Novel compounds

Abstract

Novel substituted 1,5,7-trisubstituted-1,8-napthyridin-2(1H)-one compounds; 1,5,7 trisubstituted-1,6-napthyridine-2-(1H)-one compounds and 1,5,7-trisubstituted quinoline-2(1H)-one compounds, processes for the preparation thereof, the use thereof in treating CSBP/p38 kinase mediated diseases and pharmaceutical compositions for use in such therapy.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is an optionally substituted aryl or an optionally substituted heteroaryl ring; 
 X is R 2 , OR 2 , S(O) m R 2 , (CH 2 ) n N(R 10 )S(O) m R 2  (CH 2 ) n N(R 10 )C(O)R 2  (CH 2 ) n NR 4 R 14 , NR 2 (CH 2 ) n NR 4 R 14 , O(CH 2 ) n NR 4 R 14 , S(CH 2 ) n NR 4 R 14  (CH 2 ) n J, NR 2 (CH 2 ) n J, O(CH 2 ) n J, S(CH 2 ) n J, or (CH 2 ) n N(R 2 ) 2 ; 
 J is an optionally substituted heteroaryl ring; 
 n is 0 or an integer having a value of 1 to 10; 
 m is 0 or an integer having a value of 1 or 2; 
 q is 0 or an integer having a value of 1 to 10; 
 R 2  is independently selected from hydrogen, C 1-10  alkyl, aryl, arylC 1-10  alkyl, heteroaryl, or a heteroarylC 1-10  alkyl moiety, which moieties, excluding hydrogen, are all optionally substituted, or R 2  is the moiety X 1  (CR 10 R 20 ) q C(A 1 )(A2)(A 3 ) or C(A 1 )(A 2 )(A 3 ); 
 X 1  is N(R 10 ), O, S(O) m , or CR 10 R 20 ; 
 X 2  is independently hydrogen, halogen or C 1-4  alkyl; 
 A 1  is an optionally substituted C 1-10  alkyl; 
 A 2  is an optionally substituted C 1-10  alkyl; 
 A 3  is hydrogen or is an optionally substituted C 1-10  alkyl; 
 G 2  is C—X 2 ; 
 R 3  is hydrogen, C 1-10  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl C 1-4 alkyl, aryl, arylC 1-10 alkyl, heteroaryl, heteroarylC 1-10  alkyl, heterocyclic, or a heterocyclylC 1-10  alkyl moiety, which moieties, excluding hydrogen, are optionally substituted; provided that when X 2  is hydrogen, R 1  is an optionally substituted phenyl or a methyl substituted imidazol-1-yl, X is R 2  and R 2  is hydrogen, then R 3  is other than hydrogen or methyl; 
 R 4  and R 14  are each independently selected from hydrogen, optionally substituted C 1-4  alkyl optionally substituted aryl, or optionally substituted aryl-C 1-4  alkyl arylC 1-10  alkyl heteroaryl or heteroarylC 1-10 alkyl wherein each of these moieties may be optionally substituted; 
 R 10  and R 20  are independently selected from hydrogen or C 1-4 alkyl; or 
 
       a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound according to  claim 1  which is Formula (III), or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound according to  claim 1  which is Formula (IIIa), or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The compound according to  claim 1  wherein R 1  is an optionally substituted phenyl or naphthyl. 
     
     
         5 . The compound according to  claim 4  wherein the R 1  phenyl is substituted one or more times independently by halogen, alkyl hydroxy, alkoxy, amino, or halosubstituted alkyl. 
     
     
         6 . The compound according to  claim 6  wherein the substituents are independently selected from fluorine, C 1-4  alkyl or CF 3 . 
     
     
         7 . The compound according to  claim 4  wherein the R 1  phenyl ring is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2,4,6-position. 
     
     
         8 . The compound according to  claim 1  wherein X is OR 2 , or S(O) m R 2 . 
     
     
         9 . The compound according to  claim 1  wherein X is (CH 2 ) n NR 4 R 14 , or (CH 2 ) n N(R 2 ) 2 . 
     
     
         10 . The compound according to  claim 1  wherein X is R 2  or (CH 2 ) n N(R 10 )S(O) m R 2 , or (CH 2 ) n N(R 10 )C(O)R 2 . 
     
     
         11 . The compound according to  claim 10  wherein R 2 , other then hydrogen, is optionally substituted independently one or more times with C 1-10  alkyl halo-substituted C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-7  cycloalkyl, C 3-7 cycloalkylC 1-10 alkyl, C 5-7 cycloalkenyl, C 5-7  cycloalkenyl C 1-10  alkyl, halogen, —C(O), cyano, nitro, (CR 10 R 20 ) n OR 6 , (CR 10 R 20 ) n SH, (CR 10 R 20 ) n S(O) m R 7 , (CR 10 R 20 ) n NR 10 S(O) 2 R 7 , (CR 10 R 20 ) n NR 4 R 14 , (CR 10 R 20 ) n CN, (CR 10 R 20 ) n S(O) 2 NR 4 R 14 , (CR 10 R 20 ) n C(Z)R 6 , (CR 10 R 20 ) n OC(Z)R 6 , (CR 10 R 20 ) n C(Z)OR 6 , (CR 10 R 20 ) n C(Z)NR 4 R 14 , (CR 10 R 20 ) n NR 10 C(Z)R 6 , (CR 10 R 20 ) n NR 10 C(═NR 10 )NR 4 R 14 , (CR 10 R 20 ) n C(═NOR 6 )NR 4 R 14 , (CR 10 R 20 ) n OC(Z)NR 4 R 14 , (CR 10 R 20 ) n NR 10 C(Z)NR 4 R 14 , or (CR 10 R 20 ) n NR 10 C(Z)OR 7 . 
     
     
         12 . The compound according to  claim 1  wherein X is R 2 , and R 2  is an optionally substituted C 1-10 alkyl. 
     
     
         13 . The compound according to  claim 12  wherein the C 1-10 alkyl is substituted by (CR 10 R 20 ) n C(Z)OR 6 , (CR 10 R 20 ) n OR 6 , or (CR 10 R 20 ) n NR 4 R 14 . 
     
     
         14 . The compound according to  claim 1  wherein X is R 2 , and R 2  is X 1 (CR 10 R 20 ) q C(A 1 )(A 2 )(A 3 ) or C(A 1 )(A 2 )(A 3 ). 
     
     
         15 . The compound according to  claim 14  wherein X 1  is oxygen or N(R 10 ). 
     
     
         16 . The compound according to  claim 15  wherein at least one of A 1 , A 2  or A 3  is substituted by (CR 10 R 20 ) n OR 6 . 
     
     
         17 . The compound according to claim  43  wherein q is 0 or 1, and R 2  is X 1 (CR 10 R 20 ) q C(A 1 )(A 2 )(A 3 ). 
     
     
         18 . The compound according to  claim 1  wherein R 3  is an optionally substituted C 1-10  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkylalkyl, aryl or aryl C 1-10  alkyl. 
     
     
         19 . The compound according to  claim 19  wherein R 3  is optionally substituted one or more times independently with C 1-10  alkyl, halo-substituted C 1-10  alkyl, C 2-10  alkenyl, C 2-10 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 10  alkyl, C 5-7 cycloalkenyl, C 5-7 cycloalkenylC 1-10  alkyl, halogen, cyano, nitro, (CR 10 R 20 ) n OR 6 , (CR 10 R 20 ) n SH, (CR 10 R 20 ) n S(O) m R 7 , (CR 10 R 20 ) n NR 10 S(O) 2 R 7 , (CR 10 R 20 ) n NR 4 R 14  (CR 10 R 20 ) n CN, (CR 10 R 20 ) n S(O) 2 NR 4 R 14 , (CR 10 R 20 ) n C(Z)R 6 , (CR 10 R 20 ) n OC(Z)R 6 , (CR 10 R 20 ) n C(Z)OR 6 , (CR 10 R 20 ) n C(Z)NR 4 R 14 , (CR 10 R 20 ) n NR 10 C(Z)R 6 , (CR 10 R 20 ) n NR 10 C(═NR 10 )NR 4 R 14 , (CR 10 R 20 ) n OC(Z)NR 4 R 14 , (CR 10 R 20 ) n NR 10 C(Z)NR 4 R 14 , or (CR 10 R 20 ) n NR 10 C(Z)OR 7 . 
     
     
         20 . The compound according to  claim 19  wherein R 3  is a phenyl substituted independently one or more times by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl. 
     
     
         21 . The compound according to  claim 1  wherein X 2  is hydrogen. 
     
     
         22 . The compound according to  claim 1 , which is: 
       7-Bromo-1,5-bis(2-chlorophenyl)-3,4-dihydro[1,6]naphthyridin-2(1H)-one; 
       7-Bromo-1,5-bis(2-chlorophenyl)[1,6]naphthyridin-2(1H)-one; 
       1,5-Bis(2-Chlorophenyl)-7-[(2-hydroxy-1-(hydroxymethyl)ethyl]-amino]-[1,6]naphthyridin-2(1H)-one; 
       N-[2-[[1,5-bis(2-Chlorophenyl)-2-oxo-1,2-dihydro[1,6]naphthyridin-7-yl]amino]ethyl]acetamide; 
       1,5-Bis(2-Chlorophenyl)-7-[(1H-imidazol-2-ylmethyl)amino][1,6]naphthyridin-2(1H)-one; 
       1,5-Bis(2-Chlorophenyl)-7-[[2-(Isopropylamino)ethyl]amino][1,6]naphthyridin-2(1H)-one; 
       1,5-Bis(2-Chlorophenyl)-7-amino-[1,6]naphthyridin-2(1H)-one; 
       1,5-Bis(2-Chlorophenyl)-7-chloro-[1,6]naphthyridin-2(1H)-one;
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         23 . A pharmaceutical composition comprising an effective amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier or diluent. 
     
     
         24 . A method of treating a CSBP/RK/p38 mediated disease in a mammal in need thereof comprising administering to said mammal an effective amount of a compound according to  claim 1 . 
     
     
         25 . The method according to  claim 24  wherein the CSBP/RK/p38 kinase mediated disease is psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closed head injury, asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and brain and renal reperfusion injury, congestive heart failure, coronary arterial bypass grafting (CABG) surgery, thrombosis, glomerularnephritis, chronic renal failure, diabetes, diabetic retinopathy, macular degeneration, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, neurodegenrative disease, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic disease, influenza induced pneumonia, eczema, contact dermatitis, psoriasis, sunburn, or conjunctivitis.