Histone Acetyltransferase Activators and Uses Thereof

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 . (canceled)

13 . (canceled)

14 . (canceled)

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 the pharmaceutical composition of claim 15 ,

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 Huntington's disease, 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 the subject a therapeutic amount of the pharmaceutical composition of claim 15 .

20 . The method of claim 19 , wherein the neurodegenerative disease is selected from 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, and 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 . (canceled)

23 . (canceled)

24 . A method for increasing memory retention in a subject afflicted with a neurodegenerative disease, the method comprising administering to the subject a therapeutic amount of the pharmaceutical composition of claim 15 .

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 the subject a therapeutic amount of the pharmaceutical composition of claim 15 .

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 . (canceled)

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 . (canceled)

33 . (canceled)

34 . The method of claim 27 , wherein the compound increases p53 acetylation.

35 . The method of claim 27 , wherein the compound increases Bcl6 acetylation.

36 . A compound of formula (I) having the following structure:

or a pharmaceutically acceptable salt thereof.