Bromodomain inhibitors

Abstract

The present invention provides for compounds of formula (I) wherein R 1 , R 2 , R 6 , Y 1 , Y 2 , A 1 , A 2 , A 3 , and A 4 have any of the values defined 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 - 32 . (canceled) 
     
     
         33 . A method for treating cancer in a subject comprising administering a therapeutically effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is CD 3 , C 1 -C 3  alkyl, or C 1-3  haloalkyl; 
         R 2  is H or C 1-3  alkyl; 
         Y 1  is N or CR 3 ; 
         R 3  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, C 1 -C 6  haloalkyl, —C(O)R 3a , —C(O)OR 3a , —C(O)NR 3b R 3c , —C(O)N(R 3b )NR 3b R 3c , —S(O)R 3d , —S(O) 2 R 3a , —S(O) 2 NR 3b R 3c , or G 1 ; wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G 1 , —C(O)R 3a , —C(O)OR 3a , —C(O)NR 3b R 3c , —S(O)R 3d , —S(O) 2 R 3a , —S(O) 2 NR 3b R 3c , —OR 3a , —OC(O)R 3d , —NR 3b R 3c , N(R 3b )C(O)R 3d , N(R 3b )SO 2 R 3d , N(R 3b )C(O)OR 3d , N(R 3b )C(O)NR 3b R 3c , N(R 3b )SO 2 NR 3b R 3c , and N(R 3b )C(NR 3b R 3c )═NR 3b R 3c ; 
         Y 2  is C(O), S(O) 2 , or CR 4 R 5 ; 
         R 4  is H, deuterium, C 1 -C 6  alkyl, halogen, or C 1 -C 6  haloalkyl; and 
         R 5  is H, deuterium, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, C 1 -C 6  haloalkyl, —C(O)R 5a , —C(O)OR 5a , —C(O)NR 5b R 5c , —S(O)R 5d , —S(O) 2 R 5a , —S(O) 2 NR 5b R 5c , or G 1 ; wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G 1 , —C(O)R 5a , —C(O)OR 5a , —C(O)NR 5b R 5c , —C(O)N(R 5b )NR 5b R 5c , —S(O)R 5d , —S(O) 2 R 5a , —S(O) 2 NR 5b R 5c , —OR 5a , —OC(O)R 5d , —NR 5b R 5c , N(R 5b )C(O)R 5d , N(R 5b )SO 2 R 5d , N(R 5b )C(O)OR 5d , N(R 5b )C(O)NR 5b R 5c , N(R 5b )SO 2 NR 5b R 5c , and N(R 5b )C(NR 5b R 5c )═NR 5b R 5c ; 
         R 3a , R 3b , R 3c , R 5a , R 5b , and R 5c , at each occurrence, are each independently H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, G 1 , or —(C 1 -C 6  alkylenyl)-G 1 ; 
         R 3d  and R 5d , at each occurrence, are each independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, G 1 , or —(C 1 -C 6  alkylenyl)-G 1 ; 
         G 1 , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G 1  is optionally substituted with 1, 2, 3, 4, or 5 R 1g  groups; 
         R 6  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, C 1 -C 6  haloalkyl, —C(O)R 6a , —C(O)OR 6a , —C(O)NR 6b R 6c , —S(O) 2 R 6a , —S(O) 2 NR 6b R 6c , or G 2 ; wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G 2 , —C(O)R 6a , —C(O)OR 6a , —C(O)NR 6b R 6c , —C(O)N(R 6b )NR 6b R 6c , —S(O)R 6d , —S(O) 2 R 6a , —S(O) 2 NR 6b R 6c , —OR 6a , —OC(O)R 6d , —NR 6b R 6c , N(R 6b )C(O)R 6d , N(R 6b )SO 2 R 6d , N(R 6b )C(O)OR 6d , N(R 6b )C(O)NR 6b R 6c , N(R 6b )SO 2 NR 6b R 6c , and N(R 6b )C(NR 6b R 6c )═NR 6b R 6c ; 
