Pyridones useful as inhibitors of kinases

Abstract

The present invention relates to compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing the compounds of the invention and intermediate compounds useful in these processes.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically accepted salt thereof, wherein 
       
       each R 3  and R 4  is independently H, halogen or C 1-4  aliphatic optionally substituted with halogen, C 1-2 aliphatic, OCH 3 , NO 2 , NH 2 , CN, NHCH 3 , SCH 3 , or N(CH) 2 . 
       R 2  is a phenyl ring, a cyclohexenyl ring, or a cyclohexyl ring; R 2  is optionally substituted with J R ; 
       each X 1  and X 2  is independently —C(O)—, —NR—, or —SO 2 — wherein one of X 1  or X 2  is —NR— and the other of X 1  or X 2  is —C(O)— or —SO 2 —; 
       R is H, unsubstituted C 1-6  aliphatic; 
       R 1  is -T-Q; 
       T is a bond or C 1-6  aliphatic, wherein up to three methylene units of the chain are optionally and independently replaced by G or G′ wherein G is —NR 5 —, —O—, —S—, —SO—, SO 2 —, —CS—, or —CO—; G′ is cyclopropyl, C≡C, or C═C; T is optionally substituted with J T ; 
       Q is independently hydrogen, a C 1-6  aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q is optionally substituted with J Q ; 
       R 5  is optionally substituted R, C 6-10  aryl, C 3-10  cycloaliphatic, 5-14 membered heteroaryl, or 5-14 membered heterocyclyl; or two R 5  groups, together with the atom(s) to which they are attached, form an optionally substituted 3-7 membered monocyclic or 8-14 membered bicyclic ring; 
       J R , J T , and J Q  substituents on the unsaturated carbon atom of an aryl or heteroaryl group are selected from halogen; —R o ; C 1-6 alkyl, optionally substituted with R o , wherein up to three methylene units of the chain are optionally and independently replaced by, —NR o —, —O—, —S—, —SO—, SO 2 —, —CO—, cyclopropyl, C≡C, or C═C in a chemically stable arrangement; —OCF 3 ; —SCF 2 ; C 1-4 haloalkyl; —CH 2 -halogen; C 6-10 aryl, optionally substituted with R o ; 5-12 membered heteroaryl optionally substituted with R o ; 3-12 membered heterocyclic ring optionally substituted with R o ; —O(Ph) optionally substituted with R o ; —CH═CH(Ph), optionally substituted with R o ; —CH≡CH(Ph), optionally substituted with R o ; —C 1-6 alkyl-(3-12 membered heterocyclyl), optionally substituted with R o ; —C 1-6 alkyl-(C 6-10 aryl), optionally substituted with R o ; —C 1-6 alkyl-(5-10 membered heteroaryl), optionally substituted with R o ; C 3-10 cycloaliphatic, optionally substituted with R o ; —C 1-6 alkyl-(C 3-10 cycloaliphatic), optionally substituted with R o ; —(C 1-6 alkyl)-OR o , optionally substituted with R o ; —(C 1-6 alkyl)-N(R o ) 2 , optionally substituted with R o ; —(C 1-6 alkyl)-SR o , optionally substituted with R o ; —NO 2 ; —CN; —OR o ; —SR o ; —N(R o ) 2 ; —NR o C(O)R o ; —NR o C(S)R o ; —NR o C(O)N(R o ) 2 ; —NR o C(S)N(R o ) 2 ; —NR o  CO 2 R o ; —NR o NR o  C(O)R o ; —NR o NR o  C(O)N(R 0 ) 2 ; —NR o NR o  CO 2 R o ; —C(O)C(O)R o ; —C(O)CH 2 C(O)R o ; —CO 2 R o ; —C(O)R o ; —C(S)R o ; —C(O)N(R o ) 2 ; —C(S)N(R o ) 2 ; —OC(O)N(R o ) 2 ; —OC(O)R o ; —C(O)N(OR o )R o ; —C(NOR o )R o ; —S(O) 2 R o ; —S(O) 3 R o ; —SO 2 N(R o ) 2 ; —S(O)R o ; —NR o SO 2 N(R o ) 2 ; —NR o SO 2 R o ; —N(OR o )R o ; —C(═NH)—N(R o ) 2 ; —P(O) 2 R o ; —PO(R o ) 2 ; —OPO(R o ) 2 ; and —(CH 2 ) 0-2 NHC(O)R o ; 
