Securinine and norsecurinine analogue compounds for the treatment of myeloid disorders

Abstract

The present application relates to securinine or norsecurinine analogues that, when administered to immature myeloid cells, promote differentiation of these cells to mature cells that do not readily proliferate. Therefore, the agents are useful in the treatment of myeloid disorders including myeloproliferative disorders, acute myeloid leukemia, and autoimmune diseases. The agents may also be used as a myeloablative agent in conjunction with a bone marrow transplant or stem cell therapy.

1 - 133 . (canceled) 
     
     
         134 . A compound having a formula selected from the group consisting of the following formula:
 a. Formula (I):   
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein as valence and stability permit: 
            represents a single or double bond; 
         x is 0 or 1; 
         R 1  is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino, heterocyclylamino, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, thioalkyl, or thioaryl; 
         R 2 , R 3 , R 4 , and R 5  are each independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino, heterocyclylamino, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, thioalkyl, or thioaryl; and 
         wherein adjacent R groups may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocyclyl; 
         provided that when x is 1, at least one of R 1 , R 2 , R 3 , R 4 , and R 5  is other than hydrogen; 
         provided that when x is 0,   represents a double bond and R 5  is alkoxyalkyl; 
         b. Formula I′: 
       
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein as valence and stability permit: 
            represents a single or double bond; 
         x is 0 or 1; 
         R 1  is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino, heterocyclylamino, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, thioalkyl, or thioaryl; 
         R 2 , R 3 , R 4 , and R 5  are each independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkyl alkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino, heterocyclylamino, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, thioalkyl, or thioaryl; 
         wherein adjacent R groups may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocyclyl; and 
         wherein R 6  is C 1 -C 6  alkyl; 
         provided that when x is 1, at least one of R 1 , R 2 , R 3 , R 4 , and R 5  is other than hydrogen; 
         c. Formula (II): 
       
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein as valence and stability permit: 
            represents a single or double bond; 
         x is 0 or 1; 
         R 1  is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino, heterocyclylamino, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, thioalkyl, or thioaryl; and 
         R 2  is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino, heterocyclylamino, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, thioalkyl, or thioaryl; 
         provided that when x is 1, at least one of R 1  or R 2  is other than hydrogen; 
         provided that when x is 0,   represents a double bond and R 2  is alkoxyalkyl; 
         d. Formula III: 
       
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein as valence and stability permit: 
            represents a single or double bond; 
            represents a double or triple bond; 
         x is 0 or 1; 
         R 1  is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino, heterocyclylamino, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, thioalkyl, or thioaryl; and 
         R 2  is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamide, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino, heterocyclylamino, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, thioalkyl, or thioaryl; 
         e. Formula IV: 
       
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein as valence and stability permit: 
            represents a single or double bond; 
         x is 0 or 1; and 
         R 1  is substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamide, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino, heterocyclylamino, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, thioalkyl, or thioaryl; 
         provided that wherein R 1  is substituted or unsubstituted heterocyclyl, x is 1, and   d represents a single bond, R 1  is not mono-fluoro substituted pyrrolidine; 
         provided that wherein R 1  is substituted or unsubstituted heteroarylalkylamino, x is 1, and   represents a single bond, R 1  is not indolealkylamino; 
         provided that wherein R 1  is substituted or unsubstituted arylsulfanyl, x is 1, and   represents a single bond, R 1  is not phenylsulfanyl; and 
         provided that wherein R 1  is alkylsulfanyl, x is 1, and   represents a single bond R 1  is not propylsulfanyl, and 
         f. Formula IV′: 
       
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein as valence and stability permit: 
            represents a single or double bond; 
         x is 0 or 1; 
         R 1  is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino, heterocyclylamino, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, thioalkyl, or thioaryl; and 
         wherein R 2  is C 1 -C 6  alkyl; 
         provided that wherein R 1  is substituted or unsubstituted heterocyclyl, R 1  is not mono-fluoro substituted pyrrolidine, x is 1, and   represents a single bond; 
         provided that wherein R 1  is substituted or unsubstituted heteroarylalkylamino, R 1  is not indolealkylamino, x is 1, and   represents a single bond; 
         provided that wherein R 1  is substituted or unsubstituted arylsulfanyl, R 1  is not phenylsulfanyl, x is 1, and   represents a single bond; and 
         provided that wherein R 1  is alkylsulfanyl, R 1  is not propylsulfanyl, x is 1, and   represents a single bond. 
       
     
     
         135 . The compound of  claim 134 , selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         136 . The compound of  claim 134 , selected from: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         137 . The compound of  claim 134 , selected from: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         138 . The compound of  claim 134 , selected from: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         139 . The compound of  claim 134 , having the following Formula III: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein as valence and stability permit: 
            represents a single or double bond; 
            represents a double or triple bond; 
         x is 0 or 1; 
         R 1  is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamide, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino, heterocyclylamino, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, thioalkyl, or thioaryl; and 
         R 2  is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamide, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino, heterocyclylamino, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, thioalkyl, or thioaryl. 
       
     
     
         140 . The compound of  claim 134 , selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         141 . A composition comprising a compound of  claim 134  and an anti-proliferative agent. 
     
     
         142 . The composition of  claim 141 , wherein the anti-proliferative agent is an anti-metabolite and/or a nucleoside analogue. 
     
     
         143 . The composition of  claim 141 , wherein the anti-proliferative agent is an alkylating agent. 
     
     
         144 . The composition of  claim 141 , wherein the anti-proliferative agent is an antibiotic-type agent. 
     
     
         145 . The composition of  claim 141 , wherein the anti-proliferative agent is an hormonal anticancer agent. 
     
     
         146 . The composition of  claim 141 , wherein the anti-proliferative agent is an immunological agent. 
     
     
         147 . The composition of  claim 141 , wherein the anti-proliferative agent is an interferon-type agent. 
     
     
         148 . The composition of  claim 141 , wherein the anti-proliferative agent is an antineoplastic agent. 
     
     
         149 . The composition of  claim 141  wherein the compound has the following Formula III: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein as valence and stability permit: 
            represents a single or double bond; 
            represents a double or triple bond; 
         x is 0 or 1; 
         R 1  is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino, heterocyclylamino, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, thioalkyl, or thioaryl; and 
         R 2  is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino, heterocyclylamino, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, thioalkyl, or thioaryl. 
       
     
     
         150 . The composition of  claim 141 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof.