Histone acetyltransferase modulators 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 hat modulates HAT to a subject.

1 . A method for treating cancer, the method comprising administering to a subject in need thereof, a therapeutic amount of a compound of Formula (I) or a pharmaceutical composition comprising a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein, 
         Ar is 
       
       
         
           
           
               
               
           
         
         R a  is H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, O—(C 1 -C 6 -alkyl), O—(C 1 -C 6 -haloalkyl), halogen, CN, or NO 2 ; 
         R b  is H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 8 -cycloalkyl, C 2 -C 6 -heteroalkyl, C 3 -C 8 -heterocycloalkyl, aryl, heteroaryl, O—(C 1 -C 6 -alkyl), O—(C 3 -C 8 -cycloalkyl), O—(C 2 -C 6 -alkenyl), O—(C 3 -C 8 -heterocycloalkyl), N(R 10 )—(C 1 -C 6 -alkyl), N(R 10 )—(C 3 -C 8 -cycloalkyl), S—(C 1 -C 6 -alkyl), O—(C 2 -C 6 -alkyl)-N(R 10 ) 2 , O—(C 3 -C 8 -cycloalkyl)-N(R 10 ) 2 , N(R 10 )—(C 2 -C 6 -alkyl)-N(R 10 ) 2 , —(C 1 -C 6 -alkyl)-N(R 10 ) 2 , —(C 1 -C 6 -alkyl)-R 3 , O—(C 1 -C 6 -alkyl)-R 3 , O—(C 3 -C 8 -cycloalkyl)-R 3 , N(R 10 )—(C 1 -C 6 -alkyl)-R 3 , O-aryl, or O-heteroaryl; 
         R c  is H, —(C 1 -C 6 -alkyl), O—(C 1 -C 6 -alkyl), C(═O)NH-phenyl, wherein phenyl is substituted with one or more halo or haloalkyl; 
         R d  is H, OH, —(C 1 -C 6 -alkyl), O—(C 3 -C 8 -cycloalkyl), O—(C 3 -C 8 -heterocycloalkyl), O—(C 2 -C 6 -alkenyl), O—(C 1 -C 6 -alkyl), O—(C 2 -C 6 -alkyl)-N(R 10 ) 2 , —(C 1 -C 6 -alkyl)-R 3 , O—(C 1 -C 6 -alkyl)-R 3 , N(R 10 )—(C 1 -C 6 -alkyl)-R 3 , —N(R 10 )—(C 1 -C 6 -alkyl), —N(R 10 )—(C 2 -C 6 -alkenyl), —N(R 10 )—(C 3 -C 8 -cycloalkyl), —N(R 10 )—(C 3 -C 8 -heterocycloalkyl), N(R 10 )—(C 2 -C 6 -alkyl)-N(R 10 ) 2 , —(C 1 -C 6 -alkyl)-N(R 10 ) 2 , S—(C 2 -C 6 -alkyl)-N(R 10 ) 2 , OCH 2 C(O)O-alkyl, O-aryl, N-aryl, O-heteroaryl, or N-heteroaryl; 
         W and Z are independently N or CR 1 ; 
         X is —CO—, —CON(R 10 )—, —CON(R 10 )(CH 2 ) n , —(CH 2 )CON(R 10 )—, —(CH 2 ) n CON(R 10 )(CH 2 ) n —, —SON(R 10 )—, —SON(R 10 )(CH 2 ) n —, —SO 2 N(R 10 )—, —SO 2 N(R 10 )(CH 2 ) n —, —N(R 10 )C(═O)N(R 10 )—, —N(R 10 )CO—, —N(R 10 )CO(CH 2 ) n —, or —N(R 10 )CO(CH 2 ) n —, —(CH 2 )N(R 10 )—, —C═N—; or 
         Ar and X together form 
       
       
         
           
           
               
               
           
         
