Small molecule inducers of autophagy

Abstract

Small molecule disruptors of Beclin-1/Bcl-2 protein-protein interactions induce autophagy and hence are useful for treating a variety of indications where stimulation of autophagy is therapeutically useful, including cancer, infection immunity, neurodegeneration, longevity.

1 . A method of selectively inducing autophagy, comprising treating a person in need thereof with a pharmaceutical composition comprising a compound of structure I: 
       
         
           
           
               
               
           
         
       
        wherein
 R1 is optionally substituted C5 or C6 aryl or heteroaryl; 
 R1 is optionally substituted C5 or C6 aryl or heteroaryl, having 1-3 heteroatoms selected from N, O and S; 
 R1 is optionally substituted pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, furazan, oxadiazole, thiadiazole, dioxazole, dithiazole, pyridine, pyran, thiopyran, diazine oxazine, thiazine, dioxine, dithiin and triazone; or 
 R1 is optionally substituted 2- or 3-furanyl or phenyl, 2, 3 or 4-pyridine; 
 R2 is 0-5 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R2 is 0-5 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R2 is 0-5 substituents selected from halogen, NO 2 , N, C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; or 
 R2 is 1 para substituent selected from halogen, NO 2,  N, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated, preferably methyl or fluorinated methyl; 
 R3 is 0-4 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R3 is 0-4 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R3 is 0-4 substituents selected from halogen, NO 2,  N, C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; or 
 R3 is 0 substituents; 
 R4 is H, optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl, or 
 R4 is H, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R4 is H or C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; or 
 R4 is H; 
 R5 is optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R5 is hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R5 is C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; or 
 R5 is sufonyl or ester, SO 2 R or CO 2 R, wherein R is C1-C4 alkyl, optionally fluorinated; 
 wherein R4 and R5 may be joined in a heterocylic ring; 
 or a salt, hydrate, or stereoisomer thereof, or a compound disclosed herein. 
 
     
     
         2 . The method of  claim 1  wherein:
 R1 is optionally substituted C5 or C6 aryl or heteroaryl; 
 R2 is 0-5 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R3 is 0-4 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R4 is H, optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; and 
 R5 is optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl. 
 
     
     
         3 . The method of  claim 1  wherein:
 R1 is optionally substituted C5 or C6 aryl or heteroaryl, having 1-3 heteroatoms selected from N, O and S; 
 R2 is 0-5 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R3 is 0-4 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R4 is H, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; or 
 R5 is hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl. 
 
     
     
         4 . The method of  claim 1  wherein:
 R1 is optionally substituted pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, furazan, oxadiazole, thiadiazole, dioxazole, dithiazole, pyridine, pyran, thiopyran, diazine oxazine, thiazine, dioxine, dithiin and triazone; 
 R2 is 0-5 substituents selected from halogen, NO 2,  N, C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; 
 R3 is 0-4 substituents selected from halogen, NO 2,  N, C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; 
 R4 is H or C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; and 
 R5 is C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated. 
 
     
     
         5 . The method of  claim 1  wherein:
 R1 is optionally substituted 2- or 3-furanyl or phenyl, 2, 3 or 4-pyridine; 
 R2 is 1 para substituent selected from halogen, NO 2,  N, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated, preferably methyl or fluorinated methyl; 
 R3 is 0 substituents; 
 R4 is H; and 
 R5 is sufonyl or ester, SO 2 R or CO 2 R, wherein R is C1-C4 alkyl, optionally fluorinated. 
 
     
     
         6 . A method of  claim 1 , comprising selectively inhibiting binding of Beclin 1 BH 3 domain to anti-apoptotic Bcl-2 BH3 domain, but not binding of pro-apoptotic Bax BH3 domain or pro-apoptotic Bim BH3 protein to Bcl-2 BH3 domain, comprising treating a person in need thereof with a pharmaceutical composition comprising a compound of structure I: 
       
         
           
           
               
               
           
         
       
