hTERT MODULATORS AND METHODS OF USE

Abstract

where a, n, R1, R2, R3, R11 and R12 are as defined herein.

What is claimed is: 
     
         1 . 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, R 3  is —NHC(═NH)NH 2 ; and when n=1, R 3  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, —NR 7 R 8 , —NR 7 C(O)R 8 , —C(O)NR 7 R 8 , —C(O)R 9 , —C(O)OR 9 , —S(O)R 9 , —SO 2 R 9 , —SO 2 NR 7 R 8 , —OR 9  and —SR 9 ; 
 R 1  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, —NR 4 R 5 , —NR 4 C(O)R 5 , —C(O)NR 4 R 5 , —C(O)R 6 , —C(O)OR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 NR 4 R 5 , —OR 6 , and —SR 6 ; 
 R 2  is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl and cycloalkyl; 
 each of R 4  and R 5  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl and cycloalkyl, or R 4  and R 5  together with the nitrogen atom to which they are attached to form an optionally substituted monocyclic or bicyclic ring with one or more heteroatoms; 
 R 6  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl, cycloalkyl, wherein the alkyl, alkenyl, heteroaryl, aryl and cycloalkyl are optionally substituted with one or more halo, cyano, alkylamino, alkoxy, aryl, heteroaryl or heterocyclyl groups; each of R 7  and R 8  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl and cycloalkyl, or R 7  and R 8  together with the nitrogen group to which they are attached to form an optionally substituted monocyclic or bicyclic ring with one or more heteroatoms; 
 R 9  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl cycloalkyl, wherein the alkyl, alkenyl, heteroaryl, aryl and cycloalkyl are optionally substituted with one or more halo, cyano, alkylamino, alkoxy, aryl, heteroaryl or heterocyclyl groups; 
 each R 11  and R 12  is independently —H, —COR 13  or —CH 3 ; and 
 R 13  is alkyl, haloalkyl, alkenyl, alkynyl, or cycloalkyl. 
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein R 2  is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl and a halide. 
     
     
         4 . The compound of  claim 1 , wherein R 3  is selected from the group consisting of hydrogen, methyl, ethyl, trifluoromethyl, propyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, benzyl, 2-phenylethyl, 2-methoxyethyl, 3-methoxypropyl, or a moiety selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein m is an integer from 2 to 4; each of R 14  and R 15  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl and cycloalkyl; or R 14  and R 15  together with the nitrogen atom to which they are attached to form a substituted or unsubstituted monocyclic or bicyclic heterocycloalkyl. 
     
     
         5 . The compound of  claim 1 , wherein the compound is selected from a compound of Table 1 or a pharmaceutically acceptable salt thereof, or a prodrug thereof. 
     
     
         6 . (canceled) 
     
     
         7 . 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, R 3  is —NHC(═NH)NH 2 ; and when n=1, R 3  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, —NR 7 R 8 , —NR 7 C(O)R 8 , —C(O)NR 7 R 8 , —C(O)R 9 , —C(O)OR 9 , —S(O)R 9 , —SO 2 R 9 , —SO 2 NR 7 R 8 , —OR and —SR 9 ; 
 R 1  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, —NR 4 R 5 , —NR 4 C(O)R 5 , —C(O)NR 4 R 5 , —C(O)R 6 , —C(O)OR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 NR 4 R 5 , —OR 6 , and —SR 6 ; 
 R 2  is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl and cycloalkyl; 
 each of R 4  and R 5  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl and cycloalkyl, or R 4  and R 5  together with the nitrogen atom to which they are attached to form an optionally substituted monocyclic or bicyclic ring with one or more heteroatoms; 
 R 6  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl, cycloalkyl, wherein the alkyl, alkenyl, heteroaryl, aryl and cycloalkyl are optionally substituted with one or more halo, cyano, alkylamino, alkoxy, aryl, heteroaryl or heterocyclyl groups; each of R 7  and R 8  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl and cycloalkyl, or R 7  and R 8  together with the nitrogen group to which they are attached to form an optionally substituted monocyclic or bicyclic ring with one or more heteroatoms; 
 R 9  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl cycloalkyl, wherein the alkyl, alkenyl, heteroaryl, aryl and cycloalkyl are optionally substituted with one or more halo, cyano, alkylamino, alkoxy, aryl, heteroaryl or heterocyclyl groups; 
 each R 11  and R 12  is independently —H, —COR 13  or —CH 3 ; and 
 R 13  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, 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. 
 
