Dual function molecules for histone deacetylase inhibition and ataxia telangiectasia mutated activation and methods of use thereof

Abstract

Dual function compounds are provided that may be inhibitors of histone deacetylase (HDAC) and activators of ataxia telangiectasia mutated (ATM). Pharmaceutical compositions and methods of use are also provided that utilize such compounds.

What is claimed is: 
     
         1 . A compound comprising the formula: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 3 , R 7  and R 8  are independently selected from the group consisting of H, hydroxy, halogen and, optionally substituted, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, amino, alkoxy, carboxy, carbalkoxy, carboxamido, sulfonyl, sulfinyl, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosufonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl; 
         R 2  and R 9  are independently selected from the group consisting of H and, optionally substituted, sulfinyl, sulfonyl, alkyl, alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl; 
         R 4  is selected from the group consisting of H and optionally substituted alkyl; 
         R 5  is selected from the group consisting of H, and optionally substituted alkyl and indole; 
         R 6  is selected from the group consisting of H and optionally substituted alkyl; 
         X is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein R 10  is selected from the group consisting of H and, optionally substituted, alkyl, alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl;
 n is 0 or 1; r is an integer from 0 to 3; q is an integer from 3 to 10; the dashed line indicates the presence of a single bond or a double bond as allowed; with the proviso that, where X is a substituent other than maleimide or N-carbonylmaleimide and R 5  is a substituent other than indole, then R 3  is a substituent selected from the group consisting of hydroxy, halogen and, optionally substituted, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, amino, alkoxy, carboxy, carbalkoxy, carboxamido, sulfonyl, sulfinyl, monoalkylaminosulfnyl, dialkylaminosulfinyl, monoalkylaminosufonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl, with the dashed line indicating the presence of a double bond; or the pharmaceutically acceptable salts thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein q is an integer from 4 to 6. 
     
     
         3 . The compound of  claim 1 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof. 
     
     
         4 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof. 
     
     
         5 . The compound of  claim 1 , wherein the compound comprises 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound of  claim 1 , wherein the compound comprises the formula: 
       
         
           
           
               
               
           
         
         wherein R 11 , R 13 , R 14 , and R 16  are independently selected from the group consisting of H, hydroxyl, halogen and, optionally substituted, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, amino, alkoxy, carboxy, carbalkoxy, carboxamido, sulfonyl, sulfinyl, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosufonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl; 
         X is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein R 18  is selected from the group consisting of H and, optionally substituted, alkyl, alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl;
 R 12  and R 15  is independently selected from the group consisting of H and, optionally substituted, alkyl, sulfinyl, and sulfonyl; 
 R 17  is selected from the group consisting of H and optionally substituted alkyl; 
 n is an integer from 3 to 10; the dashed line indicates the presence of a single bond or a double bond as allowed; with the proviso that, where X is amide, then R 13  is a substituent selected from the group consisting of hydroxyl, halogen and, optionally substituted, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, amino, alkoxy, carboxy, carbalkoxy, carboxamido, sulfonyl, sulfinyl, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosufonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl, when the dashed line indicates the presence of a double bond; or the pharmaceutically acceptable salts thereof. 
 
     
     
         7 . The compound of  claim 6 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof. 
     
     
         8 . The compound of  claim 6 , wherein the compound comprises 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The compound of  claim 1 , wherein the compound comprises the formula: 
       
         
           
           
               
               
           
         
         wherein R 19  and R 21  are independently selected from the group consisting of H, hydroxyl, halogen and, optionally substituted alkyl, aryl, heterocycle, heteroaryl, sulfonyl, sulfinyl, alkoxy, and amino; 
         X is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein R 23  is selected from the group consisting of H and, optionally substituted, alkyl, alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl;
 R 20  is selected from the group consisting of H and, optionally substituted, alkyl, sulfinyl, and sulfonyl; 
 R 2  is selected from the group consisting of H and optionally substituted alkyl; 
 r is an integer from 0 to 4; q is an integer from 3 to 10; the dashed line indicates the presence of a single bond or a double bond as allowed; with the proviso that, R 21  is 2-alkyl or 3-alkyl with the dashed line indicating the presence of a double bond; or the pharmaceutically acceptable salts thereof. 
 
