycloalkyl and hetero- cyclyl, include halogen, alkoxy and alkyl.
Exemplary substituents on alkyl groups include halogen and hydroxy. Examples of substituents on aromatic polycycles including, but not limited to, naphthyl and quinoline, include CrQalkyl, cycloalkylalkyl (e.g. cyclopropylmethyl), oxyalkyl, halo, nitro, amino, alkylamino, aminoalkyl, alkyl ketones, nitrile, carboxyalkyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl and OR88, such as alkoxy, wherein Rω is selected from the group consisting of H, Ci-Cealkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and -(CH2)0-6ZaRbb, wherein Za is selected from the group consisting of O, NRCC, S and S(O), and Rbb is selected from the group consisting of H, C1- C6alkyl, C4-Cc>cycloalkyl, C4-C9heterocycloalkyl, C4-C9heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, (e.g. benzyl), and heteroarylalkyl (e.g. pyridylmethyl); and Rcc is selected from the group consisting of H, C!-C6alkyl, C4- Cgcycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g. benzyl), heteroarylalkyl (e.g. pyridylmethyl) and amino acyl.
Examples of 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. Unless otherwise noted, 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!-C6alkyl, halo, hydroxy, aminoalkyl, oxyalkyl, alkylamino and ORaa, such as alkoxy. Examples of substituents for such cycloalkyl groups include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.
Examples of 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. Unless otherwise noted, polyheteroaryls are unsubstituted or substituted on a carbon atom by one or more suitable substituents, including but not limited to, straight and branched optionally substituted C1-QaIlCyI, unsaturation (i.e., there are one or more double or triple C-C bonds), acyl, cycloalky, halo, oxyalkyl, alkylamino, aminoalkyl, acylamino and OR88, for example alkoxy, and a substituent of the formula -O- (CH2CH=CH(CH3)(CH2))1-3H. 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. Examples of substituents include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl. Nitrogen atoms are unsubstituted or substituted, for example by Rcc. Examples of substituents on such nitrogen atoms include H, CrQalkyl, acyl, aminoacyl and sulfonyl.
Examples of 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. Suitable examples of 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. Unless otherwise noted, 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 CrCόalkyl, unsaturation (i.e., there are one or more double or triple C-C bonds), acyl, cycloalky, halo, oxyalkyl, alkylamino, aminoalkyl, acylamino and ORω, for example alkoxy. Examples of suitable straight and branched C!-C6alkyl substituents include but are not limited to methyl, ethyl, n-propyl, 2- propyl, n-butyl, sec-butyl, t-butyl and the like. Examples of substituents include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl. Nitrogen atoms are unsubstituted are substituted, for example, by Rcc. Examples of N substituents include H, C1-C4 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. Unless otherwise noted, mixed aryl and non-aryl polyheterocyclics are unsubstituted or substituted on a carbon atom by one or more suitable substituents including but not limited to -N-OH, =N-OH, optionally substituted 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. Nitrogen atoms are unsubstituted or substituted, for example, by Rcc. Examples of N substituents include H, C1- 4alkyl, acyl aminoacyl and sulfonyl.
The term "halogen" or "halo" as employed herein refers to chlorine, bromine, fluorine, or iodine. As herein employed, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent. The term "acylamino" refers to an amide group attached at the nitrogen atom (i.e., R-CO-NH-). The term "carbamoyl" refers to an amide group attached at the carbonyl carbon atom (i.e., NH2-CO-). The nitrogen atom of an acylamino or carbamoyl substituent is additionally optionally substituted. The term "sulfonamido" refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom. The term "amino" is meant to include NH2, alkylamino, di-alkyl-amino (wherein the alkyl groups are the same or different), arylamino, and cyclic amino groups. The term "ureido" as employed herein refers to a substituted or unsubstituted urea moiety.
The term "radical" as used herein means a chemical moiety comprising one or more unpaired electrons.
Where optional 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. In addition, substituents on cyclic moieties (i.e., cycloalkyl, heterocyclyl, aryl, hetero- aryl) 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. Substituents on 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. For example, an optionally substituted phenyl includes, but is not limited to, the following:
Figure imgf000020_0001
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. Examples of 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. Examples of 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.
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, hSIRTό and hSIRT7 (Brachmann et al. (1995) Genes Dev. 9:2888 and Frye et al. (1999) BBRC 260:273). Examples of 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. Preferably the sirtuin is a human sirtuin. In some other embodiments, the sirtuin is derived from a protozoal or fungal source.
The terms "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.
The term "inhibiting sirutin enzymatic activity" is intended to mean reducing the a functional property or biological ability of a sirtuin. For example, the inhibition of sirtuin activity may be at least about 10%. In some embodiments of the invention, such inhibition of sirtuin activity is at least about 50%, alternatively at least about 75%, and alternatively at least about 90%. In other embodiments, 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 IC50 value.
The term "inhibition 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. If the sirtuin is in a multicellular organism, 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. In certain embodiments, compounds of the invention are administered intravenously in a hospital setting. In certain other embodiments, administration may for example be by the oral route. Preferably, 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. For example, 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.
The term "therapeutically effective amount" as employed herein 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. As such, the therapeutic effect can be treatment of a disease-state. Further, 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.
The term "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.
The terms "treating", "treatment", or the like, as used herein 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. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art.
In certain embodiments, 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. In another embodiment, 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.
In another embodiment, 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.
In another embodiment, 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)", as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when 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") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic (exhibiting minimal or no undesired toxicological effects), physiologically 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, such as but not limited to an amine or a pyridine or imidazole ring, 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, hydroxyethanesulfanotes (e.g., 2- hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like. The compounds of the present invention which contain an acidic moiety, such as but not limited to a carboxylic acid, 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.
As used herein, the term "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.
Another aspect of the invention provides 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. For example, in one embodiment of the invention, 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. In other embodiments of the invention, 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. For example, 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. Additionally, 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., N5N- 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-C6alkoxymethyl esters (e.g., methoxymethyl), Q-Cόalkanoyloxymethyl esters (e.g., for example pivaloyloxymethyl), phthalidyl esters, C3- Qcycloalkoxycarbonyloxy-CrCealkyl esters (e.g., l-cyclohexylcarbonyloxyethyl); 1,3- dioxolen-2-onylmethyl esters (e.g., 5-methyl-l,3-dioxolen-2-onylmethyl; and C1- C6alkoxycarbonyloxyethyl esters (e.g., 1-methoxycarbonyloxyethyl) and may be formed at any appropriate carboxy group in the compounds of this invention.
An in vivo hydrolyzable ester of a compound of the invention containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of α-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-(N1N- dialkylaminoethyl)-iV-alkylcarbamoyl (to give carbamates), /V,/V-dialkylaminoacetyl and carboxy acetyl. Examples of 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-C6alkyl or N,N-di-d-C6alkyl amide such as TV-methyl, TV-ethyl, /V-propyl, /V,7V-dimethyl, JV-ethyl-N-methyl or TV.iV-diethyl amide.
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. Typically, in a prodrug, a polar functional group (e.g., a carboxylic acid, an amino group, a hydroxyl group, etc.) is masked by 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. Typically, the promoiety will be attached to the compound via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.
The terms "protect", "protected", and "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. Such non-reactive functional groups are herein termed "protecting groups". For example, the term "nitrogen protecting group", is intended to mean a group capable of selectively masking the reactivity of a nitrogen (N) group. The term "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. Protecting groups that are suitable for use in the processes and methods of the present invention are well known, such as but not limited to, Bn- (or -CH2Ph), -CHPh2, alloc (or CH2=CH-CH2-O-C(O)-), BOC-, -Cbz (or Z-), -F-moc, -C(O)-CF3, N-Phthalimide,l- Adoc-, TBDMS-, TBDPS-, TMS-, TIPS-, IPDMS-, -SiR3, SEM-, t-Bu-, Tr-, THP- and AUyI- . These protecting groups may be removed at a convenient stage using methods known from the art. The chemical properties of such protecting groups, methods for their introduction and their removal art known in the art and can be found for example in T. Greene and P. WuIs, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999), herein incorporated by reference in its entirety. The terms "deprotect", "deprotected", and "deprotecting" are intended to refer to the process of removing a protecting group from a compound.
Throughout the specification, embodiments of one or more chemical substituents are identified. Also encompassed are combinations of particular embodiments. For example, the invention describes particular embodiments of L in the compounds and describes particular embodiments of group Y. Thus, as an example, also contemplated as within the scope of the invention are compounds in which particular examples of L are as described and in which particular examples of group Y are as described
The foregoing merely summarizes one aspect and embodiments of the invention and is not intended to be limiting in nature. This aspect and embodiments are described more fully below.
Compounds
In one aspect, the invention provides compounds of the formula (I):
Y— L— Z — D (I) and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers and enantiomers thereof, wherein D is selected from the group consisting of
Figure imgf000029_0001
Figure imgf000029_0002
, , , and , wherein
X is O or S;
M is nitrogen, oxygen, or sulfur; wherein when M is oxygen or sulfur, Rb is absent and W is nitrogen;
W is nitrogen, oxygen, or sulfur; wherein when W is oxygen or sulfur, Rc is absent and M is nitrogen; each Ra is independently selected from the group consisting of -H, -Ci-C6alkyl, a protecting group, -Ci-Cόalkyl-aryl, aryl, -CrCόalkyl-heteroaryl, heteroaryl, -CrCόalkyl-cycloalkyl, cycloalkyl, -d-Cealkyl-heterocyclyl, heterocyclyl, -C(O)-O-C j-C6alkyl, -C(O)-O-C1- C6alkyl-heterocyclyl, -C(O)-O-C i-C6alkyl-alkenyl, -C(O)-O-C1-C6alkyl-aryl, -CO-CF3
and
Figure imgf000029_0003
each of which is optionally substituted, wherein said protecting group is preferably selected from the group consisting of Bn- (or -CH2Ph), -CHPh2, alloc (or CH2=CH-CH2-O-C(O)-), BOC-, -Cbz (or Z-), -F-moc, -C(O)-CF3, N-Phthalimide,l- Adoc-, TBDMS-, TBDPS-, TMS-, TIPS-, IPDMS-, -SiR3, SEM-, t-Bu-, Tr-, THP- and AHyI; and when M is nitrogen, Ra is additionally selected from -C(O)-H;
Rb and Rc, 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, -NH2, -NH- alkyl, -C(O)-H, a protecting group, -d-C6alkyl-aryl, aryl, -d-Cόalkyl-heteroaryl, -hetero- aryl, -Ci-Cόalkyl-cycloalkyl, cycloalkyl, -Ci-Cδalkyl-heterocyclyl, heterocyclyl, -C(O)-Co- C3alkyl-aryl, -C(O)-C0-C3alkyl-heteroaryl, -C(O)-C0-C3alkyl-cycloalkyl, -C(O)-C0- C3alkyl-heterocyclyl, -C(O)-O-C t-Cealkyl, -C(O)-O-C1-C6alkyl-heterocyclyl, -C(O)-O-C1-
C6alkyl-alkenyl, -C(O)-O-C i-Qalkyl-aryl, -CO-CF3 and
Figure imgf000030_0001
, each of which is optionally substituted; wherein, when M is nitrogen, Ra and Rb together with the nitrogen atom 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; and wherein, when Ra is -d-Cόalkyl, -Q-Cόalkyl-aryl, -d-Cόalkyl-heteroaryl, -d-Cόalkyl- heterocyclyl, or -C]-C6alkyl-cycloalkyl and Rc is -d-Cβalkyl, then Ra and Rc are optionally connected with a carbon atom to form a 5 to 10-membered heterocyclyl, heterocyclyl-aryl, heterocyclyl-heteroaryl, heterocyclyl-heterocyclyl or heterocyclyl-cycloalkyl, each of which is optionally substituted; Rf is selected from the group consisting of H, d-C6alkyl;
Rh is selected from the group consisting of H, -OH, -CN, -CrC6alkyl, -C0-C6alkyl-O-C0- C6alkyl-aryl, -Co-Cβalkyl-O-Co-Cόalkyl-heteroaryl, wherein each of said alkyl, aryl, and heteroaryl is optionally substituted; or, Rh and Rc, 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, -C3-Csalkyl-, -C0-C3alkyl-Ci- C8heteroalkyl-C0-C3alkyl-, -C0-C3alkyl-C2-C8alkenyl-C0-C3alkyl-, -C0-C3 alkyl-C2- C8alkynyl-C0-C3alkyl-, -Co-Cealkyl-aryl-Co-Cόalkyl-, -C0-C6alkyl-aryl-C2-C6heteroalkyl-,
-Co-Qalkyl-cycloalkyl-Co-Cealkyl-, -C0-C6alkyl-cycloalkyl-C2-C6heteroalkyl-, -C4- C6heterocyclyl-aryl-Co-C6alkyl-, -C4-C6heterocyclyl-aryl-Co-C6heteroalkyl-, -Co-C6alkyl- C4-C6-heterocyclyl-Co-C6alkyl-, -Co-Cealkyl^-Q-heterocyclyl-Co-Cόheteroalkyl-, -Co- Cό-alkyl-heteroaryl-Co-Cδalkyl-, -Co-Cό-alkyl-heteroaryl-Co-Cόheteroalkyl-, -C4-Cδhetero- cyclyl-heteroaryl-Co-Coalkyl-, -C4-C6heterocyclyl-heteroaryl-Co-C6heteroalkyl-, -Co- C6alkyl-aryl-C3-C6alkynyl-, -Co-C6alkyl-heteroaryl-C2-C6alkynyl-, -Co-Cόalkyl-cycloalkyl- C3-C6alkynyl-, -Co-Qalkyl-heterocyclyl-Cs-Cealkynyl-, -C0-C6alkyl-aryl-C2-C6alkynyl-
C2-C6alkenyl-, -Co-C6alkyl-aryl-C2-C6alkenyl-, -Co-C6alkyl-heteroaryl-C2-C6alkenyl-, -C0- C6alkyl-cycloalkyl-C2-C6alkenyl-, -Co-C6alkyl-heterocyclyl-C2-C6alkenyl-, -Co-Cgalkyl- aryl-aryl-Co-C6alkyl-, -Co-Cόalkyl-aryl-heteroaryl-Co-Cδalkyl-, -Co-Cόalkyl-heteroaryl- aryl-Co-C6-alkyl-, -Co-Cόalkyl-heteroaryl-heteroaryl-Co-Cδ-alkyl-, -Co-Qalkyl-heteroaryl- C0-C3alkyl- C2-C8 alkenyl-C0-C3-alkyl-, -Co-Csalkyl-aryl-Co-Qalkyl- C2-C8 alkenyl-C0-
C3-alkyl-, -Co-Csalkyl-heterocyclyl-Co-Qalkyl- C2-C8 alkenyl-C0-C3-alkyl-, -C0-C3alkyl- cycloalkyl-C0-C3alkyl- C2-C8 alkenyl-C0-C3-alkyl-, -Co-Csalkyl-heteroaryl-Co-Qalkyl- C2- C8 alkynyl-Co-Cs-alkyl-, -C0-C3alkyl-aryl-C0-C3alkyl- C2-C8 alkynyl-Co-Cralkyl-, -C0- C3alkyl-heterocyclyl-C0-C3alkyl- C2-C8 alkynyl-Co-C3-alkyl- and -C0-C3alkyl-cycloalkyl- Co-C3alkyl- C2-C8 alkynyl-Co-Cs-alkyl-, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl moiety is optionally substituted; and when W is N, Z is further selected from the group consisting of -Q-Csalkyl-CCO)-, -C1-C8 alkyl-S(O)2-, -aryl-C0-C8 alkyl-S(O)2-, -heteroaryl-Co-Cs alkyl-S(O)2-, -cycloalkyl-Co-Cs alkyl-S(O)2-, -heterocycloalkyl-C0-C8 alkyl-S(O)2-, -C1-C8 alkyl-CH=,-CrC8 alkyl- C(CH3)=, -C0-C6alkyl-CH=CH-C(O), -C0-C4alkyl-C(O)-, -C1-C8 alkyl-(NH2)C=, -C0-
C3alkyl-CrC8heteroalkyl-Co-C3alkyl-C(0)-, -C0-C3alkyl-C2-C8alkenyl-C0-C3alkyl-C(O)-, -C0-C3alkyl-C2-C8alkynyl-C0-C3alkyl-C(O)-, -C0-C6alkyl-aryl-C0-C6alkyl-C(O)-, -C0- C6alkyl-aryl-C2-C6heteroalkyl-C(O)-, -C0-C6alkyl-cycloalkyl-C0-C6alkyl-C(O)-, -C0- C6alkyl-cycloalkyl-C2-C6heteroalkyl-C(O)-, -C4-C6heterocyclyl-aryl-C0-C6alkyl-C(O)-, -C4-C6heterocyclyl-aryl-Co-C6heteroalkyl-C(0)-, -Co-C6alkyl-C4-C6-heterocyclyl-Co-
C6alkyl-C(O)-, -C0-C6alkyl-C4-C6-heterocyclyl-C0-C6heteroalkyl-C(O)-, -C0-C6-alkyl- heteroaryl-Co-C6alkyl-C(0)-, -C0-C6-alkyl-heteroaryl-Co-C6heteroalkyl-C(0)-, -C4- C6heterocyclyl-heteroaryl-Co-C6alkyl-C(0)-, -C4-C6heterocyclyl-heteroaryl-Co-C6hetero- alkyl-C(O)-, -C0-C6alkyl-aryl-C3-C6alkynyl-C(O)-, -C0-C6alkyl-heteroaryl-C2-C6alkynyl- C(O)-, -Co-C6alkyl-cycloalkyl-C3-C6alkynyl-C(0)-, -Co-C6alkyl-heterocyclyl-C3-
C6alkynyl-C(O)-, -C0-C6alkyl-aryl-C2-C6alkynyl-C2-C6alkenyl-C(O)-, -C0-C6alkyl-aryl- C2-C6alkenyl-C(O)-, -C0-C6alkyl-heteroaryl-C2-C6alkenyl-C(O)-, -Co-Cealkyl-cycloalkyl- C2-C6alkenyl-C(O)-, -C0-C6alkyl-heterocyclyl-C2-C6alkenyl-C(O)-, -Co-Cβalkyl-aryl-aryl- C0-C6alkyl-C(O)-, -C0-C6alkyl-aryl-heteroaryl-C0-C6alkyl-C(O)-, -Co-Cealkyl-heteroaryl- aryl-Co-C6-alkyl-C(0)- and -Co-C6alkyl-heteroaryl-heteroaryl-C0-C6-alkyl-C(0)-; or Z-W is selected from the group consisting of -C1-C8 alkyl-(NH2)C=N-, -C1-8alkyl-C=N- and
-C1-8alkyl-C(CH3)=N-, when Rc is absent; L is selected from the group consisting of a covalent bond, -Q-Cόalkyl-, -C0-C6alkyl- (CR3=CR3)1-2-C0-C6alkyl-, -C0-C6alkyl-(C≡C)1-2-C0-C6alkyl-, -C0-C6alkyl-aryl-C0- C6alkyl-, -Co-Qalkyl-heteroaryl-Co-Cealkyl-, -Co-Csalkyl-heterocyclyl-Co-Qalkyl-, -C0- C3alkyl-cycloalkyl-C0-C3alkyl-, -Co-C6alkyl-aryl-(CR3=CR3)1-2-Co-C6alkyl-, -C0-C6 alkyl- aryl-(C≡C)1-2-C0-C6alkyl-, -C0-C6alky-heteroaryl-(CR3=CR3)1-2-C0-C6alkyl-, -C0-C6 alkyl- heteroaryl-(C≡C)i-2-C0-C6alkyl-, -C0-C6alkyl-N(R3)-C(O)-C0-C3alkyl-, -C0-C6alkyl-N(R3)-
C(S)-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(O)-alkenyl-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(S)- alkenyl-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(O)-alkynyl-C0-C3alkyl-, -C0-C6alkyl-N(R3)- C(S)-alkynyl-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-N(R3)-C(O)-, -C0-C6alkyl- N(R3)-C(S)-d-C3alkyl-N(R3)-C(O)-, -C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-N(R3)-C(O)- C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-N(R3)-C(O)-C0-C3alkyl-, -C0-C6alkyl-
N(R3)-C(O)-C1-C3alkyl-N(R3)-C(S)-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl- N(R3)-C(S)-C0-C3alkyl-, -C0-C6alkyl-C(O)-N(R3)-C0-C3alkyl-, -C0-C6alkyl-C(S)-N(R3)- C0-C3alkyl-, -C0-C6alkyl-C(O)-N(R3)-C2-C4alkyl-O-C0-C3alkyl-, -C0-C6alkyl-C(S)-N(R3)- C2-C4alkyl-O-C0-C3alkyl-, -C0-C6alkyl-C(O)-N(R3)-C2-C4alkyl-N(R3)-C0-C3alkyl-, -C0- C6alkyl-C(S)-N(R3)-C2-C4alkyl-N(R3)-C0-C3alkyl-, -C0-C6alkyl-C(O)-C0-C3alkyl-, -C0-
C6alkyl-C(NOH)-C0-C3alkyl-, -C0-C6alkyl-C(O)-alkenyl-C0-C3alkyl-, -C0-C6alkyl- C(NOH)-alkenyl-C0-C3alkyl-, -C0-C6alkyl-S(O)2-N(R3)-C0-C3alkyl-, -C0-C6alkyl-N(R3)- S(O)2-C0-C3alkyl-, -Co-C3alkyl-N(R3)-S(0)2-N(R3)-C0-C3alkyl-, -C0-C6alkyl-C(O)-N(R3)- S(0)2-C0-C3alkyl-,-C0-C6alkyl-N(R3)-Co-C3alkyl-, -Co-C6alkyl-N(R3)-C1-C3alkyl-alkenyl-, -Co-C6alkyl-N(R3)-C1-C3alkyl-alkynyl-, -C0-C6alkyl-N(R7)-C0-C3alkyl-, -C0-C6alkyl-
N(R7)-C1-C3alkyl-alkenyl-, -Co-Cealkyl-NCR^-d-Csalkyl-alkynyl-, -C0-C6alkyl-N(R3)-C2- C4alkyl-N(R3)-C(0)-alkyl-, -Co-C6alkyl-N(R3)-C2-C4alkyl-N(R3)-C(S)-alkyl-, -C0-C6alkyl- O-C2-C4alkyl-N(R3)C(O)-C0-C3alkyl-, -C0-C6alkyl-S-C2-C4alkyl-N(R3)C(O)-C0-C3alkyl-, -C0-C6alkyl-O-C2-C4alkyl-N(R3)C(S)-C0-C3alkyl-, -C0-C6alkyl-S-C2-C4alkyl-N(R3)C(S)- C0-C3alkyl-, -Co-C6alkyl-N(R3)-C2-C3heteroalkyl-, -C0-C6alkyl-N(R7)-C2-C3heteroalkyl-,
-C0-C6alkyl-C(O)-N(R3)-C2-C3heteroalkyl-, -C0-C6alkyl-C(S)-N(R3)-C2-C3heteroalkyl-, -C0-C6alkyl-C(O)-N(R7)-C2-C3heteroalkyl-, -C0-C6alkyl-C(S)-N(R7)-C2-C3heteroalkyl-, -Co-C6alkyl-N(R3)-C(0)-C0-C3heteroalkyl-, -C0-C6alkyl-N(R3)-C(S)-C0-C3heteroalkyl-, -Co-C6alkyl-N(R7)-C(0)-C0-C3heteroalkyl-, -C0-C6alkyl-N(R7)-C(S)-C0-C3heteroalkyl-, -Co-Cealkyl-S-Co-Csalkyl-, -Co-Cealkyl-O-QrC.alkyl-, -C0-C6alkyl-S(O)-C0-C3alkyl-, -C0- C6alkyl-S(O)2-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(O)-N(R3)-C0-C3alkyl-, -C0-C6alkyl- N(R3)-C(S)-N(R3)-C0-C3alkyl-, -Co-Cealkyl-O-Co-Qalkyl-heterocyclyl-, -C0-C6alkyl-O- C0-C3alkyl-cycloalkyl-, -C0-C6alkyl-S(0)o-2-C0-C3alkyl-heterocycly-, -C0-C6alkyl-S(O)0-2- Co-Csalkyl-cycloalkyl-, -C0-C6alkyl-N(R3)-C0-C3alkyl-heterocycly-, -C0-C6alkyl-N(R3)-
C0-C3alkyl-cycloalkyl-, -heterocyclyl-Co-Cealkyl-O-Co-Csalkyl-, -cycloalkyl-C0-C6alkyl- 0-Co-C3alkyl-, -heterocyclyl-C0-C6alkyl-S(O)0-2-C0-C3alkyl-, -cycloalkyl-C0-C6alkyl- S(0)o-2-Co-C3alkyl-, -heterocyclyl-C0-C6alkyl-N(R3)-C0-C3alkyl-, -cycloalkyl-C0-C6alkyl- N(R3)-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(O)-O-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(S)-O- C0-C3alkyl-, -C0-C6alkyl-O-C(O)-N(R3)-C0-C3alkyl-, -C0-C6alkyl-O-C(S)-N(R3)-C0-
C3alkyl-, -Co-C3alkyl-N(R3)-C(0)-0-heterocyclyl-Co-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-0- heterocyclyl-Co-C3alkyl-, -Co-C3alkyl-N(R3)-C(0)-0-cycloalkyl-C0-C3alkyl-, -C0-C3alkyl- N(R3)-C(S)-O-cycloalkyl-C0-C3alkyl-, -C0-C6alkyl-S(O)2-heterocyclyl-C0-C3alkyl-, -C0- C6alkyl-S(O)2-cycloalkyl-C0-C3alkyl-, -C0-C6 alkyl-N(R3)-S(O)2-heterocyclyl-C0-C3alkyl-, -C0-C6 alkyl-N(R3)-S(O)2-cycloalkyl-C0-C3alkyl-, -C0-C3alkyl-heterocyclyl-C0-C3alkyl-O-
C0-C3alkyl-, -C0-C3alkyl-cycloalkyl-C0-C3alkyl-O-C0-C3alkyl-, -C0-C3alkyl-heterocyclyl- Co-C5alkyl-N(R3)-Co-C3alkyl-, -Co-C3alkyl-cycloalkyl-C0-C5alkyl-N(R3)-Co-C3alkyl-, -C0- C3alkyl-0-C0-C3alkyl-heterocyclyl-Co-C3alkyl-, -Co-Caalkyl-O-Co-Qalkyl-cycloalkyl-Co- C3alkyl-, -Co-Csalkyl-heterocyclyl-Co-Csalkyl-S-Co-Caalkyl-, -Co-C3alkyl-cycloalkyl-Co- C3alkyl-S-C0-C3alkyl-, -C0-C3alkyl-N(R3)-C0-C3alkyl-heterocyclyl-C0-C3alkyl-, -C0-
C3alkyl-N(R3)-C0-C3alkyl-cycloalkyl-C0-C3alkyl-, -C0-C3alkyl-S-C0-C3alkyl-heterocyclyl- C0-C3alkyl-, -Co-C3alkyl-S-C0-C3alkyl-cycloalkyl-Co-C3alkyl-, -C0-C3alkyl-S(O)2N(R3)- Co-C3alkyl-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl-S(0)2N(R3)-Co-C3alkyl-cycloalkyl-Co- C3alkyl-, -C0-C3alkyl-C(0)-N(R3)-Co-C3alkyl-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl-C(O)- N(R3)-C0-C3alkyl-cycloalkyl-Co-C3alkyl-, -C0-C3alkyl-C(S)-N(R3)-C0-C3alkyl-hetero- cyclyl-C0-C3alkyl-, -C0-C3alkyl-C(S)-N(R3)-C0-C3alkyl-cycloalkyl-Co-C3alkyl-, -C0- C3alkyl-C(O)-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl-C(O)-cycloalkyl-C0-C3alkyl-, -C0- C3alkyl-O-C(O)-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl-O-C(O)-cycloalkyl-C0-C3alkyl-, -Co-C3alkyl-0-C(0)-N(R3)-C0-C3alkyl-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl-O-C(O)- N(R3)-Co-C3alkyl-cycloalkyl-C0-C3alkyl-, -C0-C3alkyl-O-C(S)-N(R3)-C0-C3alkyl-hetero- cyclyl-C0-C3alkyl-, -C0-C3alkyl-O-C(S)-N(R3)-C0-C3alkyl-cycloalkyl-C0-C3alkyl-, -C0- C3alkyl-N(R3)-C(O)-N(R3)-C0-C3alkyl-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- N(R3)-C0-C3alkyl-cycloalkyl-Co-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-N(R3)-C0-C3alkyl- heterocyclyl-Co-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-N(R3)-C0-C3alkyl-cycloalkyl-Co- C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- cycloalkyl-Co-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl- N(R3)-C(S)-cycloalkyl-C0-C3alkyl-, -C0-C3alkyl-N(R3)-S(0)2-N(R3)-Co-C3alkyl-hetero- cyclyl-C0-C3alkyl-, -C0-C3alkyl-N(R3)-S(O)2-N(R3)-C0-C3alkyl-cycloalkyl-C0-C3alkyl-, -Co-C6alkyl-heterocyclyl-C(0)-Co-C6alkyl-, -C0-C6alkyl-cycloalkyl-C(0)-Co-C6alkyl-,
-Co-C6alkyl-N(R3)-C(0)-heterocyclyl-C(0)-C0-C6alkyl-, -C0-C6alkyl-N(R3)-C(O)- cycloalkyl-C(O)-C0-C6alkyl-, -C0-C6alkyl-N(R3)-C(S)-heterocyclyl-C(O)-C0-C6alkyl-, -Co-C6alkyl-N(R3)-C(S)-cycloalkyl-C(0)-C0-C6alkyl-, -C0-C6alkyl-heterocyclyl-S(O)2-C0- Cβalkyl-, -C0-C6alkyl-cycloalkyl-S(O)2-C0-C6alkyl-, -C0-C6alkyl-heterocyclyl-N(R3)- C(0)-Co-C6alkyl-, -Co-C6alkyl-cycloalkyl-N(R3)-C(0)-Co-C6alkyl-, -C0-C6alkyl-hetero- cyclyl-O-C(O)-C0-C6alkyl-, -C0-C6alkyl-cycloalkyl-O-C(O)-C0-C6alkyl-, -C0-C6alkyl- heterocyclyl-N(R3)-C(S)-C0-C6alkyl-, -Co-C6alkyl-cycloalkyl-N(R3)-C(S)-Co-C6alkyl-, -Co-C6alkyl-heterocyclyl-0-C(S)-C0-C6alkyl-, -C0-C6alkyl-cycloalkyl-O-C(S)-C0-C6alkyl-, -Co-C3alkyl-CH=N-0-C0-C3alkyl-, -C0-C3alkyl-C=N(OH)C(O)-N(R3)-C2-C4-alkyl-S-S- alkyl-, -C0-C6alkyl-heteroalkyl-Co-C6alkyl-C(0)-N(R3)-C0-C3alkyl-, -C0-C6alkyl-hetero- alkyl-Co-C6alkyl-C(S)-N(R3)-Co-C3alkyl-, -Co-Cealkyl-aryl-heteroaryl-Co-Cealkyl-, -C0- Cealkyl-heteroaryl-aryl-Co-Coalkyl-, -Co-Cealkyl-heteroaryl-heteroaryl-Co-Cδalkyl-, -Co- C6alkyl-aryl-aryl-Co-C6alkyl-, -Ci-C3alkyl-N(R3)-C(O)-C1-C7alkyl-, -d-C3alkyl-N(R3)- C(S)-C1-C7alkyl-, -C0-C3alkyl-alkenyl-C(O)-C0-C6alkyl-, -C0-C6alkyl-N(R3)-C(O)-N(R3)- S(0)0-2-Co-C3alkyl-, -C0-C3alkyl-O-aryl-C0-C6 alkyl-N(R3)-C(O)-C!-C3 alkyl-, -C0-
C3alkyl-S-aryl-C0-C6 alkyl-N(R3)C(O)-d-C3 alkyl-, -C0-C3alkyl-O-aryl-C0-C6 alkyl- N(R3)C(S)-C!-C3 alkyl-, -Co-Qalkyl-S-aryl-Co-Qs alkyl-N(R3)C(S)-C1-C3 alkyl-, -C0- C3alkyl-O-heteroaryl-C0-C6 alkyl-N(R3)-C(O)-d -C3alkyl-, -Co-C3alkyl-S-heteroaryl-C0- C6 alkyl-N(R3)-C(O)-d-C3alkyl-, -C0-C3alkyl-O-heteroaryl-C0-C6 alkyl-N(R3)-C(S)-d- C3alkyl-, -C0-C3alkyl-S-heteroaryl-C0-C6 alkyl-N(R3)-C(S)-d-C3alkyl-, -C0-C3alkyl-O- heterocyclyl-C0-C6 alkyl-N(R3)-C(O)-d-C3alkyl-, -C0-C3alkyl-S-heterocyclyl-C0-C6 alkyl-N(R3)-C(O)-d-C3alkyl-, -C0-C3alkyl-O-heterocyclyl-C0-C6 alkyl-N(R3)-C(S)-d- C3alkyl-, -Co-Csalkyl-S-heterocyclyl-Co-Ce alkyl-N(R3)-C(S)-d-C3alkyl-, -C0-C3alkyl-O- cycloalkyl-C0-C6alkyl-N(R3)-C(O)-d-C3alkyl-, -Co-C3alkyl-S-cycloalkyl-Co-C6alkyl- N(R3)-C(O)-d-C3alkyl-, -C0-C3alkyl-0-cycloalkyl-Co-C6alkyl-N(R3)-C(S)-d-C3alkyl-,
-C0-C3alkyl-S-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3 alkyl-N(R3)-aryl-C0- C6alkyl-N(R3)-C(O)-d-C3alkyl-, -C0-C3alkyl-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-d- C3alkyl-, -Co-C3alkyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -Co-C3alkyl- N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)-heterocyclyl-C0- C6alkyl-N(R3)-C(O)-C1-C3 alkyl-, -C0-C3alkyl-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)- C(S)-C1-C3 alkyl-, -C0-C3alkyl-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-cycloalkyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)- C(0)-0-aryl-Co-C6alkyl-N(R3)-C(0)-CrC3alkyl-, -C0-C3alkyl-N(R3)-C(S)-O-aryl-C0- C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-S-aryl-C0-C6alkyl-N(R3)-C(O)- d-C3alkyl-, -C0-C3alkyl-N(R3)-C(0)-0-aryl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-N(R3)-C(S)-0-aryl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- S-aryl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-O-heteroaryl-C0- C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -Co-C3alkyl-N(R3)-C(S)-0-heteroaryl-C0-C6alkyl-N(R3)- C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-S-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-
C3alkyl-, -C0-C3alkyl-N(R3)-C(0)-0-heteroaryl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-N(R3)-C(S)-0-heteroaryl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)- C(O)-O-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-O- heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-O-hetero- cyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-O-heterocyclyl-C0-
C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-O-cycloalkyl-C0-C6alkyl-
N(R3)-C(O)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-O-cycloalkyl-C0-C6alkyl-N(R3)-C(O)- d-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-O-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-O-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl- C(O)-N(R3)-aryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-C(S)-N(R3)-aryl-C0-
C6alkyl-N(R3)-C(O)-d-C3alkyl-, -C0-C3alkyl-C(O)-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)- d-C3alkyl-, -C0-C3alkyl-C(S)-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-d-C3alkyl-, -C0- C3alkyl-C(O)-N(R3)-heteroaryl-C0-C6alkyl-N(R3)C(O)-d-C3alkyl-, -C0-C3alkyl-C(S)- N(R3)-heteroaryl-C0-C6alkyl-N(R3)C(O)-Ci-C3alkyl-, -C0-C3alkyl-C(O)-N(R3)-heteroaryl- C0-C6alkyl-N(R3)C(S)-d-C3alkyl-, -C0-C3alkyl-C(S)-N(R3)-heteroaryl-C0-C6alkyl-
N(R3)C(S)-d-C3alkyl-, -Co-C3alkyl-C(0)-N(R3)-heterocyclyl-Co-C6alkyl-N(R3)-C(0)-d- C3alkyl-, -Co-C3alkyl-C(S)-N(R3)-heterocyclyl-Co-C6alkyl-N(R3)-C(0)-d-C3alkyl-, -C0- C3alkyl-C(O)-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-d-C3alkyl-, -C0-C3alkyl-C(S)- N(R3)-heterocyclyl-Co-C6alkyl-N(R3)-C(S)-d-C3alkyl-, -C0-C3alkyl-C(O)-N(R3)- cycloalkyl-C0-C6alkyl-N(R3)-C(O)-d-C3alkyl-, -C0-C3alkyl-C(S)-N(R3)-cycloalkyl-C0-
C6alkyl-N(R3)-C(O)-d-C3alkyl-, -C0-C3alkyl-C(O)-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)- C(S)-d-C3alkyl-, -C0-C3alkyl-C(S)-N(R3)-cycloalkyl-Co-C6alkyl-N(R3)-C(S)-d-C3alkyl-, -Co-C3alkyl-0-C(0)-N(R3)-aryl-C0-C6alkyl-N(R3)-C(0)-d-C3alkyl-, -C0-C3alkyl-O-C(S)- N(R3)-aryl-C0-C6alkyl-N(R3)-C(O)-Ci-C3alkyl-, -C0-C3alkyl-O-C(O)-N(R3)-aryl-C0- C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -Co-C3alkyl-0-C(S)-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)- Ci-C3alkyl-, -C0-C3alkyl-O-C(O)-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -Co-C3alkyl-0-C(S)-N(R3)-heteroaryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-O- C(O)-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-O-C(S)-N(R3)- heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-O-C(O)-N(R3)-heterocyclyl-
Co-C6alkyl-N(R3)-C(0)-CrC3alkyl-, -C0-C3alkyl-O-C(S)-N(R3)-heterocyclyl-C0-C6alkyl- N(R3)-C(O)-d-C3alkyl-, -C0-C3alkyl-O-C(O)-N(R3)-heterocylcyl-C0-C6alkyl-N(R3)-C(S)- d-C3alkyl-, -C0-C3alkyl-O-C(S)-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -Co-C3alkyl-0-C(0)-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -Co-C3alkyl- O-C(S)-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(O)-Ci-C3alkyl-, -C0-C3alkyl-O-C(O)-
N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-O-C(S)-N(R3)- cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-N(R3)-aryl-C0-C6alkyl- N(R3)-C(O)-C!-C3alkyl-, -C0-C3alkyl-S(O)2-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-Ci-
C3alkyl-, -C0-C3 alkyl-S(O)2-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3 alkyl-S(0)2-N(R3)-heteroaryl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-
N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-Ci-C3alkyl-, -C0-C3alkyl-S(O)2-N(R3)-hetero- cyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-N(R3)-cycloalkyl-C0-
C6alkyl-N(R3)-C(O)-Ci-C3alkyl-, -C0-C3alkyl-S(O)2-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)- C(S)-d-C3alkyl-, -C0-C3alkyl-N(R3)-S(O)2-N(R3)-aryl-C0-C6alkyl-N(R3)-C(O)-C1- C3alkyl-, -C0-C3alkyl-N(R3)-S(O)2-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-
C3alkyl-N(R3)-S(O)2-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl- N(R3)-S(O)2-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)- S(O)2-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-S(O)2- N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-S(O)2-N(R3)- cycloalkyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)- S(O)2-N(R3)- cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-heterocyclyl-O-aryl-C0-
C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-heterocyclyl-S-aryl-C0-C6alkyl-N(R3)-C(O)- d-C3alkyl-, -C0-C3alkyl-heterocyclyl-O-aryl-C0-C6alkyl-N(R3)-C(S)-d-C3alkyl-, -C0- C3alkyl-heterocyclyl-S-aryl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-heterocyclyl- 0-heteroaryl-Co-C6alkyl-N(R3)-C(0)-d-C3alkyl-, -Co-Csalkyl-heterocyclyl-S-heteroaryl-
C0-C6alkyl-N(R3)-C(O)-d-C3alkyl-, -Co-Csalkyl-heterocyclyl-O-heteroaryl-Co-Cealkyl- N(R3)-C(S)-d-C3alkyl-, -C0-C3alkyl-heterocyclyl-S-heteroaryl-C0-C6alkyl-N(R3)-C(S)- d-C3alkyl-, -C0-C3alkyl-heterocyclyl-O-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-
C3alkyl-, -C0-C3alkyl-heterocyclyl-S-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-heterocyclyl-0-heterocyclyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl- heterocyclyl-S-heterocyclyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3 alkyl-hetero- cyclyl-0-cycloalkyl-Co-C6alkyl-N(R3)-C(0)-CrC3alkyl-, -Co-Qalkyl-heterocyclyl-S- cycloalkyl-Co-C6alkyl-N(R3)-C(0)-CrC3alkyl-, -C0-C3alkyl-heterocyclyl-O-cycloalkyl- C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-heterocyclyl-S-cycloalkyl-C0-C6alkyl-
N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-O-aryl-C0-C6alkyl-N(R3)-C(O)- d-Csalkyl-, -C0-C3alkyl-C(S)-heterocyclyl-0-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -Co-C3alkyl-C(0)-heterocyclyl-S-aryl-C0-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl- C(O)-heterocyclyl-O-aryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-C(S)-hetero- cyclyl-S-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl-O-aryl-
