Novel Heteroaromatic Inhibitors of Fructose-1,6-Bisphosphatase

Abstract

Novel FBPase inhibitors of the formula I and X are useful in the treatment of diabetes and other conditions associated with elevated blood glucose.

1 . A compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein R 5  is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     wherein: 
 each G is independently selected from the group consisting of C, N, O, S, and Se, and wherein only one G may be O, S, or Se, and at most one G is N;  
 each G′ is independently selected from the group consisting of C and N and wherein no more than two G′ groups are N;  
 A is selected from the group consisting of —H, —NR 4   2 , —CONR 4   2 , —CO 2 R 3 , halo, —S(O)R 3 , —SO 2 R 3 , alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, —CH 2 OH, —CH 2 NR 4   2 , —CH 2 CN, —CN, —C(S)NH 2 , —OR 3 , —SR 3 , —N 3 , —NHC(S)NR 4   2 , —NHAc, and null;  
 each B and D are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C(O)R 11 , —C(O)SR 3 , —SO 2 R 11 , —S(O)R 3 , —CN, —NR 9   2 , —OR 3 , —SR 3 , perhaloalkyl, halo, —NO 2 , and null, all except —H, —CN, perhaloalkyl, —NO 2 , and halo are optionally substituted;  
 E is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, —C(O)OR 3 , —CONR 4   2 , —CN, —NR 9   2 , —NO 2 , —OR 3 , —SR 3 , perhaloalkyl, halo, and null, all except —H, —CN, perhaloalkyl, and halo are optionally substituted;  
 J is selected from the group consisting of —H and null;  
 X is an optionally substituted linking group that links R 5  to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there is 2 heteroatoms, measured by the shortest path between R 5  and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein there is no N in the linking group unless it is connected directly to a carbonyl or in the ring of a heterocycle; and wherein X is not a 2 carbon atom -alkyl- or -alkenyl- group;  
 with the proviso that X is not substituted with —COOR 2 , —SO 3 R 1 , or —PO 3 R 1   2 ;  
 Y is independently selected from the group consisting of —O—, and —NR 6 —;  
 when Y is —O—, then R 1  attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R 2 ) 2 OC(O)NR 2   2 , —NR 2 —C(O)—R 3 , —C(R 2 ) 2 —OC(O)R 3 , —C(R 2 ) 2 —O—C(O)OR 3 , —C(R 2 ) 2 OC(O)SR 3 , -alkyl-S—C(O)R 3 , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy,  
 when Y is —NR 6 —, then R 1  attached to —NR 6 — is independently selected from the group consisting of —H, —[C(R 2 ) 2 ] q —COOR 3 , —C(R 4 ) 2 COOR 3 , —[C(R 2 ) 2 ] q —C(O)SR, and -cycloalkylene-COOR 3 ;  
 or when either Y is independently selected from —O— and —NR 6 —, then together R 1  and R 1  are -alkyl-S—S-alkyl- to form a cyclic group, or together R 1  and R 1  are  
                     
 wherein  
 V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;  
 together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substitutent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;  
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 2 , and —(CH 2 ) p —SR 2 ;  
 p is an integer 2 or 3;  
 q is an integer 1 or 2;  
 with the provisos that:  
 a) V, Z, W, W′ are not all —H; and  
 b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;  
 R 2  is selected from the group consisting of R 3  and —H;  
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;  
 each R 4  is independently selected from the group consisting of —H, and alkyl, or together R 4  and R 4  form a cyclic alkyl group;  
 R 6  is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;  
 each R 9  is independently selected from the group consisting of —H, alkyl, aralkyl, and alicyclic, or together R 9  and R 9  form a cyclic alkyl group;  
 R 11  is selected from the group consisting of alkyl, aryl, —NR 22 , and —OR 1 ; and  
 with the provisos that:  
 1) when G′ is N, then the respective A, B, D, or E is null;  
 2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of —H or null;  
 3) when R 5  is a six-membered ring, then X is not any 2 atom linker, an optionally substituted -alkyl-, an optionally substituted -alkenyl-, an optionally substituted  
  -alkyloxy-, or an optionally substituted -alkylthio-;  
 4) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;  
 5) R 1  is not unsubstituted C1-C10 alkyl;  
 6) when X is not an -aryl- group, then R 5  is not substituted with two or more aryl groups;  
 and pharmaceutically acceptable prodrugs and salts thereof.  
 