         R 6a , R 6b , and R 6c , at each occurrence, are each independently H, alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, haloalkyl, G 2 , —(C 1 -C 6  alkylenyl)-G 2 , —(C 1 -C 6  alkylenyl)-OR a , —(C 1 -C 6  alkylenyl)-S(O) 2 R a , —(C 1 -C 6  alkylenyl)-S(O) 2 NR c R d , —(C 1 -C 6  alkylenyl)-C(O)R a , —C 1 -C 6  alkylenyl)-C(O)OR a , —(C 1 -C 6  alkylenyl)-C(O)NR c R d , —(C 1 -C 6  alkylenyl)-NR c R d , —(C 1 -C 6  alkylenyl)-N(R e )C(O)R b , —(C 1 -C 6  alkylenyl)-N(R e )S(O) 2 R b , —(C 1 -C 6  alkylenyl)-N(R e )C(O)O(R b ), —(C 1 -C 6  alkylenyl)-N(R e )C(O)NR c R d , or —(C 1 -C 6  alkylenyl)-N(R e )S(O) 2 NR c R d ; 
         R 6d , at each occurrence, is independently alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, haloalkyl, G 2 , —(C 1 -C 6  alkylenyl)-G 2 , —(C 1 -C 6  alkylenyl)-OR a , —(C 1 -C 6  alkylenyl)-S(O) 2 R a , —(C 1 -C 6  alkylenyl)-S(O) 2 NR c R d , —(C 1 -C 6  alkylenyl)-C(O)R a , —(C 1 -C 6  alkylenyl)-C(O)OR a , —(C 1 -C 6  alkylenyl)-C(O)NR c R d , —(C 1 -C 6  alkylenyl)-NR c R d , —(C 1 -C 6  alkylenyl)-N(R e )C(O)R b , —(C 1 -C 6  alkylenyl)-N(R e )S(O) 2 R b , —(C 1 -C 6  alkylenyl)-N(R e )C(O)O(R b ), —(C 1 -C 6  alkylenyl)-N(R e )C(O)NR c R d , or —(C 1 -C 6  alkylenyl)-N(R e )S(O) 2 NR c R d ; 
         G 2 , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G 2  is optionally substituted with 1, 2, 3, 4, or 5 R 2g  groups; 
         A 1  is C(R 7 ) or N; A 2  is C(R 8 ) or N; A 3  is C(R 9 ) or N; and A 4  is C(R 10 ) or N; wherein zero, one, or two of A 1 , A 2 , A 3 , and A 4  are N; 
         R 7 , R 8 , and R 9 , are each independently H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, C 1 -C 6  haloalkyl, —CN, NO 2 , —OR y1 , —OC(O)R y2 , —OC(O)NR y3 R y4 , —SR y1 , —S(O) 2 R y1 , —S(O) 2 NR y3 R y4 , —C(O)R y1 , —C(O)OR y1 , —C(O)NR y3 R y4 , —NR y3 R y4 , —N(R y3 )C(O)R y2 , —N(R y3 )S(O) 2 R y2 , —N(R y3 )C(O)O(R y2 ), —N(R y3 )C(O)NR y3 R y4 , —N(R y3 )S(O) 2 NR y3 R y4 , G 3 , —(C 1 -C 6  alkylenyl)-CN, —(C 1 -C 6  alkylenyl)-OR y1 , —(C 1 -C 6  alkylenyl)-OC(O)R y2 , —(C 1 -C 6  alkylenyl)-OC(O)NR y3 R y4 , —(C 1 -C 6  alkylenyl)-S(O) 2 R y1 , —(C 1 -C 6  alkylenyl)-S(O) 2 NR y3 R y4 , —(C 1 -C 6  alkylenyl)-C(O)R y1 , —(C 1 -C 6  alkylenyl)-C(O)OR y1 , —(C 1 -C 6  alkylenyl)-C(O)NR y3 R y4 , —(C 1 -C 6  alkylenyl)-NR y3 R y4 , —(C 1 -C 6  alkylenyl)-N(R y3 )C(O)R y2 , —(C 1 -C 6  alkylenyl)-N(R y3 )S(O) 2 R y2 , —(C 1 -C 6  alkylenyl)-N(R y3 )C(O)O(R y2 ), —(C 1 -C 6  alkylenyl)-N(R y3 )C(O)NR y3 R y4 , —(C 1 -C 6  alkylenyl)-N(R y3 )S(O) 2 NR y3 R y4 , —(C 1 -C 6  alkylenyl)-CN, or —(C 1 -C 6  alkylenyl)-G 3 ; 
         R y1 , R y3 , and R y4 , at each occurrence, are each independently H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, G 3 , —(C 1 -C 6  alkylenyl)-G 3 , —(C 1 -C 6  alkylenyl)-OR a , —(C 1 -C 6  alkylenyl)-S(O) 2 R a , —(C 1 -C 6  alkylenyl)-S(O) 2 NR c R d , —(C 1 -C 6  alkylenyl)-C(O)R a , —(C 1 -C 6  alkylenyl)-C(O)OR a , —(C 1 -C 6  alkylenyl)-C(O)NR c R d , —(C 1 -C 6  alkylenyl)-NR c R d , —(C 1 -C 6  alkylenyl)-N(R e )C(O)R b , —(C 1 -C 6  alkylenyl)-N(R e )S(O) 2 R b , —(C 1 -C 6  alkylenyl)-N(R e )C(O)O(R b ), —(C 1 -C 6  alkylenyl)-N(R e )C(O)NR c R d , or —(C 1 -C 6  alkylenyl)-N(R e )S(O) 2 NR c R d ; 