     
     
         10 . The compound of  claim 9 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof. 
     
     
         11 . The compound of  claim 1 , wherein the compound comprises the formula: 
       
         
           
           
               
               
           
         
         wherein R 24  and R 26  are independently selected from the group consisting of H, hydroxyl, halogen and, optionally substituted alkyl, aryl, heterocycle, heteroaryl, sulfonyl, sulfinyl, alkoxy, and amino; 
         R 25  is selected from the group consisting of H and, optionally substituted, alkyl, sulfinyl, and sulfonyl; 
         R 27  is selected from the group consisting of H and optionally substituted alkyl; m may be an integer from 3 to 10; the dashed line may indicate the presence of a single bond or a double bond as allowed; with the proviso that, R 26  is a substituent selected from the group consisting of hydroxyl, halogen and, optionally substituted alkyl, aryl, heterocycle, heteroaryl, sulfonyl, sulfinyl, alkoxy, and amino, with the dashed line indicating the presence of a double bond; or the pharmaceutically acceptable salts thereof. 
       
     
     
         12 . The compound of  claim 11 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof. 
     
     
         13 . A pharmaceutical formulation comprising a compound of  claim 1  in an amount effective to inhibit histone deacetylase (HDAC) and activate ataxia telangiectasia mutated (ATM) in a patient in need thereof and at least one physiologically compatible carrier medium. 
     
     
         14 . The pharmaceutical formulation of  claim 13 , comprising a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof. 
     
     
         15 . The pharmaceutical formulation of  claim 13 , comprising a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof. 
     
     
         16 . The pharmaceutical formulation of  claim 13 , wherein the compound comprises 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The pharmaceutical formulation of  claim 13 , wherein the compound comprises the formula: 
       
         
           
           
               
               
           
         
         wherein R 11 , R 13 , R 14 , and R 16  are independently selected from the group consisting of H, hydroxyl, halogen and, optionally substituted, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, amino, alkoxy, carboxy, carbalkoxy, carboxamido, sulfonyl, sulfinyl, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosufonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl; 
         X is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein R 18  is selected from the group consisting of H and, optionally substituted, alkyl, alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl;
 R 12  and R 15  is independently selected from the group consisting of H and, optionally substituted, alkyl, sulfinyl, and sulfonyl; 
 R 17  is selected from the group consisting of H and optionally substituted alkyl; 
 n is an integer from 3 to 10; the dashed line indicates the presence of a single bond or a double bond as allowed; with the proviso that, where X is amide, then R 13  is a substituent selected from the group consisting of hydroxyl, halogen and, optionally substituted, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, amino, alkoxy, carboxy, carbalkoxy, carboxamido, sulfonyl, sulfinyl, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosufonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl, when the dashed line indicates the presence of a double bond; or the pharmaceutically acceptable salts thereof. 
 
     
     
         18 . The pharmaceutical formulation of  claim 13 , wherein the compound comprises the formula: 
       
         
           
           
               
               
           
         
         wherein R 19  and R 21  are independently selected from the group consisting of H, hydroxyl, halogen and, optionally substituted alkyl, aryl, heterocycle, heteroaryl, sulfonyl, sulfinyl, alkoxy, and amino; 
         X is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein R 23  is selected from the group consisting of H and, optionally substituted, alkyl, alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl;
 R 20  is selected from the group consisting of H and, optionally substituted, alkyl, sulfinyl, and sulfonyl; 
 R 22  is selected from the group consisting of H and optionally substituted alkyl; 
 r is an integer from 0 to 4; q is an integer from 3 to 10; the dashed line indicates the presence of a single bond or a double bond as allowed; with the proviso that, R 21  is 2-alkyl or 3-alkyl with the dashed line indicating the presence of a double bond; or the pharmaceutically acceptable salts thereof. 
 