C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -Co-C3alkyl-C(0)-heterocyclyl-S-aryl-C0-C6alkyl- N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl-S-aryl-C0-C6alkyl-N(R3)-C(S)-C1- C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-O-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-
C3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl-O-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1- C3alkyl-, -Co-C3alkyl-C(0)-heterocyclyl-S-heteroaryl-C0-C6alkyl-N(R3)-C(0)-C1-
C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-O-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-
C3alkyl-, -Co-C3alkyl-C(S)-heterocyclyl-S-heteroaryl-C0-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -Co-C3alkyl-C(S)-heterocyclyl-0-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-C(O)-heterocyclyl-S-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl- C(S)-heterocyclyl-S-heteroaryl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-C(O)- heterocyclyl-0-heterocyclyl-Co-C6alkyl-N(R3)-C(0)-C i -C3alkyl-, -Co-C3alkyl-C(S)- heterocyclyl-0-heterocyclyl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-C(O)- heterocyclyl-S-heterocyclyl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-C(O)- heterocyclyl-0-heterocyclyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -Co-C3alkyl-C(S)-hetero- cyclyl-S-heterocyclyl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl-
0-heterocyclyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-S- heterocyclyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl-S-hetero- cyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-O-cycloalkyl- C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl-O-cycloalkyl-C0- C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-S-cycloalkyl-C0-C6alkyl-
N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-O-cycloalkyl-C0-C6alkyl-N(R3)- C(S)-Cj-C3alkyl-, -Co-C3alkyl-C(S)-heterocyclyl-S-cycloalkyl-Co-C6alkyl-N(R3)-C(0)-C1- C3alkyl-, -Co-C3alkyl-C(S)-heterocyclyl-0-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-C(0)-heterocyclyl-S-cycloalkyl-Co-C6alkyl-N(R3)-C(S)-CrC3alkyl-, -C0- C3alkyl-C(S)-heterocyclyl-S-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl- N(R3)-C(O)-heterocyclyl-O-aryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)- C(S)-heterocyclyl-0-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- heterocyclyl-S-aryl-Co-C6alkyl-N(R3)-C(0)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heteτo- cyclyl-0-aryl-Co-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-
S-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-O-aryl- Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-S-aryl-C0- C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-S-aryl-C0-C6alkyl- N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-O-heteroaryl-C0-C6alkyl- N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-0-heteroaryl-Co-C6alkyl-
N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(0)-heterocyclyl-S-heteroaryl-Co-C6alkyl- N(R3)-C(O)-d-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-O-heteroaryl-C0-C6alkyl- N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-S-heteroaryl-C0-C6alkyl- N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-O-heteroaryl-C0-C6alkyl- N(R3)-C(S)-C1-C3alkyl-, -Co-C3alkyl-N(R3)-C(0)-heterocyclyl-S-heteroaryl-C0-C6alkyl-
N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-S-heteroaryl-C0-C6alkyl- N(R3)-C(S)-CrC3alkyl-, -C0-C3alkyl-N(R3)-C(0)-heterocyclyl-0-heterocyclyl-Co-
C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-O-heterocyclyl- C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-S-hetero- cyclyl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-O- heterocyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-S- heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl- O-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-hetero- cyclyl-S-heterocyclyl-Co-C6alkyl-N(R3)-C(S)-CrC3alkyl-, -C0-C3alkyl-N(R3)-C(S)- heterocyclyl-S-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- heterocyclyl-0-cycloalkyl-Co-C6alkyl-N(R3)-C(0)-Cj-C3alkyl-, -Co-C3alkyl-N(R3)-C(S)- heterocyclyl-0-cycloalkyl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- heterocyclyl-S-cycloalkyl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- heterocyclyl-O-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)- heterocyclyl-S-cycloalkyl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -Co-C3alkyl-N(R3)-C(S)- heterocyclyl-O-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- heterocyclyl-S-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)- heterocyclyl-S-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-hetero- cyclyl-0-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-S-aryl- C0-C6alkyl-N(R3)-C(O)-CrC3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-O-aryl-C0-C6alkyl- N(R3)-C(S)-d-C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-S-aryl-C0-C6alkyl-N(R3)-C(S)- d-Qalkyl-, -C0-C3alkyl-S(0)2-heterocyclyl-0-heteroaryl-Co-C6alkyl-N(R3)-C(0)-C1- C3alkyl-, -C0-C3alkyl-S(0)2-heterocyclyl-S-heteroaryl-Co-C6alkyl-N(R3)-C(0)-C1- C3alkyl-, -Co-C3alkyl-S(0)2-heterocyclyl-0-heteroaryl-Co-C6alkyl-N(R3)-C(S)-C1-
C3alkyl-, -C0-C3alkyl-S(0)2-heterocyclyl-S-heteroaryl-Co-C6alkyl-N(R3)-C(S)-C1-
C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-O-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-
C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-S-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-Ci-
C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-O-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-C1- C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-S-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-C1-
C3alkyl-, -Co-C3alkyl-S(0)2-heterocyclyl-0-cycloalkyl-C0-C6alkyl-N(R3)-C(0)-C i -
C3alkyl-, -Co-C3alkyl-S(0)2-heterocyclyl-S-cycloalkyl-C0-C6alkyl-N(R3)-C(0)-C1-
C3alkyl-, -C0-C3alkyl-S(0)2-heterocyclyl-0-cycloalkyl-Co-C6alkyl-N(R3)-C(S)-Cr
C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-S-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1- C3alkyl-, -Co-C3alkyl-heterocyclyl-N(R3)-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-
C3alkyl-heterocyclyl-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-hetero- cyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-heterocyclyl- N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-heterocyclyl-N(R3)- heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C i -C3alkyl-, -C0-C3alkyl-heterocyclyl-N(R3)-hetero- cyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -Co-C3alkyl-heterocyclyl-N(R3)-cycloalkyl-C0-
C6alkyl-N(R3)-C(O)-CrC3alkyl-, -C0-C3alkyl-heterocyclyl-N(R3)-cycloalkyl-C0-C6alkyl- N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-N(R3)-aryl-C0-C6alkyl-N(R3)- C(O)-d-C3alkyl-, -Co-C3alkyl-C(S)-heterocyclyl-N(R3)-aryl-C0-C6alkyl-N(R3)-C(0)-Cr C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-
C3alkyl-C(O)-heterocyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0- C3alkyl-C(S)-heterocyclyl-N(R3)-heteroaryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0- C3alkyl-C(O)-heterocyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-C(S)-heterocyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-C(O)-heterocyclyl-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-
C3alkyl-C(S)-heterocyclyl-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0- C3alkyl-C(O)-heterocyclyl-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-C(S)-heterocyclyl-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-C(O)-heterocyclyl-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0- C3alkyl-C(S)-heterocyclyl-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0- C3alkyl-C(0)-heterocyclyl-N(R3)-cycloalkyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-C(S)-heterocyclyl-N(R3)-cycloalkyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-N(R3)-C(0)-heterocyclyl-N(R3)-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0- C3alkyl-N(R3)-C(S)-heterocyclyl-N(R3)-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-
C3alkyl-N(R3)-C(0)-heterocyclyl-N(R3)-aryl-Co-C6alkyl-N(R3)-C(S)-Cj-C3alkyl-, -C0- C3alkyl-N(R3)-C(S)-heterocyclyl-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-N(R3)-C(0)-heterocyclyl-N(R3)-heteroaryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1- C3alkyl-, -Co-C3alkyl-N(R3)-C(0)-heterocyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(S)-
C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)- C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-N(R3)-heterocyclyl-C0-C6alkyl- N(R3)-C(O)-C!-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-N(R3)-heterocyclyl-C0- C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-N(R3)-hetero- cyclyl-Co-C6alkyl-N(R3)-C(S)-CrC3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-N(R3)- heterocyclyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl- N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(O)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-hetero- cyclyl-N(R3)-cycloalkyl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- heterocyclyl-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)- C(S)-heterocyclyl-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-
S(0)2-heterocyclyl-N(R3)-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-S(O)2- heterocyclyl-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-CrC3alkyl-, -C0-C3alkyl-S(O)2-hetero- cyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-hetero- cyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(S)-CrC3alkyl-, -C0-C3alkyl-S(O)2-hetero- cyclyl-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-hetero- cyclyl-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-hetero- cyclyl-N(R3)-cycloalkyl-Co-C6alkyl-N(R3)-C(0)-CrC3alkyl-, -C0-C3alkyl-S(O)2-hetero- cyclyl-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C6alkyl-N(R3)-C(O)-C0- C6alkyl-heterocycloalkyl-C(O)-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(S)-C0-C6alkyl-hetero- cycloalkyl-C(O)-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(O)-C0-C6alkyl-heterocycloalkyl-C(S)-
C0-C3alkyl-, -Co-C6alkyl-N(R3)-C(S)-C0-C6alkyl-heterocycloalkyl-C(S)-Co-C3alkyl-, -C0- C6alkyl-N(R3)-C(O)-C0-C6alkyl-heterocycloalkyl-C(O)-N(R3)-C0-C3alkyl-, -C0-C6alkyl- N(R3)-C(S)-C0-C6alkyl-heterocycloalkyl-C(O)-N(R3)-C0-C3alkyl-, -C0-C6alkyl-N(R3)- C(O)-C0-C6alkyl-heterocycloalkyl-C(S)-N(R3)-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(S)-C0- C6alkyl-heterocycloalkyl-C(S)-N(R3)-Co-C3alkyl-, -Co-C6alkyl-C(0)-C0-C6alkyl-hetero- cycloalkyl-C(O)-N(R3)-C0-C3alkyl-, -C0-C6alkyl-C(S)-C0-C6alkyl-heterocycloalkyl-C(O)-
N(R3)-C0-C3alkyl-, -C0-C6alkyl-C(O)-C0-C6alkyl-heterocycloalkyl-C(S)-N(R3)-C0-
C3alkyl-, -Co-C6alkyl-C(S)-C0-C6alkyl-heterocycloalkyl-C(S)-N(R3)-Co-C3alkyl-, -C0- C6alkyl-O-C0-C3alkyl-C(O)-N(R3)-C0-C3alkyl- and -C0-C6alkyl-O-C(S)-N(R3)-C0-
C3alkyl-, wherein 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-C0-C3alkyl-O-C0-C3alkyl-aryl, aryl-Co-C3alkyl-S(0)0-2-C0- C3alkyl-aryl, -C0-C3alkyl-S(O)0-2-C0-C3alkyl-aryl, aryl-C0-C3alkyl-N(R3)-C0-C3alkyl-aryl, aryl-Co-C3alkyl-C(0)-N(R3)-Co-C3alkyl-aryl, aryl-Co-C3alkyl-C(S)-N(R3)-Co-C3alkyl-aryl, aryl-C0-C3alkyl-N(R3)-C(0)-Co-C3alkyl-aryl, aryl-C0-C3alkyl-N(R3)-C(S)-C0-C3alkyl-aryl, heteroaryl-heteroaryl, heteroaryl-aryl, heteroaryl-arylalkyl, aryl-alkylheteroaryl, hetero- aryl-aryl-aryl, aryl-aryl-aryl, aryl-heteroaryl-aryl, aryl-heteroaryl-heteroaryl, heteroaryl- heteroaryl-heteroaryl, heteroaryl-heteroaryl-aryl, aryl-aryl-heteroaryl, heteroaryl-aryl- arylalkyl, aryl-aryl-alkylheteroaryl, heteroaryl-aryl-alkylaryl, aryl-aryl-alkylaryl, aryl-aryl- arylalkyl, aryl-aryl-heteroarylalkyl, heteroaryl-aryl-heteroaryl, heteroaryl-aryl-hetero- arylalkyl, heteroaryl-aryl-alkylheteroaryl, heteroaryl-heteroarylalkyl, heteroaryl- alkylheteroaryl, heterocyclyl-heteroaryl, cycloalkyl-aryl, cycloalkyl-heteroaryl, heteroaryl- heterocyclyl, heteroaryl-cycloalkyl, aryl-cycloalkyl, heterocyclyl-aryl, aryl-heterocyclyl, heterocyclyl-alkyl-aryl, heterocyclyl-alkylheteroaryl, cycloalkyl-alkylaryl, cycloalkyl- alkylheteroaryl, aryl-alkyl-heterocyclyl, aryl-alkylcycloalkyl, heteroaryl-alkylcycloalkyl, heteroaryl-alkylheterocyclyl, arylalkyl-aryl, aryl-arylalkyl, aryl-heteroarylalkyl, heteroaryl-arylalkyl, heteroaryl-heteroarylalkyl, heteroaryl-C0-C3alkyl-O-C0-C3alkyl-aryl, heteroaryl-Co-C3alkyl-0-C0-C3alkyl-heteroaryl, aryl-C0-C3alkyl-0-Co-C3alkyl-heteroaryl, heteroaryl-Co-C3alkyl-N(R3)-C0-C3alkyl-aryl, aryl-C0-C3alkyl-N(R3)-C0-C3alkyl-hetero- aryl, heteroaryl-Co-C3alkyl-N(R3)-C0-C3alkyl-heteroaryl, heteroaryl-C0-C3alkyl-C(O)-
N(R3)-C0-C3alkyl-aryl, aryl-C0-C3alkyl-C(O)-N(R3)-C0-C3alkyl-heteroaryl, heteroaryl-C0- C3alkyl-C(O)-N(R3)-C0-C3alkyl-heteroaryl, aryl-C0-C3alkyl-C(S)-N(R3)-C0-C3alkyl-aryl, aryl-Co-C3alkyl-C(S)-N(R3)-C0-C3alkyl-heteroaryl, heteroaryl-C0-C3alkyl-C(S)-N(R3)-C0- C3alkyl-aryl, heteroaryl-C0-C3alkyl-C(S)-N(R3)-C0-C3alkyl-heteroaryl, heteroaryl-C0- C3alkyl-N(R3)-C(O)-C0-C3alkyl-aryl, heteroaryl-C0-C3alkyl-N(R3)-C(O)-C0-C3alkyl- heteroaryl, aryl-C0-C3alkyl-N(R3)-C(0)-Co-C3alkyl-heteroaryl, aryl-C0-C3alkyl-N(R3)- C(S)-C0-C3alkyl-aryl, aryl-C0-C3alkyl-N(R3)-C(S)-C0-C3alkyl-heteroaryl, heteroaryl-C0- C3alkyl-N(R3)-C(S)-C0-C3alkyl-aryl, heteroaryl-C0-C3alkyl-N(R3)-C(S)-C0-C3alkyl- heteroaryl, R3-heterocyclyl-C0-C3alkyl, R3-cycloalkyl-C0-C3alkyl, (R3)(R3a)N-C2-C4alkyl-
O-aryl-, (R3)(R38)N-C2-C4alkyl-S(O)0-2-aryl-, (R3)(R3a)N-C2-C4alkyl-O-heteroaryl-, (R3)(R3a)N-C2-C4alkyl-S(0)o-2-heteroaryl-, Co-C3alkyl-aryl-Co-C3alkyl, C0-C3alkyl-hetero- aryl-Co-C3alkyl, aryl-C1-C3alkyl-heteroaryl, aryl-Q-Csalkyl-aryl, heteroaryl-Ci-C3alkyl- aryl, heteroaryl-CrC3alkyl-heteroaryl, R3-heterocyclyl-C0-C3alkyl-N(R3)-C(O)-N(R3)- heteroaryl-, R3-heterocyclyl-Co-C3alkyl-N(R3)-C(O)-N(R3)-aryl-, R3-cycloalkyl-C0-
C3alkyl-N(R3)-C(O)-N(R3)-heteroaryl-, R3-cycloalkyl-Co-C3alkyl-N(R3)-C(O)-N(R3)- aryl-, R3-heterocyclyl-C0-C3alkyl-N(R3)-C(S)-N(R3)-heteroaryl-, R3-heterocyclyl-Co- C3alkyl-N(R3)-C(S)-N(R3)-aryl-, R3-cycloalkyl-C0-C3alkyl-N(R3)-C(S)-N(R3)-heteroaryl-, R3-cycloalkyl-Co-C3alkyl-N(R3)-C(S)-N(R3)-aryl-, heteroaryl-C(O)-C0-C6alkyl-hetero- aryl-, heteroaryl-C(O)-C0-C6alkyl-aryl-, aryl-C(O)-C0-C6alkyl-aryl-, aryl-C(O)-C0-
C6alkyl-heteroaryl-, heteroaryl-C(O)-N(R3)-C0-C6alkyl-aryl-, heteroaryl-C(O)-N(R3)-C0- C6alkyl-heteroaryl-, heteroaryl-S(0)2-Co-C6alkyl-heteroaryl-, heteroaryl-S(0)2-Co-C6alkyl- aryl-, aryl-S(O)0-2-C0-C6alkyl-aryl, aryl-Co-C3alkyl-S(0)o-2-Co-C6alkyl-heteroaryl, R3-O- C(O)-N(R3)-C0-C3alkyl-heteroaryl-, R3-O-C(O)-N(R3)-C0-C3alkyl-aryl-, R3-O-C(S)- N(R3)-C0-C3alkyl-heteroaryl-, R3-O-C(S)-N(R3)-C0-C3alkyl-aryl-, R3-C(O)-heterocyclyl-
C0-C3alkyl-heteroaryl-, R3-C(O)-heterocyclyl-C0-C3alkyl-aryl-, R3-C(O)-cycloalkyl-C0- C3alkyl-heteroaryl-, R3-C(O)-cycloalkyl-C0-C3alkyl-aryl-, R3-heterocyclyl-C0-C3alkyl- N(R3)-C(0)-N(R3)-Co-C3alkyl-heteroaryl-, R3-heterocyclyl-C0-C3alkyl-N(R3)-S(O)2-C0- C3alkyl-heteroaryl-, R3-heterocyclyl-C0-C3alkyl-N(R3)-S(O)2-C0-C3alkyl-aryl-, R3- cycloalkyl-Co-C3alkyl-N(R3)-S(0)2-Co-C3alkyl-heteroaryl-, R3-cycloalkyl-C0-C3alkyl-
N(R3)-S(O)2-C0-C3alkyl-aryl-, R3-heterocyclyl-C0-C3alkyl-N(R3)-C(O)-C0-C3alkyl-hetero- aryl-, R3-heterocyclyl-C0-C3alkyl-N(R3)-C(O)-C0-C3alkyl-aryl-, R3-cycloalkyl-C0-C3alkyl- N(R3)-C(O)-C0-C3alkyl-heteroaryl-, R3-cycloalkyl-C0-C3alkyl-N(R3)-C(O)-C0-C3alkyl- aryl-, R3-heterocyclyl-C0-C3alkyl-N(R3)-C(S)-C0-C3alkyl-heteroaryl-, R3-heterocyclyl-C0- C3alkyl-N(R3)-C(S)-C0-C3alkyl-aryl-, R3-cycloalkyl-C0-C3alkyl-N(R3)-C(S)-C0-C3alkyl- heteroaryl-, R3-cycloalkyl-C0-C3alkyl-N(R3)-C(S)-Co-C3alkyl-aryl-, R3-C(O)-C0-C3alkyl- heteroaryl-, R3-C(O)-C0-C3alkyl-aryl-, heterocyclyl-C(O)-, an aromatic polycycle, a non- aromatic polycycle, a mixed aryl and non-aryl polycycle, a polyheteroaryl, a non-aromatic polyheterocycle, and a mixed aryl and non-aryl polyheterocycle, each of which is optionally substituted with one or more groups selected from R3, R4 or R7; or each Y is independently selected from the group consisting of A2a-aryl-Co-C3alkyl-N(R3)-C(0)-C1-C7alkyl-, wherein the Ci-C7alkyl is optionally substituted with a moiety selected from the group consisting of -N(R3)-C(O)-C1-C5alkyl-(C2- C4alkenyl)0-i-C1-C3alkyl-O-A2b, -N(R3)-C(O)-N(R3)-C !-CSa^yI-(C2-C4 alkenyl^-rd- C3alkyl-O-A2b, -N(R3)-C(0)-0-C1-C5alkyl-(C2-C4alkenyl)o-1-C1-C3alkyl-0-A2b, -N(R3)- C1-C5alkyl-(C2-C4alkenyl)0-1-Ci-C3alkyl-O-A2b, -N(R3)-S(O)2-N(R3)-C1-C5alkyl-(C2- C4alkenyl)0-1-C1-C3alkyl-O-A2b and -N(R3)-S(0)2-C1-C5alkyl-(C2-C4alkenyl)o-rC1-
C3alkyl-O-A2b,
A2a-heteroarylene-Co-C3alkyl-N(R3)-C(0)-C1-C7alkyl-, wherein the d-C7alkyl is optionally substituted with a moeity selected from the group consisting of -N(R3)-C(O)-C1-Csalkyl- (C2-C4alkenyl)o-1-C1-C3alkyl-0-A2b, -N(R3)-C(O)-N(R3)-Ci-C5alkyl-(C2-C4alkenyl)0-1-Cr C3alkyl-O-A2b, -N(R3)-C(0)-0-C1-C5alkyl-(C2-C4alkenyl)o-1-Ci-C3alkyl-0-A2b, -N(R3)-
Ci-C5alkyl-(C2-C4alkenyl)o-1-C1-C3alkyl-0-A2b, -N(R3)-S(O)2-N(R3)-C1-C5alkyl-(C2- C4alkenyl)0-1-C1-C3alkyl-O-A2b and -N(R3)-S(0)2-Ci-C5alkyl-(C2-C4alkenyl)o-1-C1- C3alkyl-O-A2b and
B2-B1-N(R3)-C(O)-Ci-C7alkyl-, wherein the d-C7alkyl is optionally substituted with -NR3- B3 wherein the amine of B3 is connected with the acid of B2 to form a peptide bond; and wherein
A2a and A2b together are a covalent bond and are attached to form a ring; and
B , B and B are each independently a natural or synthetic amino acid and when any of B ,
B and B are linked together they are linked together via a peptide bond; each R3 and R3a are independently selected from the group consisting of -H, -OH, -C(O)H, heterocyclyl, Q-Qalkyl, C2-C6alkenyl, C2-C6alkynyl, -C2-C4alkyl-ORa, -C(O)-O-C2- C4alkyl-NRaRa, heteroalkyl, C0-C6alkylheteroaryl, C(O)CF3, -C(O)-NH2, -C(O)-NH-Cr C6alkyl, -NH2, C3-C6cycloalkyl, -d-C6alkylaryl, heteroaryl-aryl, aryl and alkylheteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and hetero- aryl moiety is optionally substituted; each R is independently selected from the group consisting of -H, -C(NRa)-N(Ra)2, C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -CrC6alkyl-Ra, -C0-C6alkyl-O-Ra, -C0-C6alkyl- S(O)0-2-R3, -C0-C6alkyl-C(O)-ORa, -C0-C6alkyl-C(O)-N(R3)(R3a), -C0-C6alkyl-C(S)- N(R3)(R3a), -CH=CH-C(O)-OR3, -CH=CH-C(O)-N(R3)(R3a), -CH=CH-C(S)-N(R3)(R3a), -N(R3)-C(O)-CF3, -N(R3)-C2-C6alkyl-N(R3)(R3a), -C0-C6alkyl-N(R3)(R3a), -N(R3)-C(O)- Ci-C6alkyl-R3, -N(R3)-C(S)-Ci-C6alkyl-R3, -N(R3)-S(O)2-C1-C6alkyl-R3, -S(O)2-N(R3)R3a, -O-C2-C6alkyl-N(R3)(R3a), -S(O)0-2-C2-C6alkyl-N(R3)(R3a), -S-R3, -S(O)0-2-C2-C6alkyl-R3, -C3-C6cycloalkyl, -C3-C6cycloalkyl-Ra, heterocyclyl, -C4-C7heterocyclyl-Ra, -O-Co- C4alkyl-cycloalkyl, -S(0)o-2-Co-C4alkyl-cycloalkyl, -O-C2-C4alkyl-heterocyclyl (when the alkyl is linked via a N in the heterocyclyl), -O-Co^alkyl-heterocyclyl (when the alkyl is linked via a C in the heterocyclyl), -S(0)0-1-Co-C4alkyl-heterocyclyl (when the alkyl is linked via a C in the heterocyclyl), -S(O)0-1-C2-C4alkyl-heterocyclyl (when the alkyl is linked via a N in the heterocyclyl, -S(O)2-C0-C4alkyl-heterocyclyl, -0-Co-C4alkyl-hetero- cyclyl-C(O)-ORa (when the alkyl is linked via a C in the heterocyclyl, -O-C2-C4alkyl- heterocyclyl-C(O)-ORa (when the alkyl is linked via a N in the heterocyclyl), -O- cycloalkyl-C(O)-OR\ -O-aryl-C(O)-ORa, -O-heteroaryl-C(O)-ORa, -S(O)0-1-C0-C4alkyl- heterocyclyl-C(O)-ORa (when the alkyl is linked via a C in the heterocyclyl), -S(O)0-1-C2- C4alkyl-heterocyclyl-C(O)-ORa (when the alkyl is linked via a N in the heterocyclyl), -S(O)2-C0-C4alkyl-heterocyclyl-C(O)-ORa, -S(O)0-2-cycloalkyl-C(O)-ORa, -S(O)0-2-aryl-
C(O)-OR3, -S(O)0-2-heteroaryl-C(O)-ORa, -O-C0-C4alkyl-aryl, -S(O)0-2-C0-C4alkyl-aryl, -0-Co-C4alkyl-heteroaryl, -S(0)0-2-Co-C4alkyl-heteroaryl, -O-C(O)-N(R3)-C0-C4alkyl-aryl, -O-C(S)-N(R3)-C0-C4alkyl-aryl, -O-C(O)-N(R3)-C0-C4alkyl-heteroaryl, -0-C(S)-N(R3)-Co- C4alkyl-heteroaryl, -O-C(O)-N(R3)-C0-C4alkyl-cycloalkyl, -O-C(S)-N(R3)-C0-C4alkyl- cycloalkyl, -O-C(O)-N(R3)-C0-C4alkyl-heterocyclyl, -O-C(S)-N(R3)-C0-C4alkyl-hetero- cyclyl, -O-C0-C4alkyl-heterocyclyl-aryl (when the alkyl is linked via a C in the heterocyclyl), -O-C2-C4alkyl-heterocyclyl-aryl (when the alkyl is linked via a N in the heterocyclyl), -O-C0-C4alkyl-heterocyclyl-heteroaryl (when the alkyl is linked via a C in the heterocyclyl), -O-C2-C4alkyl-heterocyclyl-heteroaryl (when the alkyl is linked via a N in the heterocyclyl), -O-C0-C4alkyl-heterocyclyl-cycloalkyl (when the alkyl is linked via a C in the heterocyclyl), -O-C2-C4alkyl-heterocyclyl-cycloalkyl (when the alkyl is linked via a N in the heterocyclyl), -O-C0-C4alkyl-heterocyclyl-heterocyclyl (when the alkyl is linked via a C in the heterocyclyl), -O-C2-C4alkyl-heterocyclyl-heterocyclyl (when the alkyl is linked via a N in the heterocyclyl), -S(O)0-1-C0-C4alkyl-heterocyclyl-aryl (when the alkyl is linked via a C in the heterocyclyl), -S(0)o-i-C2-C4alkyl-heterocyclyl-aryl (when the alkyl is linked via a N in the heterocyclyl), -S(0)2-Co-C4alkyl-heterocyclyl-aryl, -S(O)0-1- C0-C4alkyl-heterocyclyl-heteroaryl (when the alkyl is linked via a C in the heterocyclyl), -S(O)0-I -C2-C4alkyl-heterocyclyl-heteroaryl (when the alkyl is linked via a N in the heterocyclyl), -S(O)2-C0-C4alkyl-heterocyclyl-heteroaryl, -S(O)0-i-C0-C4alkyl-heterocyclyl- cycloalkyl (when the alkyl is linked via a C in the heterocyclyl), -S(0)o-1-C2-C4alkyl- heterocyclyl-cycloalkyl (when the alkyl is linked via a N in the heterocyclyl), -S(O)2-C0- C4alkyl-heterocyclyl-cycloalkyl, -S(0)0-1-Co-C4alkyl-heterocyclyl-heterocyclyl (when the alkyl is linked via a C in the heterocyclyl), -S(0)o-i-C2-C4alkyl-heterocyclyl-heterocyclyl (when the alkyl is linked via a N in the heterocyclyl), -S(0)2-Co-C4alkyl-heterocyclyl- heterocyclyl, -N(R3)-C2-C4alkyl-heterocyclyl, -N(R3)-C2-C4alkyl-cycloalkyl, -N(R3)-C2- C4alkyl-heteroaryl, -N(R3)-C2-C4alkyl-aryl, -N(R3)-C(O)-N(R3)-C0-C4alkyl-heterocyclyl- R3, -N(R3)-C(S)-N(R3)-C0-C4alkyl-heterocyclyl-R3, -N(R3)-C(O)-N(R3)-C0-C4alkyl- cycloalkyl-R3, -N(R3)-C(S)-N(R3)-C0-C4alkyl-cycloalkyl-R3, -N(R3)-C(O)-N(R3)-C0- C4alkyl-aryl-R3, -N(R3)-C(S)-N(R3)-C0-C4alkyl-aryl-R3, -N(R3)-C(O)-N(R3)-C0-C4alkyl- heteroaryl-R3, -N(R3)-C(S)-N(R3)-C0-C4alkyl-heteroaryl-R3, -C0-C4alkyl-O-C(O)-Ra, -C0- C4alkyl-N(R3)-C(O)-O-Ra, -C0-C4alkyl-N(R3)-C(S)-O-Ra, -C0-C4alkyl-heterocyclyl-C(O)- O-Ra, -C0-C4alkyl-cycloalkyl-C(O)-O-Ra, -C0-C4alkyl-heteroaryl-C(O)-O-Ra, -C0-C4alkyl- aryl-C(O)-O-Ra, -N(R3)-C2-C4alkyl-heterocyclyl, -N(R3)-C2-C4alkyl-cycloalkyl, -N(R3)- C2-C4alkyl-heteroaryl, -N(R3)-C2-C4alkyl-aryl, F, Cl, Br, I, -CF3,-SO3H, -CN, aryl, hetero- aryl, cycloalkyl and heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl moeity of the aformentioned R4 is optionally substituted; each R7 and R7a is independently selected from the group consisting of -H, Q-Qalkyl-, C2- Qalkenyl, C2-C6alkynyl, Q-Ceheteroalkyl, Ra-O-C2-C6alkyl-, Ra-S(O)0-2-C2-C6alkyl-, N(R3)(R3a)-C2-C6alkyl-, a protecting group, d-C6alkyl-O-C(O)-, aryl-C0-C4alkyl-O-
C(O)-, heteroaryl-C0-C4alkyl-O-C(O)-, benzyl-O-C(O)-, heterocyclyl-d-Cealkyl-, cycloalkyl-d-Cόalkyl-, heteroaryl-d-Cόalkyl-, aryl-d-C6alkyl-, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, benzyl and heterocyclyl moiety is independently optionally substituted; provided that R7 is -ORa when attached to the N atom of an indolyl moiety; and wherein in a -N(R3)(R3a) group, the R3 and R3a together with the nitrogen atom to which they are attached optionally form a heterocyclyl group.
In one embodiment of the present invention, each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl moiety of Y, L, Z, Ra, Rb, Rc, R3 and R3a is independently optionally substituted with one or more groups independently selected from R4.
In another embodiment of the present invention, each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl moiety of Y, L, Z, Ra, Rb, Rc, R3 and R3a is independently optionally substituted with one or more groups independently selected from oxo, -OH, -CN, Ci-Cβalkyl, d-C6alkoxy, -NO2, -N(Ra)2, -N(R7)(R7a), halo, -SH, -S-C1- C6alkyl, -S(O)-C1-COaIlCyI, -S-C(O)-C!-C6alkyl and mono- to per-halogenated Ci-C6alkyl.
In another embodiment of the present invention, a CrC6alkyl moiety of an R4 is optionally substituted with a substituent selected from the group consisting of -OH, -NO2 and C0-C6 alkyl-C(O)-N(R3)(R3a).
In another embodiment of the present invention 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-C6alkyl, Ci-C6alkoxy, -NO2, -N(R3)(R3a), halo, -SH and mono- to per- halogenated C i -C6alkyl .
In another embodiment of the present invention, L is selected from the group consisting of
-Co-C6alkyl-N(R3)-Co-C3alkyl-, wherein when the -C0-C6alkyl is -CrC6alkyl it is optionally substituted with a substituent selected from the group consisting of -Q-Qalkyl-OR8, -C1- C3alkyl-N(R3)(R3a), -C0-C3alkyl-C(O)ORa and C0-C3alkyl-C(O)-N(R3)(R3a);
-C0-C6alkyl-N(R3)-C(0)-Co-C3alkyl-, wherein when the -C0-C6alkyl is d-C6alkyl it is optionally substituted with a substituent selected from the group consisting of -C1-C3alkyl-
OR\ -C1-C3alkyl-NR3R3a, -C0C3alkyl-C(O)ORa and C0-C3alkyl-C(O)-N(R3)(R3a);
-C0-C6alkyl-N(R3)-C(O)-C0-C3alkyl-, wherein the -C0-C3alkyl is d-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-
C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-
C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C(S)-C0-C3alkyl-C4-
C6cycloalkyl-, -N(R3)-C0-C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0-C3alkyl-C4-C6heterocyclyl,
-N(R3)-C2-C3alkyl-N(R3)(R3a), -N(R3)-C2-C3alkyl-ORa, -N(R3)-C0-C3alkyl-C0-C3hetero- alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(S)-O-C0-C3alkyl-Y, -N(R3)-S(O)2-C0-
C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-
C(0)-C0-C3alkyl-Co-C3heterocyclyl, -N(R3)-C(S)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)-
C(0)-C0-C3alkyl-Co-C3heterocyclyl-Y, -N(R3)-C(S)-C0-C3alkyl-C0-C3heterocyclyl-Y and
-N(R3)-S(O)2-N(R3)-C0-C3alkyl-Y; -C0-C6alkyl-N(R3)-C(S)-C0-C3alkyl-, wherein the -C0-C3alkyl is CrC3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0- C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0- C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C(S)-C0-C3alkyl-C4- C6cycloalkyl-, -N(R3)-C0-C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0-C3alkyl-C4-C6heterocyclyl, -N(R3)-C2-C3alkyl-N(R3)(R3a), -N(R3)-C2-C3alkyl-ORa, -N(R3)-C0-C3alkyl-Co-C3hetero- alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(S)-O-C0-C3alkyl-Y, -N(R3)-S(O)2-C0- C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)- C(0)-Co-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(S)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)- C(0)-Co-C3alkyl-C0-C3heterocyclyl-Y, -N(R3)-C(S)-C0-C3alkyl-C0-C3heterocyclyl-Y and
-N(R3)-S(O)2-N(R3)-C0-C3alkyl-Y;
-Co-C6alkyl-C(0)-C0-C3alkyl-, wherein when the -Co-Cόalkyl is C1-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(0)-Co- C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)(R3a), -C(S)-N(R3)(R3a), -C(O)-N(R3)- C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C4-C6cycloalkyl-,
-N(R3)-C(S)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C0-C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0- C3alkyl-C4-C6heterocyclyl, - N(R3)-C2-C3alkyl-N(R3)(R3a), -N(R3)-C2-C3alkyl-ORa-, -N(R3)-C0-C3heteroalkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(S)-O-C0-C3alkyl-Y, -N(R3)-S(O)2-C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(S)-N(R3)-C0- C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(S)-C0-C3alkyl-C0-
C3heterocyclyl, -N(R3)-C(O)-C0-C3alkyl-C0-C3heterocyclyl-Y, -N(R3)-C(S)-C0-C3alkyl- C0-C3heterocyclyl-Y and -N(R3)-S(O)2-N(R3)-C0-C3alkyl-Y;
-Co-C6alkyl-C(S)-Co-C3alkyl-, wherein when the -Co-C6alkyl is C1-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0- C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)(R3a), -C(S)-N(R3)(R3a), -C(O)-N(R3)-
C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C(S)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C0-C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0- C3alkyl-C4-C6heterocyclyl, - N(R3)-C2-C3alkyl-N(R3)(R3a), -N(R3)-C2-C3alkyl-ORa-, -N(R3)-C0-C3heteroalkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(S)-O-C0-C3alkyl-Y, -N(R3)-S(O)2-C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(S)-N(R3)-CO-
C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(S)-C0-C3alkyl-C0-
C3heterocyclyl, -N(R3)-C(O)-C0-C3alkyl-C0-C3heterocyclyl-Y, -N(R3)-C(S)-C0-C3alkyl-
C0-C3heterocyclyl-Y and -N(R3)-S(O)2-N(R3)-C0-C3alkyl-Y;
-C0-C6alkyl-, wherein when the -C0-C6alkyl is C!-C6alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-
C(O)-C0-C3alkyl-heterocyclyl and -N(R3)-C(O)-C0-C3alkyl-cyclyoalkyl; -Co-C6alkyl-C(0)-N(R3)-C0-C3alkyl-, wherein when the -Co-C3alkyl is d-Qalkyl it is optionally substituted with a substituent selected from the group consisting of -C(O)- N(R3)-C0-C3alkyl-Y, -C(O)-heterocyclyl, -C(O)-N(R3)(R3a), aryl-aryl, aryl-heteroaryl,
-heteroaryl-aryl, heteraryl-heteroaryl, heteroaryl, heterocyclyl-heteroaryl and heterocyclyl; -Co-C6alkyl-heteroalkyl-C0-C6alkyl-C(0)-N(R3)-Co-C3alkyl-, wherein when the -Co-C3alkyl is C!-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -C(O)-N(R3)-C0-C3alkyl-Y, -C(O)-heterocyclyl, -C(O)-N(R3)(R3a), aryl-aryl, aryl-heteroaryl, -heteroaryl-aryl, heteraryl-heteroaryl, heteroaryl, heterocyclyl-heteroaryl and heterocyclyl; -Co-C6alkyl-C(0)-N(R3)-C0-C3alkyl-, wherein when the -C0-C6alkyl is Q-Qalkyl it is optionally substituted with a substituent selected from the group consisting of -N(R7)(R7a), -N(R3)(R3a), -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(O)-
N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y; -Co-Cealkyl-heteroaryl-Co-Csalkyl-, wherein when the -Co-C3alkyl is C!-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -C0-C3alkyl-
N(R3)-C(O)-C0-C3alkyl-N(R3)(R3a), -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O-C0- C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-Co-C6alkyl-aryl-Co-C3alkyl-, wherein when the -C0-C3alkyl is Q-Qalkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-
C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-
Co-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y; -Co-C6alkyl-aryl-heteroaryl-C0-C3alkyl-, wherein when the -C0-C3alkyl is C1-C3alkyl it is optionally substituted with a substituent selected from the group consisitng of -N(R3)-
C(0)-Co-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-
C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-Co-Cealkyl-heteroaryl-heteroaryl-Co-Csalkyl-, wherein when the -C0-C3alkyl is C!-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-
C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-
C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y; -Co-Cealkyl-heteroaryl-Co-Csalkyl-, wherein when the -C0-C3alkyl is Q-Qalkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)- C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-
C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y; -C0-C6alkyl-0-C(0)-N(R3)-Co-C3alkyl-, wherein when the -C0-C3alkyl is C1-C3 alkyl it is optionally substituted with a group selected from -C(O)-OR3, -C(S)-OR3, -C(O)-N(R3)-d-
C3alkyl, -C(S)-N(R3)-d-C3alkyl, -C(O)-N(R3)(R3a)-, -C(S)-N(R3)(R3a)-, -C(O)-N(R3)-C0- C3alkyl-aryl, -C(S)-N(R3)-C0-C3alkyl-aryl, -C(O)-N(R3)-C0-C3alkyl-heteroaryl, -C(S)- N(R3)-Co-C3alkyl-heteroaryl, -C(O)-N(R3)-C0-C3alkyl-cycloalkyl, -C(S)-N(R3)-C0- C3alkyl-cycloalkyl, -C(O)-heterocyclyl, -C(S)-heterocyclyl, -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -C(O)-N(R3)-heterocyclyl, -C(S)-N(R3)-heterocyclyl, -C(O)- N(R3)-C0-C3alkyl-heterocycloalkyl and -C(S)-N(R3)-C0-C3alkyl-heterocycloalkyl;
-Co-C6alkyl-0-C(S)-N(R3)-C0-C3alkyl-, wherein when the -C0-C3alkyl is C1-C3 alkyl it is optionally substituted with a group selected from -C(O)-OR3, -C(S)-OR3, -C(O)-N(R3)-C1-
C3alkyl, -C(S)-N(R3)-C1-C3alkyl, -C(O)-N(R3)(R3a)-, -C(S)-N(R3)(R3a)-, -C(O)-N(R3)-C0-
C3alkyl-aryl, -C(S)-N(R3)-C0-C3alkyl-aryl, -C(O)-N(R3)-C0-C3alkyl-heteroaryl, -C(S)- N(R3)-C0-C3alkyl-heteroaryl, -C(O)-N(R3)-C0-C3alkyl-cycloalkyl, -C(S)-N(R3)-C0-
C3alkyl-cycloalkyl, -C(O)-heterocyclyl, -C(S)-heterocyclyl, -C(O)-N(R3)-C0-C3alkyl-Y,
-C(S)-N(R3)-C0-C3alkyl-Y, -C(O)-N(R3)-heterocyclyl, -C(S)-N(R3)-heterocyclyl, -C(O)-
N(R3)-C0-C3alkyl-heterocycloalkyl and -C(S)-N(R3)-C0-C3alkyl-heterocycloalkyl; and
-C1-C3alkyl-N(R3)-C(O)-C1-C7alkyl-, wherein the d-C3alkyl is optionally substituted with -C(O)N(R3)-C1-C3alkyl-Ala and the Q-G/alkyl is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-O-CrC3alkyl-Alb, -N(R3)-C(O)-Cr
C3alkyl-Alb, -N(R3)-S(O)2-C1-C3alkyl-Alb, -N(R3)-S(O)2-N(R3)-CrC3alkyl-Alb, -N(R3)-
C(O)-N(R3)-C1-C3alkyl-Alb and -N(R3)-S(O)2-N(R3)-C1-C3alkyl-Alb, wherein
Ala and Alb are independently selected from the group consisting of alkyl, alkenyl and a protecting group; or
Ala and A1 together via a -C2-C6alkylene-, -C^Cβalkenylene-, -C2-C6alkynylene- or -Co- C3alky-heteroaryl-C0-C3alky- linker, form an optionally substituted ring.
In another embodiment of the present invention, L is selected from the group consisting of -C1-C6alkyl-N(R3)-C0-C3alkyl-, wherein the Ci-C6alkyl is optionally substituted with a substituted selected from the group consisting of -C1-C4 alkyl-ORa, -Cj-C6 alkyl- N(R3)(R3a)-, -C0-C4 alkyl-C(O)OR3 and -C0-C3alkyl-C(O)-N(R3)(R3a); -Co-C6alkyl-N(R3)-C(0)-C0-C3alkyl-, wherein the CrC6alkyl is optionally substituted with a substituent selected from the group consisting of -C!-C4alkyl-O(Ra)-, -C0-C6alkyl- C(O)O(R8)- and -d-C6alkyl-N(R3)(R3a)-; and
-Co-C6alkyl-C(0)-N(R3)-C0-C3alkyl-, wherein the CrC6alkyl is optionally substituted with a substituent selected from the group consisting of -Co-C6alkyl-0(Ra)-, -C0-C6alkyl- C(O)O(R3)-, -C0-C3alkyl-C(O)-N(R3)(R3a) and -C0-C6alkyl-N(R3)(R3a)-. In another embodiment of the present invention, L is selected from the group consisting of -Co-C6alkyl-N(R3)-C(0)-C1-C7alkyl-, wherein the d-C7alkyl is optionally substituted with a substituent selected from the group consisting of -N(R7)(R7a), -N(R3)C(O)-C0-C3alkyl- heterocyclyl, -N(R3)-C(O)-C0-C6alkylaryl-Ra, -N(R3)-C(O)-C1-C6alkyl-Ra and -N(R3)-
C(O)-O-C°-C3alkyl-Y wherein heterocyclyl is optionally substituted; -Co-C6alkyl-C(0)-N(R3)-Ci-C7alkyl-, wherein the d-C6alkyl is optionally substituted with
-N(R7)(R7a);
-Co-C6alkyl-C(0)-N(R3)-C1-C7alkyl-, wherein the d-C7alkyl is optionally substituted with a substituent selected from the group consisting of aryl-aryl, aryl-heteroaryl, heteroaryl- heteroaryl, heteroaryl-aryl and heteroaryl; and -C1-C3alkyl-N(R3)-C(O)-C1-C7 alkyl-, wherein the d-C3alkyl is optionally substituted with -C(O)N(R3)-C!-C3alkyl-Ala and the d-C7alkyl is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)O-C1-C3alkyl-Alb, -N(R3)-C(O)-Cr C3alkyl-Alb, -N(R3)-S(O)2-C1-C3alkyl-Alb, -N(R3)-C(O)-N(R3)-C1-C3alkyl-Alb and - N(R3)-S(O)2-N(R3)-d-C3alkyl-Alb, wherein Ala and Au, are independently selected from the group consisting of alkyl, alkenyl and a protecting group; or
Ala and A^ together via a -C2-C6alkylene, -C2-C6alkenylene, -C2-C6alkynylene, -Co-C3alkyl- heteroaryl-C0-C3alkyl- linker or -Co-dalkyl-aryl-Co-Csalkyl- linker, form an optionally substituted ring, and In another embodiment of the present invention, L is a selected from the group consisting of -C0-C7alkyl-N(R3)-C(O)-heterocyclyl-C0-C6alkyl-, wherein a Ci-C7alkyl is optionally substituted with -C0-C3alkyl-C(O)ORa or -d-C3alkyl-ORa; and
-Co-C7alkyl-0-C(0)-heterocyclyl-C0-C6alkyl-, wherein a d-C7alkyl is optionally substituted with -Co-C3alkyl-C(0)ORa or -C0-C3alkyl-ORa.
In another embodiment of the present invention, L is selected from the group consisting of a covalent bond, -(CH2)M-, -(CH2)o-4-(CR3=CR3)-(CH2)o-4-, -(CH2)0-4-(C≡C)-(CH2)0-4-, -(CH2)O-3 N(R3)C(O)-, -(CH2)0-3-C(O)N(R3)-, -(CH2)0-3 N(R3)C(O)-(CRa=CRa)-, -(CH2)0-3 -N(R3)-(CH2)2-4 N(R3)C(O)-, -(CH2)O-3 -O-(CH2)2-4-N(R3)C(O)-, -(CH2)0-3C(0)-(CH2)o-3-, -(CH2)o-3-(CRa=CRa)-C(0)-(CH2)0-3-, -(CH2)0-3C(O)-(CRa=CRa)-(CH2)0-3-, -C0-C6alkyl- N(R3)-C(0)-heterocyclyl-C0-C3alkyl-, -Co-C6alkyl-S(0)2-heterocyclyl-Co-C3alkyl-, -(CH2)O-3- S(O)2-N(R3MCH2)O-3-, -(CH2)O-3 N(R3)-S(O)2-(CH2)0-3-, -(CH2)0-3N(R3)-(CH2)0-3-, -(CH2)0- 3N(R3)-(CH2)1-3-(CRa=CRah -(CH2)O-3C=N-O-(CH2)O-3-, -(CH2)0-3N(R7)-(CH2)0-3-, -(CH2)0- 3S-(CH2)0-3-, -(CH2)O-3O-(CH2)O-3-, -(CH2)0-3S(O)-(CH2)0-3-, -(CH2)0-3S(O)2-(CH2)0-3-, -(CH2)o-3CH=CH-(CH2)2-3-, -(CH2)0-3N(R3)-C(0)-N(R3)-(CH2)o-3, -(CH2)0-3N(R3)-C(O)-O- (CH2)O-3, -(CH2)0-3O-C(O)-N(R3)-(CH2)0-3-, -(CH2)0-3 N(R3)-C(O)-N(R3)-S(O)2-(CH2)0-3-, and -(CH2)o-3N(R3)-C(0)-N(R3)-C(0)-(CH2)0-3-.
In another embodiment of the present invention, B1, B2 and B3 are independently selected from the group consisting of D-GIy, L-GIy, D-Pro, L-Pro, D-Tyr, L-Tyr, D- Tyr(ORa), L-Tyr(ORa), D-Phe, L-Phe, D-PhCR4, L-PlIeR4, D-Aib, L-Aib, D-AIa, L-AIa, D- ProR3, L-ProR3, D-IIe, L-IIe, D-Leu, L-Leu D-PheR3, L-PheR3, D-Pip and L-Pip.
In another embodiment of the present invention, each alkyl, alkenyl, alkynyl, hetero- alkyl, benzyl and heterocyclyl moiety of R7 and R7a is independently optionally substituted with one or more substituents selected from the group consisting of oxo, -OH, -CN, C1-
C6alkyl, d-C6alkoxy, -NO2, -N(R3)(R3a), halo, -SH and mono- to per-halogenated C1-
C6alkyl.
In another embodiment of the present invention, 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.
In another embodiment of the present invention, 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.
In another embodiment of the present invention, D is
Figure imgf000051_0003
, or
Figure imgf000051_0002
In another embodiment ofthe present invention, D is
In another embodiment ofthe present invention, D is
Figure imgf000051_0001
X In another embodiment of the present invention, D is
Figure imgf000052_0001
, for example
Figure imgf000052_0002
In another embodiment of the present invention, X is O. In another embodiment of the present invention, X is S. In another embodiment of the present invention, Ra, R and Rc are independently selected from the group consisting of -H, C1-C3alkyl, C3-C6cycloalkyl, aryl, heteroaryl, and aryl-Ci-Csalkyl-.
In another embodiment of the present invention, Ra and Rb 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.
In another embodiment of the present invention, R3 and R3a are independently selected from the group consisting of -H, OH, d-C6alkyl, C3-C6cycloalkyl, -C(O)CF3, -C(O)H, -C1-
C4alkyl-C(O)ORa, heterocyclyl, -C2-C4alkyl-ORa, C2-C4alkylene; C2-C6alkenyl, C2-C6 hydroxyalkyl -Ci-C6 alkylaryl, aryl, -Co-Qalkylheteroaryl, and -C1-C3alkyl-C(O)N(R3)- heteroaryl.
In another embodiment of the present invention, R3 and R3a are independently selected from the group consisting of -Q-Qalkylaryl, t-butyl, benzyl and aryl.
In another embodiment of the present invention, R3 and R3a are independently selected from the group consisting of ethanol, tetrahydro-2H-pyran, phenyl and benzyl.
In another embodiment of the present invention, R3 and R3a are independently Cj-C4 alkyl.
In another embodiment of the present invention, in a -N(R3)(R3a) group, the R3 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.
In another embodiment of the present invention, R4 is selected from the group consisting of -H, -CH3, -S(O)2-N(R3)(R3a), -SO3H, -O-C2-C4alkyl-heterocyclyl, -0-C0-
C4alkyl-aryl, -O-C0-C4alkyl-heteroaryl, -O-C(O)N(R3)-C0-C4alkyl-aryl, -O-C(O)N(R3)-C0- C4alkyl -heteroaryl, -O-C0-C4alkyl -heterocyclyl-aryl, -O-C0-C4alkyl -heterocyclyl -heteroaryl, -N(R3)-C2-C4alkyl-heterocyclyl, -(CH2)0-4ORa, -(CH2)0-4N(R3)(R3a), -F, -Cl, -Br, -CF3, -CN, -CH2OH, -OH, -OCH3, -NO2, Ph, aryl, heteroaryl, -N(R3)C(O)CH2R3, -N(R3) S O2CH2R3, -O(CH2)2-4N(R3)(R3a), -SRa, -S(O)CH2R3, -SO2CH2R3, -(CH2)O-4C(O)OR3, -CH=CHC(O)OR3, -CH=CHC(O)N(R3XR33), -N(R3)C(O)CF3 and -N(R3)(CH2)2N(R3)(R3a).
In another embodiment of the present invention, Rh is -CH3.
In another embodiment of the present invention, Rh is -CF3.
In another embodiment of the present invention, L is selected from the group consisting of
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000055_0002
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
wherein
Ala 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.
In another embodiment of the present invention, Z is selected from the group consisting of
Figure imgf000058_0003
Figure imgf000058_0002
Figure imgf000058_0004
Figure imgf000059_0001
Figure imgf000059_0002
Figure imgf000059_0003
wherein each A independently is nitrogen, -CH= or -C(R4)=, wherein there may be 0, 1 , 2 or 3 nitrogen.
In another embodiment of the present invention, each Y is independently selected from the group consisting of
Figure imgf000059_0004
Figure imgf000060_0001
Figure imgf000060_0002
Figure imgf000060_0003
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000062_0004
Figure imgf000062_0003
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
wherein each A is independently nitrogen, -C(H)= or -C(R4)=, wherein there may be 0, 1, 2 or 3 nitrogen; B^ B2 and B3 are each independently a natural or synthetic amino acid; M1-M2 is selected from the group consisting of a covalent bond, -N(R3)CH2-, -CH2N(R3)-, -S(O)0-2-CH2-, -CH2S(O)0-2-, -O-CH2-, -CH2-O-, -C(O)N(R3)-, -N(R3)C(0)-, -SO2N(R3)-, -N(R3)SO2-, -CH(Ra)CH2-, -CH2CH(R8)-, -N=C(R3)-, -C(Ra)=N-, -CH2-CH2-, -CH=CH-, -CH(Ra)-CH(Ra)-, -C(Ra)=C(Ra)-, -CH2-, -C(R3)(Ra)-, -S-, -N(R3)- and absent;
M3 is selected from the group consisting of
Figure imgf000068_0005
M4 is selected from the group consisting of
Figure imgf000068_0004
and ∞ysΛ&ni bonc| ;
wherein, when M1-M2 is covalent bond, M4 is
Figure imgf000068_0001
^ ^- ^ * ^- ^
D1-D2 is selected from the group consisting of a
Figure imgf000068_0002
Figure imgf000068_0003
wherein, * represents the point of attachment to Q;
D3 is selected from the group consisting of a covalent bond,
Figure imgf000068_0006
^ wherein the are
Figure imgf000068_0007
optionally substituted
D4 is selected from the group consisting of
Figure imgf000068_0008
;
wherein the
Figure imgf000068_0009
is optionally substituted, E1-E2 is selected from the group consisting of
Figure imgf000069_0001
E3 is selected from the group consisting of -C(O)-, -C(S)-, -CH2-, -C(OH)2- and -C=NR3-; and
R6 is selected from the group consisting of -H, -CrCgalkyl, -C2-C6alkenyl, -C2-C6alkynyl, -CrCόheteroalkyl, heterocyclyl-Co-Cόalkyl-, aryl-Co-C6alkyl-, heteroaryl-C0-C6alkyl-, C3- C6cycloalkyl-C0-C6alkyl-, N(R3)(R3a)-C1-C6alkyl-, N(R3)(R3a)-C(O)-CrC6alkyl- and N(R3)(R3a)-C(S)-C1-C6alkyl-, wherein each alkyl, alkenyl, alkynyl, heteoralkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl moiety is optionally substituted.
In another embodiment of the present invention, each alkyl, alkenyl, alkynyl, heteoralkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl moiety of R6 is independently optionally substituted with one or more groups independently selected from R4.
In another embodiment of the present invention R6 is selected from the group consisting of
Figure imgf000069_0002
In another embodiment according to the present invention, R7 is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, -(CH2)2-4ORa, -OMe, -(CH2)2- 4N(R3)(R3a), -C(O)Ot-butyl, -C(O)O-benzyl, -(CH2)2-morpholinyl and -(CH2)2-ρiperazynnyl.
In another embodiment according to the present invention,
Figure imgf000069_0003
W and M are nitrogen;
Ra and Rc are -H; Rb is -O-alkyl-aryl or -O-alkyl-heteroaryl, wherein said alkyl, aryl and heteroaryl moieties are optionally substituted; Z is -C1-C8 alkyl-;
L is covalent bond, -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, -C0-C6 alkyl-N(R3)C(S)-C0-C3 alkyl-, -C0-C6 alkyl-C(O)N(R3)-C0-C3 alkyl- or -C0-C6 alkyl-C(S)N(R3)-C0-C3 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. In an alternate embodiment, the alkyl, aryl, heteroaryl and polycycle groups are optionally substituted with aryl-C0-C6alkyl-O-, heteroaryl-Co- C6alkyl-O-, heteroaryl-O- or aryl-, said aryl-Co-Cδalkyl-O, heteroaryl-Co-Cβalkyl-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!-C6alkyl and alkoxy. In an alternate embodiment, L is -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl- or -C0-C6 alkyl-N(R3)C(S)-C0-C3 alkyl-.
In another embodiment according to the present invention,
D is
Figure imgf000070_0001
;
W is nitrogen;
Rc is -H; Rh 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-C8 alkyl-;
L is covalent bond, -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl or -C0-C6 alkyl-C(O)N(R3)-C0-C3 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. In an alternate embodiment, the alkyl, aryl, heteroaryl and polycycle groups are optionally substituted with aryl-Co-C6alkyl-0-, heteroaryl-C0- C6alkyl-O, heteroaryl-O- or aryl-, said aryl-C0-C6alkyl-O-, heteroaryl-C0-C6alkyl-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-Cβalkyl and alkoxy. In an alternate embodiment, L is -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl.
In another embodiment according to the present invention, the compounds are represented by the formula (II):
Figure imgf000071_0002
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:
Figure imgf000071_0001
D is selected from the group consisting of
Figure imgf000072_0001
wherein R1 is an optional substituent and nl is 0-4.
In another embodiment according to the present invention,
D is
Figure imgf000072_0002
; W is nitrogen or oxygen; M is nitrogen; Ra, Rb and Rc are -H; Z is -Ci-C8 alkyl- or -C1-C8 alkyl-C(O)-; L is -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl; and Y is alkyl, aryl, heteroaryl, heteroaryl-aryl or aryl-heteroaryl, wherein the alkyl, aryl and heteroaryl groups are optionally substituted. In an alternate embodiment, 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. In another embodiment according to the present invention,
Figure imgf000072_0003
W is nitrogen or oxygen; Rc is -H;
Rh is H or -C!-C6alkyl, wherein said alkyl is optionally substituted; Z is -Cj-C8 alkyl- or -C1-C8 alkyl-C(O)-; L is -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl; and
Y is alkyl, aryl, heteroaryl, heteroaryl-aryl or aryl-heteroaryl, wherein the alkyl, aryl and heteroaryl groups are optionally substituted. In an alternate embodiment, 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. In another embodiment according to the present invention,
Figure imgf000073_0001
W and M are nitrogen;
Ra, Rband Rc are -H;
R3 is -H or Ci-Cβalkyl; Z is optionally substituted -C1-C8 alkyl-;
L is selected from the group consisting of
-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, -C0-C6alkyl-N(R3)-C(O)-N(R3)-C0-C3alkyl-, or -C0-
C6alkyl-0-Co-C3alkyl-C(0)-N(R3)-Co-C3alkyl-, wherein when a Co-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3 alkyl-Y, aryl, heteroaryl, -heteroaryl-aryl, -aryl -heteroaryl, -aryl-aryl, heteroaryl-heteroaryl, -N(R3)(R3a) or -N(R3)-
Y, wherein each heteroaryl or aryl moeity is optionally substituted;
-C0-C6 alkyl-heteroalkyl-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is d-C3alkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or -N(R3)-Y; and -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)(R3a), -N(R3)- Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -NH2, -NH-S(O)2-Y, -NH-C(O)-NH-C0-C3alkyl-Y, -NH-heteroaryl-aryl or -N(R3)C(O)- C0-C3 alkyl-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(R3)-C(O)-hetero- aryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-C0-C6alkyl-
N(R3)-C(O)-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moieties are optionally substituted and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1-C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B and B are independently selected from the group consisting of D-Pro, L-ile and D-Phe- 4-CF3. In another embodiment according to the present invention,
Figure imgf000074_0001
W is nitrogen; Rc is -H;
Rh is H or -CrC6alkyl, wherein said alkyl is optionally substituted; R3 is -H or Ci-Cβalkyl;
Z is optionally substituted -Ci-C8 alkyl-;
L is selected from the group consisting of
-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, -C0-C6alkyl-N(R3)-C(O)-N(R3)-C0-C3alkyl-, or -C0-
C6alkyl-0-Co-C3alkyl-C(0)-N(R3)-Co-C3alkyl-, wherein when a Co-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3 alkyl-Y, aryl, heteroaryl,
-heteroaryl-aryl, -aryl-heteroaryl, -aryl-aryl, heteroaryl-heteroaryl, -N(R3)(R3a) or -N(R3)-
Y, wherein each heteroaryl or aryl moiety is optionally substituted; -C0-C6 alkyl-heteroalkyl-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1-C3alkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or -N(R3)- Y; and
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)(R3a), -N(R3)-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y,
-NH2, -NH-S(O)2-Y, -NH-C(O)-NH-C0-C3alkyl-Y, -NH-heteroaryl-aryl or -N(R3)C(O)-
C0-C3 alkyl-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(R3)-C(O)-hetero- aryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-C0-C6alkyl-
N(R3)-C(O)-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moieties are optionally substituted and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1-C7 alkyl-, then Z and L are covalent bonds; wherein
1 O 1X 1 when any of B , B and B are attached together, they are attached by a peptide bond, and B , B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe-
4-CF3.
In another embodiment according to the present invention,
Figure imgf000075_0001
W and M are nitrogen;
Ra, Rb and Rc are -H;
R3 is -H or C1-QaIkVl; Z is optionally substituted -C1-C8 alkyl-;
L is selected from the group consisting of
-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, -C0-C6alkyl-N(R3)-C(O)-N(R3)-C0-C3alkyl-, or -C0-
C6alkyl-O-C0-C3alkyl-C(O)-N(R3)-C0-C3alkyl-, wherein when a C0-C3alkyl is d-C3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3 alkyl-Y, -heteroaryl-aryl, heteroaryl, heteroaryl-heteroaryl, -N(R3)(R3a) or -N(R3)-Y, wherein each heteroaryl or aryl moeity is optionally substituted;
-C0-C6 alkyl-heteroalkyl-Co-Ce alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or -N(R3)-Y; and -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)-C(O)-O-C0-C3alkyl-Y, -NH2, -NH-S(O)2-Y, -NH-C(O)-NH-C0-C3alkyl-Y, -NH-heteroaryl-aryl, -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-O-, aryl-N(R3)-C(O)-heteroaryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-C0-C6alkyl-N(R3)- C(O)-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl moieties 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 CrC6alkyl, alkoxycarbonyl-, -OH, -CN, -C(O)-OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-Q-Cealkyl-aryl, optionally substituted -C(O)-O-C rC6alkyl, -NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1-
C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe- 4-CF3.
In another embodiment according to the present invention,
Figure imgf000076_0001
W is nitrogen; Rc is -H;
Rh is H or -d-Qalkyl, wherein said alkyl is optionally substituted; R3 is -H or d-Cealkyl; Z is optionally substituted -C1-C8 alkyl-; L is selected from the group consisting of
-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, -C0-C6alkyl-N(R3)-C(O)-N(R3)-C0-C3alkyl-, or -C0-
C6alkyl-O-C0-C3alkyl-C(O)-N(R3)-C0-C3alkyl-, wherein when a C0-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3 alkyl-Y, -heteroaryl-aryl, heteroaryl, heteroaryl-heteroaryl, -N(R3)(R3a) or -N(R3)- Y, wherein each heteroaryl or aryl moeity is optionally substituted;
-C0-C6 alkyl-heteroalkyl-Co-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is CrQalkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or -N(R3)-Y; and -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is d-C3alkyl, the Ci-C3 alkyl is optionally substituted with -N(R3)-C(O)-O-C0-C3alkyl-Y, -NH2, -NH-S(O)2-Y, -NH-C(O)-NH-C0-C3alkyl-Y, -NH-heteroaryl-aryl, -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-O-, aryl-N(R3)-C(O)-heteroaryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-C0-C6alkyl-N(R3)- C(O)-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl moieties 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 d-C6alkyl, alkoxycarbonyl-, -OH, -CN, -C(O)-OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-d-C6alkyl-aryl, optionally substituted -C(O)-O-C rC6alkyl, -NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C1-C7 alkyl is optionally substituted with -NR3-B and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1- C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe- 4-CF3. hi another embodiment according to the present invention,
Figure imgf000077_0001
W and M are nitrogen; Ra, Rb and Rc are -H; R3 is -H or Ci-C6alkyl; Z is optionally substituted -C1-C8 alkyl-; L is
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is Q-Qalkyl, the C1-C3 alkyl is optionally substituted with -N(R3)-C(O)-O-C0-C3alkyl-Y, -NH2, -NH-S(O)2-Y, -NH-C(O)-NH-C0-C3alkyl-Y, -NH-heteroaryl-aryl, -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)- Y; and each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-O, aryl-N(R3)-C(O)-heteroaryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-C0-C6alkyl-N(R3)- C(O)-heteroaryl and B2-B! -N(R3^C(O)-C1 -C7 alkyl-, wherein the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl groups are optionally substituted and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B* -N(R^-C(O)-C1 -C7 alkyl-, then Z and L are covalent bonds; wherein
1 0 1X 1 when any of B , B and B are attached together, they are attached by a peptide bond, and B , B and B are independently selected from the group consisting of D-Pro, L-ile and D-Phe- 4-CF3.
In another embodiment according to the present invention,
Figure imgf000078_0001
W is nitrogen;
Rc is -H;
Rh is H or -Q-Qalkyl, wherein said alkyl is optionally substituted; R3 is -H or Q-C6alkyl;
Z is optionally substituted -C1-C8 alkyl-;
L is
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)-C(O)-O-C0-C3alkyl-Y, -NH2, -NH-S(O)2-Y, -NH-C(O)-NH-C0-C3alkyl-Y, -NH-heteroaryl-aryl, -N(R3)C(O)-C0-C3 alkyl-Y,
-N(R3)(R3a) or -N(R3)- Y; and each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-O-, aryl-N(R3)-C(O)-heteroaryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-C0-C6alkyl-N(R3)- C(O)-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl groups are optionally substituted and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B! -N(R^-C(O)-C1 -C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1,
0 1X
B and B are independently selected from the group consisting of D-Pro, L-ile and D-Phe- 4-CF3.
In another embodiment according to the present invention,
Figure imgf000078_0002
W and M are nitrogen;
Ra, Rb and Rc are -H;
R3 is -H or Cj-C6alkyl;
Z is optionally substituted -C1-C8 alkyl-; L is -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is d-C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)-C(O)-O-C0-C3alkyl-Y, -NH2, -NH-S(O)2-Y, -NH-C(O)-NH-C0-C3alkyl-Y, -NH-heteroaryl-aryl, -N(R3)C(O)-C0-C3 alkyl-Y. -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-O-, aryl-N(R3)-C(O)-heteroaryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-C0-C6alkyl-N(R3)- C(O)-heteroaryl and B2-B! -N(R3J-C(O)-C1 -C7 alkyl-, wherein the 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 CrC6alkyl, alkoxycarbonyl-, -OH, -CN, -C(O)-OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-Q-Cόalkyl-aryl, optionally substitued -C(O)-O-Ci-C6alkyl, -NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1- C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe- 4-CF3.
In another embodiment according to the present invention,
D is
Figure imgf000079_0001
;
W is nitrogen;
Rc is -H; Rh is H or -C!-C6alkyl, wherein said alkyl is optionally substituted;
R3 is -H or Ci-C6alkyl;
Z is optionally substituted -C1-C8 alkyl-;
L is
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is CrC3alkyl, the Ci-C3 alkyl is optionally substituted with -N(R3)-C(O)-O-C0-C3alkyl-Y, -NH2, -NH-S(O)2-Y,
-NH-C(O)-NH-C0-C3alkyl-Y, -NH-heteroaryl-aryl, -N(R3)C(O)-C0-C3 alkyl-Y. -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-O-, aryl-N(R3)-C(O)-heteroaryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-C0-C6alkyl-N(R3)- C(O)-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the cycloalkyl, aryl, hetero- aryl, 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 Ci-Cβalkyl, 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-Cβalkyl, -NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1- C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe- 4-CF3.
In another embodiment according to the present invention,
D is
Figure imgf000080_0001
; W and M are nitrogen; Ra, Rb and Rc are -H; R3 is -H; R4 is H or F;
Z is optionally substituted -Ci-C8 alkyl-; L is selected from the group consisting of
-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3 alkyl- Y, -heteroaryl-aryl, heteroaryl, -N(R3)(R3a) or -N(R3)-Y;
-C0-C6 alkyl-heteroalkyl-Co-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1-C3alkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or
-N(R3)-Y; and -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is Ci-C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, hetero- aryl-aryl, aryl-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the aryl and heteroaryl are optionally substituted, and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B is conected with the acid of B to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-Ci-C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D- Phe-4-CF3.
In another embodiment according to the present invention,
Figure imgf000081_0001
W is nitrogen; Rc is -H;
Rh is H or -Ci-Cόalkyl, wherein said alkyl is optionally substituted;
R3 is -H;
R4 is H or F;
Z is optionally substituted -C1-C8 alkyl-; L is selected from the group consisting of
-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is d-C3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3 alkyl-Y, -heteroaryl-aryl, heteroaryl, -N(R3)(R3a) or -N(R3)-Y;
-C0-C6 alkyl-heteroalkyl-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is Ci-C3alkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or
-N(R3)- Y; and
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the aryl and heteroaryl are optionally substituted, and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B is conected with the acid of B to form a peptide bond, and wherein when Y is B2-B1 -N(R^-C(O)-C1 -C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D- Phe-4-CF3.
In another embodiment according to the present invention,
Figure imgf000082_0001
W and M are nitrogen; Ra, Rb and R° are -H;
R3 is -H;
R4 is H or F;
Z is optionally substituted -C1-C8 alkyl-;
L is selected from the group consisting of -C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is d-C3alkyl, the C1-C3 alkyl is optionally substituted with -C(0)-N(R3)-Co-C3 alkyl-Y, -heteroaryl-aryl, hetero- aryl, -N(R3)(R3a) or -N(R3)-Y;
-C0-C6 alkyl-heteroalkyl-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is Ci-C3alkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or -N(R3)-Y; and
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is Q-Qalkyl, the C1-C3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, hetero- aryl-aryl, aryl-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 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 substituted Q-Cόalkyl, alkoxycarbonyl-, -OH, -CN, -C(O)-OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-CrQsalkyl-aryl, optionally substituted -C(O)-O-C!-C6alkyl,
-NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-Ci- C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe- 4-CF3.
In another embodiment according to the present invention,
D is
Figure imgf000083_0001
;
W is nitrogen;
Rc is -H; Rh is H or -Ci-C6alkyl, wherein said alkyl is optionally substituted;
R3 is -H;
R4 is H or F;
Z is optionally substituted -C1-C8 alkyl-;
L is selected from the group consisting of -C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is d-C3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3 alkyl-Y, -heteroaryl-aryl, hetero- aryl, -N(R3)(R3a) or -N(R3)-Y;
-C0-C6 alkyl-heteroalkyl-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is Ci-C3alkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or -N(R3)-Y; and
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is d-C3alkyl, the Ci-C3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, hetero- aryl-aryl, aryl-heteroaryl and B2-B1-N(R3)-C(O)-Ci-C7 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 substituted Ci-C6alkyl, alkoxycarbonyl-, -OH, -CN, -C(O)-OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-Ci-C6alkyl-aryl, optionally substituted -C(O)-O-C !-C6alkyl,
-NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the Ci-C7 alkyl is optionally substituted with -NR3-B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1- C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe- 4-CF3.
In another embodiment according to the present invention,
D is
Figure imgf000084_0002
;
W and M are nitrogen;
Ra, Rb and Rc are -H; R3 is -H;
R4 is H or F;
Z is optionally substituted -C1-C8 alkyl-;
L is
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, hetero- aryl-aryl, aryl -heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the aryl and heteroaryl groups are optionally substituted, and the C1-C7 alkyl is optionally substituted with - NR3-B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1-C7 alkyl-, then Z and L are covalent bonds; wherein
1 O 1X when any of B , B and B are attached together, they are attached by a peptide bond, and
1 *? 1X
B , B and B are independently selected from the group consisting of D-Pro, L-ile and D- Phe-4-CF3.
In another embodiment according to the present invention,
Figure imgf000084_0001
W is nitrogen; Rc is -H; Rh is H or -Q-Qalkyl, wherein said alkyl is optionally substituted; R3 is -H; R4 is H or F;
Z is optionally substituted -C1-C8 alkyl-; L is -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is Ci-C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, hetero-
O I 1X aryl-aryl, aryl-heteroaryl and B -B -N(R ^C(O)-C1-C7 alkyl-, wherein the aryl and hetero- aryl groups are optionally substituted, and the C1-C7 alkyl is optionally substituted with -
NR3 -B3 and the amine of B is conected with the acid of B2 to form a peptide bond, and wherein when Y is B^B1 -N(R3^C(O)-C1 -C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B and B3 are independently selected from the group consisting of D-Pro, L-ile and D- Phe-4-CF3.
In another embodiment according to the present invention,
Figure imgf000085_0001
W and M are nitrogen; Ra, Rb and Rc are -H; R3 is -H; R4 is H or F;
Z is optionally substituted -C1-C8 alkyl-; L is -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is d-C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, hetero- aryl-aryl, aryl-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the aryl and hetero- aryl 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 Ci-C6alkyl, alkoxycarbonyl-, -OH, -CN, -C(O)-OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-Q-Qalkyl-aryl, optionally substituted -C(O)-O-C i-C6alkyl, -NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C1-C7 alkyl is optionally substituted with -NR3-B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1-
C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D-
Phe-4-CF3. In another embodiment according to the present invention,
D is
Figure imgf000086_0001
;
W is nitrogen;
Rc is -H;
Rh is H or -CrCόalkyl, wherein said alkyl is optionally substituted; R3 is -H;
R4 is H or F;
Z is optionally substituted -C1-C8 alkyl-;
L is
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is d-C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)- Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, hetero- aryl-aryl, aryl -heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 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 substituted Q-Qalkyl, alkoxycarbonyl-, -OH, -CN, -C(O)-OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-Q-Cόalkyl-aryl, optionally substituted -C(O)-O-C !-C6alkyl, -NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1- C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D- Phe-4-CF3.
In another embodiment according to the present invention, a substituent selected from the group consisting of optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-Q-Cόalkyl-aryl, optionally substituted -C(O)-O-C i-Cβalkyl, 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-C1- Qalkyl-alkoxy, -CF3, -O-aryl, alkoxy, -NH-C(O)-C i-C6alkyl, halogen, CrC6alkyl, -O-(halo substituted alkyl) and -O-alkyl-N(alkyl)2.
In another embodiment according to the present invention, 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
-Co-C6alkyl-N(R3)-Co-C3alkyl-, wherein when the -C0-C6alkyl is -CrQalkyl it is optionally substituted with a substituent selected from the group consisting of -C1-C3alkyl-ORa, -C1- C3alkyl-N(R3)(R3a), -C0-C3alkyl-C(O)ORa and C0-C3alkyl-C(O)-N(R3)(R3a); -Co-C6alkyl-N(R3)-C(0)-C0-C3alkyl-, wherein when the -C0-C6alkyl is Ci-C6alkyl it is optionally substituted with a substituent selected from the group consisting of -Q-Csalkyl-
ORa, -C!-C3alkyl-NR3R3a, -C0C3alkyl-C(O)ORa and C0-C3alkyl-C(O)-N(R3)(R3a);
-C0-C6alkyl-N(R3)-C(O)-C0-C3alkyl-, wherein the -C0-C3alkyl is d-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(0)-Q)- C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-
C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C(S)-C0-C3alkyl-C4-
C6cycloalkyl-, -N(R3)-C0-C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0-C3alkyl-C4-C6heterocyclyl,
-N(R3)-C2-C3alkyl-N(R3)(R3a), -N(R3)-C2-C3alkyl-ORa, -N(R3)-C0-C3alkyl-C0-C3hetero- alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(S)-O-C0-C3alkyl-Y, -N(R3)-S(O)2-C0- C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-
C(O)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(S)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)-
C(0)-Co-C3alkyl-C0-C3heterocyclyl-Y, -N(R3)-C(S)-C0-C3alkyl-C0-C3heterocyclyl-Y and
-N(R3)-S(O)2-N(R3)-C0-C3alkyl-Y; -Co-C6alkyl-N(R3)-C(S)-Co-C3alkyl-, wherein the -C0-C3alkyl is CrC3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0- C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0- C3alkyl-Y, -N(R3)-C(0)-Co-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C(S)-C0-C3alkyl-C4- Qcycloalkyl-, -N(R3)-C0-C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0-C3alkyl-C4-C6heterocyclyl,
-N(R3)-C2-C3alkyl-N(R3)(R3a), -N(R3)-C2-C3alkyl-ORa, -N(R3)-C0-C3alkyl-C0-C3hetero- alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(S)-O-C0-C3alkyl-Y, -N(R3)-S(O)2-C0- C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)- C(0)-Co-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(S)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)- C(O)-C0-C3alkyl-C0-C3heterocyclyl-Y, -N(R3)-C(S)-C0-C3alkyl-C0-C3heterocyclyl-Y and
-N(R3)-S(0)2-N(R3)-Co-C3alkyl-Y;
-Co-C6alkyl-C(0)-C0-C3alkyl-, wherein when the -C0-C6alkyl is CrQalkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0- C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)(R3a), -C(S)-N(R3)(R3a), -C(O)-N(R3)- C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C4-C6cycloalkyl-,
-N(R3)-C(S)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C0-C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0- C3alkyl-C4-C6heterocyclyl, - N(R3)-C2-C3alkyl-N(R3)(R3a), -N(R3)-C2-C3alkyl-ORa-, -N(R3)-C0-C3heteroalkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(S)-O-C0-C3alkyl-Y, -N(R3)-S(O)2-C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(S)-N(R3)-C0- C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(S)-C0-C3alkyl-C0-
C3heterocyclyl, -N(R3)-C(O)-C0-C3alkyl-C0-C3heterocyclyl-Y, -N(R3)-C(S)-C0-C3alkyl- C0-C3heterocyclyl-Y and -N(R3)-S(O)2-N(R3)-C0-C3alkyl-Y;
-C0-C6alkyl-C(S)-C0-C3alkyl-, wherein when the -C0-C6alkyl is C]-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0- C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)(R3a), -C(S)-N(R3)(R3a), -C(O)-N(R3)-
C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C(S)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C0-C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0- C3alkyl-C4-C6heterocyclyl, - N(R3)-C2-C3alkyl-N(R3)(R3a), -N(R3)-C2-C3alkyl-ORa-, -N(R3)-C0-C3heteroalkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(S)-O-C0-C3alkyl-Y, -N(R3)-S(O)2-C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(S)-N(R3)-C0-
C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(S)-C0-C3alkyl-C0- C3heterocyclyl, -N(R3)-C(O)-C0-C3alkyl-C0-C3heterocyclyl-Y, -N(R3)-C(S)-C0-C3alkyl- C0-C3heterocyclyl-Y and -N(R3)-S(O)2-N(R3)-C0-C3alkyl-Y; -C0-C6alkyl-, wherein when the -Co-C6alkyl is d-Cβalkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-
C(0)-C0-C3alkyl-heterocyclyl and -N(R3)-C(0)-Co-C3alkyl-cyclyoalkyl; -C0-C6alkyl-C(0)-N(R3)-Co-C3alkyl-, wherein when the -C0-C3alkyl is d-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -C(O)-
N(R3)-C0-C3alkyl-Y, -C(O)-heterocyclyl, -C(O)-N(R3)(R3a), aryl-aryl, aryl-heteroaryl,
-heteroaryl-aryl, heteraryl-heteroaryl, heteroaryl, heterocyclyl-heteroaryl and heterocyclyl; -Co-C6alkyl-heteroalkyl-C0-C6alkyl-C(0)-N(R3)-Co-C3alkyl-, wherein when the -Co-C3alkyl is CrC3alkyl it is optionally substituted with a substituent selected from the group consisting of -C(O)-N(R3)-C0-C3alkyl-Y, -C(O)-heterocyclyl, -C(O)-N(R3)(R3a), aryl-aryl, aryl-heteroaryl, -heteroaryl-aryl, heteraryl-heteroaryl, heteroaryl, heterocyclyl-heteroaryl and heterocyclyl; -Co-C6alkyl-C(0)-N(R3)-C0-C3alkyl-, wherein when the -C0-C6alkyl is Q-Cealkyl it is optionally substituted with a substituent selected from the group consisting of -N(R7)(R7a), -N(R3)(R3a), -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(O)-
N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y; -Co-C6alkyl-heteroaryl-Co-C3alkyl-, wherein when the -Co-C3alkyl is C1-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -C0-C3alkyl-
N(R3)-C(O)-C0-C3alkyl-N(R3)(R3a), -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O-C0- C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-Co-C6alkyl-aryl-Co-C3alkyl-, wherein when the -Co-C3alkyl is Q-Qalkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-
C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-
C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y; -C0-C6alkyl-aryl-heteroaryl-Co-C3alkyl-, wherein when the -C0-C3alkyl is C!-C3alkyl it is optionally substituted with a substituent selected from the group consisitng of -N(R3)-
C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-
C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-Co-C6alkyl-heteroaryl-heteroaryl-Co-C3alkyl-, wherein when the -C0-C3alkyl is CrC3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-
C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-
C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y; -Co-Cόalkyl-heteroaryl-Co-Csalkyl-, wherein when the -C0-C3alkyl is CrC3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)- C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)- C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-C0-C6alkyl-0-C(0)-N(R3)-Co-C3alkyl-, wherein when the -Co-C3alkyl is C1-C3 alkyl it is optionally substituted with a group selected from -C(O)-OR3, -C(S)-ORa, -C(O)-N(R3)-d- Qalkyl, -C(S)-N(R3)-CrC3alkyl, -C(O)-N(R3)(R3a)-, -C(S)-N(R3)(R3a)-, -C(O)-N(R3)-C0- C3alkyl-aryl, -C(S)-N(R3)-C0-C3alkyl-aryl, -C(O)-N(R3)-C0-C3alkyl-heteroaryl, -C(S)- N(R3)-C0-C3alkyl-heteroaryl, -C(O)-N(R3)-C0-C3alkyl-cycloalkyl, -C(S)-N(R3)-C0- C3alkyl-cycloalkyl, -C(O)-heterocyclyl, -C(S)-heterocyclyl, -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -C(O)-N(R3)-heterocyclyl, -C(S)-N(R3)-heterocyclyl, -C(O)- N(R3)-C0-C3alkyl-heterocycloalkyl and -C(S)-N(R3)-C0-C3alkyl-heterocycloalkyl;
-Co-C6alkyl-0-C(S)-N(R3)-C0-C3alkyl-, wherein when the -C0-C3alkyl is C1-C3 alkyl it is optionally substituted with a group selected from -C(O)-OR3, -C(S)-OR3, -C(O)-N(R3)-C1- C3alkyl, -C(S)-N(R3)-C1-C3alkyl, -C(O)-N(R3)(R3a)-, -C(S)-N(R3)(R3a)-, -C(O)-N(R3)-C0- C3alkyl-aryl, -C(S)-N(R3)-C0-C3alkyl-aryl, -C(O)-N(R3)-C0-C3alkyl-heteroaryl, -C(S)- N(R3)-C0-C3alkyl-heteroaryl, -C(O)-N(R3)-C0-C3alkyl-cycloalkyl, -C(S)-N(R3)-C0- C3alkyl-cycloalkyl, -C(O)-heterocyclyl, -C(S)-heterocyclyl, -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -C(O)-N(R3)-heterocyclyl, -C(S)-N(R3)-heterocyclyl, -C(O)- N(R3)-C0-C3alkyl-heterocycloalkyl and -C(S)-N(R3)-C0-C3alkyl-heterocycloalkyl; and
-C1-C3alkyl-N(R3)-C(O)-C1-C7alkyl-, wherein the C1-C3alkyl is optionally substituted with -C(O)N(R3)-C1-C3alkyl-Ala and the CrC7alkyl is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-O-CrC3alkyl-Alb, -N(R^-C(O)-C1- C3alkyl-Alb, -N(R3)-S(O)2-C1-C3alkyl-Alb, -N(R3)-S(O)2-N(R3)-C1-C3alkyl-Alb, -N(R3)-
C(O)-N(R>d-C3alkyl-A IIbD and -N(RJ)-S(O)2-N(R')-C1-C3alkyl-A Ib. Z is selected from the group consisting of optionally substituted
Figure imgf000090_0001
Figure imgf000090_0002
Figure imgf000091_0001
Figure imgf000091_0002
Figure imgf000091_0003
wherein each A independently is nitrogen, -CH= or -C(R4) =, wherein there may be 0, 1 , 2 or 3 nitrogen; and
Figure imgf000091_0004
In another embodiment of the present invention,
Figure imgf000092_0001
W is nitrogen;
Rc is -H; X is S;
Rh is -d-C6alkyl or -d-Cβalkyl-phenyl, wherein said alkyl and phenyl are optionally independently substituted;
Z is optionally substituted -C3-C8 alkyl- (for example -C4alkyl-);
L is -N(H)-C(O)-C1alkyl-, wherein the dalkyl is substituted with -N(H)-C(O)- 0-C1-C6 alkyl-phenyl or -N(H)-C(O)-O-C1-C6 alkyl; and
Y is aryl-heteroaryl- or heteroaryl-, each of which is optionally substituted. In certain perferred embodiments, Y is phenyl-thiazolyl, thiazole or imidazole. In certain other embodiments, Z is -C4alkyl-.
In another embodiment of the present invention,
D is
Figure imgf000092_0002
;
W is nitrogen; Rc is -H; X is S;
R is -d-C6alkyl or -C i-Cβalkyl -phenyl, wherein said alkyl and phenyl are optionally independently substituted;
Z is optionally substituted -C3-C8 alkyl- (for example -C4alkyl-); L is -dalkyl-, substituted with a substituent selected from the group consisting of -N(H)-C(O)-O-C1-C6 alkyl-phenyl, -N(H)-C(O)-O-C1-C6 alkyl, -NH-C(O)-hetero- cyclyl-d-Cealkyl and -NH-C(O)-C1-C6alkyl-SO2-C1-C6alkyl; and Y is heteroaryl-, which is optionally substituted. In certain other embodiments, Y is optionally substituted benzimidazole. In certain other embodiments, Y is benzimidazole substituted with -NO2 or -C(O)-NH2. In certain other embodiments, Z is -C4alkyl-.
