Novel pyrazole and pyrazoline substituted compounds

Abstract

Novel pyridyl or pyrimidinyl substituted pyrazole and pyrazoline compounds and compositions for use in therapy.

What is claimed is:  
     
         1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is 4-pyridyl, 4-pyrimidinyl, 4-pyridazinyl, 1,2,4-triazin-5-yl, 4-quinolyl, 6-isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl ring, which ring is optionally substituted independently one to three times with Y, NHR a , optionally substituted C 1-4  alkyl, halogen, hydroxyl, optionally substituted C 1-4  alkoxy, optionally substituted C 1-4  alkylthio, optionally substituted C 1-4  alkylsulfinyl, CH 2 OR 12 , amino, mono and di- C 1-6  alkyl substituted amino, N(R 10 )C(O)R b , N(R 10 )S(O) 2 R d , or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR 15 ;  
 Y is X 1 -R a ;  
 X 1  is sulfur or oxygen;  
 R a  is C 1-6  alkyl, aryl, aryl C 1-6  alkyl, heterocyclic, heterocyclyl C1 6 alkyl, heteroaryl, or heteroaryl C 1-6  alkyl, wherein each of these moieties may be optionally substituted;  
 R b  is hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, aryl, aryl C 1-4  alkyl, heteroaryl, heteroaryl C 1-4  alkyl, heterocyclyl, or heterocyclyl C 1-4  alkyl;  
 R d  is C 1-6  alkyl, C 3-7  cycloalkyl, aryl, aryl C 1 4  alkyl, heteroaryl, heteroaryl C 1-4  alkyl, heterocyclyl, or heterocyclyl C 1-4  alkyl;  
 R 4  is phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl, which is optionally substituted by one to three substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, C(Z)NR 7 R 17 , C(Z)OR 16 , (CR 10 R 20 ) v COR 12 , SR 5 , S(O)R 5 , OR 12 , halo-substituted-C 1-4  alkyl, C 1-4  alkyl, ZC(Z)R 12 , NR 10 C(Z)R 16 , or (CR 10 R 20 ) v NR 10 R 20  and which, for other positions of substitution, is halogen, cyano, nitro, phenyl, C(Z)NR 13 R 14 , C(Z)OR 3 , (CR 10 R 20 ) m″ COR 3 , S(O) m R 3 , OR 3 , halo-substituted-C 1-4  alkyl, C 1-10  alkyl, ZC(Z)R 3 , optionally substituted phenyl, (CR 10 R 20 ) m″ NR 10 C(Z)R 3 , NR 10 S(O) m′ R 8 , NR 10 S(O) m NR 7 R 17 , or (CR 10 R 20 ) m″ NR 13 R 14 ;  
 m is 0, or the integer 1 or 2;  
 m′ is an integer having a value of 1 or 2,  
 m″ is 0, or an integer having a value of 1 to 5;  
 n is 0, or an integer having a value of 1 to 10;  
 v is 0, or an integer having a value of 1 or 2;  
 R 2  is hydrogen, (CR 10 R 23 ) n  OR 9 , (CR 10 R 23 ) n OR 11 , 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  cycloalkyl C 1-10  alkyl, C 5-7  cycloalkenyl, C 5-7  cycloalkenyl C 1-10  alkyl, aryl, aryl C 1-10  alkyl, heteroaryl, heteroaryl C 1-10  alkyl, heterocyclyl, heterocyclyl C 1-10  alkyl, (CR 10 R 23 ) n S(O) m R 18 , (CR 10 R 23 ) n NHS(O) 2 R 18,  (CR 10 R 23 ) n NR 13 R 14 , (CR 10 R 23 ) n NO 2 , (CR 10 R 23 ) n CN, (CR 10 R 23 ) n S(O) m′ NR 13 R 14 , (CR 10 R 230 ) n C(Z)R 11 , (CR 10 R 23 ) n OC(Z)R 11 , (CR 10 R 23 ) n C(Z)OR 11 , (CR 10 R 23 ) n C(Z)NR 13 R 14 , (CR 10 R 23 ) n C(Z)NR 11 OR 9 , (CR 10 R 23 ) n NR 10 C(Z)R 11 , (CR 10 R 23 ) n NR 10 C(Z)NR 13 R 14 , (CR 10 R 23 ) n N(OR 6 )C(Z)NR 13 R 14 , (CR 10 R 23 ) n N(OR 6 )C(Z)R 11 , (CR 10 R 23 ) n C(═NOR 6 )R 11 , (CR 10 R 23 ) n NR 10 C(═NR  19 )NR 13 R 14 , (CR 10 R 23 ) n OC(Z)NR 13 R 14 , (CR 10 R 23 ) n NR 10  C(Z)NR 13 R 14 , (CR 10 R 23 ) n NR 10 C(Z)OR 10 , 5-(R 18 )- 1,2,4-oxadizaol-3-yl or 4-(R 12 )-5-(R 18 R 19 )-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the cycloalkyl, cycloalkyl alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted;  
 R 3  is heterocyclyl, heterocyclyl C 1-10  alkyl or R 8 ;  
 R 5  is hydrogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl or NR 7 R 17 , excluding the moieties SR 5  being SNR 7 R 17  and SOR 5  being —SOH;  
 R 6  is hydrogen, a pharmaceutically acceptable cation, C 1-10  alkyl, C 3-7  cycloalkyl, aryl, aryl C 1-4  alkyl, heteroaryl, heteroaryl C 1-4  alkyl, heterocyclic, aroyl, or C 1-10  alkanoyl;  
 R 7  and R 17  is each independently selected from hydrogen or C 1-4  alkyl or R 7  and R 17  together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 15 ;  
 R 8  is C 1-10  alkyl, halo-substituted C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-7  cycloalkyl, C 5-7  cycloalkenyl, aryl, aryl C 1-10  alkyl, heteroaryl, heteroaryl C 1-10  alkyl, (CR 10 R 20 ) n OR 11 , (CR 10 R 20 ) n S(O) m R 18 , (CR 10 R 20 ) n NHS(O) 2 R 18 , (CR 10 R 20 ) n NR 13 R 14 ; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;  
 R 9  is hydrogen, C(Z)R 11  or optionally substituted C 1-10  alkyl, S(O) 2 R 18 , optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl;  
 R 10  and R 20  is each independently selected from hydrogen or C 1-4  alkyl;  
 R 11  is hydrogen, C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, heterocyclyl C 1-10  alkyl, aryl, aryl C 1-10  alkyl, heteroaryl or heteroaryl C 1-10  alkyl, wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl or heterocyclylalkyl, may be optionally substituted;  
 R 12  is hydrogen or R 16 ;  
 R 13  and R 14  is each independently selected from hydrogen or optionally substituted C 1-4  alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9 ;  
 R 15  is hydrogen, C 1-10  alkyl or C(Z)—C 1-4  alkyl;  
 R 16  is C 1-4  alkyl, halo-substituted-C 1-4  alkyl, or C 3-7  cycloalkyl;  
 R 18  is C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, aryl, aryl C 1-10  alkyl, heterocyclyl, heterocyclyl-C 1-10  alkyl, heteroaryl or heteroarylalkyl, wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted;  
 R 19  is hydrogen, cyano, C 14  alkyl, C 3-7  cycloalkyl or aryl;  
 R 23  is hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, aryl, aryl C 1-4  alkyl, heteroaryl, heteroaryl C 1-4  alkyl, heterocyclyl, or heterocyclyl C 1-10  alkyl moiety, all of which may be optionally substituted;  
 Z is oxygen or sulfur; provided that when R 1  is a 4-pyridyl, R 4  is a 4—NH 2 S(O) 2 phenyl, then R 2  is other than a 3-position trifluoromethyl group; or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound according to  claim 1  wherein R 1  is a substituted 4-pyrimidinyl.  
     
     
         3 . The compound according to  claim 2  wherein the substituent is Y or NHR a .  
     
     
         4 . The compound according to  claim 1  wherein R 1  is a substituted 4-pyridyl.  
     
     
         5 . The compound according to  claim 4  wherein the substituent is Y or NHR a .  
     
     
         6 . The compound according to  claim 2  wherein R 4  is an optionally substituted phenyl.  
     
     
         7 . The compound according to  claim 4  wherein the phenyl is substituted one or more times independently by halogen, SR 5 , S(O)R 5 , OR 12 , halo-substituted-C 1-4  alkyl, or C 1-4  alkyl.  
     
     
         8 . The compound according to  claim 1  wherein R 2  is selected from optionally substituted C 4  to C 6  cycloalkyl, optionally substituted C 4  or C 6  cycloalkyl C 1-4  alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic C 1-4  alkyl, optionally substituted aryl, or an optionally substituted aryl C 1-4  alkyl.  
     
     
         9 . The compound according to  claim 1  which is: 
 4-[1-(4-Fluorophenyl)-3-phenyl-1H-pyrazol-5-yl]pyridine  
 4-[4-Bromo-1-(4-fluorophenyl)-3-phenyl-1H-pyrazol-5-yl]pyridine  
 4-[1-(4-Fluorophenyl)-3-[4-(methylthio)phenyl]-1H-pyrazol-5-yl]pyridine  
 4-[1-(4-Fluorophenyl)-3-[4-(methylsulfonyl)phenyl]- 1H-pyrazol-5-yl]pyridine  
 4-[1-(4-Fluorophenyl)-3-[4-(methylsulfinyl)phenyl]-1H-pyrazol-5-yl]pyridine; or a pharmaceutically acceptable salt thereof.  
 
     
     
         10 . A pharmaceutical composition comprising a compound according to any of  claims 1  to  9  and a pharmaceutically acceptable carrier or diluent.  
     
     
         11 . A method of treating a CSBP/RK/p38 kinase mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I) according to any of  claims 1  to  9 .  
     
     
         12 . The method according to  claim 11  wherein the mammal is afflicted with a CSBP/RK/p38 kinase mediated disease which is psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, Alzheimer's disease, stroke, neurotrauma, asthma, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and renal reperfusion injury, chronic renal failure, congestive heart failure, angiogenic diseases, cancer, thrombosis, glomerularnephritis, diabetes, graft vs. host reactions allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, eczema, contact dermatitis, psoriasis, sunburn, and conjunctivitis.  
     
     
         13 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is 4-pyridyl, 4-pyrimidinyl, 4-pyridazinyl, 4-triazin-5-yl, quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl ring, which ring is optionally substituted independently independently one to three times with Y, NHR a , optionally substituted C 1-4  alkyl, halogen, hydroxyl, optionally substituted C 1-4  alkoxy, optionally substituted C 1-4  alkylthio, optionally substituted C 1-4  alkylsulfinyl, CH 2 OR 12 , amino, mono and di- C 1-6  alkyl substituted amino, N(R 10 )C(O)R b ; N(R 10 )S(O) 2 R d  or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR 15 ;  
 Y is X 1 -R a ;  
 X 1  is sulfur or oxygen;  
 R a  is C 1-6  alkyl, aryl, aryl C 1-6  alkyl, heterocyclic, heterocyclyl C 1-6  alkyl, heteroaryl, or heteroaryl C 1-6  alkyl, wherein each of these moieties may be optionally substituted;  
 R b  is hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, aryl, aryl C 1-4  alkyl, heteroaryl, heteroaryl C 1-4  alkyl, heterocyclyl, or heterocyclylc C 1-4  alkyl;  
 R d  is C 1-6  alkyl, C 3-7  cycloalkyl, aryl, aryl C 1-4  alkyl, heteroaryl, heteroaryl C 1-4  alkyl, heterocyclyl, or heterocyclyl C 1-4  alkyl;  
 R 4  is phenyl, naphth-1-yl or naphth-2-yl, a fused phenyl containing ring system, or a heteroaryl, which is optionally substituted by one to three substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, C(Z)NR 7 R 17 , C(Z)OR 16 , (CR 10 R 20 ) v COR 12 , SR 5 , SOR 5 , OR 12 , halo-substituted-C 1-4  alkyl, C 1-4  alkyl, ZC(Z)R 12 , NR 10 C(Z)R 16 , or (CR 10 R 20 ) v NR 10 R 20  and which, for other positions of substitution, is halogen, cyano, C(Z)NR 13 R 14 , C(Z)OR 3 , (CR 10 R 20 )m″COR 3 , S(O) m R 3 , OR 3 , halo-substituted-C 1-4  alkyl, C 1-4  alkyl, (CR 10 R 20 )m″NR 10 C(Z)R 3 , NR 10 S(O) m′ R 8 , NR 10 S(O) m NR 7 R 17 , ZC(Z)R 3  or (CR 10 R 20 )m″NR 13 R 14 ;  
 n is 0, or an integer having a value of 1 to 10;  
 v is 0, or an integer having a value of 1 or 2;  
 m is 0, or the integer 1 or 2;  
 m′ is an integer having a value of 1 or 2,  
 m″ is 0, or an integer having a value of 1 to 5;  
 Z is oxygen or sulfur;  
 R 2  is hydrogen, (CR 10 R 23 ) n  OR 9 , (CR 10 R 23 ) n OR 11 , 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  cycloalkyl C 1-10  alkyl, C 5-7  cycloalkenyl, C 5-7  cycloalkenyl C 1-10  alkyl, aryl, aryl C 1-10  alkyl, heteroaryl, heteroaryl C 1-10  alkyl, heterocyclyl, heterocyclyl C 1-10  alkyl, (CR 10 R 23 ) n S (O) m R 18 , (CR 10 R 23 ) n NHS(O) 2 R 18 , (CR 10 R 23 ) n NR 13 R 14 , (CR 10 R 23 ) n NO 2 , (CR 10 R 23 ) n CN, (CR 10 R 23 ) n S(O) m′ NR 13 R 14 , (CR 10 R 230 ) n C(Z)R 11 , (CR 10 R 23 ) n OC(Z)R 11 , (CR 10 R 23 ) n C(Z)OR 11 , (CR 10 R 23 ) n C(Z)NR 13 R 14 , (CR 10 R 23 ) n C(Z)NR 11 OR 9 , (CR 10 R 23 ) n NR 10 C(Z)R 1 , (CR 10 R 23 ) n NR 10 C(Z)NR 13 R 14 , (CR 10 R 23 ) n N(OR 6 )C(Z)NR 13 R 14 , (CR 10 R 23 ) n N(OR 6 )C(Z)R 11 , (CR 10 R 23 ) n C(═NOR 6 )R 11 , (CR 10 R 23 ) n NR 10 C(═NR 19 )NR 13 R 14 , (CR 10 R 23 ) n OC(Z)NR 13 R 14 , (CR 10 R 23 ) n NR 10 C(Z)NR 13 R 14 , (CR 10 R 23 ) n NR 10 C(Z)OR 10 , -(R 18 )-1,2,4-oxadizaol-3-yl or 4-(R 12 )-5-(R 18 R 19 )-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the cycloalkyl, cycloalkyl alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted;  
 R 3  is heterocyclyl, heterocyclyl C 1-10  alkyl or R 8 ;  
 R 5  is hydrogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl or NR 7 R 17 , excluding the moieties SR 5  being SNR 7 R 17  and SOR 5  being SOH;  
 R 6  is hydrogen, a pharmaceutically acceptable cation, C 1-10  alkyl, C 3-7  cycloalkyl, aryl, aryl C 1-4  alkyl, heteroaryl, heteroaryl C 1-4  alkyl, heterocyclic, aroyl, or C 1-10  alkanoyl;  
 R 7  and R 17  is each independently selected from hydrogen or C 1-4  alkyl or R 7  and R 17  together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 15 ;  
 R 8  is C 1-10  alkyl, halo-substituted C 1-10  alkyl, C 2-10  alkenyl, CC 1-10  alkynyl, C 3-7  cycloalkyl, C 5-7  cycloalkenyl, aryl, aryl C 1-10  alkyl, heteroaryl, heteroaryl C 1-10  alkyl, (CR 10 R 20 ) n OR 11 , (CR 10 R 20 ) n S(O) m R 18 , (CR 10 R 20 ) n NHS(O) 2 R 18 , (CR 10 R 20 ) n NR 13 R 14 ; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;  
 R 9  is hydrogen, —C(Z)R 11  or optionally substituted C 1-10  alkyl, S(O) 2 R 18 , optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl;  
 R 10  and R 20  is each independently selected from hydrogen or C 1-4  alkyl;  
 R 11  is hydrogen, C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, heterocyclyl C 1-10  alkyl, aryl, aryl C 1-10  alkyl, heteroaryl or heteroaryl C 1-10  alkyl;  
 R 12  is hydrogen or R 16 ;  
 R 13  and R 14  is each independently selected from hydrogen or optionally substituted C 1-4  alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9 ;  
 R 15  is hydrogen, C 1-4  alkyl or C(Z)—C 1-4  alkyl;  
 R 16  is C 1-4  alkyl, halo-substituted-C 1-4  alkyl, or C 3-7  cycloalkyl;  
 R 18  is C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, aryl, aryl C 1-10  alkyl, heterocyclyl, heterocyclyl-C 1-10  alkyl, heteroaryl or heteroarylalkyl;  
 R 19  is hydrogen, cyano, C 1-4  alkyl, C 3-7  cycloalkyl or aryl;  
 R 23  is hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, aryl, aryl C 1-4  alkyl, heteroaryl, heteroaryl C 1-4  alkyl, heterocyclyl, or heterocyclylc C 1-4  alkyl moiety, all of which may be optionally substituted;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         14 . The compound according to  claim 13  wherein R 1  is a substituted 4-pyridyl or 4-pyrimidinyl.  
     
     
         15 . The compound according to  claim 14  wherein the substituent is Y, or NHR a .  
     
     
         16 . The compound according to  claim 14  wherein R 4  is an optionally substituted phenyl.  
     
     
         17 . The compound according to  claim 16  wherein the phenyl is substituted one or more times independently by halogen, —SR 5 , S(O)R 5 , OR 12 , halo-substituted-C 1-4  alkyl, or C 1-4  alkyl.  
     
     
         18 . The compound according to  claim 13  wherein R 2  is selected from optionally substituted C 4  to C 6  cycloalkyl, optionally substituted C 4  or C 6  cycloalkyl C 1-4  alkyl, optionally substituted heterocyclic, optionally substituted heterocyclicalkyl, optionally substituted aryl, or optionally substituted aryl alkyl.  
     
     
         19 . The compound according to  claim 13  which is: 
 4-[1-(4-Fluorophenyl)-4,5-dihydro-3-phenyl-1 H-pyrazol-5-yl]pyridine  
 4-[1-(4-Fluorophenyl)-4,5-dihydro-3-[4-(methylthio)phenyl]-1H-pyrazol-5-yl]pyridine, or a pharmaceutically acceptable salt thereof.  
 
     
     
         20 . A pharmaceutical composition comprising a compound according to any of  claims 13  to  19  and a pharmaceutically acceptable carrier or diluent.  
     
     
         21 . A method of treating a CSBP/RK/p38 kinase mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I) according to any of  claims 13  to  19 .  
     
     
         22 . The method according to  claim 21  wherein the mammal is afflicted with a CSBP/RK/p38 kinase mediated disease which is psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, Alzheimer's disease, stroke, neurotrauma, asthma, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and renal reperfusion injury, chronic renal failure, congestive heart failure, angiogenic diseases, cancer, thrombosis, glomerularnephritis, diabetes, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, eczema, contact dermatitis, psoriasis, sunburn, and conjunctivitis.  
     
     
         23 . A process for producing a compound of Formula (I), according to  claim 1  wherein R 1  is an optionally substituted pyrimidinyl, which process comprises cyclizing a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 2  is an optionally substituted phenyl, as defined according to formula (I); with a compound of the formula: R 4 NHNH 2 , wherein R 4  is as defined for Formula (I), to yield a compound of Formula (I), or if necessary, converting a precursor of R 1 , R 2  and R 4  to a group R 1 , R 2  and R 4 .  
     
     
         24 . A process for producing a compound of Formula (I), according to  claim 1 , wherein R 1  is an optionally substituted pyridyl, which process comprises cyclizing a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 2  is an optionally substituted phenyl, as defined according to formula (I); with a compound of the formula: R 4 NHNH 2 , wherein R 4  is as defined for Formula (I), to yield a compound of Formula (I), or if necessary, converting a precursor of R 1 , R 2  and R 4  to a group R 1 , R 2  and R 4 .