         Y is N or CR 2 ; 
         R 1  is H, halogen, O—(C 1 -C 6 -alkyl), O—(C 2 -C 6 -alkyl)N(R 10 ) 2 ; 
         R 2  is H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, O—(C 1 -C 6 -alkyl), O—(C 1 -C 6 -haloalkyl), halogen, CN, or NO 2 ; 
         R 3  is cycloalkylamino, optionally containing a heteroatom selected from N(R 10 ), O and S; 
         R 10  is independently H, —(C 1 -C 4 -alkyl), —(C 1 -C 4 -haloalkyl), —(C 3 -C 8 -cycloalkyl), —(C 3 -C 8 -heterocycloalkyl), aryl or heteroaryl; and 
         n is an integer from 1-3, or a pharmaceutically acceptable salt thereof; 
         with the proviso that Ar is not 
       
       
         
           
           
               
               
           
         
       
       or
 when 
 
       
         
           
           
               
               
           
         
       
       Ar is not 
       
         
           
           
               
               
           
         
       
       wherein
 W and Z are each CH, R b  is ethoxy, R c  is hydrogen, and R d  is —OCH 2 CH 2 N(CH 3 ) 2  or OH; or 
 W is C—OCH 2 CH 2 N(CH 3 ) 2 , Z is CH, R b  is hydrogen, R c  is hydrogen, and R d  is hydrogen; or 
 W and Z are each CH, R b  is cyclopentyloxy, R c  is hydrogen, and R d  is —OCH 2 CH 2 N(CH 3 ) 2 ; or 
 W and Z are each CH, R b  is —OCH 2 CH 2 N(CH 3 ) 2 , R c  is —C(O)NH-(3-CF 3 , 4-Cl-phenyl), and R d  is —OCH 2 CH 2 N(CH 3 ) 2 ; or 
 W is CH, Z is C-ethoxy, R b  is ethoxy, R c  is —C(O)NH-(3-CF 3 , 4-Cl-phenyl), and R d  is hydrogen; or 
 W and Z are each CH, R b  is —CH 2 CH 2 CH 2 (CH 3 ) 2 , R c  is —C(O)NH-(3-CF 3 , 4-Cl-phenyl), and R d  is —CH 2 CH 2 CH 2 N(CH 3 ) 2  or hydrogen; or 
 W and Z are each CH, R b  is ethoxy, R c  is —C(O)NH-(3-CF 3 , 4-Cl-phenyl), and R d  is hydrogen or —OCH 2 CH 2 N(CH 3 ) 2 ; or 
 W and Z are nitrogen, R b  is ethoxy, R c  is hydrogen, and R d  is-OCH 2 CH 2 N(CH 3 ) 2 ; or 
 when 
 
       
         
           
           
               
               
           
         
       
       Ar is not 
       
         
           
           
               
               
           
         
       
       wherein R b  is ethoxy, or Ar is not 
       
         
           
           
               
               
           
         
       
       wherein
 W and Z are each CH, R b  is —Sethyl, R c  is hydrogen, and R d  is n-pentyl; or 
 when 
 
       
         
           
           
               
               
           
         
       
       Ar is not 
       
         
           
           
               
               
           
         
       
       wherein
 W is CH, Z is nitrogen, R b  is —SCH 3 , R c  is hydrogen, and R d  is n-pentyl; or 
 when 
 
       
         
           
           
               
               
           
         
       
       Ar is not 
       
         
           
           
               
               
           
         
       
       wherein
 W and Z are each CH, R b  is hydrogen, R c  is hydrogen, and R d  is —OCH 2 CH 2 N(CH 3 ) 2 ; or 
 when 
 
       
         
           
           
               
               
           
         
       
       Ar is not 
       
         
           
           
               
               
           
         
       
       wherein
 W and Z are each CH, R b  is ethoxy, R c  is hydrogen, and R d  is —OCH 2 CH 2 N(CH 3 ) 2 ; or 
 when 
 
