Alpha-ketoamides and derivatives thereof

Abstract

The present invention provides low molecular weight compounds useful as cytokine inhibitors, and compositions thereof. In particular, compounds of the invention are useful as anti-inflammatory agents. There are further provided methods for the preparation of such agents and their use in preventing or treating conditions medicated by cytokines such as arthritis.

1 . A method of treating a disease mediated by cytokines which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula IA: 
       
         
           
           
               
               
           
         
         stereoisomers thereof, tautomers thereof, or pharmaceutically acceptable salts thereof, wherein: 
         X is C(O)Or C(S); 
         G is a C 3-10  carbocyclyl, a 5-8 membered monocyclic heterocyclyl, or a 8-11 membered bicyclic heterocyclyl containing 1 or more heteroatoms selected from O, N or S; wherein G is substituted by one or more R 1 , R 2  or R 3 ; 
         Ar is —(Y)—(C 0-3  alkyl)-(bicyclic aryl) wherein the bicyclic aryl is naphthyl, tetrahydronaphthyl, dihydronaphthyl, indenyl, or indanyl, or Ar is —(Y)—(C 0-3  alkyl)-(bicyclic heteroaryl), wherein the bicyclic heteroaryl is indazolyl, isoindolyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxoazolyl, dihydroisoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, or benzoisothiazolyl dioxide, and wherein Ar is optionally substituted with one or more R 4  or R 5 ; provided however, that the bicyclic aryl is not 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthyl; 
         Y is —C(O)—, —C(NNRC(O)OR)—, —C(NNRR)—, —C(NNHC(O)NRR)— or —C(NOR)—; 
         L is a covalent bond or a saturated or unsaturated branched or unbranched C 1-10  carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms chosen from O, NR and S(O) m ; and wherein L is optionally substituted with 0-2 oxo groups and one or more C 1-4  branched or unbranched alkyl optionally substituted by one or more F, Cl, Br, or I; 
         each m is independently 0, 1 or 2; 
         Q is —NR′R′, cycloalkyl, aryl, heterocyclyl, C 1-6  alkoxy, C 1-6  alkyl-S(O) m , or phenyl-S(O) m , wherein the cycloalkyl, aryl, heterocyclyl, C 1-6  alkoxy, C 1-6  alkyl-S(O) m , or phenyl-S(O) m  is each optionally substituted with one or more R 27 ; 
         each R is independently hydrogen or substituted or unsubstituted C 1-6  alkyl; 
         each R′ is independently hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted (C 0-4  alkyl)-(C 6-10  aryl) or substituted or unsubstituted (C 0-4  alkyl)-(5-10 member heterocyclyl); 
         each R 1  is independently F, Cl, Br, I, cyano, —C(O)R, —C(O)NR 2 , —C(O)OR, —OR, —NR′R′, —SiR 3 , —S(O) m R, substituted or unsubstituted straight or branched C 1-10  alkyl, C 2-10  alkenyl, or C 2-10  alkynyl, substituted or unsubstituted C 3-10  cycloalkyl, substituted or unsubstituted C 5-8  cycloalkenyl, substituted or unsubstituted C 7-20  aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms selected independently from N, O, S(O) m ; 
         each R 2 , R 4  and R 5  is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C 1-6  alkyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5-10 member heteroaryl, —OR′, —OR 6 , —C(O)R′, —C(O)OR′, —C(O)NR′ 2 , —NR′ 2 , —NO 2 , —S(O) m R″, —NR′SO 2 R″, —NR′C(O)NR′R′, —NR′C(S)NR′R′, —NR′C(O)OR′ or —SO 2 NR′ 2 ; 
         each R″ is independently substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 0-4  alkyl-C 6-10  aryl or substituted or unsubstituted (C 0-4  alkyl)-(5-10 member heterocyclyl); 
         each R 3  is independently substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms selected independently from N, O, S(O) m , substituted or unsubstituted C 3-12  cycloalkyl, substituted or unsubstituted C 5-17  cycloalkenyl, substituted or unsubstituted C 7-20  aralkyl, substituted or unsubstituted straight or branched C 1-8  alkyl, R 20 C(O)N(R 21 )—, R 22 O—, R 23 R 24 NC(O)—, R 15 (CH 2 ) m C(O)N(R 21 )—, R 26 C(O)(CH 2 ) m N(R 21 )—, substituted or unsubstituted C 2-8  alkenyl, or substituted or unsubstituted C 2-8  alkynyl, wherein one or more methylene groups of the C 1-8  alkyl, C 2-8  alkenyl, or C 2-8  alkynyl are optionally replaced by O, NH, or S(O) m ; 
         each R 6  is a C 1-6  branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R 26 ; 
         each R 26  is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C 0-4  alkyl)amino optionally partially or fully halogenated; 
         R 20  is substituted or unsubstituted C 1-10  alkyl, substituted or unsubstituted C O-6  alkyl-phenyl, substituted or unsubstituted C 0-6  alkyl-heterocyclyl, OR′ or NR′ 2 ; 
         R 21  is hydrogen or C 1-4  branched or unbranched alkyl optionally partially or fully halogenated; and 
         each R 22 , R 23  and R 24  is independently hydrogen, substituted or unsubstituted C 1-10  alkyl, wherein the C 1-10  alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C 0-6  alkyl-phenyl, substituted or unsubstituted C 0-6  alkyl-heterocyclyl; or R 23  and R 24  taken together optionally form a heterocyclic or heteroaryl ring; 
         each R 27  is independently F, Cl, Br, I, cyano, —C(O)R′, —C(O)NR′ 2 , —C(O)OR′, —OR′, —NR′R′, —SiR′ 3 , —S(O) m R′, substituted or unsubstituted straight or branched C 1-10  alkyl, C 2-10  alkenyl, or C 2-10  alkynyl, substituted or unsubstituted C 3-10  cycloalkyl, substituted or unsubstituted C 5-8  cycloalkenyl, substituted or unsubstituted C 7-20  aralkyl, substituted or unsubstituted 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms selected independently from N, O, S(O) m ; 
         provided however that when Ar is —(Y)-(bicyclic aryl) and G is N-(substituted or unsubstituted phenyl)-pyrazolyl, the pyrazolyl is additionally substituted with one or more R 1 , R 2  or R 3 ; and 
         IA is not N-(4-chloro-3-methyl-isothiazol-5-yl)-2-[2-(2,2-dimethyl-propyl)-benzooxazol-5-yl]-2-oxo-acetamide. 
       