   
   
       2 . The compound of  claim 1 , wherein said compound is of formula (X):  
     
       
         
         
             
             
         
       
       wherein:  
       G″ is selected from the group consisting of —O— and —S—;  
       A 2 , L 2 , E 2 , and J 2  are selected from the group consisting of —NR 4   2 , —NO 2 —H, —OR 2 , —SR 2 , —C(O)NR 4   2 , halo, —COR 11 , —SO 2 R 3 , guanidinyl, amidinyl, aryl, aralkyl, alkoxyalkyl, —SCN, —NHSO 2 R 9 , —SO 2 NR 4   2 , —CN, —S(O)R 3 , perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together L 2  and E 2  or E 2  and J 2  form an annulated cyclic group;  
       X 2  is an optionally substituted linking group that links R 5  to the phosphorus atom via 1-3 atoms, including 0-1 heteroatoms selected from N, O, and S and the remaining atoms are carbon, and wherein in the atom attached to the phosphorus is a carbon atom;  
       with the proviso that X 2  is not substituted with —COOR 2 , —SO 3 R 1 , or —PO 3 R 1   2 ;  
       Y is independently selected from the group consisting of —O—, and —NR 6 —;  
       when Y is —O—, then R 1  attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R 2 ) 2 OC(O)NR 2   2 , —NR 2 —C(O)—R 3 , —C(R 2 ) 2 —OC(O)R 3 , —C(R 2 ) 2 —O—C(O)OR 3 , —C(R 2 ) 2 OC(O)SR 3 , -alkyl-S—C(O)R 3 , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy,  
       when Y is —NR 6 —, then R 1  attached to —NR 6 — is independently selected from the group consisting of —H, —[C(R 2 ) 2 ] q —COOR 3 , —C(R 4 ) 2 COOR 3 , —[C(R 2 ) 2 ] q —C(O)SR 3 , and -cycloalkylene-COOR 3 ;  
       or when either Y is independently selected from —O— and —NR 6 —, then together R 1  and R 1  are -alkyl-S—S-alkyl- to form a cyclic group, or together R 1  and R 1  are  
       
         
           
           
               
               
           
         
       
       wherein  
       V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or  
       together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or  
       together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;  
       together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substitutent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;  
       together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
       together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
       Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 2 , and —(CH 2 ) p —SR 2 ;  
       p is an integer 2 or 3;  
       q is an integer 1 or 2;  
       with the provisos that:  
       a) V, Z, W, W′ are not all —H; and  
       b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;  
       R 2  is selected from the group consisting of R 3  and —H;  
       R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;  
       each R 4  is independently selected from the group consisting of —H, alkyl, or together R 4  and R 4  form a cyclic alkyl;  
       R 6  is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;  
       each R 9  is independently selected from the group consisting of —H, alkyl, aralkyl, and alicyclic, or together R 9  and R 9  form a cyclic alkyl group;  
       R 11  is selected from the group consisting of alkyl, aryl, —NR 2   2 , and —OR 2 ; and  
       pharmaceutically acceptable prodrugs or salts thereof.  
     
   
   
       3 . The compound of  claim 1 , wherein said compound is of formula XI:  
     
       
         
         
             
             
         
       
       wherein:  
       E 2  is selected from the group consisting of —NR 4   2  and lower alkyl;  
       L 2  is selected from the group consisting of —CH 3  and H;  
       each R 4  is independently selected from the group consisting of —H, and alkyl, or together R 4  and R 4  form a cyclic alkyl group;  
       or pharmaceutically acceptable prodrugs or salts thereof.  
     
   
   
       4 . The compound of  claim 1 , wherein said compound is of formula XII:  
     
       
         
         
             
             
         
       
       wherein: 
 B′ is a lower alkyl;  
 X is furan-2,5-diyl;  
 
       or pharmaceutically acceptable prodrugs or salts thereof.  
     
   
   
       5 . The compound of  claim 1  wherein R 5  is selected from the group consisting of pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,3-selenazolyl, all of which contain at least one substitutent.  
   
   
       6 . The compound of  claim 1  wherein 
 A is selected from the group consisting of —H, —NR 4   2 , —CONR 4   2 , —CO 2 R 3 , halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  perhaloalkyl, C 1 -C 6  haloalkyl, aryl, —CH 2 OH, —CH 2 NR 4   2 , —CH 2 CN, —CN, —C(S)NH 2 , —OR 4 , —SR 4 , —N 3 , —NHC(S)NR 4   2 , —NHAc, and null;    each B and D are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C(O)R 11 , —C(O)SR 3 , —SO 2 R 11 , —S(O)R 3 , —CN, —NR 2   2 , —OR 3 , —SR 3 , perhaloalkyl, halo, and null, all except —H, —CN, perhaloalkyl, and halo are optionally substituted;    E is selected from the group consisting of —H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, aryl, C 4 -C 6  alicyclic, alkoxyalkyl, —C(O)OR 3 , —CONR 4   2 , —CN, —NR 9   2 , —OR 3 , —SR 3 , C 1 -C 6  perhaloalkyl, halo, and null, all except —H, —CN, perhaloalkyl, and halo are optionally substituted; and    each R 4  is independently selected from the group consisting of —H, and C 1 -C 2  alkyl.    
   
   
       7 . The compound of  claim 1  wherein R 5  is:  
     
       
         
         
             
             
         
       
     
   
   
       8 . The compound of  claim 1  wherein R 5  is:  
     
       
         
         
             
             
         
       
     
   
   
       9 . The compound of  claim 1  wherein R 5  is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     wherein 
 A″ is selected from the group consisting of —H, —NR 4   2 , —CONR 4   2 , —CO 2 R 3 , halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  perhaloalkyl, C 1 -C 6  haloalkyl, aryl, —CH 2 OH, —CH 2 NR 4   2 , —CH 2 CN, —CN, —C(S)NH 2 , —OR 3 , —SR 3 , —N 3 , —NHC(S)NR 4   2 , and —NHAc;  
 B″ and D″ are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C(O)R 11 , —C(O)SR 3 , —SO 2 R 11 , —S(O)R 3 , —CN, —NR 9   2 , —OR 3 , —SR 3 , perhaloalkyl, and halo, all except —H, —CN, perhaloalkyl, and halo are optionally substituted;  
 E″ is selected from the group consisting of —H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 4 -C 6  alicyclic, alkoxyalkyl, —C(O)OR 3 , —CONR 4   2 , —CN, —NR 9   2 , —OR 3 , —SR 3 , C 1 -C 6  perhaloalkyl, and halo, all except H, —CN, perhaloalkyl, and halo are optionally substituted; and  
 each R 4  is independently selected from the group consisting of —H and C 1 -C 2  alkyl.  
 
   
   
       10 . The compound of  claim 9  wherein R 5  is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       11 . The compound of  claim 9 , wherein R 5  is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       12 . The compound of  claim 8  wherein R 5  is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       13 . The compound of  claim 1  wherein X is selected from the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted.  
   
   
       14 . The compound of  claim 13  wherein X is selected from the group consisting of -heteroaryl-, and -alkoxycarbonyl-.  
   
   
       15 . The compound of  claim 1  wherein said compound is a compound of formulae II, III, or IV  
     
       
         
         
             
             
         
       
     
   
   
       16 . A method of inhibiting an FBPase comprising contacting a FBPase with a compound according to  claim 1 .  
   
   
       17 . A method of treating diabetes comprising administering a compound according to  claim 1  to a mammal in an amount effective to treat diabetes.