       
         
           
           
               
               
           
         
       
       Ar is not 
       
         
           
           
               
               
           
         
       
       wherein
 W and Z are each CH, R b  is methoxy, R c  is hydrogen, and R d  is —SCH 2 CH 2 N(CH 3 ) 2 ; or 
 when 
 
       
         
           
           
               
               
           
         
       
       Ar is not 
       
         
           
           
               
               
           
         
       
       wherein
 W and Z are each CH, R b  is —OCH 2 C(O)OR wherein R is H or alkyl, R c  is hydrogen, and R d  is —Sethyl; or 
 when 
 
       
         
           
           
               
               
           
         
       
       Ar is not 
       
         
           
           
               
               
           
         
       
       wherein W and Z are each CH, R b  is ethoxy, R c  is hydrogen, and R d  is —SCH 2 CH 2 N(CH 3 ) 2 . 
     
     
         2 . The method of  claim 1 , wherein the effective amount is at least about 1 mg/kg body weight, at least about 2 mg/kg body weight, at least about 3 mg/kg body weight, at least about 4 mg/kg body weight, at least about 5 mg/kg body weight, at least about 6 mg/kg body weight, at least about 7 mg/kg body weight, at least about 8 mg/kg body weight, at least about 9 mg/kg body weight, at least about 10 mg/kg body weight, at least about 15 mg/kg body weight, at least about 20 mg/kg body weight, at least about 25 mg/kg body weight, at least about 30 mg/kg body weight, at least about 40 mg/kg body weight, at least about 50 mg/kg body weight, at least about 75 mg/kg body weight, or at least about 100 mg/kg body weight. 
     
     
         3 . The method of  claim 1 , 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-Hodgkins lymphoma, Hodgkins 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, or medullary carcinoma. 
     
     
         4 . The method of  claim 1 , wherein the compound increases histone acetylation. 
     
     
         5 . The method of  claim 4 , wherein histone acetylation comprises acetylation of histones H2B, H3, H4, or a combination thereof. 
     
     
         6 . The method of  claim 5 , wherein histone acetylation comprises acetylation of histone lysine residues H3K4, H3K9, H3K14, H4K5, H4K8, H4K12, H4K16, or a combination thereof. 
     
     
         7 . The method of  claim 1 , wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         wherein R d  is —O—(C 1 -C 6 )-alkyl, —NH—(C 1 -C 6 )-alkyl, —O—(C 2 -C 6 )-alkenyl, —NH—(C 2 -C 6 )-alkenyl, —O—(C 3 -C 8 )-cycloalkyl, —NH—(C 3 -C 8 )-cycloalkyl, —O—(C 3 -C 8 )-heterocycloalkyl, —NH—(C 3 -C 8 )-heterocycloalkyl, —O-aryl, —N-aryl, —O-heteroaryl, —N-heteroaryl, —O—(C 1 -C 6 )-alkyl-N(R 10 ) 2 , —NH—(C 1 -C 6 )-alkyl-N(R 10 ) 2 , —O—(C 1 -C 6 -alkyl)-R 3 , or —NH—(C 1 -C 6 -alkyl)-R 3 ; 
         R 3  is cycloalkylamino, optionally containing a heteroatom selected from N(R 10 ), O and S; and 
         R 10  is independently H, —(C 1 -C 4 -alkyl), —(C 1 -C 4 -haloalkyl), —(C 3 -C 8 -cycloalkyl), —(C 3 -C 8 -heterocycloalkyl), aryl or heteroaryl. 
       
     
     
         8 . A method for treating cancer, the method comprising administering to a subject in need thereof, a therapeutic amount of a compound of Formula (I) or a pharmaceutical composition comprising a compound of Formula (I) having any one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . The method of  claim 8 , where the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 8 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 8 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 8 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 8 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 8 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 8 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 8 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 8 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 8 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 8 , wherein the compound is: