Analogs of Benzoquinone-Containing Ansamycins and Methods of Use Thereof

A pharmaceutical composition, comprising a pharmaceutically acceptable excipient;

• and a compound of the formula:
• wherein independently for each occurrence:
• W is oxygen or sulfur;
• Q is oxygen, NR, N(acyl) or a bond;
• R for each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl;
• R1 is hydroxyl, alkoxyl, —OC(O)R8, —OC(O)OR9, —OC(O)NR10R11, —OSO2R12, —OC(O)NHSO2NR13R14, —NR13R14, or halide;
• and R2 is hydrogen, alkyl, or aralkyl;
• or R1 and R2 taken together, along with the carbon to which they are bonded, represent —(C═O)—, —(C═N—OR)—, —(C═N—NHR)—, or —(C═N—R)—;
• R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, and —[(CR2)p]—R16;
• or R3 taken together with R4 represent a 4-8 membered optionally substituted heterocyclic ring;
• R5 is selected from the group consisting of H, alkyl, aralkyl, and a group having the formula 1a:
• wherein R17 is selected independently from the group consisting of hydrogen, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, —COR18, —CO2R18, —N(R18)CO2R19, —OC(O)N(R18)(R19), —N(R18)SO2R19, —N(R18)C(O)N(R18)(R19), and —CH2O-heterocyclyl;
• R6 and R7 are both hydrogen;
• or R6 and R7 taken together form a bond;
• R8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or —[(CR2)p]—R16;
• R9 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or —[(CR2)p]—R16;
• R10 and R11 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, and —[(CR2)p]—R16;
• or R10 and R11 taken together with the nitrogen to which they are bonded represent a 4-8 membered optionally substituted heterocyclic ring;
• R12 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or —[(CR2)p]—R16;
• R13 and R14 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, and —[(CR2)p]—R16;
• or R13 and R14 taken together with the nitrogen to which they are bonded represent a 4-8 membered optionally substituted heterocyclic ring;
• R16 for each occurrence is independently selected from the group consisting of hydrogen, hydroxyl, acylamino, —N(R18)COR19, —N(R18)C(O)OR19, —N(R18)SO2(R19), —CON(R18)(R19), —OC(O)N(R18)(R19), —SO2N(R18)(R19), —N(R18)(R19), —OC(O)OR18, —COOR18, —C(O)N(OH)(R18), —OS(O)2OR18, —S(O)2OR18, —OP(O)(OR18)(OR19), —N(R18)P(O)(OR18)(OR19), and —P(O)(OR18)(OR19);
• p is 1, 2, 3, 4, 5, or 6;
• R18 for each occurrence is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl;
• R19 for each occurrence is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl;
• or R18 taken together with R19 represent a 4-8 membered optionally substituted ring;
• R20, R21, R22, R24, and R25, for each occurrence are independently alkyl;
• R23 is alkyl, —CH2OH, —CHO, —COOR18, or —CH(OR18)2;
• R26 and R27 for each occurrence are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl;
• provided that when R1 is hydroxyl, R2 is hydrogen, R6 and R7 taken together form a double bond, R20 is methyl, R21 is methyl, R22 is methyl, R23 is methyl, R24 is methyl, R25 is methyl, R26 is hydrogen, R27 is hydrogen, Q is a bond, and W is oxygen;
• R3 and R4 are not both hydrogen nor when taken together represent an unsubstituted azetidine;
• and
• the absolute stereochemistry at a stereogenic center of said formula may be R or S or a mixture thereof and the stereochemistry of a double bond may be E or Z or a mixture thereof.