Bromodomain inhibitors

Abstract

The present invention provides for compounds of formula (I) wherein A 1 , A 2 , A 3 , A 4 , X 1 , X 2 , Y 1 , L 1 , G 1 , R x , and R y have any of the values defined thereof in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, cancer, and AIDS. Also provided are pharmaceutical compositions comprising one or more compounds of formula (I).

1 - 55 . (canceled) 
     
     
         56 . A method for treating cancer in a subject comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 R x  is hydrogen or C 1 -C 3  alkyl; 
 R y  is C 1 -C 3  alkyl, —(C 2 -C 3  alkylenyl)-OH, or C 1 -C 3  haloalkyl; 
 X 1  is N or CR x1  wherein
 R x1  is hydrogen, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —C(O)OR ax1 , —C(O)NR bx1 R cx1 , —C(O)R dx1 , S(O) 2 R dx1 , —S(O) 2 NR bx1 R cx1 , G x1 , C 1 -C 6  haloalkyl, or C 1 -C 6  alkyl; wherein the C 1 -C 6  alkyl is optionally substituted with one substituent selected from the group consisting of OR ax1 , SR ax1 , S(O)R dx1 , S(O) 2 R dx1 , NR bx1 R cx1 , —C(O)R ax1 , —C(O)OR ax1 , —C(O)NR bx1 R cx1 , —S(O) 2 NR bx1 R cx1 , and G x1 ; 
 R ax1 , R bx1 , and R cx1 , at each occurrence, are each independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, G a , or —(C 1 -C 6  alkylenyl)-G a ; 
 R dx1 , at each occurrence, are each independently C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, G a , or —(C 1 -C 6  alkylenyl)-G a ; 
 
 X 2  is N or CR x2 ; wherein
 R x2  is hydrogen, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —C(O)OR ax2 , —C(O)NR bx2 R cx2 , —C(O)R dx2 , —C(O)H, S(O) 2 R dx2 , —S(O) 2 NR bx2 R cx2 , G x2 , C 1 -C 6  haloalkyl, or C 1 -C 6  alkyl; wherein the C 1 -C 6  alkyl is optionally substituted with one substituent selected from the group consisting of OR ax2 , SR ax2 , S(O)R dx2 , S(O) 2 R dx2 , NR bx2 R cx2 , —C(O)R ax2 , —C(O)OR ax2 , —C(O)NR bx2 R cx2 , —S(O) 2 NR bx2 R cx2 , and G x2 ; 
 R ax2 , R bx2 , and R cx2 , at each occurrence, are each independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, G b , or —(C 1 -C 6  alkylenyl)-G b ; 
 R dx2 , at each occurrence, is independently C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, G b , or —(C 1 -C 6  alkylenyl)-G b ; 
 
 Y 1  is N or CR u ; wherein R u  is hydrogen, C 1 -C 6  alkyl, halogen, or C 1 -C 6  haloalkyl; 
 A 1  is N or CR 1 , A 2  is N or CR 2 , A 3  is N or CR 3 ; and A 4  is N or CR 4 ; with the proviso that zero, one, two, or three of A 1 , A 2 , A 3 , and A 4  are N; 
 R 1 , R 3 , and R 4  are each independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, C 1 -C 6  haloalkyl, CN, or NO 2 ; 
 R 2  is hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, C 1 -C 6  haloalkyl, —CN, NO 2 , G 2a , —OR 2a , —OC(O)R 2d , —OC(O)NR 2b R 2c , —SR 2a , —S(O) 2 R 2d , —S(O) 2 NR 2b R 2c , —C(O)R 2d , —C(O)OR 2a , —C(O)NR 2b R 2c , —NR 2b R 2c , —N(R 2e )C(O)R 2d , —N(R 2e )S(O) 2 R 2d , —N(R 2e )C(O)O(R 2d ), —N(R 2e )C(O)NR 2b R 2c , —N(R 2e )S(O) 2 NR 2b R 2c , —(C 1 -C 6  alkylenyl)-G 2a , —(C 1 -C 6  alkylenyl)-OR 2a , —(C 1 -C 6  alkylenyl)-OC(O)R 2d , —(C 1 -C 6  alkylenyl)-OC(O)NR 2b R 2c , —(C 1 -C 6  alkylenyl)-S(O) 2 R 2d , —(C 1 -C 6  alkylenyl)-S(O) 2 NR 2b R 2c , —(C 1 -C 6  alkylenyl)-C(O)R 2d , —(C 1 -C 6  alkylenyl)-C(O)OR 2a , —(C 1 -C 6  alkylenyl)-C(O)NR 2b R 2c , —(C 1 -C 6  alkylenyl)-NR 2b R 2c , —(C 1 -C 6  alkylenyl)-N(R 2e )C(O)R 2d , —(C 1 -C 6  alkylenyl)-N(R 2e )S(O) 2 R 2d , —(C 1 -C 6  alkylenyl)-N(R 2e )C(O)O(R 2a ), —(C 1 -C 6  alkylenyl)-N(R 2e )C(O)NR 2b R 2c , —(C 1 -C 6  alkylenyl)-N(R 2e )S(O) 2 NR 2b R 2c , and —(C 1 -C 6  alkylenyl)-CN; 
 R 2a , R 2b , R 2c , and R 2e , at each occurrence, are each independently hydrogen, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, G 2b , or C 1 -C 6  alkyl wherein the C 1 -C 6  alkyl is optionally substituted with one substituent selected from the group consisting of —OR z1 , NR z1 R z2 , —C(O)OR z1 , —C(O)NR z1 R z2 , —S(O) 2 R z1 , —S(O) 2 NR z1 R z2 , and G 2b ; 
 R 2d , at each occurrence, is independently C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, G 2b , or C 1 -C 6  alkyl wherein the C 1 -C 6  alkyl is optionally substituted with one substituent selected from the group consisting of —OR z1 , NR z1 R z2 , —C(O)OR z1 , —C(O)NR z1 R z2 , —S(O) 2 R z1 , —S(O) 2 NR z1 R z2 , and G 2b ; 
 R z1  and R z2 , at each occurrence, are each independently hydrogen, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
 G x1 , G x2 , G a , G b , G 2a , and G 2b , at each occurrence, are each independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of R v ; 
 L 1  is absent, CH 2 , C(O), C(H)(OH), (CH 2 ) m O, (CH 2 ) m S(O) n  wherein n is 0, 1, or 2; or (CH 2 ) m N(R z ) wherein R z  is hydrogen, C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, (C 2 -C 3  alkylenyl)-OH, or unsubstituted cyclopropyl; 
 m is 0 or 1; 
 G 1  is C 1 -C 6  alkyl, alkoxyalkyl, G 1a  or —(C 1 -C 6  alkylenyl)-G 1a ; wherein each G 1a  is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each G 1a  is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of R w ; 
 R v  and R w , at each occurrence, are each independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, C 1 -C 6  haloalkyl, —CN, oxo, —OR h , —OC(O)R i , —OC(O)NR j R k , —SR h , —S(O) 2 R h , —S(O) 2 NR j R k , —C(O)R h , —C(O)-monocyclic heterocycle, —C(O)-monocyclic heteroaryl, —C(O)OR h , —C(O)NR j R k , —NR j R k , —N(R h )C(O)R i , —N(R h )S(O) 2 R i , —N(R h )C(O)O(R i ), —N(R h )C(O)NR j R k , —(C 1 -C 6  alkylenyl)-OR h , —(C 1 -C 6  alkylenyl)-OC(O)R i , —(C 1 -C 6  alkylenyl)-OC(O)NR j R k , —(C 1 -C 6  alkylenyl)-S(O) 2 R h , —(C 1 -C 6  alkylenyl)-S(O) 2 NR j R k , —(C 1 -C 6  alkylenyl)-C(O)R h , —(C 1 -C 6  alkylenyl)-C(O)OR h , —(C 1 -C 6  alkylenyl)-C(O)NR j R k , —(C 1 -C 6  alkylenyl)-NR j R k , —(C 1 -C 6  alkylenyl)-N(R h )C(O)R i , —(C 1 -C 6  alkylenyl)-N(R h )S(O) 2 R i , —(C 1 -C 6  alkylenyl)-N(R h )C(O)O(R i ), —(C 1 -C 6  alkylenyl)-N(R h )C(O)NR j R k , or —(C 1 -C 6  alkylenyl)-CN; 
 R h , R j , R k , at each occurrence, are each independently hydrogen, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; and 
 R i , at each occurrence, is independently C 1 -C 6  alkyl or C 1 -C 6  haloalkyl, to a subject in need thereof. 
 
     
     
         57 . The method of  claim 56  wherein the cancer is selected from the group consisting of: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenström's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor. 
     
     
         58 . The method of  claim 56 , further comprising administering a therapeutically effective amount of at least one additional therapeutic agent, wherein the additional therapeutic agent is selected from the group consisting of cytarabine, bortezomib, and 5-azacitidine. 
     
     
         59 - 65 . (canceled)