WO2009070533A1

WO2009070533A1 - Methods of inhibiting steroyl coa desaturase

Info

Publication number: WO2009070533A1
Application number: PCT/US2008/084544
Authority: WO
Inventors: John Swindle; Janet Ajioka; Heidi S. Hummel; Sarah Robertson
Original assignee: Complegen, Inc.
Priority date: 2007-11-29
Filing date: 2008-11-24
Publication date: 2009-06-04

Abstract

The present invention provides a method of inhibiting a steroyl coA desaturase comprising administering to a mammal in need thereof, a compound of Formula I. The present invention also provides a pharmaceutical composition including a pharmaceutically acceptable excipient and an aliquot amount of a compound of Formula I.

Description

METHODS OF INHIBITING STEROYL COA DESATURASE

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 60/991,062, filed November 29, 2007, incorporated in its entirety herein.

BACKGROUND OF THE INVENTION

[0002] The search for small molecules that inhibit the fat storage pathway has become a major approach to the prevention or reversal of the metabolic state leading to obesity and its consequences. Multiple surveys indicate that over 35 million Americans are significantly overweight to obese according to standard body mass index (BMI) charts. The trend to overweight and obesity is increasing even amongst very young people (Kim, J. et al., Obesity 14:1107-1112 (2006)). Fat accumulation and resulting dyslipidemia is clearly linked to insulin resistance and type II diabetes (Lewis, G. F. et al., Endocrine Reviews 23(2):201-229; Shulman, G.I. J. Clin. Invest. 106:171-176). One target for small molecule therapy is the enzyme, Steroyl coA desaturase (SCDl), that creates monounsaturated fatty acids with the principle substrates stearoyl-and palmitoyl-coA. SCDl is found in the endoplasmic reticulum and with cofactors cytochrome b₂, cytochrome b₂ reductase, NADH+ and iron, causes the desaturation of stearoyl-and palmitoyl coA to oleoyl- and palmitoleoyl coA triglycerides and fat storage ((a) Enoch, HG J. Biol. Chem 261;5095-5103 (1976)Vankoningsloo, S. J Cell ScL 1:119 (2006); (b) Miyazaki, M. A. J. Lipid Res. 42(7):1018-24 (2001 JuI)). SCDl has been called a "switch", controlling the flow of fatty acids into the fat storage pathway and reducing the fat burning or oxidative pathway (Fig. 1) (Cohen, P. et al., Science 297:240-243 (2002)). Scdl is upregulated in the liver and muscle of obese humans (Hulver, M. W. et al., Cell Metab. 2(4):251-61 (2005)) and appears to be involved in blocking the "reverse cholesterol pathway" in macrophage in the vascular intima which may lead to foam cell generation and atherosclerosis (Yu Sun, et al., J. Biol. Chem. 278(8): 5813-20 (2003); Wang, Y. et al., J. Biol Chem. 277:5692-7 (Feb 15 2002)). In addition, it appears that hyperlipidemia is causative in the process by which cells exit the vasculature and initiate atheroma (Chen, W. Science 44(ll):5016-22 (2003)). [0003] At the molecular level, the SCDl gene is negatively regulated by leptin ((a) Vankoningsloo, S. J Cell Sc/. 1:119 (2006); (b) Miyazaki, M. A. J. Lipid Res. 42(7): 1018-24 (2001 JuI)) and is upregulated by conditions associated with insulin resistance and obesity. SCDl is upregulated in the liver by fatty acids, hormones (insulin and steroids) and retinoids, primarily by activation of the Sterol-Regulatory Element-Binding Protein Ic

(SPEBP-Ic) which is in turn upregulated by activation of the Liver-X-Receptor (LXR) and the Retinoid-X-Receptor (RXR) (Yoshikawa, T. et al., MoI Cell Biol. 21(9):2991-3000 (2000)).

[0004] Experiments blocking the action of SCDl in rodents by direct enzyme inhibition, gene ablation or SCDl synthesis inhibition by antisense oligonucleotides supports the notion that reducing SCDl activity is a therapeutic strategy for treating obesity, insulin resistance and "metabolic syndrome". Ascebic mice resulting from a spontaneous mutation Scdl -/- are thin and the mutation overcomes the deletion of leptin or leptin receptor genes which, absent the Scdl deletion, usually leads to gross obesity (Gutierrez- Juarez R., et al., J Clin. Invest. 116(6): 1686-95 (2006); Jiang, G. et al., J Clin Invest. 115:1030-8 (2005)). Treatment of mice with antisense RNA specific for Scdl message had a similar effect and chemical targeting of SCDl activity with fatty acid analogues resulted in inhibition of fat storage (Wang, Y. et al., J. Lipid Res. 47(9) ".2028-41 (2006)). In humans, certain mutations affecting expression of the SCDl gene are associated with reduced body mass index (BMI), fat distribution and increased insulin sensitivity (Wareensjo, E. et al, Obesity (Silver Spring). 2007

JuI; 15(7): 1732-40). Finally, it appears that blocking SCD 1 directs fatty acids into the oxidation pathway whereby they are transported to the mitochondrion where they are oxidized to acetate and water (Dobrzyn, A. et al., Am J Physiol Endocrinol Metab 288:E599- E607 (2005)). [0005] Therefore it appears that SCDl is a good therapeutic target for treating obesity, dyslipidemia and resulting type II diabetes. However, the structural and enzymatic properties of SCDl make it problematic to develop a robust in vitro assay for high throughput screening of compound libraries to find compounds that specifically inhibit SCDl. The three requirements, membrane localization, requirement for cytochrome b5 and cytochrome b5 oxidase, make biochemical assays difficult to standardize for screening to identify compounds that act only on SCD 1. Surprisingly, this invention meets this and other needs. BRIEF SUMMARY OF THE INVENTION

[0006] In one embodiment, the present invention provides a method of inhibiting a steroyl coA desaturase comprising administering to a mammal in need thereof, a compound of Formula I:

wherein

A is a member selected from the group consisting of a C_1-6 alkyl, a cycloalkyl ring system with from 3 to 12 ring members, an aryl ring system having from 6 to 12 ring members and a heteroaryl ring system having from 5 to 10 ring members including 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S;