       each R o  is independently selected from hydrogen, NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(haloC 1-4  aliphatic), haloC 1-4 aliphatic, optionally substituted C 1-6  aliphatic wherein up to 2 methylene units are optionally replaced by O, N, or S, optionally substituted 5-8 membered heterocyclyl, unsubstituted 5-6 membered heteroaryl, unsubstituted 3-6 membered cycloaliphatic, unsubstituted phenyl, unsubstituted —O(Ph), unsubstituted —CH 2 (Ph), unsubstituted —CH 2 (5-7 membered heterocyclyl), or unsubstituted —CH 2 (5-6 membered heteroaryl); or, notwithstanding the definition above, two independent occurrences of R o , on the same substituent or different substituents, taken together with the atom(s) to which each R o  group is bound, form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
       optional substituents on the aliphatic group of R o  or on the ring formed by 2 R o  groups are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(haloC 1-4  aliphatic), and haloC 1-4 aliphatic, wherein each of the foregoing C 1-4 aliphatic groups of R o  is unsubstituted; 
       J R , J T , and J Q  substituents on the saturated carbon of an aliphatic group, a heteroaliphatic group, or a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: ═O, ═S, ═NNHR*, ═NN(R*) 2 , ═NNHC(O)R*, ═NNHCO 2 (alkyl), ═NNHSO 2 (alkyl), ═NOH, and ═NR*, where each R* is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic group; 
       J R , J T , and J Q  substituents on the nitrogen of a non-aromatic heterocyclic ring or on the nitrogen of the heteroaryl ring are selected from —R + , —N(R + ) 2 , —C(O)R + , —CO 2 R + , —C(O)C(O)R + , —C(O)CH 2 C(O)R + , —SO 2 R + , —SO 2 N(R + ) 2 , —C(═S)N(R +1 ) 2 , —C(═NH)—N(R + ) 2 , and —NR + SO 2 R; wherein R +  is hydrogen, an optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted —O(Ph), optionally substituted —CH 2 (Ph), optionally substituted —(CH 2 ) 2 (Ph); optionally substituted —CH═CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R + , on the same substituent or different substituents, taken together with the atom(s) to which each R +  group is bound, form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; optional substituents on the aliphatic group or the phenyl ring of R +  are selected from —NH 2 , —NH(C 1-4  aliphatic), —N(C 1-4  aliphatic) 2 , halogen, C 1-4  aliphatic, —OH, —O(C 1-4  aliphatic), —NO 2 , —CN, —CO 2 H, —CO 2 (C 1-4  aliphatic), —O(halo C 1-4  aliphatic), and halo(C 1-4  aliphatic), wherein each of the foregoing C 1-4 aliphatic groups of R +  is unsubstituted; 
       provided that
 b) 
 e) 
 
