Anti-fungal compounds

A method of treating a condition associated with a Cryptococcus neoformans infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of the formula:

• wherein:
• R1 and R6 are each independently hydrogen, halo, or a group of the formula:
• —X—Y1, wherein:
• X is C(O), O, S, or NR1′, wherein:
• R1′ is hydrogen, alkyl(C≤8), substituted alkyl(C≤8), aryl(C≤8), or substituted aryl(C≤8);
• and
• Y1 is hydrogen, hydroxy, or alkyl(C≤12), aryl(C≤12), acyl(C≤12), alkoxy(C≤12), alkylsulfonyl(C≤12), arylsulfonyl(C≤12), or a substituted version of any of these groups;
• R2 and R5 are each independently hydrogen, hydroxy, halo, alkyl(C≤12), substituted alkyl(C≤12), cycloalkyl(C≤12), substituted cycloalkyl(C≤12), alkenyl(C≤12), substituted alkenyl(C≤12), aryl(C≤12), substituted aryl(C≤12), aralkyl(C≤12), substituted aralkyl(C≤12), heteroaryl(C≤12), substituted heteroaryl(C≤12), alkoxy(C≤12), substituted alkoxy(C≤12), acyl(C≤12), substituted acyl(C≤12), or a group of the formula:
• —C(O)Y2R2′, wherein:
• Y2 is alkenediyl(C≤8) or substituted alkenediyl(C≤8);
• and
• R2′ is aryl(C≤12), heteroaryl(C≤12), arenediyl(C≤12)-O-aryl(C≤12), or a substituted version of any of these groups;
• and
• R3 and R4 are each independently hydrogen, hydroxy, halo, nitroso, alkyl(C≤12), substituted alkyl(C≤12), cycloalkyl(C≤12), substituted cycloalkyl(C≤12), alkenyl(C≤12), substituted alkenyl(C≤12), aryl(C≤18), substituted aryl(C≤18), heteroaryl(C≤18), substituted heteroaryl(C≤18), acyl(C≤18), substituted acyl(C≤18), amido(C≤18), substituted amido(C≤18), or —C(O)Ra or —S(O)2Ra wherein:
• Ra is alkyl(C≤18), cycloalkyl(C≤18), aryl(C≤18), heteroaryl(C≤18), alkoxy(C≤18), aryloxy(C≤18), -alkanediyl(C≤6)-cycloalkyl(C≤12);
• or a substituted version of any of these groups;
• or
• R2 and R3 are taken together and are a compound of the formula:
• wherein:
• Rb, Rc, Rd, and Re are each independently hydrogen, hydroxy, or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), or a substituted version of any of these groups;
• or -alkanediyl(C≤6)-alkylamino(C≤8), -alkane-diyl(C≤6)-dialkylamino(C≤8), or a substituted version of either of these groups;
• or
• R1 and R2 are taken together and are a compound of the formula:
• wherein:
• Rf, Rg, Rh, and Ri are each independently hydrogen, hydroxy, or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), or a substituted version of any of these groups;
• or -alkanediyl(C≤6)-alkylamino(C≤8), -alkane-diyl(C≤6)-dialkylamino(C≤8), or a substituted version of either of these groups;
• or
• R3 and R4 are taken together and are a compound of the formula:
• wherein:
• Rj is hydrogen, hydroxy, halo, or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), or a substituted version of any of these groups;
• or -alkanediyl(C≤6)-alkylamino(C≤8), -alkane-diyl(C≤6)-dialkylamino(C≤8), or a substituted version of either of these groups;
• or
• a compound of the formula:
• wherein:
• R7 is alkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), or a substituted version of any of these groups;
• R8 is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8);
• and
• R9 is hydrogen, alkyl(C≤12), or substituted alkyl(C≤12);
• a compound of the formula:
• wherein:
• R10 is amino, hydroxy, or aryl(C≤18), aralkyl(C≤18), aryloxy(C≤18), cycloalkylamino(C≤18), aralkoxy(C≤18), arylamino(C≤18), aralkamino(C≤18), diarylamino(C≤18), diaralkamino(C≤18), or a substituted version of any of these groups;
• R11 is hydrogen, acyl(C≤12), or substituted acyl(C≤12), or —C(O)Ra;
• wherein:
• Ra is amino, hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8);
• R12 is hydrogen, alkoxy(C≤8), or substituted alkoxy(C≤8);
• R13 is amino, cyano, halo, hydroxy, nitro, alkyl(C≤8), substituted alkyl(C≤8), acyl(C≤8), substituted acyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), substituted acyloxy(C≤8), alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), substituted dialkylamino(C≤8), amido(C≤8), or substituted amido(C≤8);
• and
• n is 1, 2, or 3;
• wherein the compound is formulated as a pharmaceutical composition comprising the compound and an excipient, further wherein the pharmaceutical composition is formulated for oral administration, intraarterial administration, intravenous administration, parenteral administration, or for administration to the lungs;
• or a pharmaceutically acceptable salt or tautomer thereof.

A pharmaceutical composition comprising:

• (A) a compound of the formula:
• wherein:
• R1 and R6 are each independently hydrogen, halo, or a group of the formula:
• —X—Y1, wherein:
• X is C(O), O, S, or NR1′, wherein:
• R1′ is hydrogen, alkyl(C≤8), substituted alkyl(C≤8), aryl(C≤8), or substituted aryl(C≤8);
• and
• Y1 is hydrogen, hydroxy, or alkyl(C≤12), aryl(C≤12), acyl(C≤12), alkoxy(C≤12), alkylsulfonyl(C≤12), arylsulfonyl(C≤12), or a substituted version of any of these groups;
• R2 and R5 are each independently hydrogen, hydroxy, halo, alkyl(C≤12), substituted alkyl(C≤12), cycloalkyl(C≤12), substituted cycloalkyl(C≤12), alkenyl(C≤12), substituted alkenyl(C≤12), aryl(C≤12), substituted aryl(C≤12), aralkyl(C≤12), substituted aralkyl(C≤12), heteroaryl(C≤12), substituted heteroaryl(C≤12), alkoxy(C≤12), substituted alkoxy(C≤12), acyl(C≤12), substituted acyl(C≤12), or a group of the formula:
• —C(O)Y2R2′, wherein:
• Y2 is alkenediyl(C≤8) or substituted alkenediyl(C≤8);
• and
• R2′ is aryl(C≤12), heteroaryl(C≤12), arenediyl(C≤12)-O-aryl(C≤12), or a substituted version of any of these groups;
• and
• R3 and R4 are each independently hydrogen, hydroxy, halo, nitroso, alkyl(C≤12), substituted alkyl(C≤12), cycloalkyl(C≤12), substituted cycloalkyl(C≤12), alkenyl(C≤12), substituted alkenyl(C≤12), aryl(C≤18), substituted aryl(C≤18), heteroaryl(C≤18), substituted heteroaryl(C≤18), acyl(C≤18), substituted acyl(C≤18), amido(C≤18), substituted amido(C≤18), or —C(O)Ra or —S(O)2Ra wherein:
• Ra is alkyl(C≤18), cycloalkyl(C≤18), aryl(C≤18), heteroaryl(C≤18), alkoxy(C≤18), aryloxy(C≤18), -alkanediyl(C≤6)-cycloalkyl(C≤12);
• or a substituted version of any of these groups;
• or
• R2 and R3 are taken together and are a compound of the formula:
• wherein:
• Rb, Rc, Rd, and Re are each independently hydrogen, hydroxy, or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), or a substituted version of any of these groups;
• or -alkanediyl(C≤6)-alkylamino(C≤8), -alkane-diyl(C≤6)-dialkylamino(C≤8), or a substituted version of either of these groups;
• or
• R1 and R2 are taken together and are a compound of the formula:
• wherein:
• Rf, Rg, Rh, and Ri are each independently hydrogen, hydroxy, or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), or a substituted version of any of these groups;
• or -alkanediyl(C≤6)-alkylamino(C≤8), -alkane-diyl(C≤6)-dialkylamino(C≤8), or a substituted version of either of these groups;
• or
• R3 and R4 are taken together and are a compound of the formula:
• wherein:
• R3 is hydrogen, hydroxy, halo, or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), or a substituted version of any of these groups;
• or -alkanediyl(C≤6)-alkylamino(C≤8), alkanediyl(C≤6)-dialkylamino(C≤8), or a substituted version of either of these groups;
• or
• a compound of the formula:
• wherein:
• R7 is alkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), or a substituted version of any of these groups;
• R8 is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8);
• and
• R9 is hydrogen, alkyl(C≤12), or substituted alkyl(C≤12);
• a compound of the formula:
• wherein:
• R10 is amino, hydroxy, or aryl(C≤18), aralkyl(C≤18), aryloxy(C≤18), cycloalkylamino(C≤18), aralkoxy(C≤18), arylamino(C≤18), aralkamino(C≤18), diarylamino(C≤18), diaralkamino(C≤18), or a substituted version of any of these groups;
• R11 is hydrogen, acyl(C≤12), or substituted acyl(C≤12), or —C(O)Ra;
• wherein:
• Ra is amino, hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8);
• R12 is hydrogen, alkoxy(C≤8), or substituted alkoxy(C≤8);
• R13 is amino, cyano, halo, hydroxy, nitro, alkyl(C≤8), substituted alkyl(C≤8), acyl(C≤8), substituted acyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), substituted acyloxy(C≤8), alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), substituted dialkylamino(C≤8), amido(C≤8), or substituted amido(C≤8);
• and
• n is 1, 2, or 3;
• or a pharmaceutically acceptable salt or tautomer thereof;
• and
• (B) a second anti-fungal compound;
• wherein the pharmaceutical composition is formulated for oral administration, intraarterial administration, intravenous administration, parenteral administration, or for administration to the lungs.