In another embodiment of the present invention, D is
Figure imgf000093_0001
W is nitrogen; Rc is -H; X is S; M is nitrogen;
Ra is H;
Rb is phenyl or Ci-C6alkyl;
Z is optionally substituted -C3-C8 alkyl- (for example -C4alkyl-); L is -N(H)-C(O)-C^IlCyI-, wherein the Qalkyl is substituted with -N(H)-C(O)- O-d-Cealkyl-phenyl; and
Y is aryl-heteroaryl-, which is optionally substituted, hi certain other embodiments, Y is optionally substituted phenyl-thiazolyl-.
In another embodiment of the present invention,
D is
Figure imgf000093_0002
; W is nitrogen;
Rc is -H; X is S;
M is nitrogen; Ra is H; Rb is phenyl or C i -C6alkyl ;
Z is optionally substituted -C3-C8 alkyl- (for example -C4alkyl-); L is -Cialkyl- substituted with -N(H)-C(O)-O-CrC6alkyl-phenyl, -N(H)-C(O)- O-d-Cβalkyl and -NH-C(O)-C1-C3alkyl-SO2-C1-C3alkyl; and
Y is optionally substituted benimidazole. hi certain embodiments, Z is -C4alkyl-. In certain other embodiments, Y is substituted with -C(O)-NH2. hi certain other embodiments, Y is further selected from optionally substituted aryl-heteroaryl, for example naphthylene-triazole. another embodiment the invention provides compounds of the formula (III):
Y-L-D (III) wherein
D is selected from the group consisting of
Figure imgf000094_0001
Rb and Rh are independently selected from the group consisting of -C1-6 alkyl, -C6-10 aryl and -Ci.Cealkyl-Q.Cearyl;
L is selected from the group consisting of -C0-6 alkylene-, -C0-3 alkylene-N(H)- C(O)-C0-6 alkylene-, optionally substituted with 0-3 R4; Y is selected from the group consisting of optionally substituted -C6-1O aryl and optionally substituted -5-10 membered heteroaryl;
R4 is selected from the group consisting of -N(H)-C(O)-R3 and -N(H)-C(O)-O-R3; and
R3 is selected from the group consisting of optionally substituted -C1-6 alkyl, -C1-6 heteroalkyl, -3-10 membered heterocyclyl and -C7-16 alkylaryl.
In one embodiment of the compounds according to Formula (III)
Figure imgf000094_0002
In another embodiment of the compounds according to Formula (III),
Figure imgf000094_0003
In another embodiment according to the present invention, 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, -CF3, -O-aryl, alkoxy, -NH-C(O)-C1-C6alkyl, halogen, CrC6alkyl, -O- (halo substituted alkyl) and -O-alkyl-N(alkyl)2.
In another embodiment according to the present invention, Y is further selected from heterocyclyl. In another embodiment according to the present invention
L is -C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is Q-Qalkyl, the C1-C3 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.
In another embodiment according to the present invention
L is -C0-C6alkyl-0-C0-C1alkyl-C(0)-N(R3)-Co-C3alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 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.
In another embodiment according to the present invention when a C0-C3alkyl is CpCsalkyl, the C1-C3 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, -CF3, optionally substituted heterocyclyl, -0-C1- C6alkyl-N(alkyl)2, -O-CrC6alkyl-NH2 and -NH-aryl.
In another embodiment according to the present invention
L is -C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3alkyl-heteroaryl, -C(O)-
N(R3)-C0-C3alkyl-aryl, wherein each heteroaryl or aryl moeity is optionally substituted; and
Y is H, optionally substituted aryl or optionally substituted heterocyclyl.
In another embodiment according to the present invention, Y is optionally substituted heteroaryl.
In another embodiment according to the present invention, 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.
In another embodiment according to the present invention, L is -Co-C6alkyl-0-C0-C1alkyl-C(0)-N(R3)-Co-C3alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3 alkyl-hetero- cyclyl or -C(O)-N(R3)-C0-C3 alkyl-aryl, wherein each heterocyclyl or aryl moeity is optionally substituted; and Y is optionally substituted aryl or optionally substituted heteroaryl.
In another embodiment according to the present invention, Y is optionally substituted aryl.
In another embodiment according to the present invention, -C(0)-N(R3)-Co-C3 alkyl- heterocyclyl is -C(O)-N(R3)-C0-C3 alkyl-heteroaryl. In another embodiment according to the present invention, Y-L- is phenyl-CH2-O-
C(O)-NH-.
In another embodiment according to the present invention,
L is -C0-C6alkyl-O-C0-C1alkyl-C(O)-N(R3)-C0-C3alkyl-, wherein when the C0-C3alkyl is C1-
C3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3 alkyl-heteroaryl or -C(O)-N(R3)-C0-C3 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, -NH2, alkyl, -C(O)-OH, -C(O)-O-alkyl, -C(O)-NH-optionally substituted aryl, -C(O)-NH-oρtionally substituted heteroaryl, -C(O)-NH-alkyl-O-alkyl, -C(O)-NH- alkyl-heterocyclyl, -alkyl-optionally substituted aryl, alkoxy, optionally substituted aryl, optionally substituted heteroaryl.
In another embodiment according to the present invention, wherein 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,
-NH-C(O)-alkyl, oxo, -CN, heterocyclyl, -O-halosubstitutedalkyl, -CF3 and -O-alkyl-0-alkyl.
In another embodiment according to the present invention, L is phenyl-CH2-O-C(O)-
NH-Q-Qalkyl-, wherein the C1-C3 alkyl is substituted with -C(O)-NH-thiazolyl, wherein the thiazolyl is optionally substituted. In another embodiment according to the present invention,
L is phenyl-CH2-O-C(O)-NH-C1-C3alkyl-, wherein the C1-C3 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.
In another embodiment according to the present invention, L is -Co-C6alkyl-N(R3)-C(0)-N(R3)-C0-C3alkyl-, wherein when the C0-C3alkyl is d-C3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3alkyl-heteroaryl-aryl, -C(O)-N(R3)-C0-C3alkyl-heteroaryl, or -C(O)-N(R3)-C0-C3alkyl-aryl, wherein each heteroaryl or aryl moeity is optionally substituted; and
Y is optionally substituted aryl, optionally substituted heterocyclyl or optionally substituted cycloalkyl.
In another embodiment according to the present invention, Y is an optionally substituted heteroaryl.
In another embodiment according to the present invention,
L is -C0-C6alkyl-0-C0-C3alkyl-C(0)-N(R3)-Co-C3alkyl-, wherein when a C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3alkyl-heteroaryl,
-C(O)-N(R3)-C0-C3alkyl-aryl, -C(O)-N(R3)-C0-C3alkyl-heteroaryl-aryl, -C(O)-N(R3)-C0- C3alkyl-heteroaryl-heteroaryl, -C(O)-N(R3)-C0-C3alkyl-aryl-aryl and -C(O)-N(R3)-C0- C3alkyl-aryl-heteroaryl, wherein each heteroaryl or aryl moeity is optionally substituted;and Y is H.
In another embodiment according to the present invention, W is further selected from O.
Figure imgf000097_0001
In another embodiment according to the present invention, X is the
structure
Figure imgf000097_0002
for example
Figure imgf000097_0003
In another embodiment according to the present invention,
Figure imgf000097_0004
is the
structure
Figure imgf000097_0005
Some examples of the compounds according to the first aspect of the invention are listed in the table below. These examples merely serve to exemplify some of the compounds of the first aspect of the invention and do not limit the scope of the invention.
Synthetic Schemes and Experimental Procedures
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.
Scheme 1
Figure imgf000098_0001
Example 1 (S)-benzyl l-oxo-l-(4-phenylthiazol-2-ylamino)-6-thioureidohexan-2-ylcarbamate (3)
Step 1 : (S)-2-(benzyloxycarbonylamino)-6-(tert-butoxycarbonylamino)hexanoic acid N-(4- phenylthiazol-2-yl)amide (1)
To Z-Lys(Boc)-OH (1.9 g, 5.0 mmol) in pyridine (20 mL) was added 2-amino-4- phenylthiazole (1.32 g, 7.5 mmol). The mixture was cooled to 0°C and then phosphorus oxychloride (0.50 mL, 5.5 mmol) was added dropwise. The mixture was stirred at 0°C for 30min, and then at room temperature for 16h. The mixture was quenched with water and extracted with ethyl acetate and the organic extract was washed with brine, dried (MgSO4), filtered, and evaporated. The residue was purified by silica gel column chromatography with ethyl acetate (20 to 40%) in hexanes to afford 1 (2.25 g, 84%) as a white solid. LRMS (ESI): (calc) 538.2; (found) 539.3 (MH)+. Step 2: (S)-benzyl 6-amino-l-oxo-l-(4-phenylthiazol-2-ylamino)hexan-2-ylcarbamate (2)
To compound 1 (2.15 g, 3.99 mmol) in dichloromethane (16 mL) was added trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 2h. Solvent was evaporated, and ethyl acetate was added to the residue. A saturated aqueous solution of Na2CO3 was added and the mixture was extracted with ethyl acetate, and the organic extract was dried (MgSO4), filtered, and evaporated. The crude colorless oil 2 was used as is for next step. LRMS (ESI): (calc) 438.2; (found) 439.1 (MH)+.
Step 3: (S)-benzyl l-oxo-l-(4-phenylthiazol-2-ylamino)-6-thioureidohexan-2-ylcarbamate (3) To compound 2 (88 mg, 0.20 mmol) in dichloromethane (1.0 mL) at 0°C was added triethylamine (42 uL, 0.30 mmol), followed by 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. The mixture was quenched with a saturated solution OfNH4Cl and extracted with ethyl acetate. The organic extract was dried (MgSO4), filtered, and evaporated and the residue was purified by silica gel column chromatography with ethyl acetate (60 to 100%) in hexanes to afford 3 (20 mg, 20%) as a white solid. (dmso-d6) δ (ppm) 1H: 12.39 (s, IH), 7.88 (d, J=7.4Hz, 2H), 7.70 (d, J=6.8Hz, IH), 7.62 (s, IH), 7.54 (bs, IH), 7.42 (t, J=7.8Hz, 2H), 7.38- 7.11 (m, 6H), 6.86 (bs, IH), 5.02 (d, J=2.5Hz, 2H), 4.26 (q, J=4.9Hz, IH), 3.33 (m, 2H), 2.97 (m, IH), 1.78-1.52 (m, 2H), 1.52-1.23 (m, 4H). LRMS (ESI): (calc) 497.2; (found) 498.2 (MH)+.
Scheme 2
Figure imgf000099_0001
Example 2 (S)-benzyl 6-ethanethioamido-l-oxo-l-(4-phenylthiazol-2-ylamino)hexan-2-ylcarbamate
(5)
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. Water was added and the mixture was extracted with ethyl acetate and the organic extract was dried (MgSO4), filtered, and evaporated and the residue was purified by silica gel column chromatography with ethyl acetate (60 to 100%) in hexanes to afford 4 (45 mg, 47%) as a white solid. LRMS (ESI): (calc) 480.2; (found) 481.2 (MH)+. Step 2: (S)-benzyl 6-ethanethioamido-l-oxo-l-(4-phenylthiazol-2-ylamino)hexan-2- ylcarbamate (5)
To acetamide 4 (35 mg, 0.07 mmol) in tetrahydrofuran (0.7 mL) at 0°C was added 2,4-bis(4-phenoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide (96 mg, 0.18 mmol, Belleau's reagent) and the mixture was stirred at room temperature for 2h. A saturated aqueous solution of Na2CO3 was added and the mixture was extracted with ethyl acetate and the organic extract was washed with dried (MgSO4), filtered, and evaporated and the residue was purified by silica gel column chromatography with ethyl acetate (10 to 60%) in hexanes to afford 5 (24 mg, 66%) as a white solid. (dmso-d6) δ (ppm) 1H: 12.40 (s, IH), 9.95 (bs, IH), 7.90 (d, J=7.0Hz, 2H), 7.71 (d, J=7.4Hz, IH), 7.63 (s, IH), 7.43 (t, J=7.2Hz, 2H), 7.41- 7.15 (m, 6H), 5.07-4.99 (m, 2H), 4.28 (q, J=4.9Hz, IH), 3.46 (q, J=6.7Hz, 2H), 2.36 (s, 3H), 1.88-1.49 (m, 4H), 1.48-1.30 (m, 2H). LRMS (ESI): (calc) 496.2; (found) 497.3 (MH)+.
Scheme 3
Figure imgf000100_0001
Example 3 (S)-benzyl 6-ethanethioamido-l-oxo-l-(phenylamino)hexan-2-ylcarbamate (8)
Step 1 : (S)-2-(benzyloxycarbonylamino)-6-(tert-butoxycarbonylamino)hexanoic acid N-
(phenyl)amide (6) To Z-Lys(Boc)-OH (190 mg, 0.50 mmol) in DMF (2.5 mL) was added aniline (55 uL,
0.60 mmol), EDC (125 mg, 0.65 mmol) and HOBT (100 mg, 0.65 mmol) and the mixture was stirred at room temperature for 16h. A saturated aqueous solution OfNa2CO3 was added and the mixture was extracted with ethyl acetate. The organic extract was dried (MgSO4), filtered, and evaporated and the residue was purified by silica gel column chromatography with ethyl acetate (10 to 40%) in hexanes to afford 6 (193 mg, 85%) as a white solid. LRMS
(ESI): (calc) 455.2; (found) 478.3 (M+Na)+.
Step 2: (S)-benzyl 6-amino-l-oxo-l-(phenylamino)hexan-2-yl carbamate (7)
Title compound 7 (145 mg, 96%) was obtained by following the general procedure B using 6 (193 mg, 0.42 mmol) as starting material. LRMS (ESI): (calc.) 355.2; (found) 356.3 (MH)+.
Step 3: (S)-benzyl 6-ethanethioamido-l-oxo-l-(phenylamino)hexan-2-yl carbamate (8)
To amine 7 (73 mg, 0.21 mmol) in tetrahydrofuran (1.0 mL) at 0°C was added triethylamine (57 uL, 0.41 mmol), followed by ethyl dithioacetate (35 uL, 0.31 mmol) and the mixture was stirred at room temperature for 16h. A saturated aqueous solution OfNa2CO3 was added and the mixture was extracted with ethyl acetate and the organic extract was dried
(MgSO4), filtered, and evaporated and the residue was purified by silica gel column chromatography with ethyl acetate (40 to 80%) in hexanes to afford 8 (63 mg, 74%) as a white solid.
(dmso-d6) δ (ppm) 1H: 10.02 (s, IH), 9.96 (bs, IH), 7.60-7.56 (m, 3H), 7.37-7.18 (m, 7H), 7.04 (t, J=7.4Hz, IH), 5.03 (s, 2H), 4.12 (q, J=4.7Hz, IH), 3.44 (q, J=7.2Hz, 2H), 2.35 (s,
3H), 1.73-1.49 (m, 4H), 1.49-1.27 (s, 2H). LRMS (ESI): (calc) 413.2; (found) 414.3 (MH)+. Scheme 4
Figure imgf000102_0001
Example 11
(S)-tert-butyl 6-ethanethioamido-l-oxo-l-(4-phenylthiazol-2-ylamino)hexan-2- ylcarbamate (18)
Step 1 : (S)-6-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-(tert- butoxycarbonylamino)hexanoic acid N-(4-phenylthiazol-2-yl)amide (16)
Title compound 16 (728 mg, 61%) was obtained as a white solid by following the general procedure A except using Boc-Lys(Fmoc)-OH (900 mg, 1.92 mmol) as starting material. LRMS (ESI): (calc.) 626.3; (found) 627.4 (MH)+. Step 2: (S)-tert-butyl 6-amino-l-oxo-l-(4-phenylthiazol-2-ylamino)hexan-2-ylcarbamate (17)
To compound 16 (728 mg, 1.16 mmol) in dichloromethane (4.6 mL) was added piperidine (1.15 mL, 12 mmol) and the mixture was stirred at room temperature for Ih. Solvent was evaporated and the residue was purified by silica gel column chromatography with methanol (0 to 10%) in dichloromethane to afford 17 (110 mg, 23%) as a white solid. LRMS (ESI): (calc.) 404.2; (found) 405.3 (MH)+.
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. (dmso-d6) δ (ppm) 1H: 12.34 (s, IH), 9.96 (s, IH), 7.90 (d, J=7.0Hz, 2H), 7.63 (s, IH), 7.43 (t, J=7.4Hz, 2H), 7.32 (t, J=7.4Hz, IH), 7.22 (d, J=7.4Hz, IH), 4.20 (q, J=4.7Hz, IH), 3.50-3.40 (m, 2H), 2.36 (s, 3H), 1.72-1.46 (m, 4H), 1.45-1.22 (m, 2H), 1.38 (s, 9H). LRMS (ESI): (calc) 462.2; (found) 463.3 (MH)+.
Example 12 (S)-tert-butyl l-oxo-l-(4-phenylthiazol-2-ylamino)-6-thioureidohexan-2-ylcarbamate
(19)
Step 1 : (S)-tert-butyl l-oxo-l-(4-phenylthiazol-2-ylamino)-6-thioureidohexan-2-ylcarbamate (19)
Title compound 19 (24 mg, 38%) was obtained as a white solid by following the procedure C except using 17 (55 mg, 0.14 mmol) as starting material. (dmso-d6) δ (ppm) 1H: 7.88 (d, J=7.0Hz, 2H), 7.59 (s, IH), 7.42 (t, J=7.4Hz, 2H), 7.32 (t, J=7.2Hz, IH), 7.17 (d, J=7.0Hz, IH), 6.84 (m, IH), 4.20-4.14 (m, IH), 3.38-3.27 (m, 2H), 3.02-2.94 (m, IH), 1.70- 1.53 (m, 2H), 1.52-1.22 (m, 4H), 1.36 (s, 9H). LRMS (ESI): (calc) 463.2; (found) 464.3 (MH)+.
The compounds exemplified in Table 1 are prepared starting with the indicated starting material and following the given preparative sequence(s) utilizing the general procedures listed in Table 4.
Figure imgf000104_0001
Figure imgf000105_0001
Additional compounds according to the present invention are indicated in Table 2
Table 2
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Scheme 5
Figure imgf000109_0001
Example 28
(S)-benzyl 5-ethanethioamido- 1 -(2-(phenylamino)thiazol-4-yl)pentyl carbamate (37)
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)-
OH (2 g, 5.26 mmol) and triethylamine (0.806 mL, 5.78 mmol) in THF (10.51 mL), at 0 0C then the reaction was slowly warmed to room temperature and stirred for 1 hr. The mixture was cooled to 0 °C and a solution of diazomethane (2.5M, 10.51 mL, 26.3 mmol) in ether was added and the resulting yellow solution was stirred for 3 hr at 0 °C. The reaction was diluted with water and extracted with EtOAc (3x). The organic extract was dried (Na2SO4), filtered and evaporated and the resulting diazoketone was re-dissolved in ether (10.5 mL) and cooled to 0 °C. A solution of 48% HBr in water (0.571 ml, 10.5 mmol) was added portion wise over Ih, and after completion of the reaction it was quenched with sat NaHCO3 and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and evaporated. The residue was purified by silica gel chromatography with EtOAc (20-40%) in hexane to afford alphabromoketone 34 (1.78 g, 74%) as a white solid. LRMS(ESI): (calc.) 457.3 (found) 479.1 , 481.2 (MNa)+
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. LRMS(ESI): (calc.) 510.6 (found) 511.4 (MH)+ Step 3: (S)-benzyl 5-amino-l-(2-(phenylamino)thiazol-4-yl)pentylcarbamate (36)
The general procedure B was followed to afford crude 36 (86.0 mg, 100%) as a yellow foam. LRMS(ESI): (calc.) 410.5 (found) 411.3 (MH)+ Step 4: (S)-benzyl 5-ethanethioamido-l-(2-(phenylamino)thiazol-4-yl)pentylcarbamate (37)
Triethylamine (58.4 μl, 0.419 mmol) and ethyl dithioacetate (36.1 μL, 0.314 mmol) were added to a solution of 36 (86.0 mg, 0.209 mmol) in THF (838 μL) 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 (Na2SO4), 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. (CD3OD) D (ppm) IH: 7.53 (d, J = 8.4 Hz, 2H), 7.36-7.32 (m, 3H), 7.30-7.25 (m, 3H). 6.97- 6.93 (m, IH), 6.45 (s, IH), 5.13-5.05 (m, 2H), 4.65-4.61 (m, IH), 3.56 (t, J = 7.2 Hz, 2H), 2.43 (s, 3H), 2.00-1.94 (m, IH), 1.81- 1.74 (m, IH), 1.73-1.64 (m, 2H), 1.47-1.37 (m, 2H). LRMS(ESI): (calc.) 468.6 (found) 469.3 (MH)+ .
Example 29 (S)-benzyl 5-ethanethioamido- 1 -(2 -phenyl- 1 H-imidazol-4-yl)pentylcarbamate (39)
Step 1: (S)-benzyl 5-(t-butoxycarbonylamino)l-(2-phenyl-lH-imidazol-4-yl)pentylcarbamate
(38)
Benzimidamide hydrochloride (0.188 mg, 1.20 mmol) was added to a solution of 34
(0.550 g, 1.20 mmol) in THF (4.0 mL), followed by a solution of potassium carbonate (0.332 g, 2.40 mmol) in water (0.500 mL) and the reaction was heated to 60 0C and stirred for 16 h.
After cooling the reaction was diluted with water and extracted with EtOAc and the organic layer was dried with Na2SO4, filtered and evaporated and the residue was purified by silica gel chromatography with EtOAc (30-80%) in hexane to afford 38 (0.107 g, 18%) as a white solid. LRMS(ESI): (calc.) 478.5 (found) 479.4 (MH)+
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%). LRMS(ESI): (calc.) 378.4 (found) 379.3 (MH)+.
To the amine (51 mg, 0.135 mmol) in THF (0.539 mL) at 0 °C was added triethylamine (37.6 μL, 0.270 mmol) and ethyl dithioacetate (23.1 μL, 0.202 mmol) as described in general procedure K. The desired compound 39 was obtained as a white solid after purification by silica gel chromatography with EtOAc (40-80%) in hexane (15 mg, 25%).
(CD3OD) D (ppm) IH: 7.82 (d, J = 7.2 Hz, 2H), 7.45-7.41 (m, 2H), 7.39-7.27 (m, 6H), 6.98 (s, IH), 5.13-5.05 (m, 2H), 4.75-4.72 (m, IH), 3.57-3.53 (m, 2H), 1.96-1.92 (m, IH), 1.84- 1.80 (m, IH), 1.70-1.64 (m, 2H), 1.48-1.40 (m, 2H).
LRMS(ESI): (calc.) 436.5 (found) 437.3 (MH)+
Scheme 6
Figure imgf000111_0001
Example 30
(S)-benzyl 5-ethanethioamido-l -(5-phenyl-l H-imidazol-2-yl)pentylcarbamate (43)
Step 1 : (S)-methyl 2-(benzyloxycarbonylamino)-6-ethanethioamidohexanoate (40)
A solution of (S)-methyl 6-amino-2-(benzyloxycarbonylamino)hexanoate.HCl (2.5 g, 7.56 mmol) in THF (30.2 ml) at 0 °C was treated with Et3N (3.16 ml, 22.67 mmol) and ethyl dithioacetate (0.910 ml, 7.94 mmol) as described in general procedure G. Compound 40 was obtained as a colorless oil after purification by silica gel chromatography with EtOAc (20% to 60%) in hexane (2.8 g, quantitative). LRMS(ESI): (calc.) 352.5 (found) 353.2 (MH)+ Step 2: (S)-2-(benzyloxycarbonylamino)-6-ethanethioamidohexanoic acid (41) To a stirred solution of ester 40 (2.66 g, 7.56 mmol) in THF (7.5 ml), MeOH (7.50 ml) and Water (7.50 ml) at 0 0C was added LiOH monohydrate (1.269 g, 30.2 mmol). The resulting solution was allowed to stir for Ih at room temperature, then it was taken to dryness, IM HCl was added up to pH~3 and the mixture was extracted with EtOAc, and the organic extracts were dried over MgSθ4, filtrated and concentrated, leaving a white solid which was used as is for the next step. LRMS(ESI): (calc.) 338.4 (found) 339.2 (MH)+ Step 3: (S)-benzyl 6-ethanethioamido-l-oxo-l-(2-oxo-2-phenylethylamino)hexan-2- ylcarbamate (42)
To a stirred solution of 41 (254 mg, 0.75 mmol) in DMF (3.75 ml) was added alpha- Amino-acetophenone hydrochloride (154 mg, 0.90 mmol), Et3N (125 μl, 0.90 mmol), EDC (187 mg, 0.975 mmol) followed by HOBT (149 mg, 0.975 mmol) and the mixture was stirred for 16 h at room temperature. Saturated Na2CO3 was added and the mixture was extracted with EtOAc, and the extracts were washed with brine, dried over MgSO4, filtrated and concentrated and the residue was purified by chromatography with EtOAc (10% to 100% EtOAc) in hexane to afford 42 as white oily solid (186 mg, 54.4% yield). LRMS(ESI): (calc.) 455.6 (found) 456.3 (MH)+; 478.3 (MNa)+.
Step 4: (S)-benzyl 5-ethanethioamido-l-(5-phenyl-lH-imidazol-2-yl)pentylcarbamate (43) To a stirred solution of 42 (186 mg, 0.408 mmol) in AcOH (2.041 mL) was added ammonium acetate (787 mg, 10.21 mmol) and the mixture was stirred for 16h at 100 °C. Saturated Na2CO3 solution was added and the mixture was extracted with EtOAc and the extracts were dried over MgSO4, filtrated and concentrated and the residue was purified by prep-HPLC (Aquasil C 18, 5-95%MeOH/H2O) to afford 43 as white solid (29 mg, 16.3%). (dmso-d6) d(ppm) IH: 11.84 (s, IH), 9.96 (s, IH), 7.73-7.71 (m, 2H), 7.66 (d, J=8.4Hz, IH), 7.46 (s, IH), 7.36-7.15 (m, 7H), 7.16 (t, J=7.2Hz, IH), 5.04 (d, J=8.2Hz, 2H), 4.64 (q, J=6.3Hz, IH), 3.44 (q, J=6.3Hz, 2H), 2.36 (s, 3H), 1.97-1.72 (m, 2H), 1.56 (quintet, J=6.5Hz, 2H), 1.42-1.22 (m, 2H). LRMS(ESI): (calc.) 436.2 (found) 437.3 (MH)+ Scheme 7
Figure imgf000113_0001
(S)-benzyl 1 -(4,5-diphenyl- 1 H-imidazol-2-yl)-5-ethanethioamidoρentylcarbamate (49) Step 1 : (2S)-2-oxo-l,2-diphenylethyl 2-(benzyloxycarbonylamino)-6- ethanethioamidohexanoate (48)
To a stirred solution of 41 (104 mg, 0.307 mmol) in DMF (1.537 mL) was added Benzoin (78 mg, 0.369 mmol), DMAP (7.51 mg, 0.061 mmol), EDC (77 mg, 0.400 mmol) followed by HOBT (61.2 mg, 0.400 mmol). The mixture was stirred for 16 h at room temperature, then H2O was added and the mixture was extracted with EtOAc, washed with brine, dried over MgSO4, filtrated and concentrated and the residue was purified by chromatography with EtOAc (20% to 60%) in hexane to furnish 48 as white solid, (80 mg, 48.9% yield). LRMS(ESI): (calc.) 532.7 (found) 533.3 (MH)+; 555.3 (MNa)+ Step 2: (S)-benzyl 1 -(4,5-diphenyl- lH-imidazol-2-yl)-5-ethanethioamidopentylcarbamate (49)
To a stirred solution of 48 (80 mg, 0.150 mmol) in toluene (1.001 mL) at room temperature was added ammonium acetate (116 mg, 1.502 mmol) and the mixture was stirred for 4h at 100 °C. The usual work-up and purification by chromatography with EtOAc (20% to 80%) in hexane gave 49 contaminated with un-reacted 48. Further purification by prep- HPLC (5-95% MeOH/H2O) gave 49 as white solid, (5 mg, 6.5%)
(dmso-d6) d(ppm) IH: 12.19 (s, IH), 9.96 (s, IH), 7.64 (d, J=8.6Hz, IH), 7.44-7.19 (m, 15H), 5.04 (q, J=5.9Hz, 2H), 4.68 (q, J=6.3Hz, IH), 3.45 (q, J=6.7Hz, 2H), 2.35 (s, 3H), 1.98-1.74 (m, 2H), 1.57 (qi, J=6.7Hz, 2H), 1.48-1.25 (m, 2H). LRMS(ESI): (calc.) 512.2 (found) 513.4 (MH)+
Figure imgf000114_0001
Example 38 (S)-benzyl 5-ethanethioamido-l-(5-(trifluoromethyl)-lH-imidazol-2-yl)pentyl carbamate (55) Step 1: (S)-benzyl 6-(t-butoxycarbonylamino)-l-hydroxyhexan-2-ylcarbamate (52)
To a stirred solution of Z-Lys(Boc)-OH (5 g, 13.14 mmol) in THF (26.3 ml) at O °C was added BH3.THF (IM in THF, 28.9 ml, 28.9 mmol) dropwise. The resulting solution was allowed to stir for 30min at O °C, and then for 2h at room temperature. The reaction was cooled to OC, quench with MeOH and was taken to dryness and the residue was purified by chromatography with EtOAc (20% to 60% EtOAc) in hexane to give 52 as colorless oil. LRMS(ESI): (calc.) 366.5 (found) 389.4 (MNa)+ Step 2: (S)-benzyl 6-(t-butoxycarbonylamino)-l-oxo-hexan-2-ylcarbarnate (53)
To a stirred solution of 52 (3.5 g, 9.55 mmol) in CH2Cl2 (38.2 ml) at room temperature was added Dess-MartinPeriodinane (5.06 g, 11.94 mmol) and the resulting solution was allowed to stir for Ih at room temperature. Saturated Na2SO3 solution was added and CH2Cl2 extracts were washed with saturated NaHCO3 solution then with brine, dried over MgSO4, filtrated and concentrated. Crude aldehyde 53 was obtained as a colorless oily solid and used as is for the next step (3.176g, 91%).
Step 3: (S)-benzyl 5-(t-butoxycarbonylamino)-l-(5-(trifluoromethyl)-lH-imidazol-2- yl)pentylcarbamate (54)
To a stirred solution of l,l-Dibromo-3,3,3-trifluoroacetone (163 mg, 0.604 mmol) in MeOH (2.195 mL) at room temperature was added a solution of ammmonia (7N in MeOH, 0.392 mL, 2.74 mmol) followed by 53 (0.549 mL, 0.549 mmol, 1 M solution in methanol). The resulting solution was allowed to stir for 5min in microwave at 100 °C, MeOH was evaporated and a saturated solution OfNaHCO3 was added and the mixture was extracted with EtOAc. After the normal work-up, the residue was purified by chromatography with EtOAC (20% to 60%) in hexane to afford imidazole 54 as white solid. LRMS(ESI): (calc.) 470.5 (found) 471.3 (MH)+ Step 4: (S)-benzyl 5-ethanethioamido-l-(5-(trifluoromethyl)-lH-imidazol-2- yl)pentylcarbamate (55)
Compound 54 (52 mg, 0.111 mmol) in THF (0.737 mL) at room temperature was treated with TFA (0.213 mL, 2.76 mmol) as described in general procedure B. The crude amine was obtained as light yellow oil and was used as is for the next step. LRMS(ESI): (calc.) 370.4 (found) 371.3 (MH)+ To the amine from above (41.1 mg, 0.111 mmol) in THF (1.11 ml) at room temperature was added Et3N (30.9 μl, 0.222 mmol) followed by Ethyl dithioacetate (14.01 μl, 0.122 mmol) as described for general procedure G and compound 55 was obtained after chromatography with EtOAc (20% to 100%) in hexane as white solid. (dmso-d6) δ(ppm) IH: 12.49 (s, IH), 9.93 (s, IH), 7.74 (d, J=8.4Hz, IH), 7.62 (d, J=I.2Hz, IH), 7.34-7.27 (m, 5H), 5.02 (q, J=9.8Hz, 2H), 4.61 (q, J=5.7Hz, IH), 3.43-3.39 (m, 2H), 2.34 (s, 3H), 1.91-1.65 (m, 2H), 1.59-1.48 (m, 2H), 1.40-1.19 (m, 2H). LRMS(ESI): (calc.) 428.1 (found) 429.2 (MH)+
Example 39
(S)-benzyl 1 -(5-bromo- 1 H-imidazol-2-yl)-5-ethanethioamidopentylcarbamate (59) Step 1 : (S)-benzyl 5-(t-butoxycarbonylamino)-l-(lH-imidazol-2-yl)pentylcarbamate (56) To a stirred solution of 53 (1 g, 2.74 mmol) in MeOH (7 ml) at room temperature was added Glyoxal trimer dihydrate (0.288 g, 1.372 mmol) followed by dropwise addition of a solution of ammonia (7N in MeOH, 1.960 ml, 13.72 mmol) and the resulting solution was allowed to stir for 16h at room temperature. Solvent was evaporated, and the residue was purified by chromatography (0% to 15% MeOH) in DCM to afford 56 (585, 53%) as white solid. LRMS(ESI): (calc.) 402.5 (found) 403.4 (MH)+
Step 2: (S)-benzyl 5-(t-butoxycarbonylamino)-l-(4,5-dibromo-lH-imidazol-2- yl)pentylcarbamate (57) To a stirred solution of 56 (143 mg, 0.355 mmol) in DMF (1.776 mL) at 0 °C was added NBS (56.9 mg, 0.320 mmol) and 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. A saturated solution OfNaHCO3 was added and the mixture was extracted with EtOAc, dried over MgSO4, filtrated and concentrated and the residue was purified by chromatography with EtOAc (20% to 60%) in hexane to afford 57 (90 mg, 45.2%) as white solid. LRMS(ESI): (calc.) 560.3 (found) 561.2 (MH)+
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
H2O(0.536 mL) at room temperature was added sodium sulfite (337 mg, 2.68 mmol) and tetrabutylammonium hydrogen sulfate (182 mg, 0.535 mmol). The resulting solution was allowed to stir for 2 days at 100 °C, but the major was starting material, so the mixture was heated in the microwave for 5min at 1600C; for 2min at 1800C; and then 15min at 1600C for the reaction to reach completion. Water was added and the mixture was extracted with EtOAc, dried over MgSO4, filtrated and concentrated and the residue was purified by chromatography with EtOAc (10% to 60%) in hexane to give 58 (39 mg, 30.3%) as white solid. LRMS(ESI): (calc.) 482.1 (found) 483.3 (MH)+ Step 4: (S)-benzyl l-(5-bromo-lH-imidazol-2-yl)-5-ethanethioamidopentylcarbamate (59) Compound 58 (39 mg, 0.081 mmol) in THF (0.0.81 mL) at room temperature was treated with TFA (0.156 mL, 2.03 mmol) as described in general procedure B. The crude amine was obtained in quantitative yield as light yellow solid and was used as is for the next step.
To the amine from above (30.9 mg, 0.081 mmol) in THF (0.81ml) at room temperature was added Et3N (23 μl, 0.16 mmol) followed by Ethyl dithioacetate (10.2 μl, 0.089 mmol) as described for general procedure G to give compound 59 (9 mg, 25.3%) was obtained after chromatography with EtOAc (10% to 100%) in hexane as white solid, (dmso- d6) δ(ppm) IH: 12.17 (s, IH), 9.93 (s, IH), 7.67 (d, J=8.2Hz, IH), 7.38-7.28 (m, 5H), 7.11 (d, J=2.2Hz, IH), 5.03 (q, J=BHz, 2H), 4.54 (q, J=5.9Hz, IH), 3.40 (q, J=5.7Hz, 2H), 2.34 (s, 3H), 1.87-1.63 (m, 2H), 1.57-1.45 (m, 2H), 1.37-1.18 (m, 2H). LRMS(ESI): (calc.) 438.1; 440.1 (found) 439.2; 441.2 (MH)+
Scheme 9
Figure imgf000117_0001
Example 40
(S)-tert-butyl l-(5-(lH-indol-3-yl)-lH-imidazol-2-yl)-5-(3-methylthioureido)pentylcarbamate
(62)
Stepl: (S)-benzyl 5-(5-(lH-indol-3-yl)-lH-imidazol-2-yl)-5-(t- butoxycarbonylamino)pentylcarbamate (60)
To a stirred solution of Boc-Lys(Z)-OH (481 mg, 1.265 mmol) in DMF (3.834 mL) was added 2-Hydroxy-l-(lH-indol-3-yl)ethanone (266 mg, 1.518 mmol), DMAP (30.9 mg,
0.253 mmol), EDC (315 mg, 1.645 mmol) followed by HOBT (252 mg, 1.645 mmol) as described in general procedure P to give the ester as a white solid after purification by chromatography with EtOAc (10% to 80%) hexane (284 mg, 41.7%). LRMS(ESI): (calc.)
537.6 (found) 560.4 (MNa)+.
The ester (284 mg, 0.528 mmol) in CH3CN (2.641 mL) at room temperature was added ammonium acetate (407 mg, 5.28 mmol) and the solution was stirred for 5min at 160
°C in the microwave. After the usual work-up, the residue was purified by chromatography with EtOAc (20% to 80%) in hexane to afford 60 (147 mg, 53.8%) as beige solid.
LRMS(ESI): (calc.) 517.6 (found) 518.4 (MH)+.
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
(10% Degussa type, 30.2 mg, 0.028 mmol) and the resulting suspension was allowed to stir for 2h at room temperature under latm of hydrogen gas. The catalyst was filtered over Celite, and the filtrate was concentrated to afford 61 (104 mg, 95%) as beige solid. LRMS(ESI):
(calc.) 383.5 (found) 384.5 (MH)+. Step 3: (S)-tert-butyl l-(5-(lH-indol-3-yl)-lH-imidazol-2-yl)-5-(3- methylthioureido)pentylcarbamate (62)
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. After the usual work-up, the residue was purified by chromatography with MeOH (5% to 15%) in DCM, and the material was purified further by prep-HPLC (Luna Cl 8 column, 20-100% MeOH/H2O) to afford 62 (35 mg, 24.5%) as beige solid.
(dmso-d6) d(ppm) IH: 11.08 (s, IH), 8.12 (s, IH), 7.85 (d, J=7.6Hz, IH), 7.56 (d, J=1.6Hz, IH), 7.40 (bs, IH), 7.36 (d, J=8.0Hz, IH), 7.30 (bs, IH), 7.19 (s, IH), 7.09 (t, J=7.8Hz, IH), 7.03 (t, J=7.8Hz, 2H), 4.60 (q, J=6.5Hz, IH), 3.29 (m, 2H), 2.76 (bs, 3H), 1.87-1.65 (m, 2H), 1.47 (qi, J=7.2Hz, 2H), 1.38 (s, 9H), 1.42-1.19 (m, 2H). LRMS(ESI): (calc.) 456.2 (found) 457.0 (MH)+
Scheme 10
Figure imgf000118_0001
Example 44
(S)-benzyl 1 -( 1 H-benzo[d]imidazol-2-yl)-5-(3-methylthioureido)pentylcarbamate (69)
Step 1 : (S)-benzyl 6-(t-butoxycarbonylamino)-l-(2-aminophenylamino)-l-oxohexan-2- ylcarbamate (66)
To a stirred solution of Cbz-Lys(Boc)-OH (1 g, 2.63 mmol) in DMF (10.51 ml) was added o-Phenylenediamine (0.341 g, 3.15 mmol), EDC (0.655 g, 3.42 mmol) followed by HOBT (0.523 g, 3.42 mmol) following the general procedure F. Compound 66 was obtained after purification by chromatography with EtOAc (20% to 80%) in hexane as a yellow solid
(461 mg, 37.3%). LRMS(ESI): (calc.) 470.6 (found) 471.4 (MH)+
Step 2: (S)-benzyl 5-(t-butoxycarbonylamino)-l-(lH-benzo[d]imidazol-2-yl)pentylcarbamate
(67) A solution of 66 (461 mg, 0.980 mmol) in AcOH (3.919 mL) was stirred for Ih at 65
°C, then it was taken to dryness, a saturated solution OfNa2CO3 was added and the mixture was extracted with EtOAc, dried over MgSO4, filtrated and concentrated. Crude 67 (322,
72.6%) was obtained as beige solid. LRMS(ESI): (calc.) 452.6 (found) 453.4 (MH)+
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.
Crude 68 (250 mg, quantitative) was obtained as beige solid. LRMS(ESI): (calc.) 352.4
(found) 353.3 (MH)+
Step 4: (S)-benzyl l-(lH-benzo[d]imidazol-2-yl)-5-(3-methylthioureido)pentylcarbamate (69)
To a stirred solution of 68 (83 mg, 0.236 mmol) in THF (1.570 mL) at 0 °C was added Et3N (0.082 mL, 0.589 mmol) followed by Methyl isothiocyanate (0.018 mL, 0.259 mmol) and the resulting solution was allowed to stir for Ih at room temperature. A solution of saturated Na2CO3 was added and the mixture was extracted with EtOAc and the extracts were dried over MgSO4, filtrated and concentrated and the residue was purified by chromatography with EtOAc (20% to 100%) in hexane to afford 69 (37 mg, 36.9%) as white solid,
(dmso-d6) d(ppm) IH: 12.21 (s, IH), 7.82 (d, J=8.2Hz, IH), 7.53 (d, J=6.7Hz, IH), 7.44-7.29
(m, 7H), 7.15-7.08 (m, 2H), 5.03 (q, J=15Hz, 2H), 4.77 (q, J=5.7Hz, IH), 3.40-3.18 (m, 2H), 2.76 (bs, 3H), 2.02-1.76 (m, 2H), 1.48 (quintet, J=6.7Hz, 2H), 1.41-1.22 (m, 2H).