D is an aryl ring system having 6 to 12 ring members, or optionally combines with R⁵ to form a heterocyclic ring system having from 5 to 12 ring members and 1 to 3 ring heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocyclic ring system is substituted with at least one fused phenyl ring; n is 0 or 1 ; each R¹ is independently a member selected from the group consisting of hydrogen, C_1-6 alkyl, C_2-O alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C₁^ haloalkyl, C_1-6 alkyl-OR , -SR , -N=CR⁷R⁸, -OR⁹, -NR⁷R⁸, -SO₂R⁷, -SO₃R⁷, -SO₂NR⁷R⁸, -C(O)R⁷, -C(O)OR⁷, -OC(O)OR⁷, -C(O)NR⁷R⁸, -OC(O)NR⁷R⁸, - NR⁷C(O)R⁷, -CN, -NO₂ and a bridging group; R² is a member selected from the group consisting of hydrogen and C_1-6 alkyl; R³ is hydrogen or a bridging group;

R⁴ is a member selected from the group consisting of hydrogen, C_1-6 alkyl, -C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁸ and a bridging group; alternatively, when n is 1 , the bridging groups of R³ and R⁴ combine to form a member selected from the group consisting of -O-C(S)-, -0-C(O)-, -CH₂-C(O)-, -CH₂-C(S)-,

-NR⁸-C(0)-, -N=C(R⁸)-, -N=C(SR⁸)-, -N=C(OR⁸)- and -N=C(-NR⁷R⁸)-, and when n is O, the bridging groups of R¹ and R⁴ optionally combine to form a member selected from the group consisting of -C(O)-, -C(S)-, -O-C(S)-, -0-C(O)-, -CH₂-C(O)-, -CH₂-C(S)-, -NR⁸-C(0)-, -N=C(R⁸)-, -N=C(SR⁸)-, -N=C(OR⁸)- and -N=C(-NR⁷R⁸)-; R³ is a member selected from the group consisting of H and C_1-6 alkyl; each R⁶ is independently a member selected from the group consisting of hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Ci_-6 alkoxy, halogen, C_1-6 haloalkyl, Ci_-6 alkyl-OR⁷, -SR⁷, -N=CR⁷R⁸, -OR⁹, -NR⁷R⁹, -SO₂R⁷, -SO₃R⁷, -SO₂NR⁷R⁸, -C(O)R⁷, -C(O)OR⁷, -OC(O)OR⁷, -C(O)NR⁷R⁸, -OC(O)NR⁷R⁸, - NR⁷C(O)R⁷, -CN and -NO₂; R⁷ and R⁸ are each independently selected from the group consisting of hydrogen and Ci_-6 alkyl;

R⁹ is a member selected from the group consisting of hydrogen, Ci.₆ alkyl, an aryl ring system having 6 to 12 ring members, optionally substituted with a C_1-6 alkyl, and a heteroaryl ring system having 5 to 10 ring members and 1 to 3 heteroatom ring members each independently selected from the group consisting of N, O and S, optionally substituted with a C ₁.₆ alkyl; and a salt, hydrate, or prodrug thereof, thereby inhibiting the steroyl coA desaturase. [0007] In a second embodiment, the present invention provides a composition comprising a pharmaceutically acceptable excipient and a compound of the present invention. [0008] In a second embodiment, the present invention provides a composition comprising a sterile solution and a compound of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 shows the synthesis of compound 302, a process that can be used for the preparation of any compound of Formula III.

[0010] Figure 2 shows the synthesis of compound 214, a process that can be used for the preparation of any compound of Formula II.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

[0011] As used herein, the term "alkenyl" refers to either a straight chain or branched alkenyl of 2 to 6 carbon atoms, such as vinyl, propenyl, isopropenyl, butenyl, isobutenyl, butadienyl, pentenyl, hexenyl or hexadienyl. One of skill in the art will appreciate that other alkenyl groups are useful in the present invention. [0012] As used herein, the term "alkoxy" refers to alkyl with the inclusion of an oxygen atom, for example, methoxy, ethoxy, propoxy, butoxy, etc. "Halo-substituted-alkoxy" is as defined for alkoxy where some or all of the hydrogen atoms are substituted with halogen atoms. For example, halo-substituted-alkoxy includes trifluoromethoxy, etc. One of skill in the art will appreciate that other alkoxy groups are useful in the present invention.

[0013] As used herein, the term "alkyl" refers to a straight-chain or branched, saturated, aliphatic radical having the number of carbon atoms indicated. For example, Ci_-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso- butyl, sec-butyl, tert-butyl, etc. Longer alkyl chains can be useful. One of skill in the art will appreciate that other alkyl groups are useful in the present invention.

[0014] As used herein, the term "alkynyl" refers to either a straight chain or branched alkynyl of 2 to 6 carbon atoms, such as acetylenyl, propynyl or butynyl. One of skill in the art will appreciate that other alkynyl groups are useful in the present invention.

[0015] As used herein, the term "aryl" refers to a monocyclic or fused bicyclic, tricyclic or greater, aromatic ring system containing 6 to 16 ring carbon atoms. For example, aryl may be phenyl, bi-phenyl, benzyl, naphthyl or anthracene. "Arylene" means a divalent radical derived from an aryl group. Aryl groups can be mono-, di- or tri-substituted by one, two or three radicals selected from alkyl, alkoxy, aryl, hydroxy, halogen, cyano, amino, amino-alkyl, trifluoromethyl, alkylenedioxy and oxy-C2-C3-alkylene; all of which are optionally further substituted, for instance as hereinbefore defined; or 1- or 2-naphthyl; or 1- or 2- phenanthrenyl. [0016] Preferred as aryl is naphthyl, phenyl or phenyl mono- or disubstituted by alkoxy, phenyl, halogen, alkyl or trifluoromethyl, especially phenyl or phenyl-mono- or disubstituted by alkoxy, halogen or trifluoromethyl, and in particular phenyl.

[0017] Examples of substituted phenyl groups as R are, e.g. 4-chlorophen-l-yl, 3,4- dichlorophen-1-yl, 4-methoxyphen-l-yl, 4-methylphen-l-yl, 4-ammomethylphen-l-yl, A- methoxyethylaminomethylphen- 1 -yl, 4-hydroxyethylaminomethylphen- 1 -yl, 4-hydroxyethyl- (methyl)-aminomethy lphen- 1 -yl, 3 -aminomethylphen- 1 -yl, 4-N-acetylaminomethylphen- 1 - yl, 4-aminophen-l-yl, 3-aminophen-l-yl, 2-aminophen-l-yl, 4-phenyl-phen-l-yl, A- (imidazol- 1 -yl)-phen-yl, 4-(imidazol- 1 -ylmethyl)-phen- 1 -yl, 4-(morpholin- 1 -yl)-phen- 1 -yl, A- (morpholin-l-ylmethyl)-phen-l-yl, 4-(2-methoxyethylaminomethyl)-phen-l-yl and A- (pyrrolidin-l-ylmethyl)-phen-l-yl, 4-(thiophenyl)-phen-l-yl, 4-(3-thiophenyl)-phen-l-yl, A- (4-methylpiperazin-l-yl)-phen-l-yl, and 4-(piperidinyl)-phenyl and 4-(pyridinyl)-phenyl optionally substituted in the heterocyclic ring. [0018] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring system containing from 3 to 12 ring atoms, or the number of atoms indicated. For example, C_3-S cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and up to cyclooctyl. Additional cycloalkyl groups include adamantyl, bicyclo[2.2.2]octane, norbornane (bicyclo[2.2.1]heptane), etc. One of skill in the art will appreciate that other cycloalkyl groups are useful in the present invention.

[0019] As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine. When halogen is used in conjunction with another functional group, such as "haloalkyl", the term refers to the functional group substituted with one or more halogen atoms. [0020] As used herein, the term "haloalkyl" refers to alkyl as defined above where some or all of the hydrogen atoms are substituted with halogen atoms. For example, haloalkyl includes trifluoromethyl, fluoromethyl, 1, 2,3,4, 5-pentafluoro-phenyl, etc. The term "perfluoro" defines a compound or radical which has at least two available hydrogens substituted with fluorine. For example, perfluorophenyl refers to 1,2,3,4,5- pentafluorophenyl, perfluoromethane refers to 1,1,1 -trifluoromethyl, and perfluoromethoxy refers to 1,1,1-trifluoromethoxy. One of skill in the art will appreciate that other haloalkyl groups are useful in the present invention.

[0021] As used herein, the term "heteroaryl" refers to a monocyclic, fused bicyclic or tricyclic aromatic ring system containing 5 to 16 ring atoms, where from 1 to 4 ring atoms are each independently selected from N, O and S. For example, heteroaryl includes, but is not limited to, pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, furanyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any other radicals substituted, especially mono- or di-substituted, by e.g. alkyl, nitro or halogen. Pyridyl represents 2-, 3- or 4-pyridyl, advantageously 2- or 3-pyridyl. Thienyl represents 2- or 3-thienyl. Quinolinyl represents preferably 2-, 3- or 4-quinolinyl. Isoquinolinyl represents preferably 1-, 3- or 4- isoquinolinyl. Benzopyranyl, benzothiopyranyl represents preferably 3-benzopyranyl or 3- benzothiopyranyl, respectively. Thiazolyl represents preferably 2- or 4-thiazolyl, and most preferred, 4-thiazolyl. Triazolyl is preferably 1-, 2- or 5-(l,2,4-triazolyl). Tetrazolyl is preferably 5 -tetrazolyl.

[0022] Preferably, heteroaryl is pyridyl, indolyl, quinolinyl, pyrrolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, furanyl, benzothiazolyl, benzofuranyl, isoquinolinyl, benzothienyl, oxazolyl, indazolyl, or any of the radicals substituted, especially mono- or di-substituted. One of skill in the art will appreciate that other heteroaryl groups are useful in the present invention.

[0023] As used herein, the term "heterocycle" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring system containing from 3 to 12 ring atoms, or the number of atoms indicated, where from 1 to 4 ring atoms are each independently selected from N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)₂-. For example, heterocycle includes, but is not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, piperidinyl, indolinyl, quinuclidinyl and l,4-dioxa-8-aza-spiro[4.5]dec-8-yl. One of skill in the art will appreciate that other heterocycle groups are useful in the present invention.

[0024] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be a variety of groups selected from: -OR', =0, =NR\ =N-0R\ -NR'R", -SR', -halogen, -SiR'R"R"\ -OC(O)R', -C(O)R', - CO₂R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(0)NR"R"', -NR"C(0)₂R', -NH- C(NH₂)=NH, -NR'C(NH₂)=NH, -NH-C(NH₂)=NR\ -S(O)R', -S(O)₂R', -S(O)₂NR⁷R", -CN and -NO₂ in a number ranging from zero to (2m'+l ), where m' is the total number of carbon atoms in such radical. R', R" and R'" each independently refer to hydrogen, unsubstituted (Ci-Cg)alkyl, unsubstituted heteroalkyl, unsubstituted aryl and unsubstituted heteroaryl. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include 1 -pyrrolidinyl and 4-morpholinyl.

[0025] Similarly, substituents for the aryl and heteroaryl groups are varied and are selected from: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO₂, -CO₂R', -CONR'R", -C(O)R', -0C(0)NR'R", -NR"C(O)R\ -NR"C(0)₂R', ,-NR'-C(0)NR"R"', -NH-C(NH₂)=NH, -NR'C(NH₂)=NH, -NH-C(NH₂)=NR\ -S(O)R', -S(O)₂R', -S(O)₂NR⁵R", - N₃, -CH(Ph)₂, perfluoro(Ci-C₄)alkoxy, and perfluoro(Ci-C₄)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R" and R'" are independently selected from hydrogen, unsubstituted (Ci-Cs)alkyl, unsubstituted heteroalkyl, unsubstituted aryl and unsubstituted heteroaryl.

[0026] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH₂)_q-U-, wherein T and U are independently -NH-, -O-, -CH₂- or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CHi)₁-B-, wherein A and B are independently -CH₂-, -O-, -NH-, -S-, -S(O)-, -S(O)₂-, -S(O)₂NR'- or a single bond, and r is an integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH₂)_S- X-(CH₂)r, where s and t are independently integers of from 0 to 3, and X is -O-, -NR'-, -S-, - S(O)-, -S(O)₂-, or -S(O)₂NR'-. The substituent R' in -NR'- and -S(O)₂NR'- is selected from hydrogen or unsubstituted (Ci-C₆)alkyl. [0027] As used herein, the term "hydrate" refers to a compound that is complexed to at least one water molecule. The compounds of the present invention can be complexed with from 1 to 10 water molecules.

[0028] As used herein, the term "inhibition", "inhibits", "inhibiting" and "inhibitor" refers to a compound that prohibits or a method of prohibiting, a specific action or function. [0029] As used herein, the term "prodrug" refers to covalently bonded carriers which are capable of releasing the active agent of the methods of the present invention, when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups by routine manipulation or in vivo. Prodrugs of the active agents of the present invention include active agents wherein a hydroxy, amidino, guanidino, amino, carboxylic or a similar group is modified.

[0030] As used herein, the term "salt" refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference. [0031] As used herein, the term "steroyl coA desaturase" (SCDl) refers to an enzyme in fatty acid metabolism that creates monounsaturated fatty acids from stearoyl-and palmitoyl- coA. SCDl is found in the endoplasmic reticulum and with cofactors cytochrome b₂, cytochrome b₂ reductase, NADH+ and iron, causes the desaturation of stearoyl-and palmitoyl coA to oleoyl- and palmitoleoyl coA triglycerides and fat storage. [0032] As used herein, the term "aliquot amount" refers to a portion of a total amount of a solution containing a compound of the present invention. The aliquot amount can be of any amount and of any portion of the total amount of the solution. Typically, the aliquot amount is less than the total amount of the solution.

II. Compounds

[0033] The compounds of the present invention are part of a library of compounds obtained from E.I. du Pont de Nemours and Company.

[0034] In some embodiments, the present invention provides a compound of Formula I:

wherein A is a member selected from the group consisting of a C₁^ alkyl, a cycloalkyl ring system with from 3 to 12 ring members, an aryl ring system having from 6 to 12 ring members and a heteroaryl ring system having from 5 to 10 ring members including 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S;

D is an aryl ring system having 6 to 12 ring members, or optionally combines with R⁵ to form a heterocyclic ring system having from 5 to 12 ring members and 1 to 3 ring heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocyclic ring system is substituted with at least one fused phenyl ring; n is 0 or 1 : each R¹ is independently a member selected from the group consisting of hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Ci_-6 alkoxy, halogen, C_1-6 haloalkyl, Ci_-6 alkyl-OR⁷, -SR⁷, -N=CR⁷R⁸, -OR⁹, -NR⁷R⁸, -SO₂R⁷, -SO₃R⁷, -SO₂NR⁷R⁸, -C(O)R⁷, -C(O)OR⁷, -OC(O)OR⁷, -C(O)NR⁷R⁸, -OC(O)NR⁷R⁸, - NR⁷C(O)R⁷, -CN, -NO₂ and a bridging group; R² is a member selected from the group consisting of hydrogen and Ci_-6 alkyl; R³ is hydrogen or a bridging group;

R⁴ is a member selected from the group consisting of hydrogen, C_1-6 alkyl, -C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁸ and a bridging group; alternatively, when n is 1, the bridging groups of R³ and R⁴ combine to form a member selected from the group consisting of -O-C(S)-, -0-C(O)-, -CH₂-C(O)-, -CH₂-C(S)-,

-NR⁸-C(0)-, -N=C(R⁸)-, -N=C(SR⁸)-, -N=C(OR⁸)- and -N=C(-NR⁷R⁸)-, and when n is O, the bridging groups of R¹ and R⁴ optionally combine to form a member selected from the group consisting of -C(O)-, -C(S)-, -O-C(S)-, -0-C(O)-, -CH₂-C(O)-, -CH₂-C(S)-, -NR⁸-C(0)-, -N=C(R⁸)-, -N=C(SR⁸)-, -N=C(OR⁸)- and -N=C(-NR⁷R⁸)-; R⁵ is a member selected from the group consisting of H and Ci_-6 alkyl; each R⁶ is independently a member selected from the group consisting of hydrogen, C_1-6 alkyl, C₂.₆ alkenyl, C_2-6 alkynyl, Ci_-6 alkoxy, halogen, Ci_-6 haloalkyl, Ci_-6 alkyl-OR⁷, -SR⁷, -N=CR⁷R⁸, -OR⁹, -NR⁷R⁹, -SO₂R⁷, -SO₃R⁷, -SO₂NR⁷R⁸, -C(O)R⁷, -C(O)OR⁷, -OC(O)OR⁷, -C(O)NR⁷R⁸, -OC(O)NR⁷R⁸, - NR⁷C(O)R⁷, -CN and -NO₂; R⁷ and R⁸ are each independently selected from the group consisting of hydrogen and Ci_-6 alkyl;

R⁹ is a member selected from the group consisting of hydrogen, Ci_-6 alkyl, an aryl ring system having 6 to 12 ring members, optionally substituted with a Ci_-6 alkyl, and a heteroaryl ring system having 5 to 10 ring members and 1 to 3 heteroatom ring members each independently selected from the group consisting of N, O and S, optionally substituted with a Ci_-6 alkyl; and a salt, hydrate, or prodrug thereof. [0035] In other embodiments, the present invention provides a compound of Formula II:

[0036] In a further embodiment, A is selected from the group consisting of aryl and heteroaryl; and D is aryl. In other embodiments, A is a member selected from the group consisting of phenyl and pyridyl; and D is phenyl. In still other embodiments, each R¹ is independently a member selected from the group consisting of hydrogen, Ci_-6 alkyl, halogen, Ci-6 haloalkyl, -SR⁷ and -OR⁹; R⁵ is H; and each R⁶ is independently a member selected from the group consisting of hydrogen, Ci_-6 alkyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, -SR⁷, -OR⁹, -NR⁷R⁹, -CN and -NO₂. In another embodiment, each R¹ is independently a member selected from the group consisting of hydrogen, halogen, Ci_-2 haloalkyl, -O-phenyl, -O-benzyl and -S- Ci-₆ alkyl; R² is selected from the group consisting of hydrogen, methyl and ethyl; and each R⁶ is selected from the group consisting of hydrogen and C_1-6 alkyl. In still another embodiment, A is phenyl; D is phenyl; each R¹ is independently a member selected from the group consisting of H, F, Cl and CF₃; R² is methyl; and R⁶ is hydrogen.

[0037] In another embodiment, the present invention provides the following compounds:

[0038] In still another embodiment, the present invention provides the following compounds:

[0039] In other embodiments, the compound of the present invention is of Formula III:

O

(R U¹^. ₃.--Ai - N-N-D-(R⁶)_1-4 R⁴ (III). [0040] In some other embodiments, A is a member selected from the group consisting of aryl and heteroaryl; and D is an aryl. In still other embodiments, A is a member selected from the group consisting of phenyl, pyridyl, benzothiophenyl and thiophenyl; and D is a phenyl. In another embodiment, each R¹ is independently a member selected from the group consisting of hydrogen, C₁^ alkyl, halogen, C_1-6 haloalkyl, C₁^ alkyl-OR⁷, -SR⁷, -OR⁹,

-C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁸ and -NO₂; and each R⁶ is independently a member selected from the group consisting of hydrogen, C_1-6 alkyl, halogen, C_1-6 haloalkyl, -OR⁹, -NR⁷R⁹, -SO₂R⁷, -SO₃R⁷, -SO₂NR⁷R⁸ and -NO₂. In still another embodiment, each R¹ is independently a member selected from the group consisting of hydrogen, -CH₃, -CH₂OH, F, Cl, Br, I, -NH₂, -CF₃, -OH, -COOH and -NO₂; R² is a member selected from the group consisting of hydrogen and -C(O)-Ci_-3 alkyl; alternatively, R¹ and R² combine to form a 5- to 6-membered ring where the combination of R¹ and R² is a member selected from the group consisting of -C(O)-, -0-C(S)- and -CH₂-C(O)-; and each R is independently a member selected from the group consisting of hydrogen, F, Cl, Br, I, -CF₃, -NO₂ and -NH₂. [0041] In a further embodiment, the present invention provides the following compounds:

[0042] In another embodiment, the present invention provides the following compounds:

[0043] The compounds of Formula III can be prepared as outlined in Figure 1 and Example 2, using any substituted phenylhydrazine and any activated carboxylic acid (such as anhydride, acid chloride, etc.) to add the R⁴ functional group. The D-C(O)- moiety can then be added using a second activated carboxylic acid. The order of addition of the R⁴ group and the D-C(O)- moiety can be interchanged. One of skill in the art will appreciate that other methods of making the compounds of Formula III are useful in the present invention. [0044] The compounds of Formula II can be prepared in a similar fashion to those of Formula III using an activated alpha-hydroxy phenylacetic acid. However, rather than reacting the hydrazine amine with a second activated carboxylic acid, the hydrazine amine is cyclized with the alpha-hydroxy group using thiocarbonyldiimidazole. One of skill in the art will appreciate that other methods of making the compounds of Formula II are useful in the present invention.

III. Methods of Identifying Compounds Inhibiting Steroyl coA Desaturase

[0045] The XenoGene™ system is a technology developed and patented by CompleGen wherein genes from a target organism (e.g. humans) functioning in a simple organism (yeast) are used to select compounds that act specifically on the protein encoded by the gene and eliminate compounds that are not specific (i.e. that also act on proteins encoded by other genes). XenoGene™ is a very high throughput screening system that allows identification of compounds active on the function of the target protein in a cell under physiological conditions on "first-pass" screening and further, to selectively counter-screen against 200 human targets or more if necessary. The "read out" of the XenoGene™ assay is simply growth (inactive compound) or no growth (active compound) or the yeast containing the target gene, and no inhibition of control strains. The system has been used to discover antagonists for a broad range of targets. [0046] Two human SCD genes have been identified, huSCDl and huSCD5. SCDl is expressed in the liver where it is regulated by hormones, lipids and retinoid effectors. It is also expressed constitutively in the muscle where it is significantly increased in obesity. SCD5 is unique to primates and is expressed primarily in the brain and pancreas. Rodents have four SCD genes, SCD 1 -4) of which SCD 1 and SCD2 very similar to huSCD 1.

[0047] XenoGene™ assays have been developed for human SCDl and SCD5, rat SCDl and mouse SCD 1-4.

IV. Methods of Inhibiting Steroyl coA Desaturase

[0048] In one embodiment, the present invention provides a method of inhibiting a steroyl co A desaturase comprising administering to a mammal in need thereof, a compound of Formula I:

A. Formulations

[0049] The compounds of the present invention can be formulated in a variety of different manners known to one of skill in the art. Pharmaceutically acceptable carriers are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there are a wide variety of suitable formulations of pharmaceutical compositions of the present invention (see, e.g., Remington 's Pharmaceutical Sciences, 20^th ed., 2003, supra). Effective formulations include oral and nasal formulations, formulations for parenteral administration, and compositions formulated for with extended release.

[0050] Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of a compound of the present invention suspended in diluents, such as water, saline or PEG 400; (b) capsules, sachets, depots or tablets, each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; (d) suitable emulsions; and (e) patches. The liquid solutions described above can be sterile solutions. The pharmaceutical forms can include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharmaceutically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, e.g., sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art.

[0051] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. The composition can, if desired, also contain other compatible therapeutic agents. Preferred pharmaceutical preparations can deliver the compounds of the invention in a sustained release formulation. [0052] Pharmaceutical preparations useful in the present invention also include extended- release formulations. In some embodiments, extended-release formulations useful in the present invention are described in U.S. Patent No. 6,699,508, which can be prepared according to U.S. Patent No. 7,125,567, both patents incorporated herein by reference.

[0053] The pharmaceutical preparations are typically delivered to a mammal, including humans and non-human mammals. Non-human mammals treated using the present methods include domesticated animals (i.e., canine, feline, murine, rodentia, and lagomorpha) and agricultural animals (bovine, equine, ovine, porcine).

[0054] In practicing the methods of the present invention, the pharmaceutical compositions can be used alone, or in combination with other therapeutic or diagnostic agents. B. Administration

[0055] The compounds of the present invention can be administered as frequently as necessary, including hourly, daily, weekly or monthly. The compounds utilized in the pharmaceutical method of the invention are administered at the initial dosage of about 0.0001 mg/kg to about 1000 mg/kg daily. A daily dose range of about 0.01 mg/kg to about 500 mg/kg, or about 0.1 mg/kg to about 200 mg/kg, or about 1 mg/kg to about 100 mg/kg, or about 10 mg/kg to about 50 mg/kg, can be used. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. For example, dosages can be empirically determined considering the type and stage of disease diagnosed in a particular patient. The dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. Doses can be given daily, or on alternate days, as determined by the treating physician. Doses can also be given on a regular or continuous basis over longer periods of time (weeks, months or years), such as through the use of a subdermal capsule, sachet or depot, or via a patch or pump.

[0056] The pharmaceutical compositions can be administered to the patient in a variety of ways, including topically, parenterally, intravenously, intradermally, subcutaneously, intramuscularly, colonically, rectally or intraperitoneally. Preferably, the pharmaceutical compositions are administered parenterally, topically, intravenously, intramuscularly, subcutaneously, orally, or nasally, such as via inhalation.

[0057] In practicing the methods of the present invention, the pharmaceutical compositions can be used alone, or in combination with other therapeutic or diagnostic agents. The additional drugs used in the combination protocols of the present invention can be administered separately or one or more of the drugs used in the combination protocols can be administered together, such as in an admixture. Where one or more drugs are administered separately, the timing and schedule of administration of each drug can vary. The other therapeutic or diagnostic agents can be administered at the same time as the compounds of the present invention, separately or at different times. Table 1: IC50 values for compounds of Formula II

< 10 μM; ++, 10-50 μM; +, > 50 μM. Table 2: IC50 values for compounds of Formula III

+++, < 10 μM; ++, 10-50 μM; +, > 50 μM.

V. Pharmaceutical Compositions

[0058] The present invention also provides pharmaceutical compositions including a pharmaceutically acceptable excipient and a compound of the present invention, as described above. In some embodiments, the pharmaceutical compositions include a compound of Formula II:

In other embodiments, the pharmaceutical compositions include a compound such as:

In some other embodiments, the pharmaceutical compositions include a compound of Formula III:

O

I

(R¹)i-3-A N-N-D-(R⁶)_1-4 R⁴ (III).

In still other embodiments, the pharmaceutical compositions include a compound such as:

VI. Examples

Example 1: Identification of compounds inhibiting steroyl coA desaturase [0059] This example provides an assay for identifying compounds that inhibit steroyl coA desaturase.

[0060] A library of compounds was tested in order to identify compounds that inhibit steroyl coA desaturase. The compound library was comprised of 230,000 compounds obtained from E.I. du Pont de Nemours and Company. [0061] The huSCDl XenoGene™ assay was used to screen the compound library to find compounds active against huSCD 1. Compounds selected were not active against other human XenoGene™ targets, nor control yeast and their activity (inhibition of huSCDl yeast cell growth) was suppressed by oleate, the product of the SCDl reaction. The compounds selected were active against rodent SCD 1 XenoGene™ assays. [0062] Several compounds were tested in human (HepG2) and rat (primary) hepatocytes and a rat insulinoma (Ins-1 ). In a representative experiment, about 40% of the input ¹⁴C- Palmitate was desaturated (16: 1 + 18: 1) and about 2% was elongated to stearate (18:0) and remained saturated.

[0063] Compounds giving <70% inhibition in the cellular assay at lOuM were further tested in biochemical and cellular assays where IC₅O¹S were determined.

Example 2: Preparation of Propanoylphenyihydrazide (302)

[0064] This example provides methods of making compounds of the present invention that inhibit steroyl coA desaturase.

[0065] Propionic anhydride (1.45 g, 11.1 mmoles) was added dropwise over 5 minutes to a vigorously stirred solution of phenylhydrazine (1.0Og, 9.25mmoles) in 10 mL of 2M NaOH at 5⁰C. After complete addition the mixture was stirred for a further 30 minutes. The resulting pink precipitate was filtered, washed with water (2 x 10 mL) and dried in vacuo to yield 0.85 g (57%) of propanoylphenylhydrazide (3).

[0066] Propanoylphenylhydrazide (3, 0.8 g, 4.872 mmoles) was dissolved in pyridine (7mL) containing dimethylaminopyridine (DMAP, lOOmg). To this mixture was added benzoic anhydride (1.1 g, 4.872 mmoles) dropwise with stirring at room temperature under nitrogen. The mixture was stirred for 16h and then evaporated and subjected to flash chromatography (0-40% ethyl acetate / hexane over 30 minutes). Fractions containing compound 302 were pooled and the solvent removed to yield 280mg of compound 302. Example 3: Preparation of Compound of Formula II

[0067] This example provides methods of making compounds of the present invention that inhibit steroyl coA desaturase.

