Novel substituted imidazole compounds

Abstract

Novel 1,4,5 substituted imidazole compounds and compositions for use in