Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof

Abstract

The present invention relates to novel “reverse amide” compounds comprising a zinc chelator group, and the use of such compounds in the inhibition of HDAC6 and in the treatment of various diseases, disorders or conditions related to HDAC6.

1 - 21 . (canceled) 
     
     
         22 . A method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination comprising a chemotherapeutic agent and a compound of formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
       
       wherein,
 B is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl; each of which may be optionally substituted by alkyl, aryl, aralkyl, haloalkyl, halo, OH, NH 2 , CN, or NO 2 ; 
 R 1  is aryl, arylalkyl, or heteroaryl, each of which may be optionally substituted by OH, halo, or alkyl; 
 R is H or alkyl; and 
 wherein the cancer is selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, ovarian cancer, pancreatic cancer, bone cancer, and uterine cancer, and the chemotherapeutic agent is selected from the group consisting of docetaxel, capecitabine, taxol, 5-fluorouracil, cytarabine, gemcitabine, vinorelbine, paclitaxel, topotecan, doxorubicin, cisplatin, and carboplatin. 
 
     
     
         23 . The method of  claim 22 , wherein the chemotherapeutic agent and the compound of formula (IV) are administered in the form of a fixed combination. 
     
     
         24 . The method of  claim 22 , wherein the chemotherapeutic agent and the compound of formula (IV) are administered as a non-fixed combination. 
     
     
         25 . The method of  claim 22 , wherein the cancer is selected from the group consisting of: breast cancer, colon cancer, lung cancer, ovarian cancer, pancreatic cancer, bone cancer, and uterine cancer. 
     
     
         26 . The method of  claim 25 , wherein the cancer is ovarian cancer. 
     
     
         27 . The method of  claim 25 , wherein the lung cancer is small cell lung cancer. 
     
     
         28 . The method of  claim 25 , wherein the cancer is pancreatic cancer. 
     
     
         29 . The method of  claim 25 , wherein the cancer is breast cancer. 
     
     
         30 . The method of  claim 22 , wherein the compound of formula (IV) is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         31 . The method of  claim 22 , wherein the compound of formula (IV) is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         32 . The method of  claim 22 , wherein the chemotherapeutic agent is selected from the group consisting of: docetaxel, 5-fluorouracil, gemcitabine, vinorelbine, paclitaxel, topotecan, doxorubicin, and carboplatin. 
     
     
         33 . The method of  claim 32 , wherein the chemotherapeutic agent is docetaxel or paclitaxel. 
     
     
         34 . A method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination comprising paclitaxel and a compound selected from: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof, and wherein the cancer is selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, ovarian cancer, pancreatic cancer, bone cancer, and uterine cancer. 
     
     
         35 . The method of  claim 34 , wherein the cancer is selected from the group consisting of breast cancer, colon cancer, lung cancer, ovarian cancer, pancreatic cancer, bone cancer, and uterine cancer. 
     
     
         36 . The method of  claim 35 , wherein the lung cancer is small cell lung cancer.