Histone acetyltransferase activators and uses thereof

Abstract

The invention provides compounds and compositions comprising compounds that modulate histone acyl transferase (HAT). The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a compound that modulates HAT to a subject.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, 
         wherein, 
         X is NH or —N(CH 3 )—; 
         R 1  is OH, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—(C 1 -C 6 -alkyl), or —O—(C 1 -C 6 -haloalkyl); 
         R 2  is OH, halogen, —O—(C 2 -C 6 -alkyl)-N(R 5 ) 2 , —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen − , —N(R 5 )—(C 2 -C 6 -alkyl)-N(R 5 ) 2 , or —O—(C 1 -C 6 -alkyl)-phenyl; 
         wherein 
         when R 1  is OH, R 2  is OH, —O—(C 1 -C 6 -alkyl)-phenyl, or —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen − ; 
         when R 1  is C 1 -C 6 -alkyl, R 2  is —O—(C 1 -C 6 -alkyl)-phenyl or —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen − ; 
         when R 1  is —O—(C 1 -C 6 -alkyl), R 2  is halogen, —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen − , or —O—(C 1 -C 6 -alkyl)-phenyl; and 
         wherein R 1  and R 2  are not both H; or 
         R 2  and X together with the atoms to which they are attached form 
       
       
         
           
           
               
               
           
         
       
       wherein R 1a  is OH; or
 R 2  and X together with the atoms to which they are attached form 
 
       
         
           
           
               
               
           
         
       
       wherein Y is —(C 1 -C 6 -alkyl);
 R 1b  is OH, O—(C 1 -C 6 -alkyl), —O—(C 2 -C 6 -alkyl)-N(R 5 ) 2 , or —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen − ; 
 R 3  is halogen or C 1 -C 2 -haloalkyl; 
 R 4  is halogen or C 1 -C 2 -haloalkyl; or 
 R 2  and X together with the atoms to which they are attached form 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 1c  is OH, O—(C 1 -C 6 -alkyl), —O—(C 2 -C 6 -alkyl)-N(R 5 ) 2 , or —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen − ; 
 R 3  is halogen or C 1 -C 2 -haloalkyl; 
 R 4  is halogen or C 1 -C 2 -haloalkyl; 
    is a double bond and R 6  is O, or 
    is a single bond and R 6  is —(C 1 -C 6 -alkyl), —(C 1 -C 6 -alkyl)-N(R 5 ) 2 , or —(C 1 -C 6 -alkyl)-N(R 5 ) 3   + halogen − ; and 
 R 5  is independently H or C 1 -C 4 -alkyl; or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein
 X is NH or —N(CH 3 )—;   R 1  is OH, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—(C 1 -C 6 -alkyl), or —O—(C 1 -C 6 -haloalkyl);   R 2  is OH, —O—(C 2 -C 6 -alkyl)-N(R 5 ) 2 , —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen − , —N(R 5 )—(C 2 -C 6 -alkyl)-N(R 5 ) 2 , or —O—(C 1 -C 6 -alkyl)-phenyl;   wherein when R 1  is OH, R 2  is OH, —O—(C 1 -C 6 -alkyl)-phenyl, or —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen − ;   when R 1  is C 1 -C 6 -alkyl, R 2  is —O—(C 1 -C 6 -alkyl)-phenyl or —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen − ; when R 1  is —O—(C 1 -C 6 -alkyl), R 2  is halogen, —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen −  or —O—(C 1 -C 6 -alkyl)-phenyl; and   wherein R 1  and R 2  are not both H; or   R 2  and X together with the atoms to which they are attached form   
       
         
           
           
               
               
           
         
       
       wherein R 1a  is OH; or
 R 2  and X together with the atoms to which they are attached form 
 
       
         
           
           
               
               
           
         
       
       wherein R 1b  is OH, O—(C 1 -C 6 -alkyl), or —O—(C 2 -C 6 -alkyl)-N(R 5 ) 2 ;
 R 3  is halogen or C 1 -C 2 -haloalkyl; 
 R 4  is halogen or C 1 -C 2 -haloalkyl; and 
 R 5  is independently H or C 1 -C 4 -alkyl. 
 