         R y2 , at each occurrence, is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, G 3 , —(C 1 -C 6  alkylenyl)-G 3 , —(C 1 -C 6  alkylenyl)-OR a , —(C 1 -C 6  alkylenyl)-S(O) 2 R a , —(C 1 -C 6  alkylenyl)-S(O) 2 NR c R d , —(C 1 -C 6  alkylenyl)-C(O)R a , —(C 1 -C 6  alkylenyl)-C(O)OR a , —(C 1 -C 6  alkylenyl)-C(O)NR c R d , —(C 1 -C 6  alkylenyl)-NR c R d , —(C 1 -C 6  alkylenyl)-N(R e )C(O)R b , —(C 1 -C 6  alkylenyl)-N(R e )S(O) 2 R b , —(C 1 -C 6  alkylenyl)-N(R e )C(O)O(R b ), —(C 1 -C 6  alkylenyl)-N(R e )C(O)NR c R d , or —(C 1 -C 6  alkylenyl)-N(R e )S(O) 2 NR c R d ; 
         G 3 , at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle; and each G 3  group is optionally substituted with 1, 2, 3, 4, or 5 R 4g  groups; 
         R 10  is H, C 1 -C 3  alkyl, halogen, C 1 -C 3  haloalkyl, or —CN; 
         R 1g , R 2g , and R 4g , at each occurrence, is independently selected from the group consisting of oxo, 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 a , —OC(O)R b , —OC(O)NR c R d , —SR a , —S(O) 2 R a , —S(O) 2 NR c R d , —C(O)R a , —C(O)OR a , —C(O)NR c R d , —NR c R d , —N(R e )C(O)R b , —N(R e )S(O) 2 R b , —N(R e )C(O)O(R b ), —N(R e )C(O)NR c R d , —N(R e )S(O) 2 NR c R d , —(C 1 -C 6  alkylenyl)-CN, —(C 1 -C 6  alkylenyl)-G 2a , —(C 1 -C 6  alkylenyl)-OR a , —(C 1 -C 6  alkylenyl)-OC(O)R b , —(C 1 -C 6  alkylenyl)-OC(O)NR c R d , —(C 1 -C 6  alkylenyl)-S(O) 2 R a , —(C 1 -C 6  alkylenyl)-S(O) 2 NR c R d , —(C 1 -C 6  alkylenyl)-C(O)R a , —(C 1 -C 6  alkylenyl)-C(O)OR a , —(C 1 -C 6  alkylenyl)-C(O)NR c R d , —(C 1 -C 6  alkylenyl)-NR c R d , —(C 1 -C 6  alkylenyl)-N(R e )C(O)R b , —(C 1 -C 6  alkylenyl)-N(R e )S(O) 2 R b , —(C 1 -C 6  alkylenyl)-N(R e )C(O)O(R b ), —(C 1 -C 6  alkylenyl)-N(R e )C(O)NR c R d , —(C 1 -C 6  alkylenyl)-N(R e )S(O) 2 NR c R d , or —(C 1 -C 6  alkylenyl)-CN; 
         R a , R c , R d , and R e , at each occurrence, are each independently H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, G 2a , or —(C 1 -C 6  alkylenyl)-G 2a ; 
         R b , at each occurrence, is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, G 2a , or —(C 1 -C 6  alkylenyl)-G 2a ; 
         G 2a , at each occurrence, are each independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G 2a  group is optionally substituted with 1, 2, 3, 4, or 5 R 3g  groups; 
         R 3g , at each occurrence, is independently oxo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, C 1 -C 6  haloalkyl, —CN, NO 2 , —OR z1 , —OC(O)R z2 , —OC(O)NR z3 R z4 , —SR z1 , —S(O) 2 R z1 , —S(O) 2 NR z3 R z4 , —C(O)R z1 , —C(O)OR z1 , —C(O)NR z3 R z4 , —NR z3 R z4 , —N(R z3 )C(O)R z2 , —N(R z3 )S(O) 2 R z2 , —N(R z3 )C(O)O(R z2 ), —N(R z3 )C(O)NR z3 R z4 , —N(R z3 )S(O) 2 NR z3 R z4 , —(C 1 -C 6  alkylenyl)-OR z1 , —(C 1 -C 6  alkylenyl)-OC(O)R z2 , —(C 1 -C 6  alkylenyl)-OC(O)NR z3 R z4 , —(C 1 -C 6  alkylenyl)-S(O) 2 R z1 , —(C 1 -C 6  alkylenyl)-S(O) 2 NR z3 R z4 , —(C 1 -C 6  alkylenyl)-C(O)R z1 , —(C 1 -C 6  alkylenyl)-C(O)OR z1 , —(C 1 -C 6  alkylenyl)-C(O)NR z3 R z4 , —(C 1 -C 6  alkylenyl)-NR z3 R z4 , —(C 1 -C 6  alkylenyl)-N(R z3 )C(O)R z2 , —(C 1 -C 6  alkylenyl)-N(R z3 )S(O) 2 R z2 , —(C 1 -C 6  alkylenyl)-N(R z3 )C(O)O(R z2 ), —(C 1 -C 6  alkylenyl)-N(R z3 )C(O)NR z3 R z4 , —(C 1 -C 6  alkylenyl)-N(R z3 )S(O) 2 NR z3 R z4 , or —(C 1 -C 6  alkylenyl)-CN; 
         R z1 , R z3 , and R z4 , at each occurrence, are each independently H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 1 -C 6  haloalkyl; and 
         R z2 , at each occurrence, is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 1 -C 6  haloalkyl 
       
       or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 
     
     
         34 . The method of  claim 33  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. 
     
     
         35 . A method for treating a disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 33  or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or condition is selected from the group consisting of Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, cardiac myopathy, cardiac hypertrophy, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, heart failure, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis. 
     
     
         36 . A method for treating a chronic kidney disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 33  or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or condition is selected from the group consisting of: diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease, and tubular interstitial nephritis. 
     
     
         37 . A method for treating an acute kidney disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 33  or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said acute kidney disease or condition is selected from the group consisting of: ischemia-reperfusion induced kidney disease, cardiac and major surgery induced kidney disease, percutaneous coronary intervention induced kidney disease, radio-contrast agent induced kidney disease, sepsis induced kidney disease, pneumonia induced kidney disease, and drug toxicity induced and pharmaceutically acceptable salts thereof. 
     
     
         38 . A method for treating an acquired immunodeficiency syndrome (AIDS) in a subject comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 33  or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 
     
     
         39 . A method for treating a disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 33  or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or condition is selected from the group consisting of: obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy, and diabetic neuropathy. 
     
     
         40 . A method of contraception in a male subject comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 33  or a pharmaceutically acceptable salt thereof, to a subject in need thereof.