Substituted indole-2-carboxylic acid benzylidene-hydrazides and analogs as activators of caspases and inducers of apoptosis and the use thereof

Abstract

The present invention is directed to substituted indole-2-carboxylic acid benzylidene-hydrazides and analogs thereof, represented by the general Formula I: wherein X, Ar 1 , R 2 -R 6 and R 12 are defined herein. The present invention also relates to the discovery that compounds having Formula I are activators of caspases and inducers of apoptosis. The compounds of this invention may be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

What is claimed is:  
     
         1 . A method of treating a disorder responsive to the induction of apoptosis in an animal suffering therefrom, comprising administering to an animal in need of such treatment an effective amount of a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 X is O, S, or N—R 1 ;  
 R 1  is hydrogen or optionally substituted alkyl;  
 R 2 -R 6  are independently hydrogen, halo, nitro or cyano; or haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, amino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol, each of which is optionally substituted;  
 R 12  is hydrogen or optionally substituted alkyl; and  
 Ar 1  is optionally substituted and is aryl or heteroaryl.  
 
     
     
         2 . The method of  claim 1 , wherein said animal is a mammal.  
     
     
         3 . The method of  claim 1 , wherein X is N—R 1 .  
     
     
         4 . The method of  claim 1 , wherein said compound has the Formula II:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein 
 R 1  and R 12  are independently hydrogen or optionally substituted alkyl; and  
 R 2 -R 11  are independently hydrogen, halo, nitro or cyano; or haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, amino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol, each of which is optionally substituted.  
 
     
     
         5 . The method of  claim 4 , wherein R 1  is hydrogen.  
     
     
         6 . The method of  claim 4 , wherein R 12  is hydrogen.  
     
     
         7 . The method of  claim 4 , wherein R 2  is optionally substituted alkyl or optionally substituted phenyl.  
     
     
         8 . The method of  claim 4 , wherein R4 is halo, nitro or cyano; or haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, amino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol, each of which is optionally substituted.  
     
     
         9 . The method of  claim 4 , wherein one or two of R 7 -R 11  is a hydroxy group.  
     
     
         10 . The method of  claim 1 , wherein said compound is selected from the group consisting of: 
 5-Chloro-3-methyl-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide;    3,5-Dimethyl-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide;    3,5-Dimethyl-indole-2-carboxylic acid (4-bromobenzylidene)-hydrazide;    5-Chloro-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide;    5-Chloro-indole-2-carboxylic acid (2-naphthylmethene)-hydrazide;    5-Chloro-benzo[b]thiophene-2-carboxylic acid (2-naphthylmethene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-methoxybenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (2-hydroxybenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-dimethylaminobenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide;    5-Chloro-3-phenyl-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide;    3-Methyl-5-ethoxy-7-nitro-indole-2-carboxylic acid (4-bromobenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (3-nitrobenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid benzylidene-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-methylbenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-chlorobenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (3-methylbenzylidene)-hydrazide;    3-Methyl-5-nitro-indole-2-carboxylic acid (4-chlorobenzylidene)-hydrazide;    5-Chloro-3-phenyl-indole-2-carboxylic acid (4-methoxybenzylidene)-hydrazide;    5-Bromo-3-phenyl-indole-2-carboxylic acid (4-methoxybenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (4-chlorobenzylidene)-hydrazide;    5-Chloro-3-phenyl-indole-2-carboxylic acid (4-bromobenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (3-chlorobenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (3-bromobenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (4-methoxybenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (2,3-dichlorobenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (1-naphthylmethene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (3,4-dimethoxybenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (3,4-methylenedioxybenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-(trifluoromethyl)benzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-methyl-α-methylbenzylidene)-hydrazide;    5-Chloro-3-phenyl-indole-2-carboxylic acid (3-indolylmethene)-hydrazide;    5-Chloro-3-phenyl-indole-2-carboxylic acid (2-chlorobenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (4-methoxybenzylidene)-hydrazide;    3-Amino-indole-2-carboxylic acid (4-methylbenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid N′-(4-methylbenzyl)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (4-methylbenzylidene)-hydrazide;    5-Bromo-3-phenyl-indole-2-carboxylic acid (2-chlorobenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (2,4-dimethoxybenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (2,3,4-trimethoxybenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (4-fluorobenzylidene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (4-dimethylaminobenzylidene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (3-(chloromethyl)benzylidene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (4-(chloromethyl)benzylidene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (4-hydroxybenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-(chloromethyl)benzylidene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (4(5)-imidazolylmethene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (N-oxide-4-pyridylmethene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (4-pyridylmethene)-hydrazide;    5-Chloro-indole-2-carboxylic acid (3-nitrobenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-carboxybenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (2-methylbenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (3-hydroxybenzylidene)-hydrazide;    5-Bromo-3-phenyl-indole-2-carboxylic acid (benzylidene)-hydrazide;    5-Chloro-3-phenyl-indole-2-carboxylic acid (benzylidene)-hydrazide;    5-Bromo-3-phenyl-indole-2-carboxylic acid (4-bromobenzylidene)-hydrazide;    3,5-Dimethyl-indole-2-carboxylic acid (2-hydroxybenzylidene)-hydrazide; and    3-Methyl-7-nitro-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide.    
     