       when R 2  is unsubstituted phenyl, R 3  and R 4 , are H, X 1  is —NR—, R is H, and X 2  is —C(O)—, then, when T is C 1 aliphatic wherein 1 methylene unit of the chain is replaced by G; G is —NR 5 —; and R 5  is H; then Q is not 2,6-di-isopropylphenyl; 
       when R 2  is unsubstituted phenyl, R 3  is H, R 4  is CH 3 , X 1  is —C(O)—, X 2  is —NR—, R is H, then
 a) when T is a bond, Q is not CH 3  or CH 2 CH 3 ; 
 b) when T is —CH 2 CH 2 —, Q is not unsubstituted phenyl or N(CH 2 CH 3 ) 2 ; 
 c) when T is —CH 2 CH 2 CH 2 —, Q is not N(CH 2 CH 3 ) 2 ; 
 d) R 1  is not NH 2 ; 
 
       when R 2  is unsubstituted phenyl, R 3  is H, R 4  is CH 3 , X 1  is —NR—, R is H, X 2  is —C(O)—, then
 a) when T is —O—CH 2 —, Q is not unsubstituted phenyl; when X 1  is —C(O)—, X 2  is —NR—, and R is H, then R 1  is not H or methyl. 
 
     
     
         2 . The compound according to  claim 1  wherein T is C 1-3 aliphatic optionally interrupted with zero or one G groups wherein G is selected from O, NR 5 , and S. 
     
     
         3 . The compound according to  claim 1  wherein T is —C 1-2 aliphatic-G- wherein G is O or NR 5 , and G is bound to Q in a chemically stable arrangement. 
     
     
         4 . The compound according to  claim 1  wherein T is C 1-3 aliphatic optionally interrupted with zero G groups. 
     
     
         5 . The compound according to  claim 1  wherein T is C 1-3 aliphatic optionally interrupted with zero or one G′ groups. 
     
     
         6 . The compound according to  claim 1  wherein T is —CH 2 —. 
     
     
         7 . The compound according to  claim 1  wherein T is a bond. 
     
     
         8 . The compound according to  claim 1  wherein each R 3  and R 4  is independently H. 
     
     
         9 . The compound according to  claim 8  wherein R 3  and R 4  are both H. 
     
     
         10 - 27 . (canceled) 
     
     
         28 . The compound according to  claim 1  wherein each J R  is selected from oxo or ═NOH. 
     
     
         29 . The compound according to  claim 1  wherein each J R  is selected from C 1-6 alkyl, C 6-10 aryl, —C 1-6 alkyl-C 6-10 aryl, C 1-4 haloalkyl, —OR o , —N(R o ) 2 , —SR o , NO 2 , CN, 3-12 membered heterocyclyl, —(C 1-6 alkyl)-OR o , —(C 1-6 alkyl)-N(R o ) 2 , —(C 1-6 alkyl)-SR o , —C(O)OR o , —NR o COR o , —COR o , —CON(R o ) 2 , —SO 2 R o , —SO 2 N(R o ) 2 , or C 1-6 alkyl wherein up to three methylene units of the chain are independently replaced by, —NR o —, —O—, —S—, —SO—, SO 2 —, or —CO— in a chemically stable arrangement; each J R  is independently and optionally substituted with R o . 
     
     
         30 . The compound according to  claim 29  wherein each J R  is independently and optionally substituted with R o  and is selected from —OR o , —N(R o ) 2 , —SR o , —(C 1-6 alkyl)-OR o , —(C 1-6 alkyl)-N(R o ) 2 , or —(C 1-6 alkyl)-SR o . 
     
     
         31 . The compound according to  claim 29  wherein each J R  is independently selected from optionally substituted 5-8 membered heterocyclyl, optionally substituted —NR(C 1-4 alkyl)N(R o ) 2 , optionally substituted —NR(C 1-4 alkyl)OR o , —N(R o ) 2 , or optionally substituted —NH(5-6 membered heterocyclyl). 
     
     
         32 . The compound according to  claim 31  wherein each J R  is independently selected from optionally substituted —NH(5-6 membered heterocyclyl). 
     
     
         33 . The compound according to  claim 32  wherein the 5-6 membered heterocyclyl contains 1-2 nitrogen atoms. 
     
     
         34 . The compound according to  claim 33  wherein the 5-6 membered heterocyclyl is selected from pyrrolidine, piperidine, or piperazine. 
     
     
         35 . The compound according to  claim 1  wherein each X 1  and X 2  is independently —C(O)— or —NR— wherein one of X 1  or X 2  is —NR— and the other of X 1  or X 2  is —C(O)—. 
     
     
         36 . The compound according to  claim 35  wherein X 1  is C(O) and X 2  is NR. 
     
     
         37 . The compound according to  claim 35  wherein X 1  is NR and X 2  is C(O). 
     
     
         38 . The compound according to  claim 1  wherein Q a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         39 . The compound according to  claim 38  wherein Q is C 6-10  aryl, C 3-10  cycloaliphatic, 5-14 membered heteroaryl, or 5-14 membered heterocyclyl. 
     
     
         40 . The compound according to  claim 39  wherein Q is C 6-10  aryl or 5-14 membered heteroaryl. 
     
     
         41 . The compound according to  claim 40  wherein Q is a 5-6 membered aryl or heteroaryl. 
     
     
         42 . The compound according to  claim 41  wherein Q is phenyl. 
     
     
         43 . The compound according to  claim 1  wherein Q is substituted with up to 3 J Q  groups wherein each J Q  is selected from CN, C 1-6 alkyl, C 1-4 haloalkyl, —OR o , —N(R o ) 2 , —SR o , —(C 1-6 alkyl)-OR o , —(C 1-6 alkyl)-N(R o ) 2 , —(C 1-6 alkyl)-SR o , C 1-10 aryl, —C 1-6 alkyl-C 6-10 aryl, C 3-10 cycloaliphatic, —C 1-6 alkyl-(C 3-10 cycloaliphatic), C 3-10 heterocyclyl, —C 1-6 alkyl-(C 3-10 heterocyclyl), —C(O)OR o , —NR o COR o , —COR o , —CON(R o ) 2 , —SO 2 R o , —SO 2 N(R o ) 2 , or C 1-6 alkyl wherein up to three methylene units are optionally and independently replaced by, —NR o —, —O—, —S—, —SO—, SO 2 —, —CO—, cyclopropyl, C≡C, or C═C in a chemically stable arrangement; each J Q  is optionally and independently substituted with R o . 
     
     
         44 . The compound according to  claim 43  wherein each J Q  is —SO 2 N(R o ) 2 , —SO 2 R o , —NR o C(O)OR o , —C≡C—R o , —C═C—R o , phenyl, —O-Ph, —O—CH 2 Ph, C 5-6 heteroaryl, C 3-7 heterocyclyl, or C 3-7 cyclyoaliphatic. 
     
     
         45 . The compound according to  claim 43  wherein each J Q  is CN, C 1-6 alkyl, —CF 3 , —OCF 3 , —OR o , —N(R o ) 2 , —SR o , —CH 2 -halogen, —SCF 2 , —(C 1-6 alkyl)-N(R o ) 2 , C 6 aryl, C 5-6 heteroaryl, —C(O)OR o , —NR o COR o , —COR o , or —CON(R o ) 2 . 
     
     
         46 . The compound according to  claim 45  wherein R o  is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl, t-butyl, OH, halogen, —CH 2 -pyrrolidine, COCH 3 , —(C 1-4 alkyl) 0-1 -O(C 1-4 alkyl), —(C 1-4 alkyl) 0-1 -O(C 1-4 alkyl)OH, —(C 1-4 alkyl) 0-1 -NH(C 1-4 alkyl), —(C 1-4 alkyl) 0-1 -N(C 1-4 alkyl) 2 , or —(C 1-4 alkyl) 0-1 -NH 2 . 
     
     
         47 . A compound selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         48 . A compound selected from the following I-82 to I-85, II-88, II-89, II-90, II-91, II-92 to II-182, III-11 to III-54, IV-1. 
     
     
         49 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         50 . A method of inhibiting Tec family kinase activity in:
 (a) a patient; or   (b) a biological sample;   
       which method comprises administering to said patient, or contacting said biological sample with a compound of  claim 1 . 
     
     
         51 . The method of  claim 50 , wherein the method comprises inhibiting Itk kinase activity. 
     
     
         52 . A method of treating or lessening the severity of a disease or condition selected from an autoimmune, inflammatory, proliferative, or hyperproliferative disease or an immunologically-mediated disease comprising administering to a patient in need thereof a compound according to  claim 1 . 
     
     
         53 . The method of  claim 52 , wherein the disease or disorder is asthma, acute rhinitis, allergic, atrophic rhinitis, chronic rhinitis, membranous rhinitis, seasonal rhinitis, sarcoidosis, farmer's lung, fibroid lung, idiopathic interstitial pneumonia, rheumatoid arthritis, seronegative spondyloarthropathis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, psoriasis, systemic sclerosis, atopical dermatitis, contact dermatitis and other eczematous dermatitis, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia, greata vernal conjunctivitis, Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, pancreatitis, Crohn's disease, ulcerative colitis, food-related allergies, multiple sclerosis, artherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia purpura, restenosis following angioplasty, tumours, artherosclerosis, systemic lupus erythematosus, allograft rejection including, without limitation, acute and chronic allograft rejection following for example transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease. 
     
     
         54 - 55 . (canceled)