     
     
         19 . The pharmaceutical formulation of  claim 13 , wherein the compound comprises the formula: 
       
         
           
           
               
               
           
         
         wherein R 24  and R 26  are independently selected from the group consisting of H, hydroxyl, halogen and, optionally substituted alkyl, aryl, heterocycle, heteroaryl, sulfonyl, sulfinyl, alkoxy, and amino; 
         R 25  is selected from the group consisting of H and, optionally substituted, alkyl, sulfinyl, and sulfonyl; 
         R 27  is selected from the group consisting of H and optionally substituted alkyl; m may be an integer from 3 to 10; the dashed line may indicate the presence of a single bond or a double bond as allowed; with the proviso that, R 26  is a substituent selected from the group consisting of hydroxyl, halogen and, optionally substituted alkyl, aryl, heterocycle, heteroaryl, sulfonyl, sulfinyl, alkoxy, and amino, with the dashed line indicating the presence of a double bond; or the pharmaceutically acceptable salts thereof. 
       
     
     
         20 . A method of treating a disease in a patient in need thereof, wherein said treatment comprises administering a therapeutically effective amount of at least one compound of  claim 1 . 
     
     
         21 . The method of  claim 20 , wherein the at least one compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof. 
     
     
         22 . The method of  claim 20 , wherein the at least one compound comprises 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The method of  claim 20 , wherein the at least one compound comprises the formula: 
       
         
           
           
               
               
           
         
         wherein R 11 , R 13 , R 14 , and R 16  are independently selected from the group consisting of H, hydroxyl, halogen and, optionally substituted, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, amino, alkoxy, carboxy, carbalkoxy, carboxamido, sulfonyl, sulfinyl, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosufonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl; 
         X is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein R 18  is selected from the group consisting of H and, optionally substituted, alkyl, alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl;
 R 12  and R 15  is independently selected from the group consisting of H and, optionally substituted, alkyl, sulfinyl, and sulfonyl; 
 R 17  is selected from the group consisting of H and optionally substituted alkyl; 
 n is an integer from 3 to 10; the dashed line indicates the presence of a single bond or a double bond as allowed; with the proviso that, where X is amide, then R 13  is a substituent selected from the group consisting of hydroxyl, halogen and, optionally substituted, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, amino, alkoxy, carboxy, carbalkoxy, carboxamido, sulfonyl, sulfinyl, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosufonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl, when the dashed line indicates the presence of a double bond; or the pharmaceutically acceptable salts thereof. 
 
     
     
         24 . The method of  claim 23 , wherein the at least one compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof. 
     
     
         25 . The method of  claim 23 , wherein the at least one compound comprises 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The method of  claim 20 , wherein the at least one compound comprises the formula: 
       
         
           
           
               
               
           
         
         wherein R 19  and R 21  are independently selected from the group consisting of H, hydroxyl, halogen and, optionally substituted alkyl, aryl, heterocycle, heteroaryl, sulfonyl, sulfinyl, alkoxy, and amino; 
         X is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein R 23  is selected from the group consisting of H and, optionally substituted, alkyl, alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl;
 R 20  is selected from the group consisting of H and, optionally substituted, alkyl, sulfinyl, and sulfonyl; 
 R 22  is selected from the group consisting of H and optionally substituted alkyl; 
 r is an integer from 0 to 4; q is an integer from 3 to 10; the dashed line indicates the presence of a single bond or a double bond as allowed; with the proviso that, R 21  is 2-alkyl or 3-alkyl with the dashed line indicating the presence of a double bond; or the pharmaceutically acceptable salts thereof. 
 
     
     
         27 . The method of  claim 26 , wherein the at least one compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof. 
     