     
     
         2 . The method according to  claim 1 , wherein the cytokine-mediated disease is rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejections, pancreatitis, insulinitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, leprosy, acute synovitis, Reiter's syndrome, gouty arthritis, Behcet's disease, spondylitis, endometriosis, non-articular inflammatory conditions, acute or chronic pain, stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, Coronary Heart Disease, Coronary Artery Disease, acute coronary syndrome, Takayasu arteritis, cardiac failure, hypercholesteremia, diseases or conditions related to blood coagulation or fibrinolysis, atherosclerosis, allergic conjunctivitis, uveitis, glaucoma, optic neuritis, retinal ischemia, diabetic retinopathy, laser induced optic damage, surgery or trauma-induced proliferative vitreoretinopathy, allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection, respiratory tract inflammation, psoriasis, eczema, atopic dermatitis, contact dermatitis, acne, Guillain-Barre syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and other demyelinating diseases, viral and bacterial meningitis, CNS trauma, spinal cord injury, seizures, convulsions, olivopontocerebellar atrophy, AIDS dementia complex, MERRF and MELAS syndromes, Leber's disease, Wemicke's encephalophathy, Rett syndrome, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety and schizophrenia, aneurism, epilepsy, diabetes, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome, obesity, anorexia and bulimia nervosa, bone resorption diseases, osteopetrosis, osteoporosis, sepsis, HIV, HCV, malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer, Castleman's disease, stem-cell therapy targets, or drug resistance. 
     
     
         3 . The method of  claim 1 , wherein the cytokine mediated disease is rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejections, pancreatitis, insulinitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, acute synovitis, Reiter's syndrome, gouty arthritis, Behcet's disease, spondylitis, endometriosis, non-articular inflammatory conditions, acute or chronic pain. 
     
     
         4 . The method of  claim 2 , wherein the cytokine mediated disease is stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, Coronary Heart Disease, Coronary Artery Disease, acute coronary syndrome, Takayasu arteritis, cardiac failure, hypercholesteremia, diseases or conditions related to blood coagulation or fibrinolysis, or atherosclerosis. 
     