LRMS(ESI): (calc.) 425.2 (found) 426.3 (MH)+ Scheme 11
S
Figure imgf000120_0001
Example 45
(S)-N-(5-ethanethioamido- 1 -(6-(4-fluorophenyl)- 1 H-benzo[d]imidazol-2-yl)pentyl)-2,2,2- trifluoroacetamide (73) Step 1 : (S)-2-(tert-butoxycarbonylamino)-6-ethanethioamidohexanoic acid (70)
To a stirred solution of Boc-Lys-OH (3.39 g, 13.78 mmol) in dioxane (7.87 ml) and H2O (31.5 ml) at room temperature was added K2CO3 (4.76 g, 34.5 mmol) and the mixture was cooled to 0 °C and Ethyl dithioacetate (1.739 ml, 15.16 mmol) was added dropwise as described in the general procedure K. Crude 70 was obtained as a yellow oil and was used as is for the next step. LRMS(ESI): (calc.) 304.4 (found) 305.3 (MH)+ Step2 : (S)-tert-butyl 1 -(4-amino-4'-fluorobiphenyl-3 -ylamino)-6-ethanethioamido- 1 - oxohexan-2-ylcarbamate (71)
To a stirred solution of 70 (4.19 g, 13.78 mmol) in DMF (55.1 ml) was added 4'- fluorobiρhenyl-3,4-diamine (3.34 g, 16.54 mmol), DMAP (0.337 g, 2.76 mmol), EDC (3.43 g, 17.91 mmol) followed by HOBT (2.74 g, 17.91 mmol) as described in general procedure N. Compound 71 was obtained after purification by chromatography with EtOAc (20% to 100%) in hexane as a light yellow solid (5.315, 79%). LRMS(ESI): (calc.) 488.6 (found) 489.4 (MH)+
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%). LRMS(ESI): (calc.) 470.6 (found) 471.4 (MH)+. The benzimidazole (4.41 g, 9.37 mmol) in DCM (23.43 ml) was treated with TFA (10.83 ml, 141 mmol) as described in general procedure B. The resulting amine was further purified by chromatography with MeOH (0% to 10%) in DCM to afford 72 (3.9 g, quantitative) as a light yellow solid. LRMS(ESI): (calc.) 370.5 (found) 371.3 (MH)+
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 NaHCO3 was added and the mixture was extracted with EtOAc and the extracts were dried over MgSO4, 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. (dmso-d6) d(ppm) IH: 12.48 (d, J=10.5Hz, IH), 10.02 (dd, J=8.0,3.1Hz, IH), 9.96 (s, IH), 7.82-7.51 (m, 3H), 7.46-7.40 (m, IH), 7.29-7.23 (m, 2H), 5.12 (q, J=7.0Hz, IH), 3.45 (qi, J=5.5Hz, 2H), 2.35 (s, 3H), 2.21-2.10 (s, IH), 2.03-1.91 (m, IH), 1.59 (qi, J=7.4Hz, 2H), 1.43-1.28 (m, 2H). LRMS(ESI): (calc.) 466.5 (found) 467.3 (MH)+
Example 46 (S)-pyridin-2-ylmethyl 5-ethanethioamido-l-(6-(4-fluorophenyl)-lH-benzo[d]imidazol-2- yl)pentylcarbamate (74)
Step 1 : (S)-pyridin-2-ylmethyl 5-ethanethioamido-l-(6-(4-fluorophenyl)-lH- benzo[d]imidazol-2-yl)pentylcarbamate (74)
To a stirred solution of 2-Pyridylcarbinol (0.053 mL, 0.55 mmol) in DCM (1.25 mL) and acetonitrile (1.25 mL) at 0 °C was added 2,6-lutidine (0.070 mL, 0.6 mmol) followed by N,N'-disuccinimidyl carbonate (141 mg, 0.550 mmol) and the resulting solution was allowed to stir for 16h at room temperature. Amine 72 (185 mg, 0.5 mmol) was added and the mixture was stirred at room temperature for 2h then a solution of saturated NaHCO3 was added and the mixture was extracted with EtOAc and the extracts were dried over MgSO4, filtrated and concentrated and the residue was purified by chromatography with MeOH (0% to 10%) in DCM and the material was further purified by Prep-HPLC (Aquasil Cl 8 column, 10-100% MeOH/H2O) to afford 74 (40 mg, 15.8%) as a white solid.
(dmso-d6) d(ppm) IH: 12.32 (d, J=IOHz, IH), 9.96 (s, IH), 8.52 (d,J=4.5Hz, IH), 7.98 (d, J=8.4Hz, IH), 7.82-7.49 (m, 5H), 7.41 (d, J=7.6Hz, 2H), 7.32-7.24 (m, 3H), 5.10 (q, J=13Hz, 2H), 4.80 (q, J=5.7Hz, IH), 3.44 (q, J=6.5Hz, 2H), 2.35 (s, 3H), 2.08-1.80 (m, 2H), 1.58 (qi, J=7.1Hz, 2H), 1.48-1.27 (m, 2H). LRMS(ESI): (calc.) 505.6 (found) 506.3 (MH)+
Example 47
(S)-N-(5-(3-benzylureido)-5-(6-(4-fluoroρhenyl)-lH-benzo[d]imidazol-2- yl)pentyl)ethanethioamide(75)
Step 1 : (S)-N-(5-(3-benzylureido)-5-(6-(4-fluorophenyl)-lH-benzo[d]imidazol-2- yl)pentyl)ethanethioamide(75)
To a stirred solution of 72 (148 mg, 0.4 mmol) in THF (1.6 μml) at 0 °C was added
Et3N (139 μl, 1.0 mmol) followed by drop-wise addition of benzyl isocyanate (49.8 μl, 0.400 mmol) and the resulting solution was allowed to stir for 16h at room temperature. After the usual work-up the residue was purified by chromatography with EtOAc (20% to 100%) in hexane and the resulting material was purified further by prep-HPLC (Luna Cl 8 column, 10-
100% MeOH/H2O) to afford 75 (9 mg, 4.5%) as a white solid.
(dmso-d6) d(ppm) IH: 9.94 (s, IH), 7.70-7.65 (m, 3H), 7.62-7.51 (m, IH), 7.40 (dd, J=8.2,1.6Hz, IH), 7.30-7.17 (m, 7H), 6.60-6.53 (m, 2H), 4.95 (q, J=6.5Hz, IH), 4.27-4.14
(m, 2H), 3.41 (q, J=5.9Hz, 2H), 2.33 (s, 3H), 1.97-1.77 (m, 2H), 1.56 (qi, J=7.8Hz, 2H), 1.38-
1.23 (m, 2H). LRMS(ESI): (calc.) 503.2 (found) 504.4 (MH)+
Scheme 12
Figure imgf000122_0001
Example 48
(S)-benzyl 1 -(7-chloro- 1 H-benzo[d]imidazol-2-yl)-5-ethanethioamidopentyl carbamate (77) Step 1: tert-butyl 5-(benzyloxycarbonylamino)-5-(7-chloro-lH-benzo[d]imidazol-2- yl)pentylcarbamate (76)
To a stirred solution of 3-chlorobenzene-l,2-diamine (263 mg, 1.844 mmol) in pyridine (9.2 mL) at room temperature was added Z-Lys(Boc)-OH (702 mg, 1.844 mmol) and triphenyl phosphite (0.582 mL, 2.21 mmol) and the resulting solution was allowed to stir for lOmin at 200 °C in the microwave. The reaction was concentrated, saturated NaHCO3 was added and the mixture was extracted with EtOAc and the extracts were dried over MgSO4, filtrated and concentrated and the residue was purified by chromatography with EtOAc (10% to 50%) in hexane to afford 76 (140 mg, 15.6%) as a white solid. LRMS(ESI): (calc.) 486.2 (found) 487.3 (MH)+.
Step 2: (S)-benzyl l-(7-chloro-lH-benzo[d]imidazol-2-yl)-5- ethanethioamidopentylcarbamate (77)
A solution of 76 (110 mg, 0.226 mmol) in DCM (1.506 mL) was treated with TFA (0.522 mL, 6.78 mmol) as described in the general procedure B. The crude amine (60 mg, 68.7%) was obtained as a brown solid. LRMS(ESI): (calc.) 386.2 (found) 387.3 (MH)+.
The amine (60 mg, 0.155 mmol) in THF (1.551 mL) was treated with Et3N (0.043 mL, 0.310 mmol) and Ethyl dithioacetate (0.020 mL, 0.171 mmol) as described in general procedure G and the crude material was purified by chromatography with EtOAc (20% to 100%) in hexane, and then purified further by Prep-HPLC (Aquasil column Cl 8, 10-100% MeOH/H2O) to afford 77 (11 mg, 15.9%) as a white solid.
(dmso-d6) d(ppm) IH: 12.63 (s, IH), 9.97 (s, IH), 7.95 (d, J=7.6Hz, IH), 7.43 (d, J=7.8Hz, IH), 7.37-7.06 (m, 7H), 5.05 (q, J=13Hz, 2H), 4.80 (q, J=4.9Hz, IH), 3.45 (q, J=6.1Hz, 2H), 2.36 (s, 3H), 2.03-1.78 (m, 2H), 1.65-1.50 (m, 2H), 1.50-1.23 (M, 2H). LRMS(ESI): (calc.) 444.1 (found) 445.2 (MH)+
Scheme 13
Figure imgf000124_0001
Example 49
(S)-benzyl 1 -(7-amino- 1 H-benzo[d]imidazol-2-yl)-5-ethanethioamidopentylcarbamate (79)
Step 1: (S)-benzyl 5-ethanethioamido-l-(7-nitro-lH-benzo[d]imidazol-2-yl)pentylcarbainate (78)
A solution of 41 (2.500 niL, 2.5 mmol) in DMF (7.5 mL), 3-Nitro-o- phenylenediamine (459 mg, 3.00 mmol), DMAP (61.1 mg, 0.500 mmol), EDC (623 mg, 3.25 mmol), and HOBT (498 mg, 3.25 mmol) was reacted as described in general procedure N. Purification by chromatography with EtOAc (20% to 80%) in hexane afforded the amide intermediate (447 mg, 37.8%.) as a yellow solid. LRMS(ESI): (calc.) 473.6 (found) 474.3 (MH)+.
The amide from above (513 mg, 1.083 mmol) was heated in AcOH (3.611 mL) at 60 °C for 4h as described in general procedure Y and after purification by chromatography with EtOAc (20% to 100%) in hexane 78 (321 mg, 65%) was obtained as yellow solid. LRMS(ESI): (calc.) 455.5 (found) 456.3 (MH)+.
Step 2: (S)-benzyl 1 -(7-amino- lH-benzo[d]imidazol-2-yl)-5- ethanethioamidopentyl carbamate (79)
To a stirred solution of 78 (321 mg, 0.705 mmol) in MeOH (5.637 mL) and AcOH (1.409 mL) at room temperature was added zinc dust (276 mg, 4.23 mmol) and the resulting suspension was allowed to stir for Ih at room temperature. The mixture was filtered over Celite, and the material was taken to dryness and saturated NaHCO3 was added and the mixture was extracted with EtOAc , and the extracts were dried with MgSO4, filtrated and concentrated. The residue was purified by chromatography with MeOH (0% to 10%) in DCM to afford 79 (217 mg, 72.4%) as off-white solid.
(dmso-d6) d(ppm) IH: 11.87 (s, IH), 9.94 (s, IH), 7.71 (d, J=8.2Hz, IH), 7.36-7.10 (m, 5H), 6.81 (t, J=7.8Hz, IH), 6.61 (d, J=8.0Hz, IH), 6.28 (d, J=7.6Hz, IH), 5.18-4.97 (m, 4H), 4.73 (q, J=5.7Hz, IH), 3.43 (q, J=6.3Hz, 2H), 2.34 (s, 3H), 2.04-1.77 (m, 2H), 1.62-1.45 (m, 2H), 1.43-1.25 (m, 2H). LRMS(ESI): (calc.) 425.2 (found) 426.3 (MH)+
Example 50
(S)-benzyl 5-ethanethioamido- 1 -(7-(4-fluorobenzamido)- 1 H-benzo[d]imidazol-2- yl)pentylcarbamate (80)
Step 1 : (S)-benzyl 5-ethanethioamido- 1 -(7-(4-fiuorobenzamido)- 1 H-benzo[d]imidazol-2- yl)pentylcarbamate (80)
A solution of 79 (100 mg, 0.235 mmol), THF (1.567 mL), and Et3N (0.082 mL, 0.587 mmol) at 0 °C was treated with 4-Fluorobenzoyl chloride (0.028 mL, 0.235 mmol) as described in general procedure D. After purification by chromatography with EtOAc (20% to 100%) in hexane, compound 80 (45 mg, 35%) was obtained as beige solid. (dmso-d6) d(ppm) IH: 11.85 (s, IH), 10.32 (s, IH), 9.94 (s, IH), 8.11-8.05 (m, 2H), 7.86 (t, J=9.0Hz, IH), 7.42- 7.26 (m, 8H), 7.15-7.11 (m, 2H), 5.08-4.97 (m, 2H), 4.85-4.76 (m, IH), 3.42 (q, J=5.9Hz, 2H), 2.33 (s, 3H), 2.02-1.77 (m, 2H), 1.63-1.50 (m, 2H), 1.50-1.25 (m, 2H). LRMS(ESI): (calc.) 547.2 (found) 548.4 (MH)+ Scheme 14
Figure imgf000125_0001
Example 121
(S)-benzyl l-oxo-l-(4-phenylthiazol-2-ylamino)-6-(3,3,3-trifluoropropanethioamido)hexan-
2-ylcarbamate (152)
Step 1: (S)-benzyl l-oxo-l-(4-phenylthiazol-2-ylamino)-6-(3,3,3- trifluoropropanamido)hexan-2-ylcarbamate (151)
To a solution of 2 (100 mg, 0.228 mmol) in DCM (4.6 ml) at room temperature was added DCC (47.0 mg, 0.228 mmol) followed by DMAP (2.79 mg, 0.023 mmol) and 3,3,3- Trifluoropropionic acid (35.0 mg, 0.274 mmol). After stirring for 16h, water was added and the mixture was extracted with EtOAc, and the extracts were dried over Na2SO4, concentrated under vacuum and purified with the chromatography with EtOAc (10 to 80%) in hexane to afford 151 (69.0 mg, 55.2 % yield). LRMS(ESI): (calc.) 548.6 (found) 549.3 (MH)+
Step 2: (S)-benzyl l-oxo-l-(4-phenylthiazol-2-ylamino)-6-(3,3,3- trifluoropropanethioamido)hexan-2-ylcarbamate (152) A solution of 151 (69.0 mg, 0.126 mmol) in THF (1 mL) at 0 °C was treated with 2,4-
Bis(4-phenoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide (166 mg, 0.314 mmol) as described in general procedure E. compound 152 was obtained after chromatography with EtOAc (10 to 80 %) in hexane (31.3 mg, 44 % yield) as a white foam. (CD3OD) d(ρpm) IH: 7.89 (dd, J = 8.4, 1.4 Hz, 2H); 7.41-7.12 (m, 9H); 5.14 (d, J = 12.3 Hz, IH); 5.09 (d, J = 12.5 Hz, IH); 4.37-4.34 (m, IH); 3.60 (t, J = 7.2 Hz, 2H); 3.54 (d, J = 10.2 Hz, IH); 3.49 (d, J = 10.4 Hz, IH); 1.91-1.70 (m, 4H); 1.51-1.48 (m, 2H). LRMS(ESI): (calc.) 564.2 (found) 565.3 (MH)+
Example 122
(S)-benzyl 6-(hydrazinecarbothioamido)- 1 -oxo- 1 -(4-phenylthiazol-2-ylamino)hexan-2- ylcarbamate (153)
Step 1: (S)-benzyl 6-(hydrazinecarbothioamido)-l-oxo-l-(4-phenylthiazol-2-ylamino)hexan- 2-ylcarbamate (153)
To a solution of l,l'-Thiocarbonyldiimidazole (122 mg, 0.684 mmol) in DMF (1 mL) at 0 °C was added 2 (300 mg, 0.684 mmol) and the mixture was stirred for 30 min. at 0 °C and then for 1 hour at room temperature. Hydrazine monohydrate (68.5 mg, 1.368 mmol) was then added and the mixture was stirred for 30 minutes after which EtOAc and a saturated solution OfNaHCO3 were added, and the organic layer was separated and dried over Na2SO4 and concentrated under vacuum and purified by chromatography using EtOAc (50 to 100%) in hexane to afford 153 (180 mg, 51.3 % yield) as a white foam. (CD3OD) d(ppm) IH: 7.89 (dd, J = 7.9, 1.4 Hz, 2H); 7.40-7.12 (m, 9H); 5.13 (d, J = 12.5 Hz, IH); 5.08 (d, J = 12.5 Hz, IH); 4.37-4.34 (m, IH); 3.56 (t, J = 7.0 Hz, 2H); 1.99-1.84 (m, IH); 1.81-1.75 (m, IH); 1.65- 1.60 (m, 2H); 1.53-1.43 (m, 2H). LRMS(ESI): (calc.) 512.2 (found) 513.3 (MH)+
Example 123
(S)-benzyl 6-(methylthiocarbonothioylamino)- 1 -oxo- 1 -(4-phenylthiazol-2-ylamino)hexan-2- ylcarbamate (154)
Step 1 : (S)-benzyl 6-(methylthiocarbonothioylamino)-l-oxo-l-(4-phenylthiazol-2- ylamino)hexan-2-ylcarbamate (154)
To a solution of 2 (75 mg, 0.171 mmol) in DCM (1.7 ml) at 0 °C was added Et3N (26.2 μl, 0.188 mmol) and CS2 (11.34 μl, 0.188 mmol) and the solution was stirred at 0 0C for. Ih then MeI (11.76 μl, 0.188 mmol) was added and the temperature was allowed to warm up to room temperature and the mixture was stirred for 16h. Saturated solution of NH4CI was added, and the mixture was extracted with EtOAc, dried over Na2SO4, concentrated and purified by chromatography with EtOAc (5 to 50%) in hexane to afford 154 (50 mg, 0.095 mmol, 55.3 % yield) as a white foam. (CD3OD) d(ppm) IH: 7.90 (dd, J = 8.4, 1.4 Hz, 2H); 7.41-7.13 (m, 9H); 5.14 (d, J = 12.3 Hz, IH); 5.08 (d, J = 12.3 Hz, IH); 4.36-4.33 (m, IH); 3.68 (t, J = 6.8 Hz, 2H); 2.53 (s, 3H); 1.88-1.67 (m, 4H); 1.50-1.46 (m, 2H). LRMS(ESI): (calc.) 528.1 (found) 529.3 (MH)+
Scheme 15
Figure imgf000127_0001
Example 124 (S)-benzyl 6-(2-hydroxyethanethioamido)- 1 -oxo- 1 -(4-phenylthiazol-2-ylamino)hexan-2- ylcarbamate (155)
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 μl) at 0 °C was added K2CO3 (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 Na2SO4 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. (CD3OD) d(ppm) IH: 7.89 (dd, J = 8.4, 1.4 Hz, 2H); 7.40-7.13 (m, 9H); 5.13 (d, J = 12.3 Hz, IH); 5.08 (d, J = 12.5 Hz, IH); 4.27 (s, 2H); 3.70 (t, J = 7.4 Hz, 2H); 1.90-1.71 (m, 4H); 1.51-1.47 (m, 2H). LRMS(ESI): (calc.) 512.2 (found) 513.3 (MH)+
Scheme 16
Figure imgf000128_0001
Example 125 benzyl (lS)-5-ethanethioamido-l-(4-phenyl-4,5-dihydrooxazol-2-yl)pentylcarbamate (158)
Step 1: benzyl (S)-6-t-butoxycarbonylamino-l-((R)-2-hydroxy-l-phenylethylamino)-l- oxohexan-2-ylcarbamate (156)
To a stirred solution of Z-Lys(Boc)-OH (500 mg, 1.314 mmol) at 0 0C were added (S)-(+)-2-Phenylglycinol (198 mg, 1.446 mmol) and DCC (298 mg, 1.446 mmol) as described in general procedure FF. compound 156 (173.4 mg, 26.4 % yield) was obtained as a white solid after chromatography with EtOAc (40 to 100%) in hexane. ). LRMS(ESI): (calc.) 499.6(found) 522.4(MNa)+
Step 2: benzyl (lS)-5-t-butoxycarbonylamino-l-(4-phenyl-4,5-dihydrooxazol-2- yl)pentylcarbamate (157)
To a solution of 156 (171 mg, 0.342 mmol) in DCM (3.4 ml) at -78 0C was added DAST (47.5 μl, 0.359 mmol) dropwise and the mixture was stirred for 2h at that temperature then K2CO3 (95 mg, 0.685 mmol) was added in one portion and the mixture was stirred for 15 min at -78 0C then for 20 min. at room temperature, poured over a saturated solution of
NaHCO3 and extracted with DCM. The extracts were dried over Na2SO4, concentrated and purified with chromatography to afford 157 (47 mg, 28.5 % yield). LRMS(ESI): (calc.) 481.6
(found) 482.4 (MH)+
Step 3: benzyl (lS)-5-ethanethioamido-l-(4-phenyl-4,5-dihydrooxazol-2-yl)pentylcarbamate
(158)
Compound 157 (47 mg, 0.098 mmol) was treated with 25% solution of TFA in DCE (2 mL) as described in general procedure B to afford the crude amine in quantitative yield. LRMS(ESI): (calc.) 381.5 (found) 382.3 (MH)+. This amine (65 mg, 0.170 mmol) in THF at 0 °C was treated with Et3N (47.5 μl, 0.341 mmol) and Ethyl dithioacetate (29.3 μl, 0.256 mmol) as described in general procedure G to afford 158 (5.6 mg, 7.5 % yield) as a yellowish gum. (CD3OD) d(ppm) IH: 7.36-7.28 (m, 10H); 5.22-5.20 (m, IH); 5.12 (s, 2H); 4.74 (t, J = 7.0 Hz, IH); 4.44 (br, IH); 4.16-4.12 (m, IH); 3.60 (br, 2H); 2.45 (s, 3H); 1.91-1.81 (m, 2H); 1.80-1.61 (m, 2H); 1.60-1.40 (m, 2H). LRMS(ESI): (calc.) 439.2 (found) 440.3 (MH)+
Scheme 17
Figure imgf000129_0001
Example 126
(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-hydrazinyl-l-oxohexan-2-ylcarbamate (159)
To a stirred solution of Z-Lys(Boc)-OH (2 g, 5.26 mmol) in DCM (52.6 ml) was added HOBT (0.805 g, 5.26 mmol) and l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.008 g, 5.26 mmol). The mixture was cooled to 0 °C and hydrazine monohydrate (1.020 ml, 21.03 mmol) was added fast. After the addition, the mixture was allowed to stir for 1 hour at 0 °C and for 16h at room temperature, after which the mixture was concentrated, water and EtOAc were added, and the organic layer was separated and dried over Na2SO4, concentrated and purified by chromatography using MeOH (0 to 10%) in DCM to afford 159 (1.6519 g, 80 % yield) as a white solid. LRMS(ESI): (calc.) 394.5 (found) 417.3(MNa)+
Step 2: (S)-benzyl 5-t-butoxycarbonylamino-l-(5-phenyl-lH-l,2,4-triazol-3- yl)pentylcarbamate (160)
To a mixture of 159 (200 mg, 0.507 mmol) in THF (5070 μl) was added methyl benzimidate hydrochloride (91 mg, 0.532 mmol) followed by Et3N (74.2 μl, 0.532 mmol) and the solution was heated at reflux for 16h. The mixture was concentrated and purified by chromatography using EtOAc (40 to 100%) in hexane to afford 160 (266 mg, quantitative yield) as a clear oil. LRMS(ESI): (calc.) 479.6 (found) 480.4 (MH)+ Step 3: (S)-benzyl 5-amino-l-(5-phenyl-lH-l,2,4-triazol-3-yl)pentylcarbamate (161)
Compound 160 (266 mg, 0.555 mmol) was treated with a solution of 255 TFA in DCE (5 mL) as described in general procedure B to afford 161 (117 mg, 42.7% yield). LRMS(ESI): (calc.) 379.5 (found) 380.3 (MH)+
Step 4: (S)-benzyl 5-(3-methylthioureido)-l-(5-phenyl-lH-l,2,4-triazol-3-yl)pentylcarbamate (162)
A solution of 161 (200 mg, 0.405 mmol), and Et3N (226 μl, 1.621 mmol) in DCM (1.6ImI) at 0 °C was treated with thiophosgene (46.6 μl, 0.608 mmol) followed by methylamine (381 mg, 4.05 mmol, 33% weight in ethanol) as described in general procedure C to afford 162 (41 mg, 22.4 % yield) as a white solid. (CD3OD) d(ppm) IH: 7.97 (br, 2H); 7.47 (br, 3H); 7.38-7.20 (m, 5H); 5.14 (d, J - 12.3 Hz, IH); 5.08 (d, J = 12.7 Hz, IH); 4.89- 4.87 (m, IH); 3.43-3.32 (m, 2H); 2.90 (br, 3H); 2.16-1.91 (m, 2H); 1.65-1.62 (m, 2H); 1.46- 1.40 (m, 2H)XRMS(ESI): (calc.) 452.2 (found) 453.3 (MH)+
Example 127
(S)-benzyl l-(5-phenyl-lH-l,2,4-triazol-3-yl)-5-thioureidopentylcarbamate (163) Amine 161 (200 mg, 0.405 mmol) and Et3N (226 μl, 1.621 mmol) in DCM (1.6 ml) at 0 °C was treated with thiophosgene (46.6 μl, 0.608 mmol) followed by ammonia (7N in MeOH, 579 μl, 4.05 mmol) as described in general procedure C to afford 164 (30 mg, 16.9 % yield) as beige solid. (CD3OD) d(ppm) IH: 7.97-7.96 (m, 2H); 7.48-7.46 (m, 3H); 7.37-7.20 (m, 5H); 5.13 (d, J = 12.3 Hz, IH); 5.07 (d, J = 12.5 Hz, IH); 4.87-4.85 (m, IH); 3.47 (br, 1.35H); 3.11 (br, 0.65H); 1.96-1.92 (m, 2H); 1.61-1.60 (m, 2H); 1.50-1.39 (m, 2H). LRMS(ESI): (calc.) 438.2 (found) 439.3 (MH)+
Example 128 (S)-benzyl 5-ethanethioamido-l-(5-phenyl-lH-l,2,4-triazol-3-yl)pentylcarbamate (164)
Amine 161 (100 mg, 0.203 mmol) and Et3N (85 μl, 0.608 mmol) in THF at 0 °C was treated with Ethyl dithioacetate (34.9 μl, 0.304 mmol) as described in general procedure G to afford 164 (21 mg, 23.7 % yield) as a clear gum after chromatography with EtOAc (40 to 100 %) in hexane. (CDCl3) δ(ppm) IH: 7.93-7.91 (m, 2H); 7.41-7.37 (m, 3H); 7.30-7.27 (m, 5H); 5.12 (d, J = 12.1 Hz, IH); 5.02-4.99 (m, 2H); 3.59-3.57 (m, 2H); 2.44 (s, 3H); 2.07-1.89 (m, 2H); 1.68-1.63 (m, 2H); 1.46-1.40 (m, 2H). LRMS(ESI): (calc.) 437.2 (found) 438.3 (MH)+
Scheme 18
Figure imgf000131_0001
Example 129
(S)-benzyl 5-ethanethioamido-l-(5-methyl-lH-l,2,4-triazol-3-yl)pentylcarbamate(167)
Step 1 : (S)-benzyl 6-t-butoxycarbonylamino-l-(2-(l-iminoethyl)hydrazinyl)-l-oxohexan-2- ylcarbamate (165)
Ethyl acetimidate hydrochloride (128 mg, 1.035 mmol) was added to a solution of sodium hydroxide (41.4 mg, 1.035 mmol) in ethanol (4.7 ml) at 0 °C. After stirring for 15 min. the suspension was filtered off and the filtrate was placed in a sealed tube and a solution of 159 (371.3 mg, 0.941 mmol) in ethanol (4.7 ml) was added dropwise. The mixture was heated at 60 0C for 16 h, concentrated and purified by chromatography to afford 165. LRMS(ESI): (calc.) 435.5 (found) 436.3 (MH)+
Step 2: (S)-benzyl 5-t-butoxycarbonylamino-l-(5-methyl-lH-l,2,4-triazol-3- yl)pentylcarbamate (166)
Compound 165 (410 mg, 0.941 mmol) was heated in a sealed tube in Xylene (9.4 ml) at 110 °C for few hours. It was then concentrated and purified by chromatography using EtOAc (50 %-100%) in hexane followed by MeOH(0-10%) in EtOAc to afford 166 (373.3 mg, 95 % yield). LRMS(ESI): (calc.) 417.5 (found) 418.4 (MH)+ Step 3: (S)-benzyl 5-ethanethioamido-l-(5-methyl-lH-l,2,4-triazol-3- yl)pentylcarbamate( 167)
Compound 166 (373 mg, 0.893 mmol) was treated with 25%TFA in DCE (4 mL) as described in general procedure B and the crude amine was used as is in the next step. The amine (145 mg, 0.336 mmol), and Et3N (187 μl, 1.344 mmol) in THF at 0 °C was treated with Ethyl dithioacetate (57.8 μl, 0.504 mmol) as described in general procedure G to afford 167 (39.7 mg, 0.106 mmol, 31.5 % yield) as a white solid after chromatography with MeOH (0 to 15%) in DCM.(CD3OD) δ(ppm) IH: 7.37-7.29 (m, 5H); 5.12 (d, J = 12.5 Hz, IH); 5.05 (d, J = 12.5 Hz, IH); 4.77 (t, J = 7.6 Hz, IH); 3.55 (t, J = 7.4 Hz, 2H); 2.43 (s, 3H); 2.39 (s, 3H); 2.01-1.83 (m, 2H); 1.70-1.63 (m, 2H); 1.43-1.29 (m, 2H). LRMS(ESI): (calc.) 375.2 (found) 376.3 (MH)+
Scheme 19
Figure imgf000132_0001
Example 147
(S)-benzyl 5-(3-methylthioureido)- 1 -(5-(naphthalen-2-yl)- 1 H-pyrazol-3 -yl)pentylcarbamate
(187)
Step 1: (S)-benzyl 8-t-butoxycarbonylamino-l-(naphthalen-2-yl)-l,3-dioxooctan-4- ylcarbamate (185)
To a stirred solution of Z-Lys(Boc)-OH (1.5 g, 3.94 mmol) in THF (19.7 ml) at room temperature was added l-Chloro-N,N,2-trimethyl-l-propenylamine (0.574 ml, 4.34 mmol) and the mixture was stirred for 1 h. In another round bottom flask, 2'-Acetonaphthone (1342 mg, 7.89 mmol) in THF was added to a freshly prepared solution of LDA -78 °C (prepared by the addition of diisopropylamine, (1.124 ml, 7.89 mmol) in THF to n-BuLi (3.15 ml, 7.89 mmol) at 0 0C) and the solution was stirred for 30 min then it was added to the prepared acyl chloride above and the reaction mixture was stirred at -78 °C for 30 min. A saturated solution OfNH4Cl was added, and the material was extracted with EtOAc, and the organic extracts were dried over Na2SO4, concentrated and purified by chromatography using EtOAc (5 to 50%) in hexane to afford 185 (825.4 mg, 39.3 % yield) as a yellowish oil. LRMS(ESI): (calc.) 532.6 (found) 531.0 (M-H)+
Step 2: (S)-benzyl 5-t-butoxycarbonylamino-l-(5-(naphthalen-2-yl)-lH-pyrazol-3- yl)pentylcarbamate (186)
A mixture of 185 (100 mg, 0.188 mmol), AcOH (9.4 ml), and hydrazine monohydrate (27.3 μl, 0.563 mmol) was heated at 90 °C in a sealed tube for 2 h. After cooling, the mixture was concentrated under reduced pressure, EtOAc and saturated solution OfNaHCO3 were added, and the organic layer was separated and dried over Na2SO4, concentrated and purified by chromatography using EtOAc (20 to 80%) in hexane to afford 186 (71.8 mg, 72.3 % yield). LRMS(ESI): (calc.) 528.6 (found) 529.5 (MH)+ Step 3: (S)-benzyl 5-(3-methylthioureido)-l-(5-(naphthalen-2-yl)-lH-pyrazol-3- yl)pentylcarbamate (187)
Compound 186 (71.8 mg, 0.136 mmol) was treated with 25%TFA in DCE (2 mL) as described in the general procedure B to afford the amine in a quantitative yield.
The crude amine (73.7 mg, 0.136 mmol) and Et3N (56.8 μl, 0.408 mmol) in THF (906 μl) was treated with methyl isothiocyanate (11.92 mg, 0.163 mmol) as described in general procedure G to afford 187 (38.2 mg, 56.1 % yield) as a white solid after chromatography with EtOAc (50 to 100%) in hexane. (CD3OD) d(ppm) IH: 8.18 (s, IH); 7.89-7.83 (m, 4H); 7.550-7.44 (m, 2H); 7.37-7.25 (m, 5H); 6.67 (s, IH); 5.13 (d, J = 12.5 Hz, IH); 5.08 (d, J = 12.3 Hz, IH); 4.85-4.81 (m, IH); 3.42 (br, 2H); 2.89 (br, 3H); 1.99-1.84 (m, 2H); 1.65-1.59 (m, 2H); 1.49-1.36 (m, 2H). LRMS(ESI): (calc.) 501.2 (found) 502.4 (MH)+
Additional compounds exemplified in Table 3 are prepared starting with the indicated starting material and following the given preparative sequence(s) utilizing the general procedures listed in Table 4.
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
The general procedures A to PP used to synthesize compounds of this invention are described in Table 4. A specific example of each general procedure is provided in the indicated step of a particular example.
Table 4
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Compositions
In a second aspect, 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. In certain other embodiments, administration may for example be by the oral route. The 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. As used herein, the term "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). Thus, 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. The preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990.
In oneembodiment of the second aspect, 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. In 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. In 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% or alternatively at least about 99% enantiomeric or diastereomeric excess. In other embodiments of the invention, a compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug is present as a substantially racemic mixture. In anotherembodiment, the composition further comprises an additional therapeutic or inhibitory agent.
As used herein, the term "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. 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). As used herein, the term "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.
In certain embodiments of the second aspect of the invention, the composition further comprises an agent, such as an antisense oligonucleotide, that inhibits the expression of a sirtuin gene. The combined use of a nucleic acid level inhibitor (e.g., antisense oligonucleotide) and 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.
Inhibition of Sirtuin Activity
In a third aspect, 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. Preferably the organism is a mammal, more preferably a human. In anotherembodiment, 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.
In another embodiment, 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. In certain embodiments, 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.
Because compounds of the invention inhibit sirtuin activity they are useful research tools for in vitro study of sirtuins and their role in biological processes.
Measurement of the enzymatic activity of a sirtuin can be achieved using known methodologies.
In some embodiments, 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)
In certain embodiments of the present invention, 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. In certain embodiments of the present invention 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.
In some embodiments, the active ingredients of such compositions act synergistically to produce a therapeutic effect.
Examples of other sirtuin inhibitors include, but are not limited to, nicotinamide, cambinol, sirtinol, splitomicin, anilinobenzamide #7 and EX527.
The following Examples are intended to further illustrate certain embodiments of the invention, and are not intended to limit the scope of the invention.
ASSAY EXAMPLES
Assay Example 1
Inhibition of Sirtuin Enzymatic Activity
SIRT1-2-3 Enzymatic Assay Protocol Buffer; 5OmM HEPES, pH 8.0, 137mM NaCl, 2.7mM KCl, ImM MgCl2
Enzyme: Sirtuin 1 (BioMol Cat #SE-239, human recombinant ) Sirtuin 2 (In-house purification, HisSIRT2) Sirtuin 3 (BioMol Cat #SE-270, human recombinant)
Substrate: CBZ-Lys(Ac)-AMC (in-house compound MG092496X) NAD+: Sigma Cat. #N-6522
Trypsin: Sigma Cat#T-8003
Nicotinamide: Sigma Cat#N-3376
Storage Solutions: [S] = 30 mM in DMSO [I] = 30 mM in DMSO
[Trypsin] = lOmg/ml in ImM HCl [Nicotinamide] = 5OmM in DMSO [E] = Depends on enzyme Assay Solutions (Storage Solutions diluted):
[S] = 0.18mM in SIRT Buffer
[E] = Depends on enzyme activity and purity
[I] = 0.5 mM in DMSO Quench solution = Trypsin 2 mg/mL and Nicotinamide 2mM in Buffer
Assay Protocol:
To a Black Flat Bottom 1Z2 area Costar #3694 plate add:
8 uL SIRT Buffer
2 uL of 0.5mM inhibitor (or DMSO for control) (20μM final) 15 uL enzyme solution (Low control wells no enzyme)
Incubate for 10 mins @ RT
25 uL substrate/NAD+ (90μM/500μM final)
Total volume = 50 uL
Incubate at 370C for 40-60 minutes (depending on enzyme activity). Quench reaction by adding 50 uL quench solution to a final concentration of 1 mg/mL
Trypsin and ImM Nicotinamide.
Incubate plate in dark for 30 minutes at 370C.
Read using fluorescence plate reader (λEX=360nm, λEm =470nm).
Reference: SIRT1-2-3 Fluorimetric Drug Discovery Kit (BioMol: Cat. #AK-555, AK-556, AK-557)
P:\Lead Discovery\SOP-Forms-Templates\SOP\Lead Discovery SOP's\HDAC Brief
Protocols\ClassIII
All compounds exemplified in the application show inhibitory activity against one or more of human sirtuins <20 uM IC50
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.