     
     
         3 . The compound of  claim 1 , wherein 
       R 1  is OH, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—(C 1 -C 6 -alkyl), or —O—(C 1 -C 6 -haloalkyl); and
 R 2  is OH, —O—(C 2 -C 6 -alkyl)-N(R 5 ) 2 , —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen − , —N(R 5 )—(C 2 -C 6 -alkyl)-N(R 5 ) 2 , or —O—(C 1 -C 6 -alkyl)-phenyl; 
 wherein when R 1  is OH, R 2  is OH, —O—(C 1 -C 6 -alkyl)-phenyl, or —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen − ; 
 when R 1  is C 1 -C 6 -alkyl, R 2  is —O—(C 1 -C 6 -alkyl)-phenyl or —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen − ; 
 when R 1  is —O—(C 1 -C 6 -alkyl), R 2  is halogen, —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen −  or —O—(C 1 -C 6 -alkyl)-phenyl; 
 and wherein R 1  and R 2  are not both H. 
 
     
     
         4 . The compound of  claim 3 , wherein
 R 1  is OH, or C 1 -C 6 -alkyl; and   R 2  is OH, —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen − , or —O—(C 1 -C 6 -alkyl)-phenyl;   wherein when R 1  is OH, R 2  is OH, —O—(C 1 -C 6 -alkyl)-phenyl, or —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen − ; and   when R 1  is C 1 -C 6 -alkyl, R 2  is OH, —O—(C 1 -C 6 -alkyl)-phenyl, or —O—(C 2 -C 6 -alkyl)-N(R 5 ) 3   + halogen − .   
     
     
         5 . The compound of  claim 4 , wherein
 R 1  is OH, or C 1 -C 2 -alkyl; and   R 2  is OH, or —O—(C 1 -C 3 -alkyl)-phenyl;   wherein when R 1  is OH, R 2  is OH or —O—(C 1 -C 3 -alkyl)-phenyl; and   when R 1  is C 1 -C 2 -alkyl, R 2  is —O—(C 1 -C 3 -alkyl)-phenyl.   
     
     
         6 . The compound of  claim 1 , wherein
 R 2  and X together with the atoms to which they are attached form   
       
         
           
           
               
               
           
         
       
       wherein R 1a  is OH; or
 R 2  and X together with the atoms to which they are attached form 
 
       
         
           
           
               
               
           
         
       
       wherein R 1b  is OH, O—(C 1 -C 6 -alkyl), or —O—(C 2 -C 6 -alkyl)-N(R 5 ) 2 . 
     
     
         7 . The compound of  claim 6 , wherein
 R 2  and X together with the atoms to which they are attached form   
       
         
           
           
               
               
           
         
       
       wherein R 1a  is OH. 
     
     
         8 . The compound of  claim 6 , wherein
 R 2  and X together with the atoms to which they are attached form   
       
         
           
           
               
               
           
         
       
       wherein R 1b  is OH, O—(C 1 -C 6 -alkyl), or —O—(C 2 -C 6 -alkyl)-N(R 5 ) 2 . 
     
     
         9 . The compound of  claim 1 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 9 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 9 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 11 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 9 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 14 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         15 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier. 
     
     
         16 . A method for reducing amyloid beta (Aβ) protein deposits in a subject, the method comprising:
 administering to the subject an effective amount of a composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof 
 thereby decreasing Aβ protein deposits in the subject. 
 
     
     
         17 . The method of  claim 16 , wherein the subject exhibits abnormally elevated levels of amyloid beta plaques. 
     
     
         18 . The method of  claim 17  wherein the subject is afflicted with Alzheimer's disease, Lewy body dementia, inclusion body myositis, or cerebral amyloid angiopathy. 
     
     
         19 . A method for treating a neurodegenerative disease in a subject, the method comprising administering to a subject a therapeutic amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         20 . The method of  claim 19 , wherein the neurodegenerative disease comprises Adrenoleukodystrophy (ALD), Alcoholism, Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig's Disease), Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjögren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, Familial fatal insomnia, Frontotemporal lobar degeneration, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, Lewy body dementia, Neuroborreliosis, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple System Atrophy, Multiple sclerosis, Narcolepsy, Niemann Pick disease, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick's disease, Primary lateral sclerosis, Prion diseases, Progressive Supranuclear Palsy, Rett's syndrome, Tau-positive FrontoTemporal dementia, Tau-negative FrontoTemporal dementia, Refsum's disease, Sandhoff disease, Schilder's disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Spielmeyer-Vogt-Sjogren-Batten disease, Batten disease, Spinocerebellar ataxia, Spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabes  dorsalis , or Toxic encephalopathy. 
     
     
         21 . The method of  claim 19 , wherein the neurodegenerative disease is selected from Alzheimer's Disease, ALS, Parkinson's Disease, and Huntington's Disease. 
     
     
         22 . The method of  claim 19 , wherein the neurodegenerative disease is Alzheimer's Disease. 
     
     
         23 . The method of  claim 16 , wherein the neurodegenerative disease is Huntington's Disease. 
     
     
         24 . A method for increasing memory retention in a subject afflicted with a neurodegenerative disease, the method comprising administering to a subject a therapeutic amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         25 . The method of  claim 24 , wherein the neurodegenerative disease comprises Adrenoleukodystrophy (ALD), Alcoholism, Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig's Disease), Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjögren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, Familial fatal insomnia, Frontotemporal lobar degeneration, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, Lewy body dementia, Neuroborreliosis, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple System Atrophy, Multiple sclerosis, Narcolepsy, Niemann Pick disease, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick's disease, Primary lateral sclerosis, Prion diseases, Progressive Supranuclear Palsy, Rett's syndrome, Tau-positive FrontoTemporal dementia, Tau-negative FrontoTemporal dementia, Refsum's disease, Sandhoff disease, Schilder's disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Spielmeyer-Vogt-Sjogren-Batten disease, Batten disease, Spinocerebellar ataxia, Spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabes  dorsalis , or Toxic encephalopathy. 
     
     
         26 . The method of  claim 24 , wherein the neurodegenerative disease is Alzheimer's Disease. 
     
     
         27 . A method for treating cancer in a subject, the method comprising administering to a subject a therapeutic amount of a compound of any of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         28 . The method of  claim 27 , wherein the cancer comprises B cell lymphoma, colon cancer, lung cancer, renal cancer, bladder cancer, T cell lymphoma, myeloma, leukemia, chronic myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, acute lymphocytic leukemia, hematopoietic neoplasias, thymoma, lymphoma, sarcoma, lung cancer, liver cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, uterine cancer, renal cell carcinoma, hepatoma, adenocarcinoma, breast cancer, pancreatic cancer, liver cancer, prostate cancer, head and neck carcinoma, thyroid carcinoma, soft tissue sarcoma, ovarian cancer, primary or metastatic melanoma, squamous cell carcinoma, basal cell carcinoma, brain cancer, angiosarcoma, hemangiosarcoma, bone sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, testicular cancer, uterine cancer, cervical cancer, gastrointestinal cancer, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, Waldenstroom's macroglobulinemia, papillary adenocarcinomas, cystadenocarcinoma, bronchogenic carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, lung carcinoma, epithelial carcinoma, cervical cancer, testicular tumor, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, retinoblastoma, leukemia, melanoma, neuroblastoma, small cell lung carcinoma, bladder carcinoma, lymphoma, multiple myeloma, follicular lymphoma or medullary carcinoma. 
     
     
         29 . The method of  claim 27 , wherein the cancer is colon cancer, lung cancer, renal cancer, leukemia, CNS cancer, melanoma, ovarian cancer, breast cancer, or prostate cancer. 
     
     
         30 . The method of  claim 28 , wherein the cancer is colon cancer, renal cancer, T cell leukemia, myeloma, leukemia, acute myeloid leukemia, acute lymphocytic leukemia, renal cell carcinoma, adenocarcinoma, glioblastoma, breast carcinoma, prostate carcinoma, or lung carcinoma. 
     
     
         31 . The method of  claim 28 , wherein the cancer is Hodgkin's lymphoma, non-Hodgkin's lymphoma, B cell lymphoma, T cell lymphoma, or follicular lymphoma. 
     
     
         32 . The method of  claim 31 , wherein the B cell lymphoma is diffuse large B-cell lymphoma. 
     
     
         33 . The method of  claim 32 , wherein the diffuse large B-cell lymphoma is a germinal center-derived diffuse large B cell lymphoma, an activated B-cell-derived (ABC) diffuse large B-cell lymphoma, or a non-germinal center diffuse large B cell lymphoma. 
     
     
         34 . The method of  claim 27 , wherein the compound increases p53 acetylation. 
     
     
         35 . The method of  claim 27 , wherein the compound increases Bcl6 acetylation.