     
         28 . The method of  claim 20 , wherein the at least one compound comprises the formula: 
       
         
           
           
               
               
           
         
         wherein R 24  and R 26  are independently selected from the group consisting of H, hydroxyl, halogen and, optionally substituted alkyl, aryl, heterocycle, heteroaryl, sulfonyl, sulfinyl, alkoxy, and amino; 
         R 25  is selected from the group consisting of H and, optionally substituted, alkyl, sulfinyl, and sulfonyl; 
         R 27  is selected from the group consisting of H and optionally substituted alkyl; m may be an integer from 3 to 10; the dashed line may indicate the presence of a single bond or a double bond as allowed; with the proviso that, R 26  is a substituent selected from the group consisting of hydroxyl, halogen and, optionally substituted alkyl, aryl, heterocycle, heteroaryl, sulfonyl, sulfinyl, alkoxy, and amino, with the dashed line indicating the presence of a double bond; or the pharmaceutically acceptable salts thereof. 
       
     
     
         29 . The method of  claim 28 , wherein the at least one compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof. 
     
     
         30 . The method of  claim 20 , wherein the compound is administered in dosage unit form. 
     
     
         31 . The method of  claim 30 , wherein the dosage unit includes a physiologically compatible carrier medium. 
     
     
         32 . The method of  claim 20 , wherein the disease is selected from the group consisting of cancer, an immunological disorder, and a neurological disorder. 
     
     
         33 . The method of  claim 32 , wherein said cancer is selected from the group consisting of acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, brain cancer, breast cancer, brochogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharygioma, cystadenocarcinoma, embryonal carcinoma, endotheliocarconima, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebacaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, stomach cancer, sweat gland carcinoma, synovioma, testicular cancer, small cell lung carcinoma, throat cancer, uterine cancer, Wilm's tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, and Waldenstrom's macroglobulinemia. 
     
     
         34 . The method of  claim 33 , wherein said cancer comprises an HPV positive (+) cancer. 
     
     
         35 . The method of  claim 34 , wherein the HPV positive (+) cancer comprises cervical cancer. 
     
     
         36 . The method of  claim 33 , further including the step of administering to said patient an amount of radiotherapy configured to treat said cancer. 
     
     
         37 . The method of  claim 32 , wherein said immunological disorder is selected from the group consisting of systemic lupus erythematosus and rheumatoid arthritis. 
     
     
         38 . The method of  claim 32 , wherein said neurological disorder is selected from the group consisting of stroke, Huntington's disease, spinal muscular atrophy (SMA), Parkinson's disease, Alzheimer's, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis (ALS). 
     
     
         39 . The method of  claim 20 , wherein the method is a second line method of treatment for the patient and administration of the compound occurs after performance of a first line therapy on the patient that failed to treat the disease. 
     
     
         40 . The method of  claim 20 , wherein the method is a third line method of treatment for the patient and administration of the compound occurs after performance of a second line therapy on the patient that failed to treat the disease. 
     
     
         41 . A method of treatment comprising sensitizing cancerous cells to radiotherapy and protecting non-cancerous cells from radiotherapy in a patient in need thereof, wherein cancerous cells are sensitized to radiotherapy by inhibiting histone deacetylase (HDAC) and non-cancerous cells are protected from radiotherapy by activating ataxia telangiectasia mutated (ATM), the method comprising administering a therapeutically effective amount of a compound of  claim 1 . 
     
     
         42 . The method of  claim 41 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof. 
     
     
         43 . The method of  claim 41 , wherein the compound comprises 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         44 . The method of  claim 41 , wherein the method comprises administering a therapeutically effective amount of a compound comprising the formula: 
       
         
           
           
               
               
           
         
         wherein R 11 , R 13 , R 14 , and R 16  are independently selected from the group consisting of H, hydroxyl, halogen and, optionally substituted, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, amino, alkoxy, carboxy, carbalkoxy, carboxamido, sulfonyl, sulfinyl, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosufonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl; 
         X is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein R 18  is selected from the group consisting of H and, optionally substituted, alkyl, alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl;
 R 12  and R 15  is independently selected from the group consisting of H and, optionally substituted, alkyl, sulfinyl, and sulfonyl; 
 R 17  is selected from the group consisting of H and optionally substituted alkyl; 
 n is an integer from 3 to 10; the dashed line indicates the presence of a single bond or a double bond as allowed; with the proviso that, where X is amide, then R 13  is a substituent selected from the group consisting of hydroxyl, halogen and, optionally substituted, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, amino, alkoxy, carboxy, carbalkoxy, carboxamido, sulfonyl, sulfinyl, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosufonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl, when the dashed line indicates the presence of a double bond; or the pharmaceutically acceptable salts thereof. 
 
     
     
         45 . The method of  claim 44 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof. 
     
     
         46 . The method of  claim 44 , wherein the compound comprises 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         47 . The method of  claim 41 , wherein the method comprises administering a therapeutically effective amount of a compound comprising the formula: 
       
         
           
           
               
               
           
         
         wherein R 19  and R 21  are independently selected from the group consisting of H, hydroxyl, halogen and, optionally substituted alkyl, aryl, heterocycle, heteroaryl, sulfonyl, sulfinyl, alkoxy, and amino; 
         X is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein R 23  is selected from the group consisting of H and, optionally substituted, alkyl, alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl;
 R 20  is selected from the group consisting of H and, optionally substituted, alkyl, sulfinyl, and sulfonyl; 
 R 2  is selected from the group consisting of H and optionally substituted alkyl; 
 r is an integer from 0 to 4; q is an integer from 3 to 10; the dashed line indicates the presence of a single bond or a double bond as allowed; with the proviso that, R 21  is 2-alkyl or 3-alkyl with the dashed line indicating the presence of a double bond; or the pharmaceutically acceptable salts thereof. 
 
     
     
         48 . The method of  claim 47 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof. 
     
     
         49 . The method of  claim 41 , wherein the method comprises administering a therapeutically effective amount of a compound comprising the formula: 
       
         
           
           
               
               
           
         
         wherein R 24  and R 26  are independently selected from the group consisting of H, hydroxyl, halogen and, optionally substituted alkyl, aryl, heterocycle, heteroaryl, sulfonyl, sulfinyl, alkoxy, and amino; 
         R 25  is selected from the group consisting of H and, optionally substituted, alkyl, sulfinyl, and sulfonyl; 
         R 27  is selected from the group consisting of H and optionally substituted alkyl; m may be an integer from 3 to 10; the dashed line may indicate the presence of a single bond or a double bond as allowed; with the proviso that, R 26  is a substituent selected from the group consisting of hydroxyl, halogen and, optionally substituted alkyl, aryl, heterocycle, heteroaryl, sulfonyl, sulfinyl, alkoxy, and amino, with the dashed line indicating the presence of a double bond; or the pharmaceutically acceptable salts thereof. 
       
     
     
         50 . The method of  claim 49 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof. 
     
     
         51 . The method of  claim 41 , wherein the compound is administered in dosage unit form. 
     
     
         52 . The method of  claim 51 , wherein the dosage unit includes a pharmaceutically compatible carrier medium. 
     
     
         53 . The method of  claim 41 , wherein the method is a second line method of treatment for the patient and administration of the compound occurs after performance of a first line therapy on the patient. 
     
     
         54 . The method of  claim 41 , wherein the method is a third line method of treatment for the patient and administration of the compound occurs after performance of a second line therapy on the patient. 
     
     
         55 . The method of  claim 41 , wherein the cancerous cells are the result of a cancer selected from the group consisting of acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, brain cancer, breast cancer, brochogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharygioma, cystadenocarcinoma, embryonal carcinoma, endotheliocarconima, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymph angiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebacaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, stomach cancer, sweat gland carcinoma, synovioma, testicular cancer, small cell lung carcinoma, throat cancer, uterine cancer, Wilm's tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, and Waldenstrom's macroglobulinemia. 
     
     
         56 . The method of  claim 41 , comprising the step of administering to said patient an amount of radiotherapy configured to treat the cancerous cells. 
     
     
         57 . The method of  claim 41 , wherein step of administering the therapeutically effective amount of the compound of  claim 1  comprises administering an additional therapeutic agent selected from the group consisting of bortezomib, dexamethasone, and a combination thereof.