     
         5 . The method of  claim 2 , wherein the cytokine mediated disease is rheumatoid arthritis and the compound of Formula IA is administered with one or more active ingredients A, wherein A is an NSAID, immunosuppressive drug, immunomodulatory drug, cytostatic drug, angiogenesis inhibitor, biological agent, glucocorticosteroid or inhibitor of cell adhesion molecule LFA-1 or ICAM-1. 
     
     
         6 . The method of  claim 1 , wherein G is phenyl, naphthyl, cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl. 
     
     
         7 . The method of  claim 1  wherein L is a covalent bond, a C 1 -C 9  alkoxy, —C(O)O—, —NH— or —O—. 
     
     
         8 . The method of  claim 1 , wherein Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. 
     
     
         9 . The method of  claim 1 , wherein each R 1  is independently C 3-10  branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three C 3-10  cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogen, C 1-6  branched or unbranched alkyl which is optionally partially or fully halogenated, C 3-8  cycloalkyl, C 5-8  cycloalkenyl, hydroxy, cyano, C 1-3  alkoxy which is optionally partially or fully halogenated and NH 2 C(O) or mono- or di-(C 1-3  alkyl)aminocarbonyl. 
     
     
         10 . The method of  claim 1 , wherein each R 1  is independently C 3-10  branched or unbranched alkyl. 
     
     
         11 . The method of  claim 1 , wherein each R 2  is independently —OR′, —OR 6 , —C(O)R′, —C(O)OR′, —C(O)NR′ 2 , —NR′ 2 , —NO 2 , —S(O) m R″, —NR′—SO 2 R″, —NR′C(O)NR′R′, —NR′C(S)NR′R′, —NR′C(O)OR′ or —SO 2 NR′ 2 . 
     
     
         12 . The method of  claim 1 , wherein R 3  is phenyl, pyridazinyl or pyridyl, each of which is optionally partially or fully halogenated and optionally substituted with C 1-6  branched or unbranched alkyl which is optionally partially or fully halogenated, hydroxy, oxo, cyano, C 1-3  alkoxy optionally partially or fully halogenated, nitro, amino, or mono- or di-(C 1-3  alkyl)amino;
 C 1-6  alkyl or C 1-6  alkoxy, each optionally partially or fully halogenated or optionally substituted with R 17 , amino, OR 18 , C 1-5  mono- or di-alkylamino optionally substituted with R 19 ;   R 20 C(O)N(R 21 )—, R 22 O—, R 23 R 24 NC(O)—, R 26 (CH 2 ) m C(O)N(R 21 )— or R 26 C(O)(CH 2 ) m N(R 21 )—.   
     
     
         13 . The method of  claim 1 , wherein X is C═O. 
     
     
         14 . The method of  claim 1 , wherein Ar is —(Y)-naphthyl-, Y is —C(O)—, or —C(═NOH)— and G is phenyl or pyridyl. 
     
     
         15 . The method of  claim 14 , wherein each R 1  is independently a substituted or unsubstituted straight or branched C 1-10  alkyl. 
     
     
         16 . The method of  claim 15 , wherein each R 3  is independently R 23 R 24 N—C(O)—, R 20 —C(O)—NR 21 —, or OR 22 . 
     
     
         17 . The method of  claim 16 , wherein each R 2  is independently —NR′SO 2 R″, —Cl, —Br, —F, —C(O)—NR′ 2  substituted or unsubstituted straight or branched C 1-6  alkyl, —NR′ 2 , or —OR′. 
     
     
         18 . The method of  claim 1 , wherein Ar is —(Y)-naphthyl-, Y is —C(O)—, or —C(═NOH)—, and G is pyrazolyl, thienyl or isoxazolyl. 
     
     
         19 . The method of  claim 18 , wherein each R 1  is independently a substituted or unsubstituted straight or branched C 1-10  alkyl. 
     
     
         20 . The method of  claim 19 , wherein each R 3  is independently phenyl or pyridinyl, optionally substituted with one, two, or three —F, —Cl, substituted or unsubstituted C 1-6  branched or unbranched alkyl or substituted or unsubstituted C 1-4  alkoxy.