Claims

What is claimed is:
1. A compound of the formula (I):
Y-L — Z — D (I) or an N-oxide, hydrate, solvate, pharmaceutically acceptable salt, prodrug, or complex thereof, or racemic or scalemic mixture, diastereomer or enantiomer thereof, wherein
D is selected from the group consisting of
Figure imgf000170_0001
Figure imgf000170_0002
Figure imgf000170_0003
and
Figure imgf000170_0004
wherein
X is O or S; M is nitrogen, oxygen, or sulfur; wherein when M is oxygen or sulfur, Rb is absent and W is nitrogen; W is nitrogen, oxygen, or sulfur; wherein when W is oxygen or sulfur, Rc is absent and M is nitrogen; each Ra is independently selected from the group consisting of -H, -Q-Qalkyl, a protecting group, -d-C6alkyl-aryl, aryl, -Cj-Cgalkyl-heteroaryl, heteroaryl, -Q-Cβalkyl-cycloalkyl, cycloalkyl, -Q-Cealkyl-heterocyclyl, heterocyclyl, -C(O)-O-C1-C6alkyl, -C(O)-O-C1- Qalkyl-heterocyclyl, -C(O)-O-C1-C6alkyl-alkenyl, -C(O)-O-C1-C6alkyl-aryl, -CO-CF3
and
Figure imgf000171_0001
, each of which is optionally substituted; and when M is nitrogen, Ra is additionally selected from -C(O)-H;
Rb and Rc ; when present, are independently selected from the group consisting of -H, -OH, -CN, -O-alkyl, -O-alkyl-aryl, -O-alkyl-heteroaryl, -Ci-C6alkyl, -C(O)-alkyl, -NH2, -NH- alkyl, -C(O)-H, a protecting group, -CrQalkyl-aryl, aryl, -CrCόalkyl-heteroaryl, -hetero- aryl, -CrCβalkyl-cycloalkyl, cycloalkyl, -d-Cόalkyl-heterocyclyl, heterocyclyl, -C(O)-C0- C3alkyl-aryl, -C(O)-C0-C3alkyl-heteroaryl, -C(O)-C0-C3alkyl-cycloalkyl, -C(O)-C0- C3alkyl-heterocyclyl, -C(O)-O-C rC6alkyl, -C(O)-O-C1-C6alkyl-heterocyclyl, -C(O)-O-C1-
Qalkyl-alkenyl, -C(O)-O-C1-C6alkyl-aryl, -CO-CF3 and
Figure imgf000171_0002
; each of which is optionally substituted; wherein, when M is nitrogen, Ra and Rb together with the nitrogen atom 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; and wherein, when Ra is -CrCδalkyl, -Ci-Qalkyl-aryl, -Ci-Cόalkyl-heteroaryl, -d-C6alkyl- heterocyclyl, or -Q-Cόalkyl-cycloalkyl and Rc is -d-C6alkyl, then Ra and Rc are optionally connected with a carbon atom to form a 5 to 10-membered heterocyclyl, heterocyclyl-aryl, heterocyclyl-heteroaryl, heterocyclyl-heterocyclyl or heterocyclyl-cycloalkyl, each of which is optionally substituted;
Rf is selected from the group consisting of H, Q-Csalkyl;
Rh is selected from the group consisting of H, -OH, -CN, -d-Cealkyl, -C0-C6alkyl-O-C0- C6alkyl-aryl, -Co-Cόalkyl-O-Co-Cealkyl-heteroaryl, wherein each of said alkyl, aryl, and heteroaryl is optionally substituted; or, Rh and Rc, 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, -C3-C8alkyl-, -Co-Qalkyl-C!- C8heteroalkyl-C0-C3alkyl-, -C0-C3alkyl-C2-C8alkenyl-C0-C3alkyl-, -C0-C3alkyl-C2- C8alkynyl-C0-C3alkyl-, -Co-Cealkyl-aryl-Co-Cealkyl-, -Co-Cealkyl-aryl^-Ceheteroalkyl-, -Co-Cealkyl-cycloalkyl-Co-Cealkyl-, -C0-C6alkyl-cycloalkyl-C2-C6heteroalkyl-, -C4- C6heterocyclyl-aryl-C0-C6alkyl-, ^-Ceneterocyclyl-aryl-Co-Coheteroalkyl-, -Co-C6alkyl- C4-C6-heterocyclyl-C0-C6alkyl-, -C0-C6alkyl-C4-C6-heterocyclyl-Co-C6heteroalkyl-, -C0- Cβ-alkyl-heteroaryl-Co-Cόalkyl-, -Co-Ce-alkyl-heteroaryl-Co-Cβheteroalkyl-, -C4-C6hetero- cyclyl-heteroaryl-Co-C6alkyl-, ^-Coheterocyclyl-heteroaryl-Co-Csheteroalkyl-, -C0- C6alkyl-aryl-C3-C6alkynyl-, -Co-C6alkyl-heteroaryl-C2-C6alkynyl-, -Co-C6alkyl-cycloalkyl- C3-C6alkynyl-, -Co-Cealkyl-heterocyclyl-Cs-Cδalkynyl-, -Co-C6alkyl-aryl-C2-C6alkynyl- C2-C6alkenyl-, -Co-C6alkyl-aryl-C2-C6alkenyl-, -Co-C6alkyl-heteroaryl-C2-C6alkenyl-, -Co- C6alkyl-cycloalkyl-C2-C6alkenyl-, -Co-Cealkyl-heterocyclyl-Q-Cόalkenyl-, -C0-C6alkyl- aryl-aryl-Co-C6alkyl-, -Co-Qalkyl-aryl-heteroaryl-Co-Cealkyl-, -Co-Cealkyl-heteroaryl- aryl-Co-C6-alkyl-, -Co-Cόalkyl-heteroaryl-heteroaryl-Co-Cβ-alkyl-, -Co-Csalkyl-heteroaryl- C0-C3alkyl- C2-C8 alkenyl-C0-C3-alkyl-, -Co-C3alkyl-aryl-Co-C3alkyl- C2-C8 alkenyl-C0- C3-alkyl-, -Co-C3alkyl-heterocyclyl-C0-C3alkyl- C2-C8 alkenyl-Co-Cs-alkyl-, -C0-C3alkyl- cycloalkyl-C0-C3alkyl- C2-C8 alkenyl-C0-C3-alkyl-, -C0-C3alkyl-heteroaryl-C0-C3alkyl- C2- C8 alkynyl-C0-C3-alkyl-, -Co-C3alkyl-aryl-Co-C3alkyl- C2-C8 alkynyl-C0-C3-alkyl-, -C0- C3alkyl-heterocyclyl-C0-C3alkyl- C2-C8 alkynyl-Co-Cs-alkyl- and -C0-C3alkyl-cycloalkyl- Co-C3alkyl- C2-C8 alkynyl-Co-Cs-alkyl-, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl moiety is optionally substituted; and when W is N, Z is further selected from the group consisting of -CrQalkyl-ClO)-, -C1-C8 alkyl-S(O)2-, -aryl-C0-C8 alkyl-S(O)2-, -heteroaryl-C0-C8 alkyl-S(O)2-, -cycloalkyl-C0-Cg alkyl-S(O)2-, -heterocycloalkyl-Co-Cs alkyl-S(O)2-, -C1-C8 alkyl-CH^rd-Cg alkyl- C(CH3)=, -C0-C6alkyl-CH=CH-C(O), -C0-C4alkyl-C(O)-, -C1-C8 alkyl-(NH2)C=, -C0- C3alkyl-C1-C8heteroalkyl-C0-C3alkyl-C(O)-, -C0-C3alkyl-C2-C8alkenyl-C0-C3alkyl-C(O)-, -C0-C3alkyl-C2-C8alkynyl-Co-C3alkyl-C(0)-, -C0-C6alkyl-aryl-C0-C6alkyl-C(O)-, -C0- C6alkyl-aryl-C2-C6heteroalkyl-C(O)-, -C0-C6alkyl-cycloalkyl-C0-C6alkyl-C(O)-, -C0- C6alkyl-cycloalkyl-C2-C6heteroalkyl-C(O)-, -C4-C6heterocyclyl-aryl-Co-C6alkyl-C(0)-, -C4-C6heterocyclyl-aryl-C0-C6heteroalkyl-C(O)-, -Co-C6alkyl-C4-C6-heterocyclyl-Co-
C6alkyl-C(O)-, -C0-C6alkyl-C4-C6-heterocyclyl-C0-C6heteroalkyl-C(O)-, -C0-C6-alkyl- heteroaryl-Co-C6alkyl-C(0)-, -Co-C6-alkyl-heteroaryl-Co-C6heteroalkyl-C(0)-, -C4- C6heterocyclyl-heteroaryl-C0-C6alkyl-C(O)-, -C4-C6heterocyclyl-heteroaryl-Co-C6hetero- alkyl-C(O)-, -C0-C6alkyl-aryl-C3-C6alkynyl-C(O)-, -C0-C6alkyl-heteroaryl-C2-C6alkynyl- C(O)-, -C0-C6alkyl-cycloalkyl-C3-C6alkynyl-C(O)-, -C0-C6alkyl-heterocyclyl-C3- C6alkynyl-C(O)-, -C0-C6alkyl-aryl-C2-C6alkynyl-C2-C6alkenyl-C(O)-, -C0-C6alkyl-aryl- C2-C6alkenyl-C(O)-, -C0-C6alkyl-heteroaryl-C2-C6alkenyl-C(O)-, -C0-C6alkyl-cycloalkyl- C2-C6alkenyl-C(O)-, -C0-C6alkyl-heterocyclyl-C2-C6alkenyl-C(O)-, -Co-Cόalkyl-aryl-aryl- C0-C6alkyl-C(O)-, -C0-C6alkyl-aryl-heteroaryl-C0-C6alkyl-C(O)-, -C0-C6alkyl-heteroaryl- aryl-Co-C6-alkyl-C(0)- and -C0-C6alkyl-heteroaryl-heteroaryl-C0-C6-alkyl-C(O)-; or
Z-W is selected from the group consisting of -C1-Cg alkyl-(NH2)C=N-, -C1-8alkyl-C=N- and -Ci-8alkyl-C(CH3)=N-, when Rc is absent;
L is selected from the group consisting of a covalent bond, -Q-Cβalkyl-, -Co-C6alkyl- (CR3=CR3)i-2-C0-C6alkyl-, -Co-C6alkyl-(C≡C)1-2-Co-C6alkyl-, -QrQalkyl-aryl-Co- C6alkyl-, -Co-Qalkyl-heteroaryl-Co-Cealkyl-, -Co-Qalkyl-heterocyclyl-Co-Csalkyl-, -C0- C3alkyl-cycloalkyl-C0-C3alkyl-, -Co-C6alkyl-aryl-(CR3=CR3)i-2-Co-C6alkyl-, -C0-C6 alkyl- aryl-(C≡C)1-2-Co-C6alkyl-, -C0-C6alky-heteroaryl-(CR3=CR3)i-2-C0-C6alkyl-, -C0-C6 alkyl- heteroaryl-(C≡C)1-2-C0-C6alkyl-, -Co-C6alkyl-N(R3)-C(0)-C0-C3alkyl-, -Co-C6alkyl-N(R3)- C(S)-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(O)-alkenyl-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(S)- alkenyl-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(O)-alkynyl-C0-C3alkyl-, -C0-C6alkyl-N(R3)- C(S)-alkynyl-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(O)-Cj-C3alkyl-N(R3)-C(O)-, -C0-C6alkyl- N(R3)-C(S)-Ci-C3alkyl-N(R3)-C(O)-, -C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-N(R3)-C(O)- C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-N(R3)-C(O)-C0-C3alkyl-, -C0-C6alkyl- N(R3)-C(O)-C1-C3alkyl-N(R3)-C(S)-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl- N(R3)-C(S)-C0-C3alkyl-, -C0-C6alkyl-C(O)-N(R3)-C0-C3alkyl-, -C0-C6alkyl-C(S)-N(R3)- C0-C3alkyl-, -C0-C6alkyl-C(O)-N(R3)-C2-C4alkyl-O-C0-C3alkyl-, -C0-C6alkyl-C(S)-N(R3)- C2-C4alkyl-O-C0-C3alkyl-, -C0-C6alkyl-C(O)-N(R3)-C2-C4alkyl-N(R3)-C0-C3alkyl-, -C0- C6alkyl-C(S)-N(R3)-C2-C4alkyl-N(R3)-C0-C3alkyl-, -C0-C6alkyl-C(O)-C0-C3alkyl-, -C0- C6alkyl-C(NOH)-C0-C3alkyl-, -C0-C6alkyl-C(O)-alkenyl-C0-C3alkyl-, -C0-C6alkyl- C(NOH)-alkenyl-C0-C3alkyl-, -C0-C6alkyl-S(0)2-N(R3)-Co-C3alkyl-, -Co-C6alkyl-N(R3)- S(O)2-C0-C3alkyl-, -C0-C3alkyl-N(R3)-S(O)2-N(R3)-C0-C3alkyl-, -C0-C6alkyl-C(O)-N(R3)- S(O)2-C0-C3alkyl-,-C0-C6alkyl-N(R3)-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C1-C3alkyl-alkenyl-, -C0-C6alkyl-N(R3)-C1-C3alkyl-alkynyl-, -C0-C6alkyl-N(R7)-C0-C3alkyl-, -C0-C6alkyl- N(R7)-Ci-C3alkyl-alkenyl-, -C0-C6alkyl-N(R7)-Ci-C3alkyl-alkynyl-, -C0-C6alkyl-N(R3)-C2- C4alkyl-N(R3)-C(O)-alkyl-, -C0-C6alkyl-N(R3)-C2-C4alkyl-N(R3)-C(S)-alkyl-, -C0-C6alkyl- O-C2-C4alkyl-N(R3)C(O)-C0-C3alkyl-, -C0-C6alkyl-S-C2-C4alkyl-N(R3)C(O)-C0-C3alkyl-, -C0-C6alkyl-O-C2-C4alkyl-N(R3)C(S)-C0-C3alkyl-, -C0-C6alkyl-S-C2-C4alkyl-N(R3)C(S)- C0-C3alkyl-, -C0-C6alkyl-N(R3)-C2-C3heteroalkyl-, -C0-C6alkyl-N(R7)-C2-C3heteroalkyl-, -C0-C6alkyl-C(O)-N(R3)-C2-C3heteroalkyl-, -C0-C6alkyl-C(S)-N(R3)-C2-C3heteroalkyl-, -Co-C6alkyl-C(0)-N(R7)-C2-C3heteroalkyl-, -Co-C6alkyl-C(S)-N(R7)-C2-C3heteroalkyl-, -Co-C6alkyl-N(R3)-C(0)-C0-C3heteroalkyl-, -C0-C6alkyl-N(R3)-C(S)-C0-C3heteroalkyl-, -C0-C6alkyl-N(R7)-C(0)-Co-C3heteroalkyl-, -Co-C6alkyl-N(R7)-C(S)-C0-C3heteroalkyl-, -Co-Cealkyl-S-Co-Qalkyl-, -Co-Cealkyl-O-Co-Qalkyl-, -C0-C6alkyl-S(O)-C0-C3alkyl-, -C0- C6alkyl-S(0)2-Co-C3alkyl-, -C0-C6alkyl-N(R3)-C(0)-N(R3)-Co-C3alkyl-, -C0-C6alkyl- N(R3)-C(S)-N(R3)-Co-C3alkyl-, -Co-Cealkyl-O-Co-Csalkyl-heterocyclyl-, -C0-C6alkyl-O- C0-C3alkyl-cycloalkyl-, -Co-C6alkyl-S(0)0-2-C0-C3alkyl-heterocycly-, -C0-C6alkyl-S(O)0-2- C0-C3alkyl-cycloalkyl-, -C0-C6alkyl-N(R3)-C0-C3alkyl-heterocycly-, -Co-C6alkyl-N(R3)- C0-C3alkyl-cycloalkyl-, -heterocyclyl-Co-Cealkyl-O-Co-Csalkyl-, -cycloalkyl-C0-C6alkyl- O-C0-C3alkyl-, -heterocyclyl-Co-C6alkyl-S(0)o-2-C0-C3alkyl-, -cycloalkyl-C0-C6alkyl- S(0)0-2-Co-C3alkyl-, -heterocyclyl-Co-C6alkyl-N(R3)-C0-C3alkyl-, -cycloalkyl-Co-Cealkyl- N(R3)-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(O)-O-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(S)-O- C0-C3alkyl-, -C0-C6alkyl-O-C(O)-N(R3)-C0-C3alkyl-, -C0-C6alkyl-O-C(S)-N(R3)-C0- C3alkyl-, -C0-C3alkyl-N(R3)-C(0)-0-heterocyclyl-Co-C3alkyl-, -Co-C3alkyl-N(R3)-C(S)-0- heterocyclyl-Co-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-O-cycloalkyl-C0-C3alkyl-, -C0-C3alkyl- N(R3)-C(S)-O-cycloalkyl-C0-C3alkyl-, -C0-C6alkyl-S(O)2-heterocyclyl-C0-C3alkyl-, -C0- C6alkyl-S(O)2-cycloalkyl-C0-C3alkyl-, -C0-C6 alkyl-N(R3)-S(O)2-heterocyclyl-C0-C3alkyl-, -C0-C6 alkyl-N(R3)-S(O)2-cycloalkyl-C0-C3alkyl-, -Co-Csalkyl-heterocyclyl-Co-Csalkyl-O- C0-C3alkyl-, -Co-Csalkyl-cycloalkyl-Co-Caalkyl-O-Co-Csalkyl-, -C0-C3alkyl-heterocyclyl- Co-C5alkyl-N(R3)-C0-C3alkyl-, -Co-C3alkyl-cycloalkyl-C0-C5alkyl-N(R3)-C0-C3alkyl-, -C0- C3alkyl-0-Co-C3alkyl-heterocyclyl-C0-C3alkyl-, -Co-Csalkyl-O-Co-Csalkyl-cycloalkyl-Co- C3alkyl-, -Co-C3alkyl-heterocyclyl-Co-C3alkyl-S-Co-C3alkyl-, -C0-C3alkyl-cycloalkyl-C0- C3alkyl-S-C0-C3alkyl-, -C0-C3alkyl-N(R3)-C0-C3alkyl-heterocyclyl-C0-C3alkyl-, -C0- C3alkyl-N(R3)-C0-C3alkyl-cycloalkyl-Co-C3alkyl-, -C0-C3alkyl-S-C0-C3alkyl-heterocyclyl- C0-C3alkyl-, -Co-C3alkyl-S-Co-C3alkyl-cycloalkyl-C0-C3alkyl-, -C0-C3alkyl-S(O)2N(R3)- Co-C3alkyl-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl-S(O)2N(R3)-C0-C3alkyl-cycloalkyl-C0- C3alkyl-, -Co-C3alkyl-C(0)-N(R3)-Co-C3alkyl-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl-C(O)- N(R3)-C0-C3alkyl-cycloalkyl-Co-C3alkyl-, -C0-C3alkyl-C(S)-N(R3)-C0-C3alkyl-hetero- cyclyl-Co-C3alkyl-, -C0-C3alkyl-C(S)-N(R3)-C0-C3alkyl-cycloalkyl-C0-C3alkyl-, -C0- C3alkyl-C(O)-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl-C(O)-cycloalkyl-C0-C3alkyl-, -C0- C3alkyl-O-C(O)-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl-O-C(O)-cycloalkyl-C0-C3alkyl-, -Co-C3alkyl-0-C(0)-N(R3)-C0-C3alkyl-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl-O-C(O)- N(R3)-C0-C3alkyl-cycloalkyl-C0-C3alkyl-, -C0-C3alkyl-O-C(S)-N(R3)-C0-C3alkyl-hetero- cyclyl-C0-C3alkyl-, -C0-C3alkyl-O-C(S)-N(R3)-C0-C3alkyl-cycloalkyl-C0-C3alkyl-, -C0- C3alkyl-N(R3)-C(0)-N(R3)-Co-C3alkyl-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- N(R3)-Co-C3alkyl-cycloalkyl-C0-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-N(R3)-C0-C3alkyl- heterocyclyl-Co-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-N(R3)-Co-C3alkyl-cycloalkyl-Co- C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- cycloalkyl-Co-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-C0-C3alkyl-, -C0-C3alkyl- N(R3)-C(S)-cycloalkyl-C0-C3alkyl-, -C0-C3alkyl-N(R3)-S(O)2-N(R3)-C0-C3alkyl-hetero- cyclyl-C0-C3alkyl-, -C0-C3alkyl-N(R3)-S(0)2-N(R3)-Co-C3alkyl-cycloalkyl-Co-C3alkyl-, -C0-C6alkyl-heterocyclyl-C(0)-Co-C6alkyl-, -C0-C6alkyl-cycloalkyl-C(O)-C0-C6alkyl-, -Co-C6alkyl-N(R3)-C(0)-heterocyclyl-C(0)-Co-C6alkyl-, -C0-C6alkyl-N(R3)-C(O)- cycloalkyl-C(0)-Co-C6alkyl-, -C0-C6alkyl-N(R3)-C(S)-heterocyclyl-C(O)-C0-C6alkyl-, -Co-C6alkyl-N(R3)-C(S)-cycloalkyl-C(0)-C0-C6alkyl-, -C0-C6alkyl-heterocyclyl-S(O)2-C0- C6alkyl-, -C0-C6alkyl-cycloalkyl-S(O)2-C0-C6alkyl-, -C0-C6alkyl-heterocyclyl-N(R3)- C(O)-C0-C6alkyl-, -C0-C6alkyl-cycloalkyl-N(R3)-C(O)-C0-C6alkyl-, -C0-C6alkyl-hetero- cyclyl-O-C(O)-C0-C6alkyl-, -C0-C6alkyl-cycloalkyl-O-C(O)-C0-C6alkyl-, -C0-C6alkyl- heterocyclyl-N(R3)-C(S)-C0-C6alkyl-, -C0-C6alkyl-cycloalkyl-N(R3)-C(S)-C0-C6alkyl-, -C0-C6alkyl-heterocyclyl-O-C(S)-C0-C6alkyl-, -Co-C6alkyl-cycloalkyl-0-C(S)-C0-C6alkyl-, -C0-C3alkyl-CH=N-0-Co-C3alkyl-, -C0-C3alkyl-C=N(OH)C(O)-N(R3)-C2-C4-alkyl-S-S- alkyl-, -C0-C6alkyl-heteroalkyl-C0-C6alkyl-C(O)-N(R3)-C0-C3alkyl-, -C0-C6alkyl-hetero- alkyl-Co-C6alkyl-C(S)-N(R3)-Co-C3alkyl-, -C0-C6alkyl-aryl-heteiOaryl-C0-C6alkyl-, -C0- Cealkyl-heteroaryl-aryl-Co-Cealkyl-, -Co-Cealkyl-heteroaryl-heteroaryl-Co-Cealkyl-, -C0- Cealkyl-aryl-aryl-Co-Cealkyl-, -C,-C3alkyl-N(R3)-C(O)-CrC7alkyl-, -d-Csalkyl-NCR3)- C(S)-C1-C7alkyl-, -C0-C3alkyl-alkenyl-C(O)-C0-C6alkyl-, -C0-C6alkyl-N(R3)-C(O)-N(R3)- S(0)o-2-C0-C3alkyl-, -C0-C3alkyl-O-aryl-C0-C6 alkyl-N(R3)-C(O)-d-C3 alkyl-, -C0- C3alkyl-S-aryl-C0-C6 alkyl-N(R3)C(O)-C1-C3 alkyl-, -Co-Csalkyl-O-aryl-Co-Cβ alkyl- N(R3)C(S)-CrC3 alkyl-, -C0-C3alkyl-S-aryl-C0-C6 alkyl-N(R3)C(S)-C1-C3 alkyl-, -C0- C3alkyl-O-heteroaryl-C0-C6 alkyl-N(R3)-C(O)-Ci-C3alkyl-, -C0-C3alkyl-S-heteroaryl-C0- C6 alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-O-heteroaryl-C0-C6 alkyl-N(R3)-C(S)-d- C3alkyl-, -C0-C3alkyl-S-heteroaryl-C0-C6 alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-O- heterocyclyl-Co-C6 alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-S-heterocyclyl-Co-C6 alkyl-N(R3)-C(O)-CrC3alkyl-, -C0-C3alkyl-O-heterocyclyl-C0-C6 alkyl-N(R3)-C(S)-C!- C3alkyl-, -C0-C3alkyl-S-heterocyclyl-C0-C6 alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-O- cycloalkyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-S-cycloalkyl-C0-C6alkyl- N(R3)-C(O)-CrC3alkyl-, -C0-C3alkyl-O-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -Co-C3alkyl-S-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-aryl-C0- C6alkyl-N(R3)-C(O)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-C1- C3alkyl-, -C0-C3alkyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl- N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-heterocyclyl-C0- C6alkyl-N(R3)-C(O)-d-C3 alkyl-, -C0-C3alkyl-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)- C(S)-C1-C3 alkyl-, -C0-C3alkyl-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -Co-C3alkyl-N(R3)-cycloalkyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)- C(0)-0-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-O-aryl-C0- C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(0)-S-aryl-Co-C6alkyl-N(R3)-C(0)- Ci-C3alkyl-, -Co-C3alkyl-N(R3)-C(0)-0-aryl-Co-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0- C3alkyl-N(R3)-C(S)-O-aryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- S-aryl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-O-heteroaryl-C0- C6alkyl-N(R3)-C(O)-CrC3alkyl-, -Co-C3alkyl-N(R3)-C(S)-0-heteroaryl-Co-C6alkyl-N(R3)- CCOJ-Ct-Csalkyl-, -C0-C3alkyl-N(R3)-C(0)-S-heteroaryl-Co-C6alkyl-N(R3)-C(0)-C1-
C3alkyl-, -C0-C3alkyl-N(R3)-C(0)-0-heteroaryl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-N(R3)-C(S)-O-heteroaryl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)- C(O)-O-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-O- heterocyclyl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-O-hetero- cyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-O-heterocyclyl-C0- C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-O-cycloalkyl-C0-C6alkyl-
N(R3)-C(O)-CrC3alkyl-, -C0-C3alkyl-N(R3)-C(S)-O-cycloalkyl-C0-C6alkyl-N(R3)-C(O)- Ci-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-O-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-0-cycloalkyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -Co-C3alkyl- C(O)-N(R3)-aryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-C(S)-N(R3)-aryl-C0- C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-C(O)-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)- CrCsalkyl-, -C0-C3alkyl-C(S)-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-C(0)-N(R3)-heteroaryl-Co-C6alkyl-N(R3)C(0)-CrC3alkyl-, -Co-C3alkyl-C(S)- N(R3)-heteroaryl-C0-C6alkyl-N(R3)C(O)-C1-C3alkyl-, -C0-C3alkyl-C(O)-N(R3)-heteroaryl- C0-C6alkyl-N(R3)C(S)-C1-C3alkyl-, -C0-C3alkyl-C(S)-N(R3)-heteroaryl-C0-C6alkyl-
N(R3)C(S)-C1-C3alkyl-, -C0-C3alkyl-C(O)-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1- C3alkyl-, -C0-C3alkyl-C(S)-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0- C3alkyl-C(O)-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-C(S)- N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-C(O)-N(R3)- cycloalkyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-C(S)-N(R3)-cycloalkyl-C0- C6alkyl-N(R3)-C(O)-CrC3alkyl-, -C0-C3alkyl-C(O)-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)- C(S)-C1-C3alkyl-, -Co-C3alkyl-C(S)-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-0-C(0)-N(R3)-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-O-C(S)- N(R3)-aryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-O-C(O)-N(R3)-aryl-C0- C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-0-C(S)-N(R3)-aryl-Co-C6alkyl-N(R3)-C(S)- d-C3alkyl-, -C0-C3alkyl-O-C(O)-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -Co-C3alkyl-0-C(S)-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(0)-Ci-C3alkyl-, -C0-C3alkyl-O- C(0)-N(R3)-heteroaryl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-O-C(S)-N(R3)- heteroaryl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-O-C(O)-N(R3)-heterocyclyl- C0-C6alkyl-N(R3)-C(O)-Ci-C3alkyl-, -Co-C3alkyl-0-C(S)-N(R3)-heterocyclyl-Co-C6alkyl- N(R3)-C(O)-CrC3alkyl-, -C0-C3alkyl-0-C(0)-N(R3)-heterocylcyl-Co-C6alkyl-N(R3)-C(S)- d-C3alkyl-, -Co-C3alkyl-0-C(S)-N(R3)-heterocyclyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-O-C(O)-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl- O-C(S)-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(O)-Ci-C3alkyl-, -C0-C3alkyl-O-C(O)-
N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-O-C(S)-N(R3)- cycloalkyl-Co-C6alkyl-N(R3)-C(S)-CrC3alkyl-, -C0-C3alkyl-S(O)2-N(R3)-aryl-C0-C6alkyl- N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-Cr
C3alkyl-, -C0-C3 alkyl-S(O)2-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3 alkyl-S(O)2-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-S(O)2- N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-N(R3)-hetero- cyclyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-N(R3)-cycloalkyl-C0-
C6alkyl-N(R3)-C(O)-CrC3alkyl-, -C0-C3alkyl-S(O)2-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)- C(S)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)-S(O)2-N(R3)-aryl-C0-C6alkyl-N(R3)-C(O)-Cr
C3alkyl-, -C0-C3alkyl-N(R3)-S(O)2-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-N(R3)-S(O)2-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl- N(R3)-S(O)2-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)- S(0)2-N(R3)-heterocyclyl-Co-C6alkyl-N(R3)-C(0)-CrC3alkyl-, -C0-C3alkyl-N(R3)-S(O)2- N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3 alkyl-N(R3)- S(O)2-N(R3)- cycloalkyl-C0-C6alkyl-N(R3)-C(O)-CrC3alkyl-, -C0-C3alkyl-N(R3)- S(O)2-N(R3)- cycloalkyl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-heterocyclyl-O-aryl-C0-
C6alkyl-N(R3)-C(O)-CrC3alkyl-, -Co-C3alkyl-heterocyclyl-S-aryl-C0-C6alkyl-N(R3)-C(0)- d-C3alkyl-, -C0-C3alkyl-heterocyclyl-O-aryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-heterocyclyl-S-aryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-heterocyclyl- 0-heteroaryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -Co-Csalkyl-heterocyclyl-S-heteroaryl- C0-C6alkyl-N(R3)-C(O)-CrC3alkyl-, -Co-Csalkyl-heterocyclyl-O-heteroaryl-Co-Cealkyl- N(R3)-C(S)-C!-C3alkyl-, -C0-C3alkyl-heterocyclyl-S-heteroaryl-C0-C6alkyl-N(R3)-C(S)- d-C3alkyl-, -C0-C3alkyl-heterocyclyl-O-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-Ci-
C3alkyl-, -C0-C3alkyl-heterocyclyl-S-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-Ci-C3alkyl-, -Co-C3alkyl-heterocyclyl-0-heterocyclyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -Co-C3alkyl- heterocyclyl-S-heterocyclyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3 alkyl-hetero- cyclyl-0-cycloalkyl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -Co-Qalkyl-heterocyclyl-S- cycloalkyl-Co-C6alkyl-N(R3)-C(0)-CrC3alkyl-, -Co-Qalkyl-heterocyclyl-O-cycloalkyl- C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-heterocyclyl-S-cycloalkyl-C0-C6alkyl- N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-O-aryl-C0-C6alkyl-N(R3)-C(O)- d-C3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl-O-aryl-C0-C6alkyl-N(R3)-C(O)-Ci-C3alkyl-, -Co-C3alkyl-C(0)-heterocyclyl-S-aryl-C0-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -Co-C3alkyl- C(O)-heterocyclyl-O-aryl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-C(S)-hetero- cyclyl-S-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl-O-aryl- C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-S-aryl-C0-C6alkyl- N(R3)-C(S)-C1-C3alkyl-, -Co-C3alkyl-C(S)-heterocyclyl-S-aryl-C0-C6alkyl-N(R3)-C(S)-C1- C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-O-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-
C3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl-O-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-
C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-S-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-
C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-O-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-
C3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl-S-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl-O-heteroaryl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0- C3alkyl-C(O)-heterocyclyl-S-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl- C(S)-heterocyclyl-S-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-C(O)- heterocyclyl-0-heterocyclyl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-C(S)- heterocyclyl-O-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-C(O)- heterocyclyl-S-heterocyclyl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-C(O)- heterocyclyl-0-heterocyclyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-C(S)-hetero- cyclyl-S-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl- 0-heterocyclyl-Co-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-S- heterocyclyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl-S-hetero- cyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-O-cycloalkyl- Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl-O-cycloalkyl-C0- C6alkyl-N(R3)-C(O)-d-C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-S-cycloalkyl-C0-C6alkyl- N(R3)-C(O)-Ci-C3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-O-cycloalkyl-C0-C6alkyl-N(R3)- C(S)-Ci-C3alkyl-, -Co-C3alkyl-C(S)-heterocyclyl-S-cycloalkyl-C0-C6alkyl-N(R3)-C(0)-C1- C3alkyl-, -Co-C3alkyl-C(S)-heterocyclyl-0-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -Co-C3alkyl-C(0)-heterocyclyl-S-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-C(S)-heterocyclyl-S-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl- N(R3)-C(O)-heterocyclyl-O-aryl-C0-C6alkyl-N(R3)-C(O)-Cj-C3alkyl-, -C0-C3 alkyl-N(R3)- C(S)-heterocyclyl-0-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- heterocyclyl-S-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-hetero- cyclyl-0-aryl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl- S-aryl-C0-C6alkyl-N(R3)-C(O)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-O-aryl- C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-S-aryl-C0- C6alkyl-N(R3)-C(S)-d-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-S-aryl-C0-C6alkyl- N(R3)-C(S)-CrC3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-O-heteroaryl-C0-C6alkyl- N(R3)-C(O)-CrC3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-O-heteroaryl-C0-C6alkyl- N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-S-heteroaryl-C0-C6alkyl- N(R3)-C(O)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-O-heteroaryl-C0-C6alkyl- N(R3)-C(S)-CrC3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-S-heteroaryl-C0-C6alkyl- N(R3)-C(O)-CrC3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-O-heteroaryl-C0-C6alkyl- N(R3)-C(S)-C!-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-S-heteroaryl-C0-C6alkyl- N(R3)-C(S)-CrC3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-S-heteroaryl-C0-C6alkyl- N(R3)-C(S)-d-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-O-heterocyclyl-C0-
C6alkyl-N(R3)-C(O)-d-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-O-heterocyclyl- C0-C6alkyl-N(R3)-C(O)-d-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-S-hetero- cyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-O- heterocyclyl-Co-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-S- heterocyclyl-Co-C6alkyl-N(R3)-C(0)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl- 0-heterocyclyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-hetero- cyclyl-S-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)- heterocyclyl-S-heterocyclyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- heterocyclyl-O-cycloalkyl-C0-C6alkyl-N(R3)-C(O)-d-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)- heterocyclyl-O-cycloalkyl-C0-C6alkyl-N(R3)-C(O)-d-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- heterocyclyl-S-cycloalkyl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- heterocyclyl-O-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)- heterocyclyl-S-cycloalkyl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-5 -Co-C3alkyl-N(R3)-C(S)- heterocyclyl-O-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-d-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)- heterocyclyl-S-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-d-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)- heterocyclyl-S-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-d-C3alkyl-, -C0-C3alkyl-S(O)2-hetero- cyclyl-0-aryl-Co-C6alkyl-N(R3)-C(0)-Ci-C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-S-aryl- C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-O-aryl-C0-C6alkyl- N(R3)-C(S)-d-C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-S-aryl-C0-C6alkyl-N(R3)-C(S)- Q-C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-O-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1- C3alkyl-, -C0-C3alkyl-S(0)2-heterocyclyl-S-heteroaryl-Co-C6alkyl-N(R3)-C(0)-Ci-
C3alkyl-, -Co-C3alkyl-S(0)2-heterocyclyl-0-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-
C3alkyl-, -C0-C3alkyl-S(0)2-heterocyclyl-S-heteroaryl-Co-C6alkyl-N(R3)-C(S)-C1-
C3alkyl-, -Co-C3alkyl-S(0)2-heterocyclyl-0-heterocyclyl-C0-C6alkyl-N(R3)-C(0)-C1- C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-S-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-
C3alkyl-, -Co-C3alkyl-S(0)2-heterocyclyl-0-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-C1-
C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-S-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-C1-
C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-O-cycloalkyl-C0-C6alkyl-N(R3)-C(O)-C1-
C3alkyl-, -Co-C3alkyl-S(0)2-heterocyclyl-S-cycloalkyl-C0-C6alkyl-N(R3)-C(0)-Ci-
C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-O-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-C1-
C3alkyl-, -C0-C3alkyl-S(O)2-heterocyclyl-S-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-Ci-
C3alkyl-, -Co-C3alkyl-heterocyclyl-N(R3)-aryl-Co-C6alkyl-N(R3)-C(0)-CrC3alkyl-, -C0- C3alkyl-heterocyclyl-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-hetero- cyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-heterocyclyl- N(R3)-heteroaryl-Co-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-heterocyclyl-N(R3)- heterocyclyl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0-C3alkyl-heterocyclyl-N(R3)-hetero- cyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-heterocyclyl-N(R3)-cycloalkyl-Co- C6alkyl-N(R3)-C(O)-CrCjalkyl-, -C0-C3alkyl-heterocyclyl-N(R3)-cycloalkyl-C0-C6alkyl- N(R3)-C(S)-CrC3alkyl-, -C0-C3alkyl-C(O)-heterocyclyl-N(R3)-aryl-C0-C6alkyl-N(R3)- C(O)-C1-C3alkyl-, -Co-C3alkyl-C(S)-heterocyclyl-N(R3)-aryl-Co-C6alkyl-N(R3)-C(0)-Cr C3alkyl-, -Co-C3alkyl-C(0)-heterocyclyl-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-CrC3alkyl-, -C0-C3alkyl-C(S)-heterocyclyl-N(R3)-aryl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-
C3alkyl-C(O)-heterocyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0- C3alkyl-C(S)-heterocyclyl-N(R3)-heteroaryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0- C3alkyl-C(0)-heterocyclyl-N(R3)-heteroaryl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-C(S)-heterocyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-C(O)-heterocyclyl-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0- C3alkyl-C(S)-heterocyclyl-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0- C3alkyl-C(O)-heterocyclyl-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0- C3alkyl-C(S)-heterocyclyl-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-Cι-C3alkyl-, -C0- C3alkyl-C(O)-heterocyclyl-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(O)-C,-C3alkyl-, -C0- C3alkyl-C(S)-heterocyclyl-N(R3)-cycloalkyl-Co-C6alkyl-N(R3)-C(0)-CrC3alkyl-, -C0- C3alkyl-C(0)-heterocyclyl-N(R3)-cycloalkyl-Co-C6alkyl-N(R3)-C(S)-CrC3alkyl-, -C0- C3alkyl-C(S)-heterocyclyl-N(R3)-cycloalkyl-Co-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0- C3alkyl-N(R3)-C(0)-heterocyclyl-N(R3)-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0- C3alkyl-N(R3)-C(S)-heterocyclyl-N(R3)-aryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -C0- C3alkyl-N(R3)-C(O)-heterocyclyl-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-N(R3)-C(S)-heterocyclyl-N(R3)-aryl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0- C3alkyl-N(R3)-C(0)-heterocyclyl-N(R3)-heteroaryl-Co-C6alkyl-N(R3)-C(0)-C1-C3alkyl-, -Co-C3alkyl-N(R3)-C(S)-heterocyclyl-N(R3)-heteroaryl-Co-C6alkyl-N(R3)-C(0)-C1- C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(S)- Ci-C3alkyl-, -Co-C3alkyl-N(R3)-C(S)-heterocyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)- C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-N(R3)-heterocyclyl-C0-C6alkyl- N(R3)-C(O)-CrC3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-N(R3)-heterocyclyl-C0- C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl-N(R3)-hetero- cyclyl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-heterocyclyl-N(R3)- heterocyclyl-Co-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(O)-heterocyclyl- N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-N(R3)-C(S)-hetero- cyclyl-N(R3)-cycloalkyl-Co-C6alkyl-N(R3)-C(0)-CrC3alkyl-, -C0-C3alkyl-N(R3)-C(O)- heterocyclyl-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-Ci-C3alkyl-, -C0-C3alkyl-N(R3)- C(S)-heterocyclyl-N(R3)-cycloalkyl-Co-C6alkyl-N(R3)-C(S)-CrC3alkyl-, -C0-C3alkyl- S(0)2-heterocyclyl-N(R3)-aryl-Co-C6alkyl-N(R3)-C(0)-CrC3alkyl-, -C0-C3alkyl-S(O)2- heterocyclyl-N(R3)-aryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-hetero- cyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-hetero- cyclyl-N(R3)-heteroaryl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-hetero- cyclyl-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(O)-Ci-C3alkyl-, -C0-C3alkyl-S(O)2-hetero- cyclyl-N(R3)-heterocyclyl-C0-C6alkyl-N(R3)-C(S)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-hetero- cyclyl-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(O)-C1-C3alkyl-, -C0-C3alkyl-S(O)2-hetero- cyclyl-N(R3)-cycloalkyl-C0-C6alkyl-N(R3)-C(S)-Cj-C3alkyl-, -C0-C6alkyl-N(R3)-C(O)-C0- C6alkyl-heterocycloalkyl-C(O)-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(S)-C0-C6alkyl-hetero- cycloalkyl-C(O)-C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(O)-C0-C6alkyl-heterocycloalkyl-C(S)- C0-C3alkyl-, -C0-C6alkyl-N(R3)-C(S)-Co-C6alkyl-heterocycloalkyl-C(S)-Co-C3alkyl-, -C0- C6alkyl-N(R3)-C(O)-C0-C6alkyl-heterocycloalkyl-C(O)-N(R3)-C0-C3alkyl-, -C0-C6alkyl- N(R3)-C(S)-C0-C6alkyl-heterocycloalkyl-C(0)-N(R3)-Co-C3alkyl-, -C0-C6alkyl-N(R3)- C(0)-C0-C6alkyl-heterocycloalkyl-C(S)-N(R3)-Co-C3alkyl-, -C0-C6alkyl-N(R3)-C(S)-C0- C6alkyl-heterocycloalkyl-C(S)-N(R3)-C0-C3alkyl-, -C0-C6alkyl-C(O)-C0-C6alkyl-hetero- cycloalkyl-C(O)-N(R3)-C0-C3alkyl-, -C0-C6alkyl-C(S)-C0-C6alkyl-heterocycloalkyl-C(O)- N(R3)-C0-C3alkyl-, -C0-C6alkyl-C(O)-C0-C6alkyl-heterocycloalkyl-C(S)-N(R3)-C0-
C3alkyl-, -C0-C6alkyl-C(S)-Co-C6alkyl-heterocycloalkyl-C(S)-N(R3)-C0-C3alkyl-, -C0- C6alkyl-0-C0-C3alkyl-C(0)-N(R3)-Co-C3alkyl- and -C0-C6alkyl-0-C(S)-N(R3)-Co- C3alkyl-, wherein 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-C0-C3alkyl-O-C0-C3alkyl-aryl, aryl-C0-C3alkyl-S(0)o-2-C0- C3alkyl-aryl, -C0-C3alkyl-S(O)0-2-C0-C3alkyl-aryl, aryl-C0-C3alkyl-N(R3)-C0-C3alkyl-aryl, aryl-C0-C3alkyl-C(0)-N(R3)-Co-C3alkyl-aryl, aryl-Co-C3alkyl-C(S)-N(R3)-Co-C3alkyl-aryl, aryl-C0-C3alkyl-N(R3)-C(0)-Co-C3alkyl-aryl, aryl-Co-C3alkyl-N(R3)-C(S)-Co-C3alkyl-aryl, heteroaryl-heteroaryl, heteroaryl-aryl, heteroaryl-arylalkyl, aryl-alkylheteroaryl, hetero- aryl-aryl-aryl, aryl-aryl-aryl, aryl-heteroaryl-aryl, aryl-heteroaryl-heteroaryl, heteroaryl- heteroaryl-heteroaryl, heteroaryl-heteroaryl-aryl, aryl-aryl-heteroaryl, heteroaryl-aryl- arylalkyl, aryl-aryl-alkylheteroaryl, heteroaryl-aryl-alkylaryl, aryl-aryl-alkylaryl, aryl-aryl- arylalkyl, aryl-aryl-heteroarylalkyl, heteroaryl-aryl-heteroaryl, heteroaryl-aryl-hetero- arylalkyl, heteroaryl-aryl-alkylheteroaryl, heteroaryl-heteroarylalkyl, heteroaryl- alkylheteroaryl, heterocyclyl-heteroaryl, cycloalkyl-aryl, cycloalkyl-heteroaryl, heteroaryl- heterocyclyl, heteroaryl-cycloalkyl, aryl-cycloalkyl, heterocyclyl-aryl, aryl-heterocyclyl, heterocyclyl-alkyl-aryl, heterocyclyl-alkylheteroaryl, cycloalkyl-alkylaryl, cycloalkyl- alkylheteroaryl, aryl-alkyl-heterocyclyl, aryl-alkylcycloalkyl, heteroaryl-alkylcycloalkyl, heteroaryl-alkylheterocyclyl, arylalkyl-aryl, aryl-arylalkyl, aryl-heteroarylalkyl, heteroaryl-arylalkyl, heteroaryl-heteroarylalkyl, heteroaryl-Co-C3alkyl-0-Co-C3alkyl-aryl, heteroaryl-Co-C3alkyl-0-C0-C3alkyl-heteroaryl, aryl-Co-C3alkyl-0-C0-C3alkyl-heteroaryl, heteroaryl-Co-C3alkyl-N(R3)-Co-C3alkyl-aryl, aryl-C0-C3alkyl-N(R3)-C0-C3alkyl-hetero- aryl, heteroaryl-C0-C3alkyl-N(R3)-C0-C3alkyl-heteroaryl, heteroaryl-C0-C3alkyl-C(O)- N(R3)-C0-C3alkyl-aryl, aryl-C0-C3alkyl-C(O)-N(R3)-C0-C3alkyl-heteroaryl, heteroaryl-C0- C3alkyl-C(0)-N(R3)-Co-C3alkyl-heteroaryl, aryl-Co-C3alkyl-C(S)-N(R3)-Co-C3alkyl-aryl, aryl-Co-C3alkyl-C(S)-N(R3)-C0-C3alkyl-heteroaryl, heteroaryl-C0-C3alkyl-C(S)-N(R3)-C0- C3alkyl-aryl, heteroaryl-C0-C3alkyl-C(S)-N(R3)-C0-C3alkyl-heteroaryl, heteroaryl-C0- C3alkyl-N(R3)-C(O)-C0-C3alkyl-aryl, heteroaryl-C0-C3alkyl-N(R3)-C(O)-C0-C3alkyl- heteroaryl, aryl-Co-C3alkyl-N(R3)-C(0)-C0-C3alkyl-heteroaryl, aryl-C0-C3alkyl-N(R3)- C(S)-Co-C3alkyl-aryl, aryl-C0-C3alkyl-N(R3)-C(S)-Co-C3alkyl-heteroaryl, heteroaryl-Co- C3alkyl-N(R3)-C(S)-Co-C3alkyl-aryl, heteroaryl-C0-C3alkyl-N(R3)-C(S)-C0-C3alkyl- heteroaryl, R3-heterocyclyl-C0-C3alkyl, R3-cycloalkyl-C0-C3alkyl, (R3)(R3a)N-C2-C4alkyl- O-aryl-, (R3)(R3a)N-C2-C4alkyl-S(O)0-2-aryl-, (R3)(R3a)N-C2-C4alkyl-O-heteroaryl-, (R3)(R3a)N-C2-C4alkyl-S(0)o-2-heteroaryl-, Co-C3alkyl-aryl-Co-C3alkyl, Co-C3alkyl-hetero- aryl-Co-C3alkyl, aryl-C1-C3alkyl-heteroaryl, aryl-C1-C3alkyl-aryl, heteroaryl-Ci-C3alkyl- aryl, heteroaryl-C j -C3alkyl-heteroaryl, R3-heterocyclyl-C0-C3alkyl-N(R3)-C(O)-N(R3)- heteroaryl-, R3-heterocyclyl-Co-C3alkyl-N(R3)-C(O)-N(R3)-aryl-, R3-cycloalkyl-C0- C3alkyl-N(R3)-C(O)-N(R3)-heteroaryl-, R3-cycloalkyl-Co-C3alkyl-N(R3)-C(O)-N(R3)- aryl-, R3-heterocyclyl-C0-C3alkyl-N(R3)-C(S)-N(R3)-heteroaryl-, R3-heterocyclyl-Co- C3alkyl-N(R3)-C(S)-N(R3)-aryl-, R3-cycloalkyl-C0-C3alkyl-N(R3)-C(S)-N(R3)-heteroaryl-, R3-cycloalkyl-Co-C3alkyl-N(R3)-C(S)-N(R3)-aryl-, heteroaryl-C(O)-C0-C6alkyl-hetero- aryl-, heteroaryl-C(O)-C0-C6alkyl-aryl-, aryl-C(O)-C0-C6alkyl-aryl-, aryl-C(O)-C0- C6alkyl-heteroaryl-, heteroaryl-C(O)-N(R3)-C0-C6alkyl-aryl-, heteroaryl-C(O)-N(R3)-C0- C6alkyl-heteroaryl-, heteroaryl-S(0)2-Co-C6alkyl-heteroaryl-, heteroaryl-S(O)2-C0-C6alkyl- aryl-, aryl-S(0)o-2-C0-C6alkyl-aryl, aryl-C0-C3alkyl-S(O)0-2-C0-C6alkyl-heteroaryl, R3-O- C(O)-N(R3)-C0-C3alkyl-heteroaryl-, R3-O-C(O)-N(R3)-C0-C3alkyl-aryl-, R3-O-C(S)- N(R3)-C0-C3alkyl-heteroaryl-, R3-O-C(S)-N(R3)-C0-C3alkyl-aryl-, R3-C(O)-heterocyclyl- C0-C3alkyl-heteroaryl-, R3-C(O)-heterocyclyl-C0-C3alkyl-aryl-, R3-C(O)-cycloalkyl-C0- C3alkyl-heteroaryl-, R3-C(O)-cycloalkyl-C0-C3alkyl-aryl-, R3-heterocyclyl-C0-C3alkyl- N(R3)-C(O)-N(R3)-C0-C3alkyl-heteroaryl-, R3-heterocyclyl-C0-C3alkyl-N(R3)-S(O)2-C0- C3alkyl-heteroaryl-, R3-heterocyclyl-C0-C3alkyl-N(R3)-S(O)2-C0-C3alkyl-aryl-, R3- cycloalkyl-Co-C3alkyl-N(R3)-S(0)2-Co-C3alkyl-heteroaryl-, R3-cycloalkyl-C0-C3alkyl- N(R3)-S(O)2-C0-C3alkyl-aryl-, R3-heterocyclyl-C0-C3alkyl-N(R3)-C(O)-C0-C3alkyl-hetero- aryl-, R3-heterocyclyl-C0-C3alkyl-N(R3)-C(O)-C0-C3alkyl-aryl-, R3-cycloalkyl-C0-C3alkyl- N(R3)-C(O)-C0-C3alkyl-heteroaryl-, R3-cycloalkyl-C0-C3alkyl-N(R3)-C(O)-C0-C3alkyl- aryl-, R3-heterocyclyl-C0-C3alkyl-N(R3)-C(S)-C0-C3alkyl-heteroaryl-, R3-heterocyclyl-C0- C3alkyl-N(R3)-C(S)-C0-C3alkyl-aryl-, R3-cycloalkyl-C0-C3alkyl-N(R3)-C(S)-C0-C3alkyl- heteroaryl-, R3-cycloalkyl-C0-C3alkyl-N(R3)-C(S)-C0-C3alkyl-aryl-, R3-C(O)-C0-C3alkyl- heteroaryl-, R3-C(0)-Co-C3alkyl-aryl-, heterocyclyl-C(O)-, an aromatic polycycle, a non- aromatic polycycle, a mixed aryl and non-aryl polycycle, a polyheteroaryl, a non-aromatic polyheterocycle, and a mixed aryl and non-aryl polyheterocycle, each of which is optionally substituted with one or more groups selected from R3, R4 or R7; or each Y is independently selected from the group consisting of
A2a-aryl-Co-C3alkyl-N(R3)-C(0)-C1-C7alkyl-, wherein the CrC7alkyl is optionally substituted with a moiety selected from the group consisting of -N(R3)-C(O)-C1-C5alkyl-(C2- C4alkenyl)0-1-C1-C3alkyl-O-A2b, -N(R3)-C(O)-N(R3)-C i-C5alkyl-(C2-C4 alkenyl)o-i-Ci- C3alkyl-O-A2b, -N(R3)-C(0)-0-C1-C5alkyl-(C2-C4alkenyl)o-1-C1-C3alkyl-0-A2b, -N(R3)- C1-C5alkyl-(C2-C4alkenyl)0-1-C1-C3alkyl-O-A2b, -N(R3)-S(O)2-N(R3)-C1-C5alkyl-(C2- C4alkenyl)0-1-C1-C3alkyl-O-A2b and -N(R3)-S(O)2-C1-C5alkyl-(C2-C4alkenyl)0-1-C1- C3alkyl-O-A2b,
A2a-heteroarylene-Co-C3alkyl-N(R3)-C(0)-C1-C7alkyl-, wherein the d-C7alkyl is optionally substituted with a moeity selected from the group consisting of -N(R3)-C(O)-C1-Csalkyl- (C2-C4alkenyl)0-1-C1-C3alkyl-O-A2b, -N(R3)-C(O)-N(R3)-C1-C5alkyl-(C2-C4alkenyl)0-1-C1- C3alkyl-O-A2b, -N(R3)-C(O)-O-Ci-C5alkyl-(C2-C4alkenyl)0-i-C1-C3alkyl-O-A2b, -N(R3)- C1-C5alkyl-(C2-C4alkenyl)o-i-C1-C3alkyl-0-A2b, -N(R3)-S(O)2-N(R3)-C1-C5alkyl-(C2- C4alkenyl)0-1-C1-C3alkyl-O-A2b and -N(R3)-S(O)2-C1-C5alkyl-(C2-C4alkenyl)0-1-C1- C3alkyl-O-A2b and
B2-B1-N(R3)-C(O)-C1-C7alkyl-, wherein the CrC7alkyl is optionally substituted with -NR3- B3 wherein the amine of B3 is connected with the acid of B2 to form a peptide bond; and wherein
A2a and A2b together are a covalent bond and are attached to form a ring; and
B , B and B are each independently a natural or synthetic amino acid and when any of B , B2 and B3 are linked together they are linked together via a peptide bond; each R3 and R3a are independently selected from the group consisting of -H, -OH, -C(O)H, heterocyclyl, d-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C2-C4alkyl-ORa, -C(O)-O-C2- C4alkyl-NRaR\ heteroalkyl, C0-C6alkylheteroaryl, C(O)CF3, -C(O)-NH2, -C(O)-NH-Cj- C6alkyl, -NH2, C3-C6cycloalkyl, -Q-Cόalkylaryl, heteroaryl-aryl, aryl and alkylheteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and hetero- aryl moiety is optionally substituted; each R4 is independently selected from the group consisting of -H, -C(NRa)-N(Ra)2, C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -Ci-C6alkyl-Ra, -C0-C6alkyl-O-Ra, -C0-C6alkyl- S(O)0-2-R3, -C0-C6alkyl-C(O)-ORa, -C0-C6alkyl-C(O)-N(R3)(R3a), -C0-C6alkyl-C(S)- N(R3)(R3a), -CH=CH-C(O)-OR3, -CH=CH-C(O)-N(R3)(R3a), -CH=CH-C(S)-N(R3)(R3a), -N(R3)-C(O)-CF3, -N(R3)-C2-C6alkyl-N(R3)(R3a), -C0-C6alkyl-N(R3)(R3a), -N(R3)-C(O)- d-C6alkyl-R3, -N(R3)-C(S)-C1-C6alkyl-R3, -N(R3)-S(O)2-CrC6alkyl-R3, -S(O)2-N(R3)R3a, -O-C2-C6alkyl-N(R3)(R3a), -S(O)0-2-C2-C6alkyl-N(R3)(R3a), -S-R3, -S(O)0-2-C2-C6alkyl-R3, -C3-C6cycloalkyl, -C3-C6cycloalkyl-Ra, heterocyclyl, -C4-C7heterocyclyl-Ra, -0-C0- C4alkyl-cycloalkyl, -S(0)o-2-C0-C4alkyl-cycloalkyl, -O-C2-C4alkyl-heterocyclyl (when the alkyl is linked via a N in the heterocyclyl), -O-Co^alkyl-heterocyclyl (when the alkyl is linked via a C in the heterocyclyl), -S(0)o-i-Co-C4alkyl-heterocyclyl (when the alkyl is linked via a C in the heterocyclyl), -S(0)o-i-C2-C4alkyl-heterocyclyl (when the alkyl is linked via a N in the heterocyclyl, -S(0)2-Co-C4alkyl-heterocyclyl, -O-Co-Cialkyl-hetero- cyclyl-C(O)-ORa (when the alkyl is linked via a C in the heterocyclyl, -O-C2-C4alkyl- heterocyclyl-C(O)-ORa (when the alkyl is linked via a N in the heterocyclyl), -O- cycloalkyl-C(O)-ORa, -O-aryl-C(O)-ORa, -O-heteroaryl-C(O)-ORa, -S(0)o-rC0-C4alkyl- heterocyclyl-C(O)-ORa (when the alkyl is linked via a C in the heterocyclyl), -S(O)0-1-C2- C4alkyl-heterocyclyl-C(O)-ORa (when the alkyl is linked via a N in the heterocyclyl), -S(O)2-C0-C4alkyl-heterocyclyl-C(O)-ORa, -S(O)0-2-cycloalkyl-C(O)-ORa, -S(O)0-2-aryl- C(O)-OR3, -S(O)0-2-heteroaryl-C(O)-ORa, -O-C0-C4alkyl-aryl, -S(O)0-2-C0-C4alkyl-aryl, -O-C0-C4alkyl-heteroaryl, -S(O)0-2-C0-C4alkyl-heteroaryl, -O-C(O)-N(R3)-C0-C4alkyl-aryl, -O-C(S)-N(R3)-C0-C4alkyl-aryl, -O-C(O)-N(R3)-C0-C4alkyl-heteroaryl, -O-C(S)-N(R3)-C0- C4alkyl-heteroaryl, -O-C(O)-N(R3)-C0-C4alkyl-cycloalkyl, -O-C(S)-N(R3)-C0-C4alkyl- cycloalkyl, -O-C(O)-N(R3)-C0-C4alkyl-heterocyclyl, -O-C(S)-N(R3)-C0-C4alkyl-hetero- cyclyl, -0-Co-C4aUcyl-heterocyclyl-aryl (when the alkyl is linked via a C in the heterocyclyl), -O-C2-C4alkyl-heterocyclyl-aryl (when the alkyl is linked via a N in the heterocyclyl), -0-Co-C4alkyl-heterocyclyl-heteroaryl (when the alkyl is linked via a C in the heterocyclyl), -O-C2-C4alkyl-heterocyclyl-heteroaryl (when the alkyl is linked via a N in the heterocyclyl), -O-Co^alkyl-heterocyclyl-cycloalkyl (when the alkyl is linked via a C in the heterocyclyl), -O-C2-C4alkyl-heterocyclyl-cycloalkyl (when the alkyl is linked via a N in the heterocyclyl), -O-Co^alkyl-heterocyclyl-heterocyclyl (when the alkyl is linked via a C in the heterocyclyl), -O-C2-C4alkyl-heterocyclyl-heterocyclyl (when the alkyl is linked via a N in the heterocyclyl), -S(0)0-i-Co-C4alkyl-heterocyclyl-aryl (when the alkyl is linked via a C in the heterocyclyl), -S(0)o-i-C2-C4alkyl-heterocyclyl-aryl (when the alkyl is linked via a N in the heterocyclyl), -S(0)2-Co-C4alkyl-heterocyclyl-aryl, -S(O)0-1- Co-Ctalkyl-heterocyclyl-heteroaryl (when the alkyl is linked via a C in the heterocyclyl), -S(0)o-1-C2-C4alkyl-heterocyclyl-heteroaryl (when the alkyl is linked via a N in the heterocyclyl), -S(O)2-C0-C4alkyl-heterocyclyl-heteroaryl, -S(O)0-1 -C0-C4alkyl-heterocyclyl- cycloalkyl (when the alkyl is linked via a C in the heterocyclyl), -S(0)o-i-C2-C4alkyl- heterocyclyl-cycloalkyl (when the alkyl is linked via a N in the heterocyclyl), -S(O)2-Co- C4alkyl-heterocyclyl-cycloalkyl, -S(O)O-1 -Co^alkyl-heterocyclyl-heterocyclyl (when the alkyl is linked via a C in the heterocyclyl), -S(O)0-I -C2-C4alkyl-heterocyclyl-heterocyclyl (when the alkyl is linked via a N in the heterocyclyl), -S(0)2-Co-C4alkyl-heterocyclyl- heterocyclyl, -N(R3)-C2-C4alkyl-heterocyclyl, -N(R3)-C2-C4alkyl-cycloalkyl, -N(R3)-C2- C4alkyl-heteroaryl, -N(R3)-C2-C4alkyl-aryl, -N(R3)-C(O)-N(R3)-C0-C4alkyl-heterocyclyl- R3, -N(R3)-C(S)-N(R3)-C0-C4alkyl-heterocyclyl-R3, -N(R3)-C(O)-N(R3)-C0-C4alkyl- cycloalkyl-R3, -N(R3)-C(S)-N(R3)-C0-C4alkyl-cycloalkyl-R3, -N(R3)-C(O)-N(R3)-C0- C4alkyl-aryl-R3, -N(R3)-C(S)-N(R3)-C0-C4alkyl-aryl-R3, -N(R3)-C(0)-N(R3)-Co-C4alkyl- heteroaryl-R3, -N(R3)-C(S)-N(R3)-C0-C4alkyl-heteroaryl-R3, -C0-C4alkyl-O-C(O)-Ra, -C0- C4alkyl-N(R3)-C(O)-O-Ra, -C0-C4alkyl-N(R3)-C(S)-O-Ra, -C0-C4alkyl-heterocyclyl-C(O)- O-Ra, -C0-C4alkyl-cycloalkyl-C(O)-O-Ra, -C0-C4alkyl-heteroaryl-C(O)-O-Ra, -C0-C4alkyl- aryl-C(O)-O-Ra, -N(R3)-C2-C4alkyl-heterocyclyl, -N(R3)-C2-C4alkyl-cycloalkyl, -N(R3)- C2-C4alkyl-heteroaryl, -N(R3)-C2-C4alkyl-aryl, F, Cl, Br, I, -CF35-SO3H, -CN, aryl, hetero- aryl, cycloalkyl and heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl moeity of the aformentioned R4 is optionally substituted; each R7 and R7a is independently selected from the group consisting of -H, CrQalkyl-, C2- C6alkenyl, C2-C6alkynyl, CrC6heteroalkyl, Ra-O-C2-C6alkyl-, Ra-S(O)0-2-C2-C6alkyl-, N(R3)(R3a)-C2-C6alkyl-, a protecting group, Cj-C6alkyl-O-C(O)-, aryl-C0-C4alkyl-O- C(O)-, heteroaryl-Co-C4alkyl-0-C(0)-, benzyl-O-C(O)-, heterocyclyl-CrQalkyl-, cycloalkyl-Q-Qalkyl-, heteroaryl-d-Cδalkyl-, aryl-CpCόalkyl-, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, benzyl and heterocyclyl moiety is independently optionally substituted; provided that
R7 is -ORa when attached to the N atom of an indolyl moiety; and wherein in a -N(R3)(R3a) group, the R3 and R3a together with the nitrogen atom to which they are attached optionally form a heterocyclyl group.
2. The compound according to claim 1, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl moiety of Y, L, Z, Ra, Rb, Rc, R3 and R3a is independently optionally substituted with one or more groups independently selected from R4.
3. The compound according to claim 1, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl moiety of Y, L, Z, Ra, Rb, Rc, R3 and R3a is independently optionally substituted with one or more groups independently selected from oxo, -OH, -CN, C!-C6alkyl, CrC6alkoxy, -NO2, -N(Ra)2, -N(R7)(R7a), halo, -SH, -S-d-C6alkyl, -S(O)-CrC6alkyl, -S-C(O)-d-C6alkyl and mono- to per-halogenated Q-Qalkyl.
4. The compound according to claim 1 or claim 2, wherein the C!-C6alkyl moiety of an R4 is optionally substituted with a substituent selected from the group consisting of -OH, -NO2 and C0-C6 alkyl-C(O)-N(R3)(R3a).
5. The compound according to any of claims 1 - 4, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, 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, Q-Cealkyl, CrC6alkoxy, -NO2, -N(R3)(R3a), halo, -SH and mono- to per-halogenated Ci-C6alkyl.
6. The compound according to any of claims 1 - 5, wherein L is selected from the group consisting of
-Co-C6alkyl-N(R3)-Co-C3alkyl-, wherein when the -C0-C6alkyl is -d-Cealkyl it is optionally substituted with a substituent selected from the group consisting Of -C1- C3alkyl-ORa, -C1-C3alkyl-N(R3)(R3a), -C0-C3alkyl-C(O)ORa and C0-C3alkyl-C(O)- N(R3)(R3a);
-Co-C6alkyl-N(R3)-C(0)-C0-C3alkyl-, wherein when the -C0-C6alkyl is C1- Cβalkyl it is optionally substituted with a substituent selected from the group consisting of -Ci-C3alkyl-ORa, -Ci-C3alkyl-NR3R3a, -C0C3alkyl-C(O)ORa and C0- C3alkyl-C(O)-N(R3)(R3a);
-Co-C6alkyl-N(R3)-C(0)-Co-C3alkyl-, wherein the -Co-C3alkyl is Ci-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C(S)- C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C0-C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0-C3alkyl- C4-C6heterocyclyl, -N(R3)-C2-C3alkyl-N(R3)(R3a), -N(R3)-C2-C3alkyl-OR\ -N(R3)- Co-C3alkyl-C0-C3heteroalkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(S)-O-C0- C3alkyl-Y, -N(R3)-S(O)2-C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y, -N(R3)- C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(S)- C0-C3alkyl-Co-C3heterocyclyl, -N(R3)-C(0)-C0-C3alkyl-Co-C3heterocyclyl-Y, -N(R3)- C(S)-Co-C3alkyl-C0-C3heterocyclyl-Y and -N(R3)-S(0)2-N(R3)-C0-C3alkyl-Y;
-Co-C6alkyl-N(R3)-C(S)-Co-C3alkyl-, wherein the -C0-C3alkyl is CrC3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C(S)- C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C0-C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0-C3alkyl- C4-C6heterocyclyl, -N(R3)-C2-C3alkyl-N(R3)(R3a), -N(R3)-C2-C3alkyl-ORa, -N(R3)- C0-C3alkyl-C0-C3heteroalkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(S)-O-C0- C3alkyl-Y, -N(R3)-S(O)2-C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y, -N(R3)- C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(S)- C0-C3alkyl-Co-C3heterocyclyl, -N(R3)-C(O)-C0-C3alkyl-C0-C3heterocyclyl-Y, -N(R3)- C(S)-C0-C3alkyl-Co-C3heterocyclyl-Y and -N(R3)-S(0)2-N(R3)-C0-C3alkyl-Y;
-C0-C6alkyl-C(O)-C0-C3alkyl-, wherein when the -C0-C6alkyl is Q-Qalkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)(R3a), -C(S)- N(R3)(R3a), -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0- C3alkyl-C4-C6cycloalkyl-, -N(R3)-C(S)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C0- C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0-C3alkyl-C4-C6heterocyclyl, - N(R3)-C2-C3alkyl- N(R3)(R3a), -N(R3)-C2-C3alkyl-ORa-, -N(R3)-C0-C3heteroalkyl-Y, -N(R3)-C(O)-O-C0- C3alkyl-Y, -N(R3)-C(S)-O-C0-C3alkyl-Y, -N(R3)-S(O)2-C0-C3alkyl-Y, -N(R3)-C(O)- N(R3)-C0-C3alkyl-Y, -N(R3)-C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C0- C3heterocyclyl, -N(R3)-C(S)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(O)-C0-C3alkyl- C0-C3heterocyclyl-Y, -N(R3)-C(S)-C0-C3alkyl-C0-C3heterocyclyl-Y and -N(R3)- S(O)2-N(R3)-C0-C3alkyl-Y;
-Co-C6alkyl-C(S)-Co-C3alkyl-, wherein when the -C0-C6alkyl is CrC3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)(R3a), -C(S)- N(R3)(R3a), -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0- C3alkyl-C4-C6cycloalkyl-, -N(R3)-C(S)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C0- C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0-C3alkyl-C4-C6heterocyclyl, - N(R3)-C2-C3alkyl- N(R3)(R3a), -N(R3)-C2-C3alkyl-ORa-, -N(R3)-C0-C3heteroalkyl-Y, -N(R3)-C(O)-O-C0- C3alkyl-Y, -N(R3)-C(S)-O-C0-C3alkyl-Y, -N(R3)-S(O)2-C0-C3alkyl-Y, -N(R3)-C(O)- N(R3)-C0-C3alkyl-Y, -N(R3)-C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C0- C3heterocyclyl, -N(R3)-C(S)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(O)-C0-C3alkyl- C0-C3heterocyclyl-Y, -N(R3)-C(S)-Co-C3alkyl-C0-C3heterocyclyl-Y and -N(R3)- S(O)2-N(R3)-C0-C3alkyl-Y;
-C0-C6alkyl-, wherein when the -C0-C6alkyl is Q-Qalkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(0)-Co- C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-heterocyclyl and -N(R3)-C(O)-C0-C3alkyl- cyclyoalkyl;
-C0-C6alkyl-C(O)-N(R3)-C0-C3alkyl-, wherein when the -C0-C3alkyl is C1- C3alkyl it is optionally substituted with a substituent selected from the group consisting of -C(O)-N(R3)-C0-C3alkyl-Y, -C(O)-heterocyclyl, -C(O)-N(R3)(R3a), aryl- aryl, aryl-heteroaryl, -heteroaryl-aryl, heteraryl-heteroaryl, heteroaryl, heterocyclyl- heteroaryl and heterocyclyl;
-Co-C6alkyl-heteroalkyl-Co-C6alkyl-C(0)-N(R3)-Co-C3alkyl-, wherein when the -Co-C3alkyl is C!-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -C(O)-N(R3)-C0-C3alkyl-Y, -C(O)-heterocyclyl, -C(O)- N(R3)(R3a), aryl-aryl, aryl-heteroaryl, -heteroaryl-aryl, heteraryl-heteroaryl, heteroaryl, heterocyclyl-heteroaryl and heterocyclyl;
-C0-C6alkyl-C(0)-N(R3)-Co-C3alkyl-, wherein when the -C0-C6alkyl is C1- C6alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R7)(R7a), -N(R3)(R3a), -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O- C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-Co-C6alkyl-heteroaryl-Co-C3alkyl-, wherein when the -C0-C3alkyl is C1- C3alkyl it is optionally substituted with a substituent selected from the group consisting of -C0-C3alkyl-N(R3)-C(O)-C0-C3alkyl-N(R3)(R3a), -N(R3)-C(O)-C0- C3alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-C0-C6alkyl-aryl-C0-C3alkyl-, wherein when the -C0-C3alkyl is CrC3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)- C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-Co-Coalkyl-aryl-heteroaryl-Co-Qalkyl-, wherein when the -C0-C3alkyl is C1- C3alkyl it is optionally substituted with a substituent selected from the group consisitng of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O- C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y; -Co-Cδalkyl-heteroaryl-heteroaryl-Co-Qalkyl-, wherein when the -Co-C3alkyl is Ci-Csalkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O- C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-Co-Cealkyl-heteroaryl-Co-Csalkyl-, wherein when the -Co-C3alkyl is C1- C3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O- Co-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-Co-C6alkyl-0-C(0)-N(R3)-Co-C3alkyl-, wherein when the -C0-C3alkyl is C1- C3 alkyl it is optionally substituted with a group selected from -C(O)-OR3, -C(S)-OR3, -C(O)-N(R3)-C1-C3alkyl, -C(S)-N(R3)-Ci-C3alkyl, -C(O)-N(R3)(R3a)-, -C(S)- N(R3XR33)-, -C(O)-N(R3)-C0-C3alkyl-aryl, -C(S)-N(R3)-C0-C3alkyl-aryl, -C(O)- N(R3)-C0-C3alkyl-heteroaryl, -C(S)-N(R3)-C0-C3alkyl-heteroaryl, -C(O)-N(R3)-C0- C3alkyl-cycloalkyl, -C(S)-N(R3)-C0-C3alkyl-cycloalkyl, -C(O)-heterocyclyl, -C(S)- heterocyclyl, -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -C(O)-N(R3)- heterocyclyl, -C(S)-N(R3)-heterocyclyl, -C(O)-N(R3)-C0-C3alkyl-heterocycloalkyl and -C(S)-N(R3)-C0-C3alkyl-heterocycloalkyl;
-Co-C6alkyl-0-C(S)-N(R3)-C0-C3alkyl-, wherein when the -C0-C3alkyl is C1- C3 alkyl it is optionally substituted with a group selected from -C(O)-OR3, -C(S)-OR3, -C(O)-N(R3)-C1-C3alkyl, -C(S)-N(R3)-CrC3alkyl, -C(O)-N(R3)(R3a)-, -C(S)- N(R3)(R33)-, -C(O)-N(R3)-C0-C3alkyl-aryl, -C(S)-N(R3)-C0-C3alkyl-aryl, -C(O)- N(R3)-C0-C3alkyl-heteroaryl, -C(S)-N(R3)-C0-C3alkyl-heteroaryl, -C(O)-N(R3)-C0- C3alkyl-cycloalkyl, -C(S)-N(R3)-C0-C3alkyl-cycloalkyl, -C(O)-heterocyclyl, -C(S)- heterocyclyl, -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -C(O)-N(R3)- heterocyclyl, -C(S)-N(R3)-heterocyclyl, -C(O)-N(R3)-C0-C3alkyl-heterocycloalkyl and -C(S)-N(R3)-C0-C3alkyl-heterocycloalkyl; and
-Ci-C3alkyl-N(R3)-C(O)-C1-C7alkyl-, wherein the d-C3alkyl is optionally substituted with -C(O)N(R3)-C1-C3alkyl-Ala and the Q-Oyalkyl is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-O- Ci-C3alkyl-Alb, -N(R3)-C(O)-C1-C3alkyl-Alb, -N(R3)-S(O)2-C1-C3alkyl-Alb, -N(R3)- S(O)2-N(R3)-C1-C3alkyl-Alb, -N(R3)-C(O)-N(R3)-Ci-C3alkyl-Alb and -N(R3)-S(O)2- N(R3)-C!-C3alkyl-Alb, wherein
Ala and Alb are independently selected from the group consisting of alkyl, alkenyl and a protecting group; or Ala and Alb together via a -C2-C6alkylene-, -Ca-Cδalkenylene-, -C2- C6alkynylene- or -Co-dalky-heteroaryl-Co-dalky- linker, form an optionally substituted ring.
7. The compound according to any of claims 1 - 5, wherein L is selected from the group consisting of
-C1-C6alkyl-N(R3)-Co-C3alkyl-, wherein the d-C6alkyl is optionally substituted with a substitutent selected from the group consisting of -Ci-C4 alkyl-ORa, -C1-C6 alkyl-N(R3)(R3a)-, -C0-C4 alkyl-C(O)ORa and -C0-C3alkyl-C(O)-N(R3)(R3a);
-C0-C6alkyl-N(R3)-C(0)-Co-C3alkyl-, wherein the d-C6alkyl is optionally substituted with a substituent selected from the group consisting of -C1-C4alkyl- O(Ra)-, -C0-C6alkyl-C(O)O(Ra)- and -C1-C6alkyl-N(R3)(R3a)-; and
-Co-C6alkyl-C(0)-N(R3)-C0-C3alkyl-, wherein the Q-Qalkyl is optionally substituted with a substituent selected from the group consisting of -C0-C6alkyl- O(Ra)-, -C0-C6alkyl-C(O)O(Ra)-, -C0-C3alkyl-C(O)-N(R3)(R3a) and -C0-C6alkyl- N(R3)(R3a)-.
8. The compound according to any of claims 1 - 5, wherein L is selected from the group consisting of
-C0-C6alkyl-N(R3)-C(O)-C1-C7alkyl-, wherein the C1-C7alkyl is optionally substituted with a substituent selected from the group consisting of -N(R7)(R7a), -N(R3)C(O)-C0-C3alkyl-heterocyclyl, -N(R3)-C(O)-C0-C6alkylaryl-Ra, -N(R3)-C(O)- d-C6alkyl-Ra and -N(R3)-C(O)-O-C°-C3alkyl-Y wherein heterocyclyl is optionally substituted;
-C0-C6alkyl-C(O)-N(R3)-C1-C7alkyl-, wherein the d-C6alkyl is optionally substituted with -N(R7)(R7a);
-C0-C6alkyl-C(O)-N(R3)-Ci-C7alkyl-, wherein the d-C7alkyl is optionally substituted with a substituent selected from the group consisting of aryl-aryl, aryl- heteroaryl, heteroaryl-heteroaryl, heteroaryl-aryl and heteroaryl; and
-d-C3alkyl-N(R3)-C(O)-Ci-C7 alkyl-, wherein the Ci-C3alkyl is optionally substituted with -C(O)N(R3)-C1-C3alkyl-Ala and the d-C7alkyl is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)O-C1- C3alkyl-Alb, -N(R3)-C(O)-d-C3alkyl-Alb, -N(R3)-S(O)2-d-C3alkyl-Alb, -N(R3)- C(O)-N(R3)-d-C3alkyl-Alb and -N(R3)-S(O)2-N(R3)-d-C3alkyl-Alb, wherein Ala and An> are independently selected from the group consisting of alkyl, alkenyl and a protecting group; or
Ala and Aib together via a -C2-C6alkylene, -C2-C6alkenylene, -C2- C6alkynylene, -Co-Csalkyl-heteroaryl-Co-Csalkyl- linker or -Co-C3alkyl-aryl-Co- C3alkyl- linker, form an optionally substituted ring, and
9. The compound according to any of claims 1 - 5, wherein L is a selected from the group consisting of
-Co-C7alkyl-N(R3)-C(0)-heterocyclyl-Co-C6alkyl-, wherein a Ci-C7alkyl is optionally substituted with -C0-C3alkyl-C(O)ORa or -Q-Qalkyl-ORa; and
-C0-C7alkyl-O-C(O)-heterocyclyl-C0-C6alkyl-, wherein a C1-C7alkyl is optionally substituted with -C0-C3alkyl-C(O)ORa or -C0-C3alkyl-ORa.
10. The compound according to any of claims 1 - 5, wherein L is selected from the group consisting of a covalent bond, -(CH2)I-4-, -(CH2)o-4-(CR3=CR3)-(CH2)o-4-, -(CH2)0-4- (C≡C)-(CH2)0-4-, -(CH2)O-3 N(R3)C(O)-, -(CH2)0-3-C(O)N(R3)-, -(CH2)C3 N(R3)C(O)- (CRa=CRa)-, -(CH2)O-3.N(R3)-(CH2)2-4 N(R3)C(O)-, -(CH2)0-3.0-(CH2)2-4-N(R3)C(O)-, -(CH2)O-3C(O)-(CH2)O-3-, -(CH2)o-3-(CRa=CRa)-C(0)-(CH2)o-3-, -(CH2)0-3C(O)- (CRa=CRa)-(CH2)0-3-, -Co-C6alkyl-N(R3)-C(0)-heterocyclyl-Co-C3alkyl-, -Co-C6alkyl- S(O)2-heterocyclyl-C0-C3alkyl-, -(CH2)0-3-S(O)2-N(R3)-(CH2)0-3-, -(CH2)0-3 N(R3)- S(O)2-(CH2)O-3-, -(CH2)o-3N(R3)-(CH2)o-3-, -(CH2)0-3N(R3)-(CH2)1-3-(CRa=CRa)-, -(CH2)O-3C=N-O-(CH2)O-3-, -(CH2)O-3N(R7MCH2)O-3-, -(CH2)0-3S-(CH2)0-3-, -(CH2)0. 30-(CH2)o-3-, -(CH2)O-3S(O)-(CH2)O-3-, -(CH2)0-3S(O)2-(CH2)0-3-, -(CH2)0-3 CH=CH- (CH2)2-3-, -(CH2)o-3N(R3)-C(0)-N(R3)-(CH2)o-3, -(CH2)0-3N(R3)-C(O)-O-(CH2)0-3, -(CH2)O-3O-C(O)-N(R3HCH2)O-3-, -(CH2)0-3 N(R3)-C(O)-N(R3)-S(O)2-(CH2)0-3-, and -(CH2)o-3N(R3)-C(0)-N(R3)-C(0)-(CH2)o-3-.
11. The compound according to any of claims 1 - 10, wherein Bi, B2 and B3 are independently selected from the group consisting of D-GIy, L-GIy, D-Pro, L-Pro, D- Tyr, L-Tyr, D-Tyr(ORa), L-Tyr(ORa), D-Phe, L-Phe, D-PlIeR4, L-PhCR4, D-Aib, L- Aib, D-AIa, L-AIa, D-PmR3, L-ProR3, D-IIe, L-IIe, D-Leu, L-Leu D-PheR3, L-PheR3, D-Pip and L-Pip.
12. The compound according to any of claims 1 - 11, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, benzyl and heterocyclyl moiety of R7 and R7a is independently optionally substituted with one or more substituents selected from the group consisting of oxo, -OH, -CN, CrC6alkyl, d-C6alkoxy, -NO2, -N(R3)(R3a), halo, -SH and mono- to per-halogenated CrCόalkyl.
13. The compound according to any of claims 1 - 12, wherein 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.
14. The compound according to any of claims 1 - 12, wherein 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.
15. The compound according to any of claims 1 - 14, wherein D is
Figure imgf000193_0001
or
Figure imgf000193_0002
16. The compound according to any of claims 1 - 14, wherein D is
17. The compound according to any of claims 1 - 14, wherein D is
18. The compound according to any of claims 1 - 14, wherein D is
19. The compound according to any of claims 1 - 14, wherein D is
Figure imgf000193_0003
20. The compound according to any of claims 1 -17, wherein X is O.
21. The compound according to any of claims 1 -17, wherein X is S.
22. The compound according to any of claims 1 - 16, wherein Ra, Rb and Rc are independently selected from the group consisting of -H, Cj-C3alkyl, C3-C6cycloalkyl, aryl, heteroaryl, and aryl-CrQsalkyl-.
23. The compound according to any of claims 1 -16, wherein Ra and Rb together with the nitrogen atom to which they are attached form a 3 to 9-membered heterocyclyl, heteroaryl, or heterocyclyl-aryl, wherein each of the heterocyclyl, heteroaryl and heterocyclyl-aryl is optionally substituted.
24. The compound according to any of claims 1 - 23, wherein R3 and R3a are independently selected from the group consisting of -H, OH, Ci-Cealkyl, C3- C6cycloalkyl, -C(O)CF3, -C(O)H, -Ci-C4alkyl-C(O)ORa, heterocyclyl, -C2-C4alkyl- ORa, C2-C4alkylene; C2-C6alkenyl, C2-C6 hydroxyalkyl -C1-C6 alkylaryl, aryl, -C0- C6alkylheteroaryl, and -C1-C3alkyl-C(O)N(Ra)-heteroaryl.
25. The compound according to any of claims 1 - 23, wherein R3 and R3a are independently selected from the group consisting of -Ci-C6alkylaryl, t-butyl, benzyl and aryl.
26. The compound according to any of claims 1 - 23, wherein R3 and R3a are independently selected from the group consisting of ethanol, tetrahydro-2H-pyran, phenyl and benzyl.
27. The compound according to any of claims 1 - 23, wherein R3 and R3a are independently C1-C4 alkyl.
28. The compound according to any of claims 1 - 23, wherein in the -N(R3)(R3a) group, the R and the R3a 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.
29. The compound according to any of claims 1 - 28, wherein R4 is selected from the group consisting of -H, -CH3, -S(O)2-N(R3)(R3a), -SO3H, -O-C2-C4alkyl-heterocyclyl, -O-C0-C4alkyl-aryl, -O-C0-C4alkyl-heteroaryl, -O-C(O)N(R3)-C0-C4alkyl-aryl, -O- C(O)N(R3)-C0-C4alkyl-heteroaryl, -O-C0-C4alkyl-heterocyclyl-aryl, -O-C0-C4alkyl- heterocyclyl-heteroaryl, -N(R3)-C2-C4alkyl-heterocyclyl, -(CH2)0-4ORa, -(CH2)o- 4N(R3)(R3a), -F, -Cl, -Br, -CF3, -CN, -CH2OH, -OH, -OCH3, -NO2, Ph, aryl, heteroaryl, -N(R3)C(O)CH2R3, -N(R3)SO2CH2Ra, -O(CH2)2-4N(R3)(R3a), -SR8, -S(O)CH2R3, -SO2CH2R3, -(CH2)o_4C(0)ORa, -CH=CHC(O)ORa, -CH=CHC(O)N(R3)(R3a), -N(R3)C(O)CF3 and -N(R3)(CH2)2N(R3)(R3a).
30. The compound according to any of claims 1 - 29, wherein Rh is -CH3.
31. The compound according to any of claims 1 - 29, wherein Rh is -CF3.
32. The compound according to any of claims 1 - 5 and 11 - 31, wherein L is selected
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000199_0002
Figure imgf000200_0001
Figure imgf000200_0002
wherein
Ala and A^ 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.
33. The compound according to any of claims 1 - 32, wherein Z is selected from the group consisting of
Figure imgf000200_0003
Figure imgf000201_0001
Figure imgf000201_0002
Figure imgf000201_0003
wherein each A independently is nitrogen, -CH= or -C(R4)=, wherein there may be 0, 1 , 2 or 3 nitrogen.
34. The compound according to any of claims 1 - 33, wherein each Y is independently selected from the group consisting of
Figure imgf000201_0004
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000203_0002
Figure imgf000203_0003
Figure imgf000203_0006
Figure imgf000203_0005
Figure imgf000203_0007
Figure imgf000203_0004
Figure imgf000203_0008
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
wherein each A is independently nitrogen, -C(H)= or -C(R4)=, wherein there may be 0, 1, 2 or 3 nitrogen;
B^ B2 and B3 are each independently a natural or synthetic amino acid; M1-M2 is selected from the group consisting of a covalent bond, -N(R3)CH2-, -CH2N(R3)-, -S(O)0-2-CH2-, -CH2S(O)0-2-, -O-CH2-, -CH2-O-, -C(O)N(R3)-, -N(R3)C(O)-, -SO2N(R3)-, -N(R3)SO2-, -CH(Ra)CH2-, -CH2CH(R3)-, -N=C(R3)-, -C(Ra)=N-, -CH2-CH2-, -CH=CH-, -CH(Ra)-CH(R3)-, -C(Ra)=C(Ra)-, -CH2-, -C(Ra)(Ra)-, -S-, -N(R3)- and absent;
M3 is selected from the group consisting of
Figure imgf000210_0001
; M4 is selected from the group consisting of
and ∞va'e11* bond :
Figure imgf000210_0005
wherein, when Mi-M2 is covalent bond, M4 is
Figure imgf000210_0004
:
D1-D2 is selected from the group consisting of a
Figure imgf000210_0002
Figure imgf000210_0003
wherein, * represents the point of attachment to Q; D3 is selected from the group consisting of a covalent bond,
Figure imgf000211_0001
w whhfierTReiinn t thhee
Figure imgf000211_0002
are optionally substituted
D4 is selected from the group consisting of
Figure imgf000211_0003
wherein the
Figure imgf000211_0004
is optionally substituted,
E1-E2 is selected from the group consisting of
;
Figure imgf000211_0005
E3 is selected from the group consisting of -C(O)-, -C(S)-, -CH2-, -C(OH)2- and -C=NR3-; and
R6 is selected from the group consisting of -H, -d-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -Q-Cόheteroalkyl, heterocyclyl-Co-Cόalkyl-, aryl-C0-C6alkyl-, hetero- aryl-C0-C6alkyl-, C3-C6cycloalkyl-C0-C6alkyl-, N(R3)(R3a)-d-C6alkyl-, N(R3)(R3a)- C(O)-Ci-C6alkyl- and N(R3)(R3a)-C(S)-C1-C6alkyl-, wherein each alkyl, alkenyl, alkynyl, heteoraUcyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl moiety is optionally substituted.
35. The compound according to claim 34, wherein each alkyl, alkenyl, alkynyl, heteoralkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl moiety of R6 is independently optionally substituted with one or more groups independently selected from R4.
36. The compound according to claim 34, wherein R6 is selected from the group consisting of
Figure imgf000211_0006
Figure imgf000212_0001
and
37. The compound according to claim any of claims 1 - 36, wherein R7 is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, -(CH2)2-4θRa, -OMe, -CH2)2-4N(R3)(R3a), -C(O)Ot-butyl, -C(O)O-benzyl, -(CH2)2-morpholinyl and -(CH2)2-piperazynnyl.
38. The compound according to any of claims 1 - 5, wherein
D is
Figure imgf000212_0002
;
W and M are nitrogen;
Ra and Rc are -H;
Rb is -O-alkyl-aryl or -O-alkyl-heteroaryl, wherein said alkyl, aryl and hetero- aryl moieties are optionally substituted;
Z is -C1-C8 alkyl-;
L is covalent bond, -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, -C0-C6 alkyl- N(R3)C(S)-C0-C3 alkyl-, -C0-C6 alkyl-C(O)N(R3)-C0-C3 alkyl- or -C0-C6 alkyl- C(S)N(R3)-Co-C3 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.
39. The compound according to any of claims 1 - 5, wherein
D is
Figure imgf000212_0003
;
W is nitrogen;
Rc is -H;
Rh is -Co-C6alkyl-0-C0-C6alkyl-aryl or -C0-C6alkyl-O-C0-C6alkyl-heteroaryl, wherein the alkyl, aryl and heteroaryl moieties are optionally substituted;
Z is -C1-C8 alkyl-;
L is covalent bond, -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl or -C0-C6 alkyl- C(O)N(R3VC0-C3 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.
40. A compound of formula (II):
Figure imgf000213_0002
or an N-oxide, hydrate, solvate, pharmaceutically acceptable salt, prodrug or complex thereof, or a racemic and scalemic mixture, diastereomer or enantiomer thereof, wherein R is selected from the group consisting of:
Figure imgf000213_0001
Figure imgf000214_0001
and
D is selected from the group consisting of
Figure imgf000214_0002
wherein R1 is an optional substituent and nl is 0-4.
41. The compound according to any of claims 1 - 5, wherein
Figure imgf000214_0003
W is nitrogen or oxygen; M is nitrogen; Ra, Rb and Rc are -H; Z is -C1-C8 alkyl- or -C1-C8 alkyl-C(O)-; L is -C0-C6 alkyl-N(R3)C(0)-Co-C3 alkyl; and
Y is alkyl, aryl, heteroaryl, heteroaryl-aryl or aryl-heteroaryl, wherein the alkyl, aryl and heteroaryl groups are optionally substituted.
42. The compound according to claim 41, wherein the alkyl, aryl and heteroaryl groups of Y are optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, aryl, -O-alkyl-heteroaryl and -O-alkyl-aryl.
43. The compound according to any of claims 1 - 5, wherein
Figure imgf000215_0001
W is nitrogen or oxygen; Rc is -H;
Rh is H or -Q-Qalkyl, wherein said alkyl is optionally substituted; Z is -C1-C8 alkyl- or -C1-C8 alkyl-C(O)-; L is -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl; and
Y is alkyl, aryl, heteroaryl, heteroaryl-aryl or aryl-heteroaryl, wherein the alkyl, aryl and heteroaryl groups are optionally substituted.
44. The compound according to claim 43, wherein the alkyl, aryl and heteroaryl groups of Y are optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, aryl, -O-alkyl-heteroaryl and -O-alkyl-aryl.
45. The compound according to any of claims 1 - 5, wherein
D is
Figure imgf000215_0002
;
W and M are nitrogen;
R\ Rb and Rc are -H;
R3 is -H or Ci-Cβalkyl;
Z is optionally substituted -C1-Cg alkyl-;
L is selected from the group consisting of
-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, -C0-C6alkyl-N(R3)-C(O)-N(R3)-C0- C3alkyl-, or -C0-C6alkyl-0-Co-C3alkyl-C(0)-N(R3)-C0-C3alkyl-, wherein when a C0- C3alkyl is Ci-C3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0- C3 alkyl-Y, aryl, heteroaryl, -heteroaryl-aryl, -aryl-heteroaryl, -aryl-aryl, heteroaryl- heteroaryl, -N(R3)(R3a) or -N(R3)- Y, wherein each heteroaryl or aryl moeity is optionally substituted;
-C0-C6 alkyl-heteroalkyl-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the Co-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or -N(R3)-Y; and
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)(R3a), -N(R3)-Y, -N(R3)- C(0)-0-Co-C3alkyl-Y, -NH2, -NH-S(O)2-Y, -NH-C(O)-NH-C0-C3alkyl-Y, -NH- heteroaryl-aryl or -N(R3)C(O)-C0-C3 alkyl-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(R3)-C(O)-heteroaryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-Co-C6alkyl-N(R3)-C(0)-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moieties are optionally substituted and the Ci-C7 alkyl is optionally substituted with -NR3 -B3 and the amine
1X 0 of B is conected with the acid of B to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1-C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D- Pro, L-ile and D-Phe-4-CF3.
46. The compound according to any of claims 1 - 5, wherein
D is
Figure imgf000216_0001
;
W is nitrogen;
Rc is -H;
Rh is H or -Ci-C6alkyl, wherein said alkyl is optionally substituted;
R3 is -H or CrC6alkyl;
Z is optionally substituted -C1-C8 alkyl-;
L is selected from the group consisting of
-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, -C0-C6alkyl-N(R3)-C(O)-N(R3)-C0- C3alkyl-, or -C0-C6alkyl-O-C0-C3alkyl-C(O)-N(R3)-C0-C3alkyl-, wherein when a C0- C3alkyl is d-C3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0- C3 alkyl-Y, aryl, heteroaryl, -heteroaryl-aryl, -aryl-heteroaryl, -aryl-aryl, heteroaryl- heteroaryl, -N(R3)(R3a) or -N(R3)- Y, wherein each heteroaryl or aryl moiety is optionally substituted;
-C0-C6 alkyl-heteroalkyl-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the Co-C3alkyl is Q-C^lkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or -N(R3)-Y; and -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)(R3a), -N(R3)-Y, -N(R3)- C(O)-O-C0-C3alkyl-Y, -NH2, -NH-S(O)2-Y, -NH-C(O)-NH-C0-C3alkyl-Y, -NH- heteroaryl-aryl or -N(R3)C(O)-C0-C3 alkyl-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(R3)-C(O)-heteroaryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-Co-C6alkyl-N(R3)-C(0)-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moieties are optionally substituted and the C1-C7 alkyl is optionally substituted with -NR3-B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1-C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D- Pro, L-ile and D-Phe-4-CF3.
47. The compound according to any of claims 1 - 5, wherein
D is
Figure imgf000217_0001
;
W and M are nitrogen;
Ra, Rb and Rc are -H;
R3 is -H or Ci-Cβalkyl;
Z is optionally substituted -C1-C8 alkyl-;
L is selected from the group consisting of
-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, -C0-C6alkyl-N(R3)-C(O)-N(R3)-C0- C3alkyl-, or -C0-C6alkyl-O-C0-C3alkyl-C(O)-N(R3)-C0-C3alkyl-, wherein when a C0- C3alkyl is d-C3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0- C3 alkyl-Y, -heteroaryl-aryl, heteroaryl, heteroaryl-heteroaryl, -N(R3)(R3a) or -N(R3)- Y, wherein each heteroaryl or aryl moeity is optionally substituted;
-C0-C6 alkyl-heteroalkyl-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the Co-C3alkyl is Q-Qalkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or -N(R3)-Y; and -C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)-C(O)-O-C0-C3alkyl-Y, -NH2, -NH-S(O)2-Y, -NH-C(O)-NH-C0-C3alkyl-Y, -NH-heteroaryl-aryl, -N(R3)C(O)- C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-O-, aryl- N(R3)-C(O)-heteroaryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-Co-C6alkyl-N(R3)-C(0)-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl moieties are optionally substituted with one, two or three substituents selected from the group consisting of halo, alkoxy, optionally substituted Q-Qalkyl, alkoxycarbonyl-, -OH, -CN, -C(O)- OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-Q-Cδalkyl-aryl, optionally substituted -C(O)-O-C rC6alkyl, -NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C1-C7 alkyl is optionally substituted with -NR3-B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1-C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B , B and B are independently selected from the group consisting of D- Pro, L-ile and D-Phe-4-CF3.
48. The compound according to any of claims 1 - 5, wherein
D is
Figure imgf000218_0001
;
W is nitrogen; Rc is -H;
Rh is H or -d-C6alkyl, wherein said alkyl is optionally substituted; R3 is -H or d-Cealkyl; Z is optionally substituted -C1-C8 alkyl-; L is selected from the group consisting of
-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, -C0-C6alkyl-N(R3)-C(O)-N(R3)-C0- C3alkyl-, or -C0-C6alkyl-O-C0-C3alkyl-C(O)-N(R3)-C0-C3alkyl-, wherein when a C0- C3alkyl is d-C3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0- C3 alkyl-Y, -heteroaryl-aryl, heteroaryl, heteroaryl-heteroaryl, -N(R3)(R3a) or -N(R3)- Y, wherein each heteroaryl or aryl moeity is optionally substituted;
-C0-C6 alkyl-heteroalkyl-Co-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the Co-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or -N(R3)-Y; and
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)-C(O)-O-C0-C3alkyl-Y, -NH2, -NH-S(O)2-Y, -NH-C(O)-NH-C0-C3alkyl-Y, -NH-heteroaryl-aryl, -N(R3)C(O)- C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-O-, aryl- N(R3)-C(O)-heteroaryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-Co-C6alkyl-N(R3)-C(0)-heteroaryl and B2-B1-N(R3)-C(O)-CrC7 alkyl-, wherein the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl moieties are optionally substituted with one, two or three substituents selected from the group consisting of halo, alkoxy, optionally substituted d-Cόalkyl, alkoxycarbonyl-, -OH, -CN, -C(O)- OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-Q-Cealkyl-aryl, optionally substituted -C(O)-O-C1-C6alkyl, -NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1-C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D- Pro, L-ile and D-Phe-4-CF3.
49. The compound according to any of claims 1 - 5, wherein
Figure imgf000219_0001
W and M are nitrogen; Ra, Rband Rc are -H;
R3 is -H or Ci-C6alkyl;
Z is optionally substituted -C1-C8 alkyl-;
L is
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)-C(O)-O-C0-C3alkyl-Y, -NH2, -NH-S(O)2-Y, -NH-C(O)-NH-C0-C3alkyl-Y, -NH-heteroaryl-aryl, -N(R3)C(O)- C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)- Y; and each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-0-, aryl- N(R3)-C(O)-heteroaryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-C0-C6alkyl-N(R3)-C(O)-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl groups are optionally substituted and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B! -N(R3VC(O)-C1 -C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B , B and B are independently selected from the group consisting of D- Pro, L-ile and D-Phe-4-CF3.
50. The compound according to any of claims 1 - 5, wherein
D is
Figure imgf000220_0001
;
W is nitrogen;
Rc is -H;
Rh is H or -CrC6alkyl, wherein said alkyl is optionally substituted;
R3 is -H or d-C6alkyl;
Z is optionally substituted -Ci-C8 alkyl-;
L is
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)-C(O)-O-C0-C3alkyl-Y, -NH2, -NH-S(O)2-Y, -NH-C(O)-NH-C0-C3alkyl-Y, -NH-heteroaryl-aryl, -N(R3)C(O)- C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-O-, aryl- N(R3)-C(O)-heteroaryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-Co-C6alkyl-N(R3)-C(0)-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl groups are optionally substituted and the C1-C7 alkyl is optionally substituted with -NR -B3 and the amine of B is conected with the acid of B to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-Ci-C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D- Pro, L-ile and D-Phe-4-CF3.
51. The compound according to any of claims 1 - 5, wherein
Figure imgf000221_0001
W and M are nitrogen;
Ra, Rband Rc are -H;
R3 is -H or d-C6alkyl;
Z is optionally substituted -C1-C8 alkyl-;
L is
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the Ci-C3 alkyl is optionally substituted with -N(R3)-C(O)-O-C0-C3alkyl-Y, -NH2, -NH-S(O)2-Y, -NH-C(O)-NH-C0-C3alkyl-Y, -NH-heteroaryl-aryl, -N(R3)C(O)- C0-C3 alkyl-Y. -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-O-, aryl- N(R3)-C(O)-heteroaryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-Co-C6alkyl-N(R3)-C(0)-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl groups are optionally substituted with one, two or three substituents selected from the group consisting of halo, alkoxy, optionally substituted C!-C6alkyl, 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-C6alkyl, -NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C1-C7 alkyl is optionally substituted with -NR3- B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1-C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D- Pro, L-ile and D-Phe-4-CF3.
52. The compound according to any of claims 1 - 5, wherein
Figure imgf000222_0001
W is nitrogen;
Rc is -H;
Rh is H or -Q-Qalkyl, wherein said alkyl is optionally substituted;
R3 is -H or Ci-Cβalkyl;
Z is optionally substituted -C1-C8 alkyl-;
L is
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the Ci-C3 alkyl is optionally substituted with -N(R3)-C(O)-O-C0-C3alkyl-Y, -NH2, -NH-S(O)2-Y, -NH-C(O)-NH-C0-C3alkyl-Y, -NH-heteroaryl-aryl, -N(R3)C(O)- C0-C3 alkyl-Y. -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl, heterocyclyl-O-, aryl- N(R3)-C(O)-heteroaryl, heteroaryl-N(R3)-C(O)-heteroaryl, aryl-N(R3)-C(O)-aryl, heterocyclyl-C0-C6alkyl-N(R3)-C(O)-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl groups are optionally substituted with one, two or three substituents selected from the group consisting of halo, alkoxy, optionally substituted Ci-C6alkyl, alkoxycarbonyl-, -OH, -CN, -C(O)- OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-Ci-Cealkyl-aryl, optionally substitued -C(O)-O-C i-C6alkyl, -NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C1-C7 alkyl is optionally substituted with -NR3- B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-Ci-C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D- Pro, L-ile and D-Phe-4-CF3.
53. The compound according to any of claims 1 - 5, wherein
D is
Figure imgf000223_0001
;
W and M are nitrogen;
Ra, Rband Rc are -H;
R3 is -H;
R4 is H or F;
Z is optionally substituted -C1-C8 alkyl-;
L is selected from the group consisting of
-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3 alkyl-Y, -heteroaryl-aryl, heteroaryl, -N(R3)(R3a) or -N(R3)-Y;
-C0-C6 alkyl-heteroalkyl-Co-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is Q-Qalkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or -N(R3)-Y; and
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the CpC3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the aryl and heteroaryl are optionally substituted, and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1-C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and
B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe-4-CF3.
54. The compound according to any of claims 1 - 5, wherein
D is
Figure imgf000224_0001
;
W is nitrogen;
Rc is -H;
Rh is H or -Ci-Cβalkyl, wherein said alkyl is optionally substituted;
R3 is -H;
R4 is H or F;
Z is optionally substituted -C1-C8 alkyl-;
L is selected from the group consisting of
-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3 alkyl-Y, -heteroaryl-aryl, heteroaryl, -N(R3)(R3a) or -N(R3)-Y;
-C0-C6 alkyl-heteroalkyl-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is Ci-C3alkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or -N(R3)- Y; and
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the aryl and heteroaryl are optionally substituted, and the C1-C7 alkyl is optionally substituted with -NR3-B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1-C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe-4-CF3.
55. The compound according to any of claims 1 - 5, wherein
Figure imgf000225_0001
W and M are nitrogen;
Ra, Rband Rc are -H;
R3 is -H;
R4 is H or F;
Z is optionally substituted -C1-Cg alkyl-;
L is selected from the group consisting of
-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3 alkyl-Y, -heteroaryl-aryl, heteroaryl, -N(R3)(R3a) or -N(R3)-Y;
-C0-C6 alkyl-heteroalkyl-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the Co-C3alkyl is C1-C3alkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or -N(R3)- Y; and
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the aryl and heteroaryl groups are optionally substituted with one, two or three substituents selected from the group consisting of halo, alkoxy, optionally substituted Ci-C6alkyl, alkoxycarbonyl-, -OH, -CN, -C(O)-OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-Q-Cealkyl-aryl, optionally substituted -C(O)-O-CrC6alkyl, -NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B^B1- N(R3VC(O)-C1 -C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B^ B2 and B3 are independently selected from the group consisting of D- Pro, L-ile and D-Phe-4-CF3.
56. The compound according to any of claims 1 - 5, wherein
D is
Figure imgf000226_0001
;
W is nitrogen;
Rc is -H;
Rh is H or -Q-Qsalkyl, wherein said alkyl is optionally substituted;
R3 is -H;
R4 is H or F;
Z is optionally substituted -C1-C8 alkyl-;
L is selected from the group consisting of
-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3 alkyl-Y, -heteroaryl-aryl, heteroaryl, -N(R3)(R3a) or -N(R3)-Y;
-C0-C6 alkyl-heteroalkyl-C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the Co-C3alkyl is Ci-C3alkyl, the C1-C3 alkyl is optionally substituted with heteroaryl, -N(R3)(R3a) or -N(R3)- Y; and
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the aryl and heteroaryl groups are optionally substituted with one, two or three substituents selected from the group consisting of halo, alkoxy, optionally substituted Q-Cόalkyl, alkoxycarbonyl-, -OH, -CN, -C(O)-OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-Q-Cealkyl-aryl, optionally substituted -C(O)-O-C rC6alkyl, -NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B to form a peptide bond, and wherein when Y is B -B - N(R3)-C(O)-Ci-C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and B1, B2 and B3 are independently selected from the group consisting of D- Pro, L-ile and D-Phe-4-CF3.
57. The compound according to any of claims 1 - 5, wherein
Figure imgf000227_0001
W and M are nitrogen;
Ra, Rband Rc are -H;
R3 is -H;
R4 is H or F;
Z is optionally substituted -Cj-Cg alkyl-;
L is
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is d- Qalkyl, the C1-C3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl- Y, -N(R3)(R3a) or -N(R3)- Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the aryl and heteroaryl groups are optionally substituted, and the C1-C7 alkyl is optionally substituted with -NR3-B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B^B1 -N(R3^C(O)-C1 -C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and
B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe-4-CF3.
58. The compound according to any of claims 1 - 5, wherein
Figure imgf000227_0002
W is nitrogen; Rc is -H;
Rh is H or -Q-Cβalkyl, wherein said alkyl is optionally substituted;
R3 is -H;
R4 is H or F;
Z is optionally substituted -C1-C8 alkyl-;
L is
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl- Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the aryl and heteroaryl groups are optionally substituted, and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B2 to form a peptide bond, and wherein when Y is B2-B1-N(R3)-C(O)-C1-C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and
B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe-4-CF3.
59. The compound according to any of claims 1 - 5, wherein
D is
Figure imgf000228_0001
;
W and M are nitrogen;
Ra, Rb and Rc are -H;
R3 is -H;
R4 is H or F;
Z is optionally substituted -C1-C8 alkyl-;
L is
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)-Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the aryl and heteroaryl groups are optionally substituted with one, two or three substituents selected from the group consisting of halo, alkoxy, optionally substituted Q-Qalkyl, alkoxycarbonyl-, -OH, -CN, -C(O)-OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-Q-Cealkyl-aryl, optionally substituted -C(O)-O-C1-C6alkyl, -NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle, and the C1-C7 alkyl is optionally substituted with -NR3 -B3 and the amine of B3 is conected with the acid of B to form a peptide bond, and wherein when Y is B -B - N(R3^C(O)-C1-C7 alkyl-, then Z and L are covalent bonds; wherein when any of B1, B2 and B3 are attached together, they are attached by a peptide bond, and
B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe-4-CF3.
60. The compound according to any of claims 1 - 5, wherein
Figure imgf000229_0001
W is nitrogen;
Rc is -H;
R is H or -Ci-C6alkyl, wherein said alkyl is optionally substituted;
R3 is -H;
R4 is H or F;
Z is optionally substituted -C1-Cg alkyl-;
L is
-C0-C6 alkyl-N(R3)C(O)-C0-C3 alkyl-, wherein when the C0-C3alkyl is C1- C3alkyl, the C1-C3 alkyl is optionally substituted with -N(R3)C(O)-C0-C3 alkyl-Y, -N(R3)(R3a) or -N(R3)- Y; and each Y is independently selected from the group consisting of alkyl, aryl, heteroaryl, heteroaryl-aryl, aryl-heteroaryl and B2-B1-N(R3)-C(O)-C1-C7 alkyl-, wherein the aryl and heteroaryl groups are optionally substituted with one, two or three substituents selected from the group consisting of halo, alkoxy, optionally substituted Ci-C6alkyl, alkoxycarbonyl-, -OH, -CN, -C(O)-OH, optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-d-Qalkyl-aryl, optionally substituted -C(O)-O-C rQalkyl, -NH2, optionally substituted -aryl-heterocyclyl and optionally substituted fused heterocyle,
1X ^ 1X and the C1-C7 alkyl is optionally substituted with -NR -B and the amine of B is r\ 0 1 conected with the acid of B to form a peptide bond, and wherein when Y is B -B - N(R3)-C(O)-Ci-C7 alkyl-, then Z and L are covalent bonds; wherein when any of B , B and B3 are attached together, they are attached by a peptide bond, and
B1, B2 and B3 are independently selected from the group consisting of D-Pro, L-ile and D-Phe-4-CF3.
61. The compound according to any of claims 1 - 37, wherein a substituent selected from the group consisting of optionally substituted aryl, optionally substituted -alkylaryl, optionally substituted heteroaryl, optionally substituted -O-d-Qalkyl-aryl, optionally substituted -C(O)-O-C i-C6alkyl, 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 -O-Q-Cjalkyl-alkoxy, -CF3, -O-aryl, alkoxy, -NH-C(O)-C1- C6alkyl, halogen, d-C6alkyl, -O-(halo substituted alkyl) and -O-alkyl-N(alkyl)2.
62. The compound according to any of claims 1 - 5, wherein each Y is independently selected from the group consisting of alkyl, aryl, aryl- aryl, heteroaryl, aryl-heteroaryl, heteroaryl-aryl, cycloalkyl, heterocyclyl and hetero- cyclyl-heteroaryl, each of which is optionally substituted;
L is selected from the group consisting of
-C0-C6alkyl-N(R3)-C0-C3alkyl-, wherein when the -C0-C6alkyl is -CrC6alkyl it is optionally substituted with a substituent selected from the group consisting Of -C1- C3alkyl-ORa, -C1-C3alkyl-N(R3)(R3a), -C0-C3alkyl-C(O)ORa and C0-C3alkyl-C(O)- N(R3)(R3a);
-C0-C6alkyl-N(R3)-C(O)-C0-C3alkyl-, wherein when the -C0-C6alkyl is C1- C6alkyl it is optionally substituted with a substituent selected from the group consisting of -Q-Csalkyl-OR3, -d-C3alkyl-NR3R3a, -C0C3alkyl-C(O)ORa and C0- C3alkyl-C(O)-N(R3)(R3a); -Co-C6alkyl-N(R3)-C(0)-C0-C3alkyl-, wherein the -C0-C3alkyl is d-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C(S)- C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C0-C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0-C3alkyl- C4-C6heterocyclyl, -N(R3)-C2-C3alkyl-N(R3)(R3a), -N(R3)-C2-C3alkyl-ORa, -N(R3)- Co-C3alkyl-C0-C3heteroalkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(S)-O-C0- C3alkyl-Y, -N(R3)-S(O)2-C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y, -N(R3)- C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(S)- Co-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(O)-C0-C3alkyl-C0-C3heterocyclyl-Y, -N(R3)- C(S)-Co-C3alkyl-C0-C3heterocyclyl-Y and -N(R3)-S(0)2-N(R3)-Co-C3alkyl-Y;
-Co-C6alkyl-N(R3)-C(S)-Co-C3alkyl-, wherein the -C0-C3alkyl is d-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C(S)- C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C0-C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0-C3alkyl- C4-C6heterocyclyl, -N(R3)-C2-C3alkyl-N(R3)(R3a), -N(R3)-C2-C3alkyl-ORa, -N(R3)- Co-C3alkyl-C0-C3heteroalkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(S)-O-C0- C3alkyl-Y, -N(R3)-S(0)2-Co-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y, -N(R3)- C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(S)- Co-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(O)-C0-C3alkyl-C0-C3heterocyclyl-Y, -N(R3)- C(S)-Co-C3alkyl-Co-C3heterocyclyl-Y and -N(R3)-S(0)2-N(R3)-Co-C3alkyl-Y;
-Co-C6alkyl-C(0)-C0-C3alkyl-, wherein when the -C0-C6alkyl is Cj-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)(R3a), -C(S)- N(R3)(R3a), -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0- C3alkyl-C4-C6cycloalkyl-, -N(R3)-C(S)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C0- C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0-C3alkyl-C4-C6heterocyclyl, - N(R3)-C2-C3alkyl- N(R3)(R3a), -N(R3)-C2-C3alkyl-ORa-, -N(R3)-C0-C3heteroalkyl-Y, -N(R3)-C(O)-O-C0- C3alkyl-Y, -N(R3)-C(S)-O-C0-C3alkyl-Y, -N(R3)-S(O)2-C0-C3alkyl-Y, -N(R3)-C(O)- N(R3)-C0-C3alkyl-Y, -N(R3)-C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C0- C3heterocyclyl, -N(R3)-C(S)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(O)-C0-C3alkyl- C0-C3heterocyclyl-Y, -N(R3)-C(S)-C0-C3alkyl-C0-C3heterocyclyl-Y and -N(R3)- S(O)2-N(R3)-C0-C3alkyl-Y; -Co-C6alkyl-C(S)-Co-C3alkyl-, wherein when the -C0-C6alkyl is CrC3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(S)-C0-C3alkyl-Y, -C(O)-N(R3)(R3a), -C(S)- N(R3)(R3a), -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0- C3alkyl-C4-C6cycloalkyl-, -N(R3)-C(S)-C0-C3alkyl-C4-C6cycloalkyl-, -N(R3)-C0- C3alkyl-Y, -N(R3)(R3a), -N(R3)-C0-C3alkyl-C4-C6heterocyclyl, - N(R3)-C2-C3alkyl- N(R3)(R3a), -N(R3)-C2-C3alkyl-ORa-, -N(R3)-C0-C3heteroalkyl-Y, -N(R3)-C(O)-O-C0- C3alkyl-Y, -N(R3)-C(S)-O-C0-C3alkyl-Y, -N(R3)-S(O)2-C0-C3alkyl-Y, -N(R3)-C(O)- N(R3)-C0-C3alkyl-Y, -N(R3)-C(S)-N(R3)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-C0- C3heterocyclyl, -N(R3)-C(S)-C0-C3alkyl-C0-C3heterocyclyl, -N(R3)-C(O)-C0-C3alkyl- C0-C3heterocyclyl-Y, -N(R3)-C(S)-C0-C3alkyl-C0-C3heterocyclyl-Y and -N(R3)- S(O)2-N(R3)-C0-C3alkyl-Y;
-Co-C6alkyl-, wherein when the -C0-C6alkyl is Q-Qalkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0- C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-heterocyclyl and -N(R3)-C(O)-C0-C3alkyl- cyclyoalkyl;
-Co-C6alkyl-C(0)-N(R3)-C0-C3alkyl-, wherein when the -Co-C3alkyl is C1- C3alkyl it is optionally substituted with a substituent selected from the group consisting of -C(O)-N(R3)-C0-C3alkyl-Y, -C(O)-heterocyclyl, -C(O)-N(R3)(R3a), aryl- aryl, aryl-heteroaryl, -heteroaryl-aryl, heteraryl-heteroaryl, heteroaryl, heterocyclyl- heteroaryl and heterocyclyl;
-C0-C6alkyl-heteroalkyl-C0-C6alkyl-C(O)-N(R3)-C0-C3alkyl-, wherein when the -Co-C3alkyl is C1-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -C(O)-N(R3)-C0-C3alkyl-Y, -C(O)-heterocyclyl, -C(O)- N(R3)(R3a), aryl-aryl, aryl-heteroaryl, -heteroaryl-aryl, heteraryl-heteroaryl, heteroaryl, heterocyclyl-heteroaryl and heterocyclyl;
-C0-C6alkyl-C(0)-N(R3)-Co-C3alkyl-, wherein when the -C0-C6alkyl is C1- C6alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R7)(R7a), -N(R3)(R3a), -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O- C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-Co-C6alkyl-heteroaryl-CQ-C3alkyl-, wherein when the -C0-C3alkyl is C1- C3alkyl it is optionally substituted with a substituent selected from the group consisting of -C0-C3alkyl-N(R3)-C(O)-C0-C3alkyl-N(R3)(R3a), -N(R3)-C(O)-C0- C3alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-C0-C6alkyl-aryl-C0-C3alkyl-, wherein when the -C0-C3alkyl is d-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)- C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O-C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-Co-Cόalkyl-aryl-heteroaryl-Co-Qalkyl-, wherein when the -Co-C3alkyl is C1- C3alkyl it is optionally substituted with a substituent selected from the group consisitng of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O- C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-Co-Cealkyl-heteroaryl-heteroaryl-Co-Csalkyl-, wherein when the -Co-C3alkyl is C!-C3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O- C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-Co-C6alkyl-heteroaryl-C0-C3alkyl-, wherein when the -C0-C3alkyl is C1- C3alkyl it is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-C0-C3alkyl-Y, -N(R3)-C(O)-O- C0-C3alkyl-Y, -N(R3)-C(O)-N(R3)-C0-C3alkyl-Y and -N(R3)-S(O)2-C0-C3alkyl-Y;
-Co-C6alkyl-0-C(0)-N(R3)-C0-C3alkyl-, wherein when the -C0-C3alkyl is C1- C3 alkyl it is optionally substituted with a group selected from -C(O)-OR3, -C(S)-OR3, -C(O)-N(R3)-C1-C3alkyl, -C(S)-N(R3)-Ci-C3alkyl, -C(O)-N(R3)(R3a)-, -C(S)- N(R3)(R3a)-, -C(O)-N(R3)-C0-C3alkyl-aryl, -C(S)-N(R3)-C0-C3alkyl-aryl, -C(O)- N(R3)-C0-C3alkyl-heteroaryl, -C(S)-N(R3)-C0-C3alkyl-heteroaryl, -C(O)-N(R3)-C0- C3alkyl-cycloalkyl, -C(S)-N(R3)-C0-C3alkyl-cycloalkyl, -C(O)-heterocyclyl, -C(S)- heterocyclyl, -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -C(O)-N(R3)- heterocyclyl, -C(S)-N(R3)-heterocyclyl, -C(O)-N(R3)-C0-C3alkyl-heterocycloalkyl and -C(S)-N(R3)-C0-C3alkyl-heterocycloalkyl;
-Co-C6alkyl-0-C(S)-N(R3)-C0-C3alkyl-, wherein when the -C0-C3alkyl is C1- C3 alkyl it is optionally substituted with a group selected from -C(O)-OR3, -C(S)-OR3, -C(O)-N(R3)-C!-C3alkyl, -C(S)-N(R3)-C!-C3alkyl, -C(O)-N(R3)(R3a)-, -C(S)- N(R3)(R3a)-, -C(O)-N(R3)-C0-C3alkyl-aryl, -C(S)-N(R3)-C0-C3alkyl-aryl, -C(O)- N(R3)-C0-C3alkyl-heteroaryl, -C(S)-N(R3)-C0-C3alkyl-heteroaryl, -C(O)-N(R3)-C0- C3alkyl-cycloalkyl, -C(S)-N(R3)-C0-C3alkyl-cycloalkyl, -C(O)-heterocyclyl, -C(S)- heterocyclyl, -C(O)-N(R3)-C0-C3alkyl-Y, -C(S)-N(R3)-C0-C3alkyl-Y, -C(O)-N(R3)- heterocyclyl, -C(S)-N(R3)-heterocyclyl, -C(O)-N(R3)-C0-C3alkyl-heterocycloalkyl and -C(S)-N(R3)-C0-C3alkyl-heterocycloalkyl; and
-C1-C3alkyl-N(R3)-C(O)-C1-C7alkyl-, wherein the d-C3alkyl is optionally substituted with -C(O)N(R3)-C1-C3alkyl-Ala and the CrC7alkyl is optionally substituted with a substituent selected from the group consisting of -N(R3)-C(O)-O- C1-C3alkyl-Alb, -N(R3)-C(O)-C!-C3alkyl-Alb, -N(R3)-S(O)2-CrC3alkyl-Alb, -N(R3)- S(O)2-N(R3)-d-C3alkyl-Alb, -N(R3)-C(O)-N(R3)-C1-C3alkyl-Alb and -N(R3)-S(O)2- N(R3)-C1-C3alkyl-Alb;
Z is selected from the group consisting of
Figure imgf000234_0001
Figure imgf000234_0002
Figure imgf000235_0001
wherein each A independently is nitrogen, -CH= or -C(R )=, wherein there may be 0, 1 , 2 or 3 nitrogen; and
Figure imgf000235_0002
63. The compound according to any of claims 1 to 5, wherein
D is
Figure imgf000235_0003
;
W is nitrogen;
Rc is -H;
X is S;
Rh is -Cj-C6alkyl or -C !-C6alkyl -phenyl, wherein said alkyl and phenyl are optionally independently substituted;
Z is optionally substituted -C3-C8 alkyl-;
L is -N(H)-C(O)-C1alkyl-, wherein the Qalkyl is substituted with -N(H)- C(O)-O-C1-C6 alkyl-phenyl or -N(H)-C(O)-O-C1-C6 alkyl; and
Y is aryl-heteroaryl- or heteroaryl-, each of which is optionally substituted.
64. The compound according to claim 63, wherein Y is phenyl-thiazolyl, thiazole or imidazole.
65. The compound according to claim 63, wherein Z is -C4alkyl-.
66. The compound according to any of claims 1 to 5, wherein
D is
Figure imgf000236_0001
;
W is nitrogen;
Rc is -H;
X is S;
R is -CrCβalkyl or -C !-C6alkyl -phenyl, wherein said alkyl and phenyl are optionally independently substituted;
Z is optionally substituted -C3-C8 alkyl-;
L is -Qalkyl-, substituted with a substituent selected from the group consisting of -N(H)-C(O)-O-C1-C6 alkyl-phenyl, -N(H)-C(O)-O-C1-C6 alkyl, -NH-C(O)-hetero- cyclyl-CrC6alkyl and -NH-C(O)-C1-C6alkyl-SO2-C1-C6alkyl; and Y is heteroaryl-, which is optionally substituted.
67. The compound according to claim 66, wherein Y is optionally substituted benzimidazole.
68. The compound according to claim 66, wherein Y is benzimidazole substituted with -NO2 or -C(O)-NH2.
69. The compound according to claim 66, wherein Z is -C4alkyl-.
70. The compound according to any of claims 1 to 5, wherein
D is
Figure imgf000236_0002
;
W is nitrogen;
Rc is -H;
X is S;
M is nitrogen;
Ra is H; Rb is phenyl or d-C6alkyl; Z is optionally substituted -C3-C8 alkyl-;
L is -N(H)-C(O)-C^IlCyI-, wherein the Qalkyl is substituted with -N(H)-C(O)- O-Ct-Cβalkyl-phenyl; and
Y is aryl-heteroaryl-, which is optionally substituted.
71. The compound according to any of claims 1 to 5, wherein
D is
Figure imgf000237_0001
;
W is nitrogen; Rc is -H; X is S;
M is nitrogen; Ra is H;
Rb is phenyl or Ci-C6alkyl; Z is optionally substituted -C3-C8alkyl-;
L is -Cialkyl- substituted with -N(H)-C(O)-O-d-C6alkyl-phenyl, -N(H)-C(O)- O-Ci-Cβalkyl and -NH-C(O)-C1-C3alkyl-SO2-C1-C3alkyl; and
Y is optionally substituted benimidazole.
72. The compound according to claim 71, wherein Z is -C4alkyl-.
73. The compound according to claim 71, wherein Y is substituted with -C(O)-NH2.
74. The compound according to claim 71, wherein Y is further selected from optionally substituted aryl-heteroaryl.
75. A compound of the formula (IIII):
Y-L-D (III)
or an N-oxide, hydrate, solvate, pharmaceutically acceptable salt, prodrug, or complex thereof, or racemic or scalemic mixture, diastereomer or enantiomer thereof, wherein
D is selected from the group consisting of
Figure imgf000238_0001
Rb and Rh are independently selected from the group consisting Of-C1-6 alkyl, -C6-1O aryl and -C7-16 alkylaryl;
L is selected from the group consisting of -Co-6 alkylene-, -C0-3 alkylene-N(H)-C(0)-Co-6 alkylene—, optionally substituted with 0-3 R4;
Y is selected from the group consisting of optionally substituted -C6-10 aryl and optionally substituted -5-10 membered heteroaryl;
R4 is selected from the group consisting of -N(H)-C(O)-R3 and -N(H)-C(O)-O-R3; and
R3 is selected from the group consisting of optionally substituted -C1-6 alkyl, -C1-6 heteroalkyl, -3-10 membered heterocyclyl and -C7-16 alkylaryl.
76. The compound according to claim 75,
wherein D is
Figure imgf000238_0002
77. The compound according to claim 75, wherein D is
Figure imgf000238_0003
78. The compound according to any of claims 1 - 37 and 62, wherein 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-CrCβalkyl-alkoxy, -CF3, -O-aryl, alkoxy, -NH-C(O)-C1-C6alkyl, halogen, Q-Qalkyl, -O-(halo substituted alkyl) and -O-alkyl- N(alkyl)2.
79. The compound according to any of claims 1 - 63, wherein Y is further selected from heterocyclyl.
80. The compound according to any of claims 1 - 5, wherein
L is -C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with aryl, heteroaryl, -heteroaryl- aryl, -aryl-heteroaryl, -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.
81. The compound according to any of claims 1 - 5, wherein
L is -Co-C6alkyl-0-Co-Cialkyl-C(0)-N(R3)-Co-C3alkyl-, wherein when the C0- C3alkyl is d-Csalkyl, the C1-C3 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.
82. The compound according to any of claims 1 - 37, wherein when a C0-C3alkyl is C1- C3alkyl, the C1-C3 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, -CF3, optionally substituted heterocyclyl, -O-C1-C6alkyl-N(alkyl)2, -O-C1-C6alkyl-NH2 and -NH-aryl.
83. The compound according to any of claims 1 - 5, wherein
L is -C0-C6 alkyl-C(O)-N(R3)-C0-C3 alkyl-, wherein when the C0-C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3alkyl- heteroaryl, -C(O)-N(R3)-C0-C3alkyl-aryl, wherein each heteroaryl or aryl moeity is optionally substituted; and
Y is H, optionally substituted aryl or optionally substituted heterocyclyl.
84. The compound according to any of claims 1 - 12 and 62, wherein Y is optionally substituted heteroaryl.
85. The compound according to any of claims 1 — 12 and 62, wherein 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.
86. The compound according to any of claims 1 - 5, wherein
L is -Co-C6alkyl-0-Co-C1alkyl-C(0)-N(R3)-Co-C3alkyl-, wherein when the C0- C3alkyl is d-C3alkyl, the CrC3 alkyl is optionally substituted with -C(O)-N(R3)-C0- C3 alkyl-heterocyclyl or -C(O)-N(R3)-C0-C3 alkyl-aryl, wherein each heterocyclyl or aryl moeity is optionally substituted; and
Y is optionally substituted aryl or optionally substituted heteroaryl.
87. The compound according to any of claims 1 - 12 and 62, wherein Y is optionally substituted aryl.
88. The compound according to claim 86, wherein -C(O)-N(R3)-C0-C3 alkyl-heterocyclyl is -C(O)-N(R3)-C0-C3 alkyl-heteroaryl.
89. The compound according to any of claims 1 - 5, wherein Y-L- is phenyl-CH2-O- C(O)-NH-.
90. The compound according to any of claims 1 - 5, wherein
L is -C0-C6alkyl-0-Co-C1alkyl-C(0)-N(R3)-Co-C3alkyl-, wherein when the C0- C3alkyl is d-C3alkyl, the Ci-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0- C3 alkyl-heteroaryl or -C(O)-N(R3)-C0-C3 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, -NH2, alkyl, -C(O)-OH, -C(O)-O-alkyl, -C(O)-NH- optionally substituted aryl, -C(O)-NH-optionally substituted heteroaryl, -C(O)-NH- alkyl-O-alkyl, -C(O)-NH-alkyl-heterocyclyl, -alkyl-optionally substituted aryl, alkoxy, optionally substituted aryl, optionally substituted heteroaryl.
91. The compound according to any of claims 1 - 37, wherein substituents selected from the group consisting of -C(O)-NH-optionally substituted aryl, -C(0)-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, -NH-C(O)-alkyl, oxo, -CN, heterocyclyl, -O- halosubstitutedalkyl, -CF3 and -O-alkyl-O-alkyl.
92. The compound according to any of claims 1 - 5, wherein L is phenyl-CH2-O-C(O)- NH-CrC3alkyl-, wherein the C1-C3 alkyl is substituted with -C(O)-NH-thiazolyl, wherein the thiazolyl is optionally substituted.
93. The compound according to any of claims 1 - 5, wherein
L is phenyl-CH2-O-C(O)-NH-C1-C3alkyl-, wherein the C1-C3 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-oρtionally 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.
94. The compound according to any of claims 1 - 5, wherein
L is -Co-C6alkyl-N(R3)-C(0)-N(R3)-C0-C3alkyl-, wherein when the C0-C3alkyl is Ci-C3alkyl, the Ci-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0-C3alkyl- heteroaryl-aryl, -C(O)-N(R3)-C0-C3alkyl-heteroaryl, or -C(O)-N(R3)-C0-C3alkyl-aryl, wherein each heteroaryl or aryl moeity is optionally substituted; and
Y is optionally substituted aryl, optionally substituted heterocyclyl or optionally substituted cycloalkyl.
95. The compound according to any of claims 1 - 11, wherein Y is an optionally substituted heteroaryl.
96. The compound according to any of claims 1 - 5, wherein
L is -C0-C6alkyl-0-Co-C3alkyl-C(0)-N(R3)-Co-C3alkyl-, wherein when a C0- C3alkyl is CrC3alkyl, the C1-C3 alkyl is optionally substituted with -C(O)-N(R3)-C0- C3alkyl-heteroaryl, -C(O)-N(R3)-C0-C3alkyl-aryl, -C(0)-N(R3)-Co-C3alkyl-heteroaryl- aryl, -C(O)-N(R3)-C0-C3alkyl-heteroaryl-heteroaryl, -C(O)-N(R3)-C0-C3alkyl-aryl- aryl and -C(O)-N(R3)-C0-C3alkyl-aryl-heteroaryl, wherein each heteroaryl or aryl moeity is optionally substituted;and
Y is H.
97. The compound according to any of claims 1 - 18, wherein W is O.
98. The compound according to any of claims 1 - 16, 41, 45, 47, 49, 51, 53, 55, 57, 59,
and 62, wherein
Figure imgf000242_0002
is the structure
Figure imgf000242_0003
99. The compound according to claim 98, wherein
Figure imgf000242_0004
is the structure
Figure imgf000242_0001
100. The compound according to any of claims 1 - 14, 17, 39, 43, 46, 48, 50, 52, 54, 56,
58, 60, and 62 wherein
Figure imgf000242_0005
is the structure
Figure imgf000242_0006
101. A composition comprising a compound according to any of claims 1 - 100 and a pharmaceutically acceptable carrier.
102. A method of inhibiting sirtuin activity, the method comprising contacting the sirtuin or a cell comprising the sirtuin with an inhibiting effective amount of a compound according to any of claims 1 - 100.
103. A method of inhibiting sirtuin activity, the method comprising contacting the sirtuin or a cell comprising the sirtuin with an inhibiting effective amount of a composition according to claim 101.
104. A method of treating a disease responsive to an inhibitor of sirtuin activity, comprising administering to an individual in need thereof an effective amount of a compound according to any of claims 1 - 100.
105. A method of treating a disease responsive to an inhibitor of sirtuin activity, comprising administering to an individual in need thereof an effective amount of a composition according to claim 101.
106. A method of treating a SIRT protein mediated disease or disorder selected from the group consisting of brain cancer, breast cancer, colon cancer, liver cancer, spleenic cancer testicular cancer and thyroid cancer, comprising: administering to a patient in need of treatment a therapeutically effective amount of a compound according to any of claims 1 to 100.
107. A method of treating a SIRT protein mediated disease or disorder selected from the group consisting of age related disorders, loss of subcutaneous fat and decreased bone mineral density, comprising: administering to a patient in need of treatment a therapeutically effective amount of a compound according to any of claims 1 to 100.
108. A method of treating a SIRT protein mediated disease or disorder selected from the group consisting of Type I and Type II diabetes , comprising: administering to a patient in need of treatment a therapeutically effective amount of a compound according to any of claims 1 to 100.
109. A method of treating obesity, comprising: administering to a patient in need of treatment a therapeutically effective amount of a compound according to any of claims 1 to 100.
110. A method of treating a SIRT protein mediated disease or disorder selected from the group consisting of inflammation, heart failure, axonal degeneration, AIDS and adaptive thermogenesis, comprising: administering to a patient in need of treatment a therapeutically effective amount of a compound according to any of claims 1 to 100.
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