 
     
     
         8 . The method of  claim 7 , wherein said clinical condition associated with said transcription-activating genetic change associated with the hTERT core promoter region comprises a tumor. 
     
     
         9 . The method of  claim 8 , wherein said tumor comprises brain tumor, bladder cancer, melanoma, thyroid, liver cancer, kidney cancer, stomach, esophagus cancer, lung cancer or neuroblastoma. 
     
     
         10 . The method of  claim 9 , wherein said brain tumor comprises glioblastomas. 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 7 , wherein said mutation in or associated with the hairpin loop of hTERT in said cancer cell is in or associated with a nucleotide sequence of the hairpin loop of hTERT at a location −146, −139, −138, −125, −124 or a combination thereof. 
     
     
         14 . The method of  claim 7 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 7 , wherein R 2  is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl and a halide. 
     
     
         16 . The method of  claim 7 , wherein R 3  is selected from the group consisting of hydrogen, methyl, ethyl, trifluoromethyl, propyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, benzyl, 2-phenylethyl, 2-methoxyethyl, 3-methoxypropyl, or a moiety selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein m is an integer from 2 to 4; each of R 14  and R 15  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl and cycloalkyl; or R 14  and R 15  together with the nitrogen atom to which they are attached to form a substituted or unsubstituted monocyclic or bicyclic heterocycloalkyl. 
     
     
         17 . The method of  claim 7 , wherein the compound is selected from a compound of Table 1 or a pharmaceutically acceptable salt thereof, or a prodrug thereof. 
     
     
         18 . The method of  claim 7 , wherein the patient is a human patient. 
     
     
         19 . 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 I: 
 
       
         
           
           
               
               
           
         
       
       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, R 3  is —NHC(═NH)NH 2 ; and when n=1, R 3  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, —NR 7 R 8 , —NR 7 C(O)R 8 , —C(O)NR 7 R 8 , —C(O)R 9 , —C(O)OR 9 , —S(O)R 9 , —SO 2 R 9 , —SO 2 NR 7 R 8 , —OR 9  and —SR 9 ; 
 R 1  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, —NR 4 R 5 , —NR 4 C(O)R 5 , —C(O)NR 4 R 5 , —C(O)R 6 , —C(O)OR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 NR 4 R 5 , —OR 6 , and —SR 6 ; 
 R 2  is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl and cycloalkyl; 
 each of R 4  and R 5  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl and cycloalkyl, or R 4  and R 5  together with the nitrogen atom to which they are attached to form an optionally substituted monocyclic or bicyclic ring with one or more heteroatoms; 
 R 6  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl, cycloalkyl, wherein the alkyl, alkenyl, heteroaryl, aryl and cycloalkyl are optionally substituted with one or more halo, cyano, alkylamino, alkoxy, aryl, heteroaryl or heterocyclyl groups; each of R 7  and R 8  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl and cycloalkyl, or R 7  and R 8  together with the nitrogen group to which they are attached to form an optionally substituted monocyclic or bicyclic ring with one or more heteroatoms; 
 R 9  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl cycloalkyl, wherein the alkyl, alkenyl, heteroaryl, aryl and cycloalkyl are optionally substituted with one or more halo, cyano, alkylamino, alkoxy, aryl, heteroaryl or heterocyclyl groups; 
 each R 11  and R 12  is independently —H, —COR 13  or —CH 3 ; and 
 R 13  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, 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. 
 
     
     
         20 . The kit of  claim 19 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R 2  is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl and a halide. 
       
     
     
         21 . The kit of  claim 19 , wherein R 3  is selected from the group consisting of hydrogen, methyl, ethyl, trifluoromethyl, propyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, benzyl, 2-phenylethyl, 2-methoxyethyl, 3-methoxypropyl, or a moiety selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein m is an integer from 2 to 4; each of R 14  and R 15  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroaryl, aryl and cycloalkyl; or R 14  and R 15  together with the nitrogen atom to which they are attached to form a substituted or unsubstituted monocyclic or bicyclic heterocycloalkyl. 
     
     
         22 . The kit of  claim 19 , wherein the compound is selected from a compound of Table 1 or a pharmaceutically acceptable salt thereof, or a prodrug thereof. 
     
     
         23 . The kit of  claim 19 , wherein the patient is a human patient.