        wherein
 R1 is optionally substituted C5 or C6 aryl or heteroaryl; 
 R1 is optionally substituted C5 or C6 aryl or heteroaryl, having 1-3 heteroatoms selected from N, O and S; 
 R1 is optionally substituted pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, furazan, oxadiazole, thiadiazole, dioxazole, dithiazole, pyridine, pyran, thiopyran, diazine oxazine, thiazine, dioxine, dithiin and triazone; or 
 R1 is optionally substituted 2- or 3-furanyl or phenyl, 2, 3 or 4-pyridine; 
 R2 is 0-5 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R2 is 0-5 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R2 is 0-5 substituents selected from halogen, NO 2, N, C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; or 
 R2 is 1 para substituent selected from halogen, NO 2, N, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated, preferably methyl or fluorinated methyl; 
 R3 is 0-4 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R3 is 0-4 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R3 is 0-4 substituents selected from halogen, NO 2, N, C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; or 
 R3 is 0 substituents; 
 R4 is H, optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl, or 
 R4 is H, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R4 is H or C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; or 
 R4 is H; 
 R5 is optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R5 is hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R5 is C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; or 
 R5 is sufonyl or ester, SO 2 R or CO 2 R, wherein R is C1-C4 alkyl, optionally fluorinated; 
 wherein R4 and R5 may be joined in a heterocylic ring; 
 or a salt, hydrate, or stereoisomer thereof, or a compound disclosed herein. 
 
     
     
         7 . The method of  claim 6  wherein:
 R1 is optionally substituted C5 or C6 aryl or heteroaryl; 
 R2 is 0-5 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R3 is 0-4 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R4 is H, optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; and 
 R5 is optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl. 
 
     
     
         8 . The method of  claim 6  wherein:
 R1 is optionally substituted C5 or C6 aryl or heteroaryl, having 1-3 heteroatoms selected from N, O and S; 
 R2 is 0-5 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R3 is 0-4 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R4 is H, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; or 
 R5 is hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl. 
 
     
     
         9 . The method of  claim 6  wherein:
 R1 is optionally substituted pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, furazan, oxadiazole, thiadiazole, dioxazole, dithiazole, pyridine, pyran, thiopyran, diazine oxazine, thiazine, dioxine, dithiin and triazone; 
 R2 is 0-5 substituents selected from halogen, NO 2, N, C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; 
 R3 is 0-4 substituents selected from halogen, NO 2 ,N, C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; 
 R4 is H or C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; and 
 R5 is C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated. 
 
     
     
         10 . The method of  claim 6  wherein:
 R1 is optionally substituted 2- or 3-furanyl or phenyl, 2, 3 or 4-pyridine; 
 R2 is 1 para substituent selected from halogen, NO 2, N, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated, preferably methyl or fluorinated methyl; 
 R3 is 0 substituents; 
 R4 is H; and 
 R5 is sufonyl or ester, SO 2 R or CO 2 R, wherein R is C1-C4 alkyl, optionally fluorinated. 
 
     
     
         11 . A pharmaceutical composition formulated for administration to a person in need thereof, comprising a compound of structure I: 
       
         
           
           
               
               
           
         
       
        wherein
 R1 is optionally substituted C5 or C6 aryl or heteroaryl; 
 R1 is optionally substituted C5 or C6 aryl or heteroaryl, having 1-3 heteroatoms selected from N, O and S; 
 R1 is optionally substituted pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, furazan, oxadiazole, thiadiazole, dioxazole, dithiazole, pyridine, pyran, thiopyran, diazine oxazine, thiazine, dioxine, dithiin and triazone; or 
 R1 is optionally substituted 2- or 3-furanyl or phenyl, 2, 3 or 4-pyridine; 
 R2 is 0-5 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R2 is 0-5 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R2 is 0-5 substituents selected from halogen, NO 2, N, C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; or 
 R2 is 1 para substituent selected from halogen, NO 2, N, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated, preferably methyl or fluorinated methyl; 
 R3 is 0-4 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R3 is 0-4 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R3 is 0-4 substituents selected from halogen, NO 2, N, C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; or 
 R3 is 0 substituents; 
 R4 is H, optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl, or 
 R4 is H, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R4 is H or C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; or 
 R4 is H; 
 R5 is optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R5 is hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R5 is C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; or 
 R5 is sufonyl or ester, SO 2 R or CO 2 R, wherein R is C1-C4 alkyl, optionally fluorinated; 
 wherein R4 and R5 may be joined in a heterocylic ring; 
 or a salt, hydrate, or stereoisomer thereof, or a compound disclosed herein. 
 
     
     
         12 . The composition of  claim 11  wherein:
 R1 is optionally substituted C5 or C6 aryl or heteroaryl; 
 R2 is 0-5 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R3 is 0-4 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R4 is H, optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; and 
 R5 is optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl. 
 
     
     
         13 . The composition of  claim 11  wherein:
 R1 is optionally substituted C5 or C6 aryl or heteroaryl, having 1-3 heteroatoms selected from N, O and S; 
 R2 is 0-5 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R3 is 0-4 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R4 is H, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl, or 
 R5 is hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl. 
 
     
     
         14 . The composition of  claim 11  wherein:
 R1 is optionally substituted pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, furazan, oxadiazole, thiadiazole, dioxazole, dithiazole, pyridine, pyran, thiopyran, diazine oxazine, thiazine, dioxine, dithiin and triazone; 
 R2 is 0-5 substituents selected from halogen, NO 2, N, C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; 
 R3 is 0-4 substituents selected from halogen, NO 2, N, C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; 
 R4 is H or C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; and 
 R5 is C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated. 
 
     
     
         15 . The composition of  claim 11  wherein:
 R1 is optionally substituted 2- or 3-furanyl or phenyl, 2, 3 or 4-pyridine; 
 R2 is 1 para substituent selected from halogen, NO 2, N, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated, preferably methyl or fluorinated methyl; 
 R3 is 0 substituents; 
 R4 is H; and 
 R5 is sufonyl or ester, SO 2 R or CO 2 R, wherein R is C1-C4 alkyl, optionally fluorinated. 
 
     
     
         16 . A compound, excluding library compound SW076956, of structure I: 
       
         
           
           
               
               
           
         
       
       wherein
 R1 is optionally substituted C5 or C6 aryl or heteroaryl; 
 R1 is optionally substituted C5 or C6 aryl or heteroaryl, having 1-3 heteroatoms selected from N, O and S; 
 R1 is optionally substituted pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, furazan, oxadiazole, thiadiazole, dioxazole, dithiazole, pyridine, pyran, thiopyran, diazine oxazine, thiazine, dioxine, dithiin and triazone; or 
 R1 is optionally substituted 2- or 3-furanyl or phenyl, 2, 3 or 4-pyridine; 
 R2 is 0-5 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R2 is 0-5 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R2 is 0-5 substituents selected from halogen, NO 2, N, C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; or 
 R2 is 1 para substituent selected from halogen, NO 2, N, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated, preferably methyl or fluorinated methyl; 
 R3 is 0-4 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R3 is 0-4 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R3 is 0-4 substituents selected from halogen, NO 2, N, C 1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated, or 
 R3 is 0 substituents; 
 R4 is H, optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl, or 
 R4 is H, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R4 is H or C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; or 
 R4 is H; 
 R5 is optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R5 is hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R5 is C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; or 
 R5 is sufonyl or ester, SO 2 R or CO 2 R, wherein R is C1-C4 alkyl, optionally fluorinated; wherein R4 and R5 may be joined in a heterocylic ring; 
 or a salt, hydrate, or stereoisomer thereof, or a compound disclosed herein. 
 
     
     
         17 . The compound of  claim 16  wherein:
 R1 is optionally substituted C5 or C6 aryl or heteroaryl; 
 R2 is 0-5 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R3 is 0-4 substituents independently selected from optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; 
 R4 is H, optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl; and 
 R5 is optionally substituted heteroatom or optionally substituted, optionally hetero-, optionally cyclic C1-C10 hydrocarbyl. 
 
     
     
         18 . The compound of  claim 16  wherein:
 R1 is optionally substituted C5 or C6 aryl or heteroaryl, having 1-3 heteroatoms selected from N, O and S; 
 R2 is 0-5 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R3 is 0-4 substituents independently selected from halogen, amide, amine, imine, imide, nitro, nitroso, nitrate, nitrite, cyano, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; 
 R4 is H, hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl; or 
 R5 is hydroxyl or hydrocarbyloxy, or aldehyde, ketone, carboxyl, ether, ester, alkyl, alkenyl, alkynyl, sulfinyl, sulfonyl. 
 
     
     
         19 . The compound of  claim 16  wherein:
 R1 is optionally substituted pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, furazan, oxadiazole, thiadiazole, dioxazole, dithiazole, pyridine, pyran, thiopyran, diazine oxazine, thiazine, dioxine, dithiin and triazone; 
 R2 is 0-5 substituents selected from halogen, NO 2, N, C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; 
 R3 is 0-4 substituents selected from halogen, NO 2 , N, C 1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; 
 R4 is H or C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated; and 
 R5 is C1-C4 alkyl (Me, Et, cPr, iPr, cBu, tBu), C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated. 
 
     
     
         20 . The compound of  claim 16  wherein:
 R1 is optionally substituted 2- or 3-furanyl or phenyl, 2, 3 or 4-pyridine; 
 R2 is 1 para substituent selected from halogen, NO 2, N, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 carbonyl, C1-C4 carboxyl, C1-C4 cyano, C1-C4 sulfinyl, C1-C4 sulfonyl, each optionally fluorinated, preferably methyl or fluorinated methyl; 
 R3 is 0 substituents; 
 R4 is H; and 
 R5 is sufonyl or ester, SO 2 R or CO 2 R, wherein R is C1-C4 alkyl, optionally fluorinated.