     
         11 . A method for treating or preventing cancer, comprising administering to an animal in need of such treatment an effective amount of a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 X is O, S, or N—R 1 ;  
 R 1  is hydrogen or optionally substituted alkyl;  
 R 2 -R 6  are independently hydrogen, halo, nitro or cyano; or haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, amino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol, each of which is optionally substituted;  
 R 12  is hydrogen or optionally substituted alkyl; and  
 Ar 1  is optionally substituted and is aryl or heteroaryl.  
 
     
     
         12 . The method of  claim 11 , wherein said animal is a mammal.  
     
     
         13 . The method of  claim 11 , wherein said cancer is selected from the group consisting of Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoides, head or neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer and prostatic carcinoma.  
     
     
         14 . A method for the treatment of drug resistant cancer, comprising administering to an animal in need of such treatment an effective amount of a compound of the Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 X is O, S, or N—R 1 ;  
 R 1  is hydrogen or optionally substituted alkyl;  
 R 2 -R 6  are independently hydrogen, halo, nitro or cyano; or haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, amino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol, each of which is optionally substituted;  
 R 12  is hydrogen or optionally substituted alkyl; and  
 Ar 1  is optionally substituted and is aryl or heteroaryl.  
 
     
     
         15 . The method of  claim 14 , wherein said animal is a mammal.  
     
     
         16 . The method of  claim 11  or  14 , additionally comprising administering at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent.  
     
     
         17 . The method of  claim 16 , wherein said known cancer therapeutic agent is selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2′-deoxy-uridine, ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Herceptin®, Rituxan® and alanosine.  
     
     
         18 . The method of  claim 11  or  14 , additionally comprising treating said animal with radiation-therapy.  
     
     
         19 . The method of  claim 11  or  14 , wherein said compound is administered after surgical treatment of said animal for cancer.  
     
     
         20 . The method of  claim 1 , wherein said disorder is an autoimmune disease.  
     
     
         21 . The method of  claim 1 , wherein said disorder is rheumatoid arthritis.  
     
     
         22 . The method of  claim 1 , wherein said disorder is inflammation.  
     
     
         23 . The method of  claim 1 , wherein said disorder is inflamatory bowel disease  
     
     
         24 . The method of  claim 1 , wherein said disorder is Crohn's disease.  
     
     
         25 . The method of  claim 1 , wherein said disorder is ulcerative colitis.  
     
     
         26 . The method of  claim 1 , wherein said disorder is a skin disease.  
     
     
         27 . The method of  claim 26 , wherein said disorder is psoriasis.  
     
     
         28 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 X is O, S, or N—R 1 ;  
 R 1  is hydrogen or optionally substituted alkyl;  
 R 2 -R 6  are independently hydrogen, halo, nitro or cyano; or haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, amino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol, each of which is optionally substituted;  
 R 12  is hydrogen or optionally substituted alkyl; and  
 Ar 1  is optionally substituted and is aryl or heteroaryl;  
 with the proviso that when X is NH and R 2  is unsubstituted methyl or unsubstituted phenyl, then Ar 1  is other than 2-hydroxyphenyl or 2-hydroxy-5-methylphenyl.  
 
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein said compound is selected from the group consisting of: 
 5-Chloro-3-methyl-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide;    3,5-Dimethyl-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide;    3,5-Dimethyl-indole-2-carboxylic acid (4-bromobenzylidene)-hydrazide;    5-Chloro-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide;    5-Chloro-indole-2-carboxylic acid (2-naphthylmethene)-hydrazide;    5-Chloro-benzo[b]thiophene-2-carboxylic acid (2-naphthylmethene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-methoxybenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (2-hydroxybenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-dimethylaminobenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide;    5-Chloro-3-phenyl-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide;    3-Methyl-5-ethoxy-7-nitro-indole-2-carboxylic acid (4-bromobenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (3-nitrobenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid benzylidene-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-methylbenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-chlorobenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (3-methylbenzylidene)-hydrazide;    3-Methyl-5-nitro-indole-2-carboxylic acid (4-chlorobenzylidene)-hydrazide;    5-Chloro-3-phenyl-indole-2-carboxylic acid (4-methoxybenzylidene)-hydrazide;    5-Bromo-3-phenyl-indole-2-carboxylic acid (4-methoxybenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (4-chlorobenzylidene)-hydrazide;    5-Chloro-3-phenyl-indole-2-carboxylic acid (4-bromobenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (3-chlorobenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (3-bromobenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (4-methoxybenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (2,3-dichlorobenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (1-naphthylmethene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (3,4-dimethoxybenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (3,4-methylenedioxybenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-(trifluoromethyl)benzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-methyl-α-methylbenzylidene)-hydrazide;    5-Chloro-3-phenyl-indole-2-carboxylic acid (3-indolylmethene)-hydrazide;    5-Chloro-3-phenyl-indole-2-carboxylic acid (2-chlorobenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (4-methoxybenzylidene)-hydrazide;    3-Amino-indole-2-carboxylic acid (4-methylbenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid N′-(4-methylbenzyl)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (4-methylbenzylidene)-hydrazide;    5-Bromo-3-phenyl-indole-2-carboxylic acid (2-chlorobenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (2,4-dimethoxybenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (2,3,4-trimethoxybenzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (4-fluorobenzylidene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (4-dimethylaminobenzylidene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (3-(chloromethyl)benzylidene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (4-(chloromethyl)benzylidene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (4-hydroxybenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-(chloromethyl)benzylidene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (4(5)-imidazolylmethene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (N-oxide-4-pyridylmethene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (4-pyridylmethene)-hydrazide;    5-Chloro-indole-2-carboxylic acid (3-nitrobenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-carboxybenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (2-methyl-benzylidene)-hydrazide;    5-Nitro-3-phenyl-indole-2-carboxylic acid (3-hydroxybenzylidene)-hydrazide;    5-Bromo-3-phenyl-indole-2-carboxylic acid (benzylidene)-hydrazide;    5-Chloro-3-phenyl-indole-2-carboxylic acid (benzylidene)-hydrazide;    5-Bromo-3-phenyl-indole-2-carboxylic acid (4-bromobenzylidene)-hydrazide;    3,5-Dimethyl-indole-2-carboxylic acid (2-hydroxybenzylidene)-hydrazide; and    3-Methyl-7-nitro-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide.    
     
     
         30 . The pharmaceutical composition of  claim 28  or 29, additionally comprising at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent.  
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein said known cancer therapeutic agent is selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2′-deoxy-uridine, ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Herceptin®, Rituxan® and alanosine.  
     
     
         32 . A compound of Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 X is S;  
 Ar 1  is optionally substituted and is aryl or heteroaryl.  
 R 2 -R 6  are independently hydrogen, halo, nitro or cyano; or haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, amino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol, each of which is optionally substituted; and  
 R 12  is hydrogen or optionally substituted alkyl.  
 
     
     
         33 . The compound of  claim 32 , wherein Ar 1  is selected from the group consisting of phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, thienyl, furyl and pyrrolyl, each of which is optionally substituted.  
     
     
         34 . The compound of  claim 33 , wherein Ar 1  is optionally substituted naphthyl.  
     
