Compositions and Methods of Modulating Short-Chain Dehydrogenase Activity

1 . A compound having the formula (V):

wherein n=0-2;

R 1 and R 3 are the same or different and are each selected from the group consisting of:

R 2 is N or CR 7 ;

R 4 is selected from the group consisting of H, Cl, F, NH 2 , and N(R 6 ) 2 ;

R 5 is selected from the group consisting of branched or linear alkyl including —(CH 2 )n 1 CH 3 (n 1 =0-7),

wherein n 2 =0-6 and X is any of the following: CF y H z (y+z=3), CCl y H z (y+z=3), OH, OAc, OMe, R 6 , OR 6 , CN, N(R 6 ) 2 ,

(n 3 =0-5, m=1-5), and

(n 4 =0-5);

each R 6 and R 7 are the same or different and are one or more substituent selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, (wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S), heteroaryl or heterocyclyl containing from 5-14 ring atoms, (wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S), C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl (including C 2 -C 24 alkylcarbonyl (—CO-alkyl) and C 6 -C 20 arylcarbonyl (—CO-aryl)), acyloxy (—O-acyl), C 2 -C 24 alkoxycarbonyl (—(CO)—O-alkyl), C 6 -C 20 aryloxycarbonyl (—(CO)—O-aryl), C 2 -C 24 alkylcarbonato (—O—(CO)—O-alkyl), C 6 -C 20 arylcarbonato (—O—(CO)—O-aryl), carboxy (—COOH), carboxylato (—COO − ), carbamoyl (—(CO)—NH 2 ), C 1 -C 24 alkyl-carbamoyl (—(CO)—NH(C 1 -C 24 alkyl)), arylcarbamoyl (—(CO)—NH-aryl), thiocarbamoyl (—(CS)—NH 2 ), carbamido (—NH—(CO)—NH 2 ), cyano (—CN), isocyano (—N + C − ), cyanato (—O—CN), isocyanato (—O—N + ═C − ), isothiocyanato (—S—CN), azido (—N═N + ═N − ), formyl (—(CO)—H), thioformyl (—(CS)—H), amino (—NH 2 ), C 1 -C 24 alkyl amino, C 5 -C 20 aryl amino, C 2 -C 24 alkylamido (—NH—(CO)-alkyl), C 6 -C 20 arylamido (—NH—(CO)-aryl), sulfanamido (—SO2NR2 where R is independently H, alkyl, aryl or heteroaryl), imino (—CR═NH where R is hydrogen, C 1 -C 24 alkyl, C 5 -C 20 aryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, etc.), alkylimino (—CR═N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (—CR═N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO 2 ), nitroso (—NO), sulfo (—SO 2 —OH), sulfonato (—SO 2 —O − ), C 1 -C 24 alkylsulfanyl (—S-alkyl; also termed “alkylthio”), arylsulfanyl (—S-aryl; also termed “arylthio”), C 1 -C 24 alkylsulfinyl (—(SO)-alkyl), C 5 -C 20 arylsulfinyl (—(SO)-aryl), C 1 -C 24 alkylsulfonyl (—SO 2 -alkyl), C 5 -C 20 arylsulfonyl (—SO 2 -aryl), sulfonamide (—SO 2 —NH2, —SO 2 NY 2 (wherein Y is independently H, aryl or alkyl), phosphono (—P(O)(OH) 2 ), phosphonato (—P(O)(O − ) 2 ), phosphinato (—P(O)(O − )), phospho (—PO 2 ), phosphino (—PH 2 ), polyalkyl ethers (—[(CH 2 ) n O] m ), phosphates, phosphate esters [—OP(O)(OR) 2 where R=H, methyl or other alkyl], groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof;

R 3 is not hydrogen if R 1 is H, an unsubstituted thiophene, or an unsubstituted thiazole and R 5 is butyl; or R 3 is not an unsubstituted phenyl if R 1 is H, or an unsubstituted phenyl, thiophene, or thiazole and R 5 is benzyl or (CH 2 )n 5 (CH 3 ) (n 5 =0-5); or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 , wherein R 2 is N or CH.

3 . The compound of of claim 1 , wherein R 1 is a substituted or unsubstituted heterocyclyl containing 5-6 ring atoms.

4 . The compound of of claim 1 , wherein R 1 is a substituted or unsubstituted thiophene, thiazole, oxazole, imidazole, pyridine, or phenyl.

5 . The compound of of claim 1 , wherein n is 1.

6 . The compound of of claim 1 , wherein R 1 is a substituted or unsubstituted thiophene, thiazole, oxazole, imidazole, pyridine, or phenyl.

7 . The compound of claim 1 , wherein R 3 is selected from the group consisting of H, substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl, alkyl, or carboxy including carboxylic acid (—CO2H), carboxy ester (—CO 2 alkyl) and carboxamide [—CON(H)(alkyl) or —CO 2 N(alkyl) 2 ].

8 . The compound of claim 1 , including a compound including formula (V 1 )

wherein n=0-2;

R 3 is selected from the group consisting of:

R 2 is N or CR 7 ;

R 4 is selected from the group consisting of H, Cl, F, NH 2 , and N(R 6 ) 2 ;

R 5 is selected from the group consisting of branched or linear alkyl including —(CH 2 )n 1 CH 3 (n 1 =0-7),

wherein n 2 =0-6 and X is any of the following: CF y H z (y+z=3), CCl y H z (y+z=3), OH, OAc, OMe, R 6 , OR 6 , CN, N(R 6 ) 2 ,

(n 3 =0-5, m=1-5), and

(n 4 =0-5);

each R 6 and R 7 are the same or different and are one or more substituent selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, (wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S), heteroaryl containing from 5-14 ring atoms, (wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S), C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl (including C 2 -C 24 alkylcarbonyl (—CO-alkyl) and C 6 -C 20 arylcarbonyl (—CO-aryl)), acyloxy (—O-acyl), C 2 -C 24 alkoxycarbonyl (—(CO)—O-alkyl), C 6 -C 20 aryloxycarbonyl (—(CO)—O-aryl), C 2 -C 24 alkylcarbonato (—O—(CO)—O-alkyl), C 6 -C 20 arylcarbonato (—O—(CO)—O-aryl), carboxy (—COOH), carboxylato (—COO − ), carbamoyl (—(CO)—NH 2 ), C 1 -C 24 alkyl-carbamoyl (—(CO)—NH(C 1 -C 24 alkyl)), arylcarbamoyl (—(CO)—NH-aryl), thiocarbamoyl (—(CS)—NH 2 ), carbamido (—NH—(CO)—NH 2 ), cyano (—CN), isocyano (—N + C − ), cyanato (—O—CN), isocyanato (—O—N + ═C − ), isothiocyanato (—S—CN), azido (—N═N + ═N − ), formyl (—(CO)—H), thioformyl (—(CS)—H), amino (—NH 2 ), C 1 -C 24 alkyl amino, C 5 -C 20 aryl amino, C 2 -C 24 alkylamido (—NH—(CO)-alkyl), C 6 -C 20 arylamido (—NH—(CO)-aryl), sulfanamido (—SO2NR2 where R is independently H, alkyl, aryl or heteroaryl), imino (—CR═NH where R is hydrogen, C 1 -C 24 alkyl, C 5 -C 20 aryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, etc.), alkylimino (—CR═N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (—CR═N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO 2 ), nitroso (—NO), sulfo (—SO 2 —OH), sulfonato (—SO 2 —O − ), C 1 -C 24 alkylsulfanyl (—S-alkyl; also termed “alkylthio”), arylsulfanyl (—S-aryl; also termed “arylthio”), C 1 -C 24 alkylsulfinyl (—(SO)-alkyl), C 5 -C 20 arylsulfinyl (—(SO)-aryl), C 1 -C 24 alkylsulfonyl (—SO 2 -alkyl), C 5 -C 20 arylsulfonyl (—SO 2 -aryl), sulfonamide (—SO 2 —NH2, —SO 2 NY 2 (wherein Y is independently H, aryl or alkyl), phosphono (—P(O)(OH) 2 ), phosphonato (—P(O)(O − ) 2 ), phosphinato (—P(O)(O − )), phospho (—PO 2 ), phosphino (—PH 2 ), polyalkyl ethers (—[(CH 2 ) n O] m ), phosphates, phosphate esters [—OP(O)(OR) 2 where R=H, methyl or other alkyl], groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof;

R 3 is not hydrogen if R 5 is butyl; or R 3 is not an unsubstituted phenyl if R 5 is benzyl or (CH 2 )n 5 (CH 3 ) (n 5 =0-5);

or a pharmaceutically acceptable salts thereof.

9 . The compound of claim 8 , wherein R 2 is N or CH.

10 . The compound of claim 8 , wherein n is 1.

11 . The compound of claim 8 , wherein R 3 is selected from the group consisting of H, substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl, alkyl, or carboxy including carboxylic acid (—CO2H), carboxy ester (—CO 2 alkyl) and carboxamide [—CON(H)(alkyl) or —CO 2 N(alkyl) 2 ].

12 . The compound of claim 1 , having a formula selected from the group consisting of:

or pharmaceutically acceptable salts thereof.

13 . The compound of claim 1 , having the formula:

or a pharmaceutically acceptable salt thereof.

14 . The compound of claim 1 , having the formula:

or a pharmaceutically acceptable salt thereof.

15 . The compound of claim 1 , having the formula:

or a pharmaceutically acceptable salts thereof.

16 . The compound of claim 1 , consisting essentially of the (+) optical isomer of a compound of the formula:

or a pharmaceutically acceptable salts thereof.

17 - 79 . (canceled)

80 . A method of treating a disease, disorder, or condition where it is desired to modulate 15-PGDH activity, the method comprising:

administering the compound of claim 1 to a subject in need of treatment.