Taccalonolide microtubule stabilizers

A compound of the formula:

• wherein:
• ------ is present and is a single bond;
• R1 is hydrogen, amino, cyano, azido, halo, hydroxy, oxo, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
• R2 is hydrogen, amino, cyano, azido, halo, hydroxy, oxo, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12, or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2,
• or R2 is taken together with R3 to form an epoxide at C-2/C-3;
• R3 is hydrogen, amino, cyano, azido, halo, hydroxy, oxo, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12, or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2,
• or R3 is taken together with R2 as defined above;
• R5 is absent, hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12, or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
• R6 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12, or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2,
• or R6 is taken together with R7 to form an epoxide at C-6/C-7;
• R6′ when present is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
• R7 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2, or oxo if R7′ is not present,
• or R7 is taken together with R6 as defined above;
• R7′ when present is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
• R11 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
• R12 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
• R15 is hydrogen, amino, cyano, azido, halo, hydroxy, oxo, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
• R20 is hydrogen, amino, cyano, azido, halo, hydroxy, hydroperoxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio((C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C<12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
• R21 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C<12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
• R25 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, A, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
• R26 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C<12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2, or oxo if R26′ is not present;
• R26′ when present is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
• R27 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
• and
• X is O, NR′, or CR′2, wherein each R′ is independently hydrogen or alkyl(C≤6);
• or a pharmaceutically acceptable salt thereof,
• provided, however, that Formula I does not include the compound wherein R1 is acetoxy, R2 taken together with R3 forms an epoxide at C-2/C-3, R5 is hydrogen, R6 is oxo and R6′ is not present, R7 is hydroxy and R7′ is hydrogen, each of R11, R12, and R15 are acetoxy, one of R20 or R21 is methyl and the other is hydrogen, R25 is OH, R26 is oxo and R26′ is not present, R27 is methyl, and X is O.