     
         35 . The compound of  claim 34 , wherein said compound is 5-chloro-benzo[b]thiophene-2-carboxylic acid (2-naphthylmethene)-hydrazide.  
     
     
         36 . A compound of Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 X is N—R 1 ;  
 Ar 1  is optionally substituted imidazolyl or optionally substituted pyridyl;  
 R 1  is hydrogen or optionally substituted alkyl;  
 R 2 -R 6  are independently hydrogen, halo, nitro or cyano; or haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, amino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol, each of which is optionally substituted; and  
 R 12  is hydrogen or optionally substituted alkyl.  
 
     
     
         37 . The compound of  claim 36 , wherein said compound is selected from the group consisting of: 
 5-Methyl-3-phenyl-indole-2-carboxylic acid (4(5)-imidazolylmethene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (N-oxide-4-pyridylmethene)-hydrazide; and    5-Methyl-3-phenyl-indole-2-carboxylic acid (4-pyridylmethene)-hydrazide.    
     
     
         38 . A compound of Formula II:  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts or prodrugs thereof, wherein 
 R 1  and R 12  are independently hydrogen or optionally substituted alkyl; and  
 R 2 -R 11  are independently hydrogen, halo, nitro or cyano; or haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, amino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol, each of which is optionally substituted;  
 wherein at least one of R 7 -R 11  is carboxy or haloalkyl.  
 
     
     
         39 . The compound of  claim 38 , wherein at least one of R 7 -R 11  is carboxy.  
     
     
         40 . The compound of  claim 39 , wherein said compound is 5-chloro-3-methyl-indole-2-carboxylic acid (4-carboxybenzylidene)-hydrazide.  
     
     
         41 . The compound of  claim 38 , wherein at least one of R 7 -R 11  is haloalkyl.  
     
     
         42 . The compound of  claim 41 , wherein said compound is selected from the group consisting of: 
 5-Chloro-3-methyl-indole-2-carboxylic acid (4-(trifluoromethyl)benzylidene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (3-(chloromethyl)benzylidene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (4-(chloromethyl)benzylidene)-hydrazide; and    5-Chloro-3-methyl-indole-2-carboxylic acid (4-(chloromethyl)benzylidene)-hydrazide.    
     
     
         43 . A compound of Formula II:  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts or prodrugs thereof, wherein 
 R 1  and R 12  are independently hydrogen or optionally substituted alkyl;  
 R 2 -R 6  are independently hydrogen, halo, nitro or cyano; or haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, amino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol, each of which is optionally substituted; and  
 R 7 -R 11  are independently hydrogen or unsubstituted alkyl.  
 
     
     
         44 . The compound of  claim 43 , wherein said compound is selected from the group consisting of: 
 5-Chloro-3-methyl-indole-2-carboxylic acid (4-methylbenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (3-methylbenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (2-methylbenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid (4-methyl-α-methylbenzylidene)-hydrazide;    3-Amino-indole-2-carboxylic acid (4-methylbenzylidene)-hydrazide;    5-Chloro-3-methyl-indole-2-carboxylic acid N′-(4-methylbenzyl)-hydrazide; and    5-Methyl-3-phenyl-indole-2-carboxylic acid (4-methylbenzylidene)-hydrazide.    
     
     
         45 . A compound, selected from the group consisting of: 
 5-Chloro-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide;    5-Chloro-indole-2-carboxylic acid (3-nitrobenzylidene)-hydrazide;    5-Chloro-indole-2-carboxylic acid (2-naphthylmethene)-hydrazide;    5-Methyl-3-phenyl-indole-2-carboxylic acid (4-hydroxybenzylidene)-hydrazide; and    5-Methyl-3-phenyl-indole-2-carboxylic acid (4-dimethylaminobenzylidene)-hydrazide.    
     
     
         46 . A pharmaceutical composition, comprising the compound of any one of claims  32 ,  36 ,  38 ,  43  and  45 , and a pharmaceutically acceptable carrier.  
     
     
         47 . The pharmaceutical composition of  claim 46 , further comprising at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent.  
     
     
         48 . The pharmaceutical composition of  claim 47 , wherein said known cancer chemotherapeutic agent is selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2′-deoxy-uridine, ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Herceptin®, Rituxan® and alanosine.