Indole derivatives and their metal conjugates and uses thereof

Abstract

Provided are compounds which are indole derivatives, as well as pharmaceutical compositions containing the compounds. Also provided are methods of using the indole compounds for preventing or treating a disease, or a condition that predisposes to a disease, wherein the disease or condition is associated with activation of the serine/threonine kinase B (Akt) in an animal. The method comprises administering to the animal a preventive or treatment effective amount of the indole compound. Further provided is a method for increasing apoptosis of an animal cell comprising contacting the cell with the indole compound.

1 - 13 . (canceled) 
     
     
         14 . A method of preventing or treating a disease, or a condition that predisposes to a disease, wherein the disease or condition is associated with activation of the serine/threonine kinase B (Akt) in an animal, the method comprising administering to the animal a preventive or treatment effective amount of a compound of Formula (I) 
       
         
           
           
               
               
           
         
         wherein R is selected from 
       
       
         
           
           
               
               
           
         
         wherein Z is oxygen or sulfur; 
         wherein R 1  and R 2  are each independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, or phenyl; 
         wherein X is selected from hydrogen, (C 1 -C 4 ) alkyl, hydroxyl, (C 1 -C 4 ) alkoxy, fluorine, chlorine, bromine, iodine, nitro, or amino; 
         wherein R 3 , R 4 , R 5  and R 6  are each independently selected from hydrogen or (C 1 -C 4 ) alkyl; 
         wherein R′ is selected from (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 3 ) haloalkyl, —CH 2 CN, —CH 2 —CH(NH 2 )(COOH), —CH(CH 2 CH 2 Cl) 2 , —O—CH 2 -Ph, —CH 2 -Ph, 3-indolyl, 5-indolyl, 7-indolyl, 2-pyrazolyl, 3-pyrazolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, purine, 
       
       
         
           
           
               
               
           
         
         where Ph is phenyl; 
         and the corresponding metal conjugates, and pharmaceutically acceptable salts of the compounds and metal conjugates. 
       
     
     
         15 . The method of  claim 14 , wherein the animal is a mammal. 
     
     
         16 . The method of  claim 15 , wherein the mammal is a human. 
     
     
         17 . The method of  claim 14 , wherein the disease or condition is a cancer or precancerous lesion, a rheumatologic disease, a pulmonary disease, an opthalmic disease, a cardiovascular disease, a dermatologic disease, a gynecological disease, a vascular disease, a neurologic disease, or an infectious disease. 
     
     
         18 . The method of  claim 17 , wherein the disease is a cancer or precancerous lesion. 
     
     
         19 . The method of  claim 18 , wherein the cancer is breast cancer, lung cancer, ovarian cancer, uterine cancer, brain cancer, sarcoma, melanoma, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, or liver cancer. 
     
     
         20 . The method of  claim 17 , wherein the rheumatologic disease is rheumatoid arthritis or osteoarthritis. 
     
     
         21 . The method of  claim 17 , wherein the pulmonary disease is chronic obstructive pulmonary disease (COPD). 
     
     
         22 . The method of  claim 17 , wherein the opthalmic disease is retinopathy. 
     
     
         23 . The method of  claim 17 , wherein the infectious disease is a bacterial, viral, retroviral, or parasitic disease. 
     
     
         24 . A method of increasing apoptosis of an animal cell comprising contacting the cell with a compound of Formula (I) 
       
         
           
           
               
               
           
         
         wherein R is selected from 
       
       
         
           
           
               
               
           
         
         wherein Z is oxygen or sulfur; 
         wherein R 1  and R 2  are each independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, or phenyl; 
         wherein X is selected from hydrogen, (C 1 -C 4 ) alkyl, hydroxyl, (C 1 -C 4 ) alkoxy, fluorine, chlorine, bromine, iodine, nitro, or amino; 
         wherein R 3 , R 4 , R 5  and R 6  are each independently selected from hydrogen or (C 1 -C 4 ) alkyl; 
         wherein R′ is selected from (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 3 ) haloalkyl, —CH 2 CN, —CH 2 —CH(NH 2 )(COOH), —CH(CH 2 CH 2 C 1 ) 2 , —O—CH 2 -Ph, —CH 2 -Ph, 3-indolyl, 5-indolyl, 7-indolyl, 2-pyrazolyl, 3-pyrazolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, purine, 
       
       
         
           
           
               
               
           
         
         where Ph is phenyl; 
         and the corresponding metal conjugates, and pharmaceutically acceptable salts of the compounds and metal conjugates. 
       
     
     
         25 . (canceled) 
     
     
         26 . A method for the treatment of a cancer in an animal comprising administering to said animal an effective amount of a compound according to  claim 14  before, after or simultaneously with an effective amount of gemcitabine. 
     
     
         27 . The method of  claim 26 , wherein the animal is a human. 
     
     
         28 . A method for the treatment of a cancer in an animal comprising administering to said animal an effective amount of a compound according to  claim 14  before, after or simultaneously with an effective amount of erlotinib. 
     
     
         29 . The method of  claim 28 , wherein the animal is a human.