[0068] Compounds of Formula II of the present invention can be prepared according to the procedures set forth in U.S. Patent No. 5,552,554, incorporated in its entirety herein. Example 4: Inhibition of steroyl coA desaturase

[0069] This example demonstrates that the compounds of the present invention inhibit steroyl coA desaturase in vivo.

[0070] Compounds active in the XenoGene™ assay were tested in rat primary hepatocytes, rat -cells (insulinoma- 1 ) and human hepatoma (HepG2) cells. In some experiments cells were treated with fatty acid dexamethazone, insulin and Tl 327 (an LXR ligand), to maximally induce enzymes such as SCDl . SCDl is highly induced (estimated at over 50x) when hepatocytes are treated with glucose, insulin, steroid, fatty acids and the Liver X Receptor (LXR) ligand, Tl 327.

[0071] Cells were incubated with compounds to the presence of ¹⁴C-palmitate. After 18hr, lipids were extracted and chromatographed on TLC and HPLC (after saponification). General lipid metabolism was monitored by TLC and specific inhibition of SCD was measured by the ratio of ¹⁴C-palmitate and stearate to ¹⁴C-palmitoleate and oleate. ¹⁴C- products were identified by radiofluorimetry (TLC radiographs) or flowthrough scintillation counting (HPLC). Note that fatty acid elongases can convert palmitolate to stearate and palmitoleate to oleate (Wang, Y. et al, J. Lipid Res. 47(9):2028-41 (2006)). See Tables 1 and 2 for results. [0072] Many compounds were identified as specifically active on human SCDl in the XenoGene™ screening system. The compounds have similar activities against human, rat and mouse SCDl in the XenoGene™ system. The compounds are not active on other targets and are suppressed by oleic acid, the product of SCDl, demonstrating that the compounds are very specific for the delta 9 desaturase activity of SCD.

[0073] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

Claims

WHAT IS CLAIMED IS:

L A method of inhibiting a steroyl coA desaturase comprising administering to a mammal in need thereof, a compound of Formula I:

wherein A is a member selected from the group consisting of a Ci_-6 alkyl, a cycloalkyl ring system with from 3 to 12 ring members, an aryl ring system having from 6 to 12 ring members and a heteroaryl ring system having from 5 to 10 ring members including 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S; D is an aryl ring system having 6 to 12 ring members, or optionally combines with R⁵ to form a heterocyclic ring system having from 5 to 12 ring members and 1 to 3 ring heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocyclic ring system is substituted with at least one fused phenyl ring; n is 0 or 1; each R¹ is independently a member selected from the group consisting of hydrogen, C₁^ alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, Ci_-6 alkyl-OR⁷, -SR⁷, -N=CR⁷R⁸, -OR⁹, -NR⁷R⁸, -SO₂R⁷, -SO₃R⁷, -SO₂NR⁷R⁸, -C(O)R⁷, -C(O)OR⁷, -OC(O)OR⁷, -C(O)NR⁷R⁸, -OC(O)NR⁷R⁸, - NR⁷C(O)R⁷, -CN, -NO₂ and a bridging group; R² is a member selected from the group consisting of hydrogen and Ci_-6 alkyl; R³ is hydrogen or a bridging group; R⁴ is a member selected from the group consisting of hydrogen, C_1-6 alkyl, -C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁸ and a bridging group; alternatively, when n is 1, the bridging groups of R³ and R⁴ combine to form a member selected from the group consisting of -O-C(S)-, -O-C(O)-, -CH₂-C(O)-, -CH₂-C(S)-, -NR⁸-C(0)-, -N=C(R⁸)-, -N=C(SR⁸)-, -N=C(OR⁸)- and -N=C(-NR⁷R⁸)-, and when n is O, the bridging groups of R¹ and R⁴ optionally combine to form a member selected from the group consisting of -C(O)-, -C(S)-, -O-C(S)-, -0-C(O)-, -CH₂-C(O)-, -CH₂-C(S)-, -NR⁸-C(0)-, -N=C(R⁸)-, -N=C(SR⁸)-, -N=C(OR⁸)- and -N=C(-NR⁷R⁸)-; R⁵ is a member selected from the group consisting of H and Ci_₆ alkyl; each R⁶ is independently a member selected from the group consisting of hydrogen, Ci_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Ci_-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 alkyl-OR⁷, -SR⁷, -N=CR⁷R⁸, -OR⁹, -NR⁷R⁹, -SO₂R⁷, -SO₃R⁷, -SO₂NR⁷R⁸, -C(O)R⁷, -C(O)OR⁷, -OC(O)OR⁷, -C(O)NR⁷R⁸, -OC(O)NR⁷R⁸, - NR⁷C(O)R⁷, -CN and -NO₂; R⁷ and R⁸ are each independently selected from the group consisting of hydrogen and Ci_-6 alkyl; R⁹ is a member selected from the group consisting of hydrogen, Ci_-6 alkyl, an aryl ring system having 6 to 12 ring members, optionally substituted with a Ci_-6 alkyl, and a heteroaryl ring system having 5 to 10 ring members and 1 to 3 heteroatom ring members each independently selected from the group consisting of N, O and S, optionally substituted with a d.₆ alkyl; and a salt, hydrate, or prodrug thereof, thereby inhibiting the steroyl coA desaturase.

2. The method of claim 1, wherein the compound is of Formula II:

3. The method of claim 2, wherein: A is selected from the group consisting of aryl and heteroaryl; and D is aryl.

4. The method of claim 3, wherein: A is a member selected from the group consisting of phenyl and pyridyl; and D is phenyl.

5. The method of claim 4, wherein A is phenyl.

6. The method of claim 2, wherein: each R¹ is independently a member selected from the group consisting of hydrogen, Ci_-6 alkyl, halogen, C_[-6 haloalkyl, -SR⁷ and -OR⁹; R⁵ is H; and each R⁶ is independently a member selected from the group consisting of hydrogen, C_1-6 alkyl, C_1-6 alkoxy, halogen, C₁., haloalkyl, -SR⁷, -OR⁹, -NR⁷R⁹, -CN and -NO₂.

7. The method of claim 6, wherein: each R¹ is independently a member selected from the group consisting of hydrogen, halogen, Ci_-2 haloalkyl, -O-phenyl, -O-benzyl and -S-Ci_-6 alkyl;

R' is selected from the group consisting of hydrogen, methyl and ethyl; and each R⁶ is selected from the group consisting of hydrogen and C_1-6 alkyl.

8. The method of claim 7, wherein: A is phenyl;

D is phenyl; each R¹ is independently a member selected from the group consisting of H, F,

Cl and CF₃;

R is methyl; and R is hydrogen.

9. The method of claim 2, wherein the compound is a member selected from the group consisting of:

10. The method of claim 2, wherein the compound is a member selected from the group consisting of:

11. The method of claim 1 , wherein the compound is of Formula III:

O R⁵ (R¹)i-₃-A— °-N-N-D-(R⁶)_1-4 R⁴ (III).

12. The method of claim 11, wherein: A is a member selected from the group consisting of aryl and heteroaryl; and D is an aryl.

13. The method of claim 12, wherein A is a member selected from the group consisting of phenyl, pyridyl, benzothiophenyl and thiophenyl; and D is a phenyl.

14. The method of claim 11 , wherein: each R¹ is independently a member selected from the group consisting of hydrogen, Ci_-6 alkyl, halogen, C_L6 haloalkyl, Ci_-6 alkyl-OR⁷, -SR⁷, -OR⁹, -C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁸ and -NO₂; and each R⁶ is independently a member selected from the group consisting of hydrogen, d.₆ alkyl, halogen, Ci_-6 haloalkyl, -OR⁹, -NR⁷R⁹, -SO₂R⁷, -SO₃R⁷, -SO₂NR⁷R⁸ and -NO₂.

15. The method of claim 14, wherein: each R¹ is independently a member selected from the group consisting of hydrogen, -CH₃, -CH₂OH, F, Cl, Br, I, -NH₂, -CF₃, -OH, -COOH and -NO₂; R² is a member selected from the group consisting of hydrogen and -C(O)-Ci_-3 alkyl; alternatively, R¹ and R² combine to form a 5- to 6-membered ring where the combination of R¹ and R² is a member selected from the group consisting of -C(O)-, -OC(S)- and -CH₂-C(O)-; and each R³ is independently a member selected from the group consisting of hydrogen, F, Cl, Br, I, -CF₃, -NO₂ and -NH₂.

16. The method of claim 11, wherein the compound is a member selected from the group consisting of:

17. The method of claim 11 , wherein the compound is a member selected from the group consisting of:

18. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an aliquot amount of a compound of Formula I:

wherein A is a member selected from the group consisting of a C_1-6 alkyl, a cycloalkyl ring system with from 3 to 12 ring members, an aryl ring system having from 6 to 12 ring members and a heteroaryl ring system having from 5 to 10 ring members including 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S; D is an aryl ring system having 6 to 12 ring members, or optionally combines with R⁵ to form a heterocyclic ring system having from 5 to 12 ring members and 1 to 3 ring heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocyclic ring system is substituted with at least one fused phenyl ring; n is 0 or 1 ; each R¹ is independently a member selected from the group consisting of hydrogen, C_1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 alkyl-OR⁷, -SR⁷, -N=CR⁷R⁸, -OR⁹, -NR⁷R⁸, -SO₂R⁷, -SO₃R⁷, -SO₂NR⁷R⁸, -C(O)R⁷, -C(O)OR⁷, -OC(O)OR⁷, -C(O)NR⁷R⁸, -OC(O)NR⁷R⁸, - NR⁷C(O)R⁷, -CN, -NO₂ and a bridging group; R' is a member selected from the group consisting of hydrogen and C_1-6 alkyl; R³ is hydrogen or a bridging group; R⁴ is a member selected from the group consisting of hydrogen, Ci.6 alkyl, -C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁸ and a bridging group; alternatively, when n is 1, the bridging groups of R³ and R⁴ combine to form a member selected from the group consisting of -O-C(S)-, -O-C(O)-, -CH₂-C(O)-, -CH₂-C(S)-, -NR⁸-C(0)-, -N=C(R⁸)-, -N=C(SR⁸)-, -N=C(OR⁸)- and -N=C(-NR⁷R⁸)-, and when n is O, the bridging groups of R¹ and R⁴ optionally combine to form a member selected from the group consisting of -C(O)-, -C(S)-, -O-C(S)-, -O-C(O)-, -CH₂-C(O)-, -CH₂-C(S)-, -NR⁸-C(0)-, -N=C(R⁸)-, -N=C(SR⁸)-, -N=C(OR⁸)- and -N=C(-NR⁷R⁸)-; R⁵ is a member selected from the group consisting of H and C_1-6 alkyl; each R⁶ is independently a member selected from the group consisting of hydrogen, C_1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C₁^ alkoxy, halogen, C₁^ haloalkyl, C_1-6 alkyl-OR⁷, -SR⁷, -N=CR⁷R⁸, -OR⁹, -NR⁷R⁹, -SO₂R⁷, -SO₃R⁷, -SO₂NR⁷R⁸, -C(O)R⁷, -C(O)OR⁷, -OC(O)OR⁷, -C(O)NR⁷R⁸, -OC(O)NR⁷R⁸, - NR⁷C(O)R⁷, -CN and -NO₂;

R⁷ and R⁸ are each independently selected from the group consisting of hydrogen and Ci.6 alkyl;

R⁹ is a member selected from the group consisting of hydrogen, C_1-6 alkyl, an aryl ring system having 6 to 12 ring members, optionally substituted with a C_1-6 alkyl, and a heteroaryl ring system having 5 to 10 ring members and 1 to 3 heteroatom ring members each independently selected from the group consisting of N, O and S, optionally substituted with a C i-6 alkyl; and a salt, hydrate, or prodrug thereof.

19. The pharmaceutical composition of claim 18, wherein the compound is a member selected from the group consisting of:

20. The pharmaceutical composition of claim 18, wherein the compound is a member selected from the group consisting of: