COMPOSITIONS AND METHODS FOR THE TREATMENT OF METABOLIC DISORDERS

1 . A compound of the general formula:

wherein R 1 is hydrogen, methyl, ethyl or propyl;

R 2 , R 3 , and R 4 are the same or different and are selected from the group consisting of:

a1) hydrogen;

a) hydroxy;

b) substituted or unsubstituted C 1-10 alkyl;

c) substituted or unsubstituted C 2-10 alkenyl;

d) substituted or unsubstituted C 2-10 alkynyl;

e) substituted or unsubstituted C 3-6 cycloalkyl;

f) substituted or unsubstituted aryl;

g) substituted or unsubstituted heteroaryl;

wherein said substitutions in b), c), d), e), f), and/or g) are optionally further substituted with 1-5 groups selected from the group consisting of:

1) hydroxy;

2) —(C═O)R a ;

3) —(C═O)OR a ;

4) —(C═O)H;

5) —(C═O)OH;

6) —O(CH 2 ) n COOR a , wherein n=1-10;

7) halo;

8) cyano;

9) carboxy;

10) amino;

11) mono-substituted amino;

12) di-substituted amino;

13) amido;

14) mono-substituted amido;

15) di-substituted amido; and

16) any combination thereof,

wherein in 2), 3), or 6) R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl, or heteroaryl;

h) —(C═O)R a ;

i) —(C═O)OR a ;

j) —(C═O)H;

k) —(C═O)OH;

l) —O(CH 2 ) n COOR a , wherein n=1-10,

wherein in h), i), or l), R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl or heteroaryl;

m) halo;

n) cyano;

o) carboxy;

p) amino;

q) mono-substituted amino;

r) di-substituted amino,

s) amido;

t) mono-substituted amido; and

u) di-substituted amido;

wherein one or more of said mono-substituted amino, di-substituted amino, mono-substituted amido, and di-substituted amido have a substitution selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, sulfoxide, sulfone, sulfonate, alkyl sulfonate, sulfonic acid, and any combination thereof,

wherein in u) said alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl are optionally further substituted with 1-5 groups selected from the group consisting of:

i) hydroxy;

ii) —(C═O)R a ;

iii) —(C═O)OR a ;

iv) —(C═O)H;

v) —(C═O)OH;

vi) —O(CH 2 ) n COOR a , wherein n=1-10,

wherein in ii), iii), or vi) R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl or heteroaryl;

vii) halo;

viii) cyano;

ix) carboxy;

x) amino;

xi) mono-substituted amino;

xii) di-substituted amino;

xiii) amido;

xiv) mono-substituted amido;

xv) di-substituted amido; and

xvi) any combination thereof;

R 5 is substituted alkyl or —SO 2 R wherein R is a substituted alkyl, aryl or heteroaryl; and

Y 1 is nitrogen, Y 2 and Y 3 are the same or different and are sulfur or —CH═;

or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 where the pyridine ring is attached at its 4-position to the thiazole ring.

3 . The compound of claim 2 wherein R 1 is methyl, ethyl, or propyl.

4 . The compound of claim 2 where R 2 is H.

5 . The compound of claim 2 where R 3 is halo.

6 . The compound of claim 2 where R 3 is H.

7 . The compound of claim 2 where R 4 is H.

8 . The compound of claim 2 where R 2 and R 4 are H.

9 . The compound of claim 8 where R 3 is halo.

10 . The compound of claim 2 where R 2 , R 3 , and R 4 are H.

11 . The compound of claim 2 , 9 , or 10 where R 5 is —SO 2 R.

12 . The compound of claim 11 where R is substituted alkyl.

13 . The compound of claim 12 where the alkyl in R is substituted with 1-5 groups selected from the group consisting of hydroxy, —(C═O)R a , —(C═O)OR a , —(C═O)H, —(C═O)OH, —O(CH 2 ) n COOR a , aryl, heteroaryl, fluoro, chloro, bromo, iodo, cyano, carboxy, amino, mono-substituted amino, di-substituted amino, mono-substituted amido, and di-substituted amido and any combination thereof; and wherein n=1-10 and wherein R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 3-6 cycloalkyl.

14 . The compound of claim 13 where R is substituted with 1-5 fluoro.

15 . The compound of claim 8 where R 5 is substituted alkyl.

16 . The compound of claim 15 where R 5 is alkyl substituted with 1-5 groups selected from the group consisting of hydroxy, —(C═O)R a , —(C═O)OR a , —(C═O)H, —(C═O)OH, —O(CH 2 ) n COOR a , aryl, heteroaryl, fluoro, chloro, bromo, iodo, cyano, carboxy, amino, mono-substituted amino, di-substituted amino, mono-substituted amido, and di-substituted amido and any combination thereof; and wherein n=1-10 and wherein R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 3-6 cycloalkyl.

17 . The compound of claim 16 where R 5 is alkyl substituted with aryl or heteroaryl.

18 . A compound of the general formula:

wherein R 1 is hydrogen, methyl, ethyl, or propyl;

R 2 , and R 3 are the same or different and are selected from the group consisting of:

a1) hydrogen;

a) hydroxy;

b) substituted or unsubstituted C 1-10 alkyl;

c) substituted or unsubstituted C 2-10 alkenyl;

d) substituted or unsubstituted C 2-10 alkynyl;

e) substituted or unsubstituted C 3-6 cycloalkyl;

f) substituted or unsubstituted aryl;

g) substituted or unsubstituted heteroaryl;

wherein said substitutions in b), c), d), e), f), and/or g) are optionally further substituted with 1-5 groups selected from the group consisting of:

1) hydroxy;

2) —(C═O)R a ;

3) —(C═O)OR a ;

4) —(C═O)H;

5) —(C═O)OH;

6) —O(CH 2 ) n COOR a , wherein n=1-10;

7) halo;

8) cyano;

9) carboxy;

10) amino;

11) mono-substituted amino;

12) di-substituted amino;

13) amido;

14) mono-substituted amido;

15) di-substituted amido; and

16) any combination thereof,

wherein in 2), 3), or 6) R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl, or heteroaryl;

h) —(C═O)R a ;

i) —(C═O)OR a ;

j) —(C═O)H;

k) —(C═O)OH;

l) —O(CH 2 ) n COOR a , wherein n=1-10,

wherein in h), i), or 1), R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl or heteroaryl;

m) halo;

n) cyano;

o) carboxy;

p) amino;

q) mono-substituted amino;

r) di-substituted amino,

s) amido;

t) mono-substituted amido; and

u) di-substituted amido;

wherein one or more of said mono-substituted amino, di-substituted amino, mono-substituted amido, and di-substituted amido have a substitution selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, sulfoxide, sulfone, sulfonate, alkyl sulfonate, sulfonic acid, and any combination thereof,

wherein in u) said alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl are optionally further substituted with 1-5 groups selected from the group consisting of:

i) hydroxy;

ii) —(C═O)R a ;

iii) —(C═O)OR a ;

iv) —(C═O)H;

v) —(C═O)OH;

vi) —O(CH 2 ) n COOR a , wherein n=1-10,

wherein in ii), iii), or vi) R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl or heteroaryl;

vii) halo;

viii) cyano;

ix) carboxy;

x) amino;

xi) mono-substituted amino;

xii) di-substituted amino;

xiii) amido;

xiv) mono-substituted amido;

xv) di-substituted amido; and

xvi) any combination thereof;

Y 1 is nitrogen, Y 2 and Y 3 are the same or different and are sulfur or —CH═;

R 4 is mono-substituted amino or di-substituted amino wherein said mono-substituted amino and di-substituted amino have a substitution independently selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, sulfoxide, sulfone, sulfonate, alkyl sulfonate, sulfonic acid, and any combination thereof,

wherein in u), said alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl are optionally further substituted with 1-5 groups selected from the group consisting of:

i) hydroxy;

ii) —(C═O)R a ;

iii) —(C═O)OR a ;

iv) —(C═O)H;

v) —(C═O)OH;

vi) —O(CH 2 ) n COOR a , wherein n=1-10,

wherein in ii), iii), or vi) R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl or heteroaryl;

vii) halo;

viii) cyano;

ix) carboxy;

x) amino;

xi) mono-substituted amino;

xii) di-substituted amino;

xiii) amido;

xiv) mono-substituted amido;

xv) di-substituted amido; and

xvi) any combination thereof;

or a pharmaceutically acceptable salt thereof.

19 . The compound of claim 18 where R 1 is methyl, ethyl, or propyl.

20 . The compound of claim 18 where R 2 is H.

21 . The compound of claim 18 where R 3 is halo.

22 . The compound of claim 18 where R 3 is H.

23 . The compound of claim 18 where R 2 and R 3 are H.

24 . The compound of claim 18 , 20 , or 23 where R 4 is mono-substituted amino.

25 . The compound of claim 24 wherein the R 4 mono-substituted amino has a —S(O) 2 —C 1-10 -alkyl, —S(O) 2 —C 3-6 -cycloalkyl, —S(O) 2 —C 1-10 -alkyl-C 3-6 -cycloalkyl, —S(O) 2 -aryl, —S(O) 2 —C 1-10 alkyl-aryl, —S(O) 2 -aryl-C 1-10 alkyl, —S(O) 2 -heteroaryl or —S(O) 2 —C 1-10 alkyl-heteroaryl substitution.

26 . The compound of claim 24 wherein the R 4 mono-substituted amino has a —C 3-6 -cycloalkyl, —C 1-10 alkyl-C 3-6 -cycloalkyl, aryl, —C 1-10 -alkyl-aryl, heteroaryl, or —C 1-10 -alkyl-heteroaryl substitution.

27 . The compound of claim 18 selected from the group consisting of N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)-8-quinolinesulfonamide and N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)-2-thiophenesulfonamide.

28 . The compound of claim 18 selected from the group consisting of 4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)-N-tosylbenzenamine; and N-cyclohexyl-4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)benzenamine.

29 . A pharmaceutical composition comprising a compound of any one of claims 1 - 28 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

30 . A method of blocking cancer cell growth by selectively inhibiting SREBP activation comprising administering a therapeutically effective amount of a compound according to any one of claims 1 - 28 or a composition according to claim 29 .

31 . The method of claim 30 wherein the cancer cell is a prostate cancer cell.

32 . A method of treating cancer comprising administering a therapeutically effective amount of a compound according to any one of claims 1 - 28 or a composition according to claim 29 .

33 . The method of claim 32 wherein the cancer is prostate cancer.

34 . A method of treating a metabolic disorder comprising administering a therapeutically effective amount of a compound of according to any one of claims 1 - 28 or a composition according to claim 29 .

35 . The method of claim 34 wherein the metabolic disorder is selected from the group consisting of obesity; hyperlipemia; diabetes; fatty liver; hypertension; prostate cancer; cardiovascular disease; a glycogen storage disease; a disorder that affect carbohydrate metabolism; a fatty oxidation disorder; a mitochondrial disorder; GSD type I; GSD type II; GSD type III; GSD type IV; GSD type V; GSD type VI; GSD type VII; GSD type IX; GSD type XI; a coenzyme A dehydrogenase deficiency; a coenzyme A enzyme deficiency; a carnitine-related disorder; a lipid storage disorder; very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD); long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD); medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD); short-chain acyl-coenzyme A dehydrogenase deficiency (SCAD); short chain L-3-hydroxyacyl-coA dehydrogenase deficiency (SCHAD); 2,4 Dienoyl-CoA reductase deficiency; 3-hydroxy-3-methylglutaryl-CoA lyase deficiency; malonyl-CoA decarboxylase deficiency; primary carnitine deficiency; carnitine-acylcarnitine translocase deficiency; carnitine palmitoyltransferase I deficiency (CPT); carnitine palmitoyltransferase II deficiency (CPT); an acid lipase diseases; Wolman disease; cholesteryl ester storage disease; Gaucher disease; Niemann-Pick disease; Fabry disease; Farber's disease; gangliosidoses; Krabbe disease; metachromatic leukodystrophy; a fatty acid metabolism disorder; mitochondrial trifunctional protein deficiency; electron transfer flavoprotein (ETF) dehydrogenase deficiency (GAII & MADD); Tangier disease; acute fatty liver of pregnancy; progressive external ophthalmoplegia (PEO); diabetes mellitus and deafness (DAD); Leber hereditary optic neuropathy (LHON); Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like syndrome (MELAS); Myoclonic Epilepsy and Ragged-Red Fibers (MERRF); Leigh syndrome; subacute sclerosing encephalopathy; Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP); Kearns-Sayre syndrome (KSS); and Myoneurogenic gastrointestinal encephalopathy (MNGIE).

36 . The method of claim 34 wherein the metabolic disorder is selected from the group consisting of obesity, hyperlipemia, diabetes, fatty liver, hypertension, prostate cancer, and cardiovascular disease.

37 . The method of claim 34 where the metabolic disorder is obesity and the method further comprises dietary therapy, physical therapy (exercise), drug therapy, behavioral therapy, liposuction, and gastric bypass.

38 . The method of claim 34 where the metabolic disorder is diabetes and the method further comprises administration of pioglitizone, ACTOSPlus Met®, glimepiride, Avandaryl®, rosiglitazone, Avandamet®, Byettap, Duetact®, Vildagliptin, Glipizide®, metformin, Glimepiride, glyburide/metformin, Glucotrol XL®, Glyburide, Glyset (miglitol) glucosidase inhibitor, sitagliptin phosphate, Metaglip® (glipizide+metformin), Metformin—biguanide, repaglinide, Precose® (acarbose), troglitazone, and nateglinide.