Direct ampk activators

Abstract

Disclosed are benzimidazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structureand pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein R1, R2, R3, R4, Y and X are as described herein. In certain embodiments, a compound disclosed herein activates AMPK, and can be used to treat disease by activating the AMPK pathway.

1 . A compound having the structure of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  together with the atoms to which they are attached form ring A, wherein ring A is a 5- or 6-membered Het optionally substituted with one or more R A  groups that are each independently C 3-8 Cak(C 0-6 alkyl), Hca(C 0-6 alkyl), Ar(C 0-6 alkyl), Het(C 0-6 alkyl), —O—C 0-6 alkyl-C 3-8 Cak, —O—C 0-6 alkyl-Hca, —O—C 0-6 alkyl-Ar, —O—C 0-6 alkyl-Het, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR)2 or —CH 2 —OP(O)(OR) wherein each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —R Ax  groups,
 wherein each —R Ax  is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR)2 or —CH 2 —OP(O)(OR); 
 
 or one of R 1  and R 2  is Ar or Het, wherein Ar and Het are optionally substituted with one or more independently selected R A  groups, and the other is hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR)2 or —CH 2 —OP(O)(OR); 
 R 3  and R 4  are independently hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2  or —CH 2 —OP(O)(OR); 
 X is —O—, —S—, —NR— or —CF 2 —; 
 
       
         
           
           
               
               
           
         
         
           wherein R Y  is hydrogen or C 1-6 alkyl; and 
         
         each R is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano; 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , wherein
 R 1  and R 2  together with the atoms to which they are attached form ring A, wherein ring A is 5- or 6-membered Het optionally substituted with one or more R A  groups that are each independently C 3-8 Cak(C 0-6 alkyl), Hca(C 0-6 alkyl), Ar(C 0-6 alkyl), Het(C 0-6 alkyl), —O—C 0-6 alkyl-C 3-8 Cak, —O—C 0-6 alkyl-Hca, —O—C 0-6 alkyl-Ar, —O—C 0-6 alkyl-Het, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, -OP(O)(OR)2 or —CH 2 —OP(O)(OR), wherein each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —R Ax  groups,
 wherein each —R Ax  is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2  or —CH 2 —OP(O)(OR); 
   or one of R 1  and R 2  is Ar or Het, wherein Ar and Het are substituted with one or more R A  groups, and the other is hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2  or —CH 2 —OP(O)(OR).   
     
     
         3 . The compound of  claim 1 , wherein
 R 1  and R 2  together with the atoms to which they are attached form a 5- or 6-membered Het optionally substituted with one or more R A  groups,   or one of R 1  and R 2  is Ar.   
     
     
         4 . The compound of  claim 1 , wherein
 R 1  and R 2  together with the atoms to which they are attached form a 5- or 6-membered Het optionally substituted with one or more R A  groups.   
     
     
         5 . The compound of  claim 1 , wherein
 R 1  is Ar optionally substituted with one or more R A  groups.   
     
     
         6 . The compound of  claim 1 , wherein
 X is —O—.   
     
     
         7 . The compound of  claim 1 , wherein
 each R A  is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2  or —CH 2 —OP(O)(OR), wherein each alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —R Ax  groups,
 wherein each —R Ax  is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2  or —CH 2 —OP(O)(OR). 
   
     
     
         8 . The compound of  claim 1 , wherein R Y  is methyl. 
     
     
         9 . The compound of  claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt. 
     
     
         10 . The compound of  claim 1 , wherein the compound is in the form of a solvate. 
     
     
         11 . A compound that is
 1-(5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one;   1-(5-((6-fluoro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one;   1-(54(6-fluoro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one;   5-((6-fluoro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;   1-(5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one;   1-(5-((6-fluoro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one;   or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof.   
     
     
         12 . The compound of  claim 1 , having the structure of formula (II): 
       
         
           
           
               
               
           
         
       
       wherein
 ring A is a 5- or 6-membered Het; and 
 n is 1, 2, 3 or 4. 
 
     
     
         13 . The compound of  claim 12 , wherein
 ring A is a 5-membered Het.   
     
     
         14 . The compound of  claim 12 , wherein
 ring A is a 6-membered Het.   
     
     
         15 . The compound of  claim 12 , wherein
 ring A is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl or thiazolyl.   
     
     
         16 . The compound of  claim 13 , wherein
 ring A is pyrrolyl.   
     
     
         17 . The compound of  claim 13 , wherein
 ring A is N-methylpyrrolyl.   
     
     
         18 . The compound of  claim 12 , wherein
 each R A  is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2  or —CH 2 —OP(O)(OR), wherein each alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —R Ax  groups,
 wherein each —R Ax  is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2  or —CH 2 —OP(O)(OR). 
   
     
     
         19 . The compound of  claim 12 , wherein
 X is —O—.   
     
     
         20 . A method for activating the AMPK pathway in a cell, the method comprising contacting the cell with an effective amount of the compound of  claim 1 . 
     
     
         21 . The method of  claim 20 , wherein the cell is in a subject.