Bromodomain inhibitors

Abstract

wherein Y1, Y2, R1, R2, R3, A1, A2, A3, and A4, have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents for the treatment of diseases and conditions, including inflammatory diseases, cancer, and AIDS. Also provided are pharmaceutical compositions comprised of one or more compounds of formula (I).

1 - 26 . (canceled) 
     
     
         27 . A method for treating a disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, to a subject in need thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is C 1 -C 3  alkyl or C 1 -C 3  haloalkyl; 
 R 2  is H; 
 R 3  is —O—C 1 -C 6  alkyl, —OCD 2 CH 3 , or —OCD 2 CD 3 ; 
 Y 1  is N or CR 4 , wherein R 4  is H, C 1 -C 3  alkyl, or C 1 -C 3  haloalkyl; 
 A 2  is CR 5 , and A 1 , A 3 , and A 4  are CR 6 ; or 
 A 2  is CR 5 , A 1  and A 3  are CR 6 , and A 4  is N; 
 R 5  is —N(R 5d )—C 1 -C 6  alkylenyl-R 5a , —N(R 5d )C(O)—C 1 -C 6  alkylenyl-R 5b , —N(R 5d )SO 2 —C 1 -C 6  alkylenyl-R 5c , —N(R 5d )C(O)N(R 5d )-G 1 , —N(R 5d )C(O)N(R 5d )—C 1 -C 6  alkylenyl-R 5a , —N(R 5d )SO 2 N(R d )—C 1 -C 6  alkylenyl-R a , —C(O)N(R 5d )—C 1 -C 6  alkylenyl-R 5a , or —SO 2 N(R 5d )—C 1 -C 6  alkylenyl-R 5a ,
 wherein 
 R 5a , at each occurrence, is independently G 1 , —OR 5aa , —OC(O)R 5dd , —SR 5aa , —S(O)R 5aa , —SO 2 R 5aa , —SO 2 NR 5bb R 5cc , —NR 5bb R 5cc , —NR 5bb C(O)R 5dd , —NR 5bb SO 2 R 5dd , —NR 5bb C(O)OR 5dd , —NR 5bb C(O)NR 5bb R 5cc , —NR 5bb SO 2 NR 5bb R 5cc , —C(O)R 5aa , —C(O)OR 5aa  or —C(O)NR 5bb R 5cc , 
 R 5b  is G 1 , —OR 5aa , —OC(O)R 5dd , —SR 5aa , —S(O)R 5aa , —SO 2 R 5aa , —SO 2 NR 5bb R 5cc , —N(R 5bb )(G 1 ), —NR 5bb (C 1 -C 6  alkylenyl)-G 1 , —NR 5bb C(O)R 5dd , —NR 5bb SO 2 R 5dd , —NR 5bb C(O)OG 1 , —NR 5bb C(O)O—(C 1 -C 6  alkylenyl)-G 1 , —NR 5bb C(O)NR 5bb R 5cc , —NR 5bb SO 2 NR 5bb R 5cc , —C(O)R 5a , —C(O)OR 5aa  or —C(O)NR 5bb R 5cc , 
 R 5c  is —OR 5aa , —OC(O)R 5dd , —SR 5aa , —S(O)R 5a , —SO 2 R 5aa , —SO 2 NR 5bb R 5cc , —NR 5bb R 5cc , —NR 5bb C(O)R 5dd , —NR 5bb SO 2 R 5dd , —NR 5bb C(O)OR 5dd , —NR 5bb C(O)NR 5bb R 5cc , —NR 5bb SO 2 NR 5bb R 5cc , —C(O)R 5aa , —C(O)OG 1 , —C(O)O—(C 1 -C 6  alkylenyl)-G 1 , or —C(O)NR 5bb R 5cc , 
 R 5d , at each occurrence, is 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 5aa , —OC(O)R 5dd , —SR 5aa , —S(O)R 5aa , —SO 2 R 5aa , —SO 2 NR 5bb R 5cc , —NR 5bb R 5cc , —NR 5bb C(O)R 5dd , —NR 5bb SO 2 R 5dd , —NR 5bb C(O)OR 5dd , —NR 5bb C(O)NR 5bb R 5cc , —NR 5bb SO 2 NR 5bb R 5cc , —C(O)R 5aa , —C(O)OR 5aa , —C(O)NR 5bb R 5cc , —(C 1 -C 6  alkylenyl)-G 1 , —(C 1 -C 6  alkylenyl)-OR 5aa , —(C 1 -C 6  alkylenyl)-OC(O)R 5dd , —(C 1 -C 6  alkylenyl)-SR 5aa , —(C 1 -C 6  alkylenyl)-S(O)R 5aa , —(C 1 -C 6  alkylenyl)-SO 2 R 5aa , —(C 1 -C 6  alkylenyl)-SO 2 NR 5bb R 5cc , —(C 1 -C 6  alkylenyl)-NR 5bb R 5cc , —(C 1 -C 6  alkylenyl)-NR 5bb C(O)R 5dd , —(C 1 -C 6  alkylenyl)-NR 5bb SO 2 R 5dd , —(C 1 -C 6  alkylenyl)-NR 5bb C(O)OR 5dd , —(C 1 -C 6  alkylenyl)-NR 5bb C(O)NR 5bb R 5cc , —(C 1 -C 6  alkylenyl)-NR 5bb SO 2 NR 5bb R 5cc , —(C 1 -C 6  alkylenyl)-C(O)R 5aa , —(C 1 -C 6  alkylenyl)OC(O)OR 5aa , or —(C 1 -C 6  alkylenyl)OC(O)NR 5bb R 5cc ; 
 
 R 6  is H, C 1 -C 6  alkyl, halogen, C 1 -C 6  haloalkyl, or —CN; 
 R 5aa , R 5bb , and R 5cc , 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 5dd , 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 1 , or —(C 1 -C 6  alkylenyl)-G 1 ; 
 G 1 , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 R 1g  groups, 
 Y 2  is -L-G 2 ; wherein
 L is O or N(R x ) wherein R x  is H or C 1 -C 6  alkyl; 
 G 2  is aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 R 2g  groups; 
 
 R 1g  and R 2g , at each occurrence, are each 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 , G 3 , —(C 1 -C 6  alkylenyl)-CN, —(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 , —(C 1 -C 6  alkylenyl)-CN, or —(C 1 -C 6  alkylenyl)-G 3 ; 
 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, C 1 -C 6  haloalkyl, G 3 , or —C 1 -C 6  alkylenyl-G 3 ; 
 R z2 , 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 , or —C 1 -C 6  alkylenyl-G 3 ; 
 G 3  is aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, each of which 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 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 c )C(O)R b , —N(R c )S(O) 2 R b , —N(R c )C(O)O(R b ), —N(R c )C(O)NR c R d , —N(R c )S(O) 2 NR c R d , —(C 1 -C 6  alkylenyl)-CN, —(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 c )C(O)R b , —(C 1 -C 6  alkylenyl)-N(R c )S(O) 2 R b , —(C 1 -C 6  alkylenyl)-N(R c )C(O)O(R b ), —(C 1 -C 6  alkylenyl)-N(R c )C(O)NR c R d , —(C 1 -C 6  alkylenyl)-N(R c )S(O) 2 NR c R d , or —(C 1 -C 6  alkylenyl)-CN, 
 R a , R c , and R d , 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 b , 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,
 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, 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. 
 
     
     
         28 . 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 27  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. 
     
     
         29 . 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 27  or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 
     
     
         30 . 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 27  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. 
     
     
         31 . A method of contraception in a male subject comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 27  or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 
     
     
         32 . 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 27  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 kidney disease. 
     
     
         33 . A method of 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 27  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.