hTERT MODULATORS AND METHODS OF USE

A method for treating a patient suffering from a clinical condition, said method comprising administering to a patient

• a) a therapeutically effective amount of compound I:
• or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a mixture thereof;
• or
• b) a therapeutically effective amount of a compound of the formula:
• wherein
• X is O or N such that when X is O, bond a is absent and when X is N, bond a is present;
• n is 0 or 1 such that:
• when n=0, R3 is —NHC(═NH)NH2;
• and when n=1, R3 is hydrogen, alkyl, cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl or optionally substituted aryl, wherein each substituent is independently selected from the group consisting of halogen, cyano, nitro, azido, haloalkyl, cycloalkyl, heteroaryl, aryl, —NR7R8, —NR7C(O)R8, —C(O)NR7R8, —C(O)R9, —C(O)OR9, —S(O)R9, —SO2R9, —SO2NR7R8, —OR9 and —SR9;
• R1 is optionally substituted aryl or optionally substituted heteroaryl, wherein each substituent is independently selected from the group consisting of halogen, cyano, nitro, azido, haloalkyl, cycloalkyl, —NR4R5, —NR4C(O)R5, —C(O)NR4R5, —C(O)R6, —C(O)OR6, —S(O)R6, —SO2R6, —SO2NR4R5, —OR6, and —SR6;
• R2 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl and cycloalkyl;
• each of R4 and R5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl and cycloalkyl, or R4 and R5 together with the nitrogen atom to which they are attached to form an optionally substituted monocyclic or bicyclic ring with one or more heteroatoms;
• R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteraryl, aryl, cycloalkyl, wherein the alkyl, alkenyl, heteraryl, aryl and cycloalkyl are optionally substituted with one or more halo, cyano, alkylamino, alkoxy, aryl, heteroaryl or heterocyclyl groups;
• each of R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl and cycloalkyl, or R7 and R8 together with the nitrogen group to which they are attached to form an optionally substituted monocyclic or bicyclic ring with one or more heteroatoms;
• R9 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteraryl, aryl cycloalkyl, wherein the alkyl, alkenyl, heteraryl, aryl and cycloalkyl are optionally substituted with one or more halo, cyano, alkylamino, alkoxy, aryl, heteroaryl or heterocyclyl groups;
• each R11 and R12 is independently —H, —COR13 or —CH3;
• and
• R13 is alkyl, haloalkyl, alkenyl, alkynyl, or cycloalkyl, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a mixture thereof,
• wherein the clinical condition is one or more clinical conditions selected from:
• a clinical condition associated with hTERT overexpression due to copy number changes, translocations, missense mutations, and epigenetic changes or other genetic mechanisms;
• a clinical condition associated with a transcription-activating genetic change associated with the hTERT core promoter region;
• a cancer selected from the group consisting of glioblastomas, bladder cancer, melanoma, thyroid cancer, liver cancer, kidney cancer, stomach cancer, esophagus cancer, lung cancer and neuroblastoma;
• a cancer having a mutation in or associated with a hairpin loop of hTERT in a cancer cell.

A kit comprising one or more of:

• a) a composition comprising compound I:
• or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a mixture thereof;
• or
• b) a composition comprising a compound of the formula II:
• wherein
• X is O or N such that when X is O, bond a is absent and when X is N, bond a is present;
• n is 0 or 1 such that:
• when n=0, R3 is —NHC(═NH)NH2;
• and when n=1, R3 is hydrogen, alkyl, cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl or optionally substituted aryl, wherein each substituent is independently selected from the group consisting of halogen, cyano, nitro, azido, haloalkyl, cycloalkyl, heteroaryl, aryl, —NR7R8, —NR7C(O)R8, —C(O)NR7R8, —C(O)R9, —C(O)OR9, —S(O)R9, —SO2R9, —SO2NR7R8, —OR9 and —SR9;
• R1 is optionally substituted aryl or optionally substituted heteroaryl, wherein each substituent is independently selected from the group consisting of halogen, cyano, nitro, azido, haloalkyl, cycloalkyl, —NR4R5, —NR4C(O)R5, —C(O)NR4R5, —C(O)R6, —C(O)OR6, —S(O)R6, —SO2R6, —SO2NR4R5, —OR6, and —SR6;
• R2 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl and cycloalkyl;
• each of R4 and R5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl and cycloalkyl, or R4 and R5 together with the nitrogen atom to which they are attached to form an optionally substituted monocyclic or bicyclic ring with one or more heteroatoms;
• R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteraryl, aryl, cycloalkyl, wherein the alkyl, alkenyl, heteraryl, aryl and cycloalkyl are optionally substituted with one or more halo, cyano, alkylamino, alkoxy, aryl, heteroaryl or heterocyclyl groups;
• each of R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl and cycloalkyl, or R7 and R8 together with the nitrogen group to which they are attached to form an optionally substituted monocyclic or bicyclic ring with one or more heteroatoms;
• R9 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteraryl, aryl cycloalkyl, wherein the alkyl, alkenyl, heteraryl, aryl and cycloalkyl are optionally substituted with one or more halo, cyano, alkylamino, alkoxy, aryl, heteroaryl or heterocyclyl groups;
• each R11 and R12 is independently —H, —COR13 or —CH3;
• and
• R13 is alkyl, haloalkyl, alkenyl, alkynyl, or cycloalkyl, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a mixture thereof;
• and
• c) instructions for administration of compound I or a compound of formula II to a patient suffering from a clinical condition, wherein the clinical condition is one or more clinical conditions selected from:
• a clinical condition associated with hTERT overexpression due to copy number changes, translocations, missense mutations, and epigenetic changes or other genetic mechanisms;
• a clinical condition associated with a transcription-activating genetic change associated with the hTERT core promoter region;
• a cancer selected from the group consisting of glioblastomas, bladder cancer, melanoma, thyroid cancer, liver cancer, kidney cancer, stomach cancer, esophagus cancer, lung cancer and neuroblastoma;
• a cancer having a mutation in or associated with a hairpin loop of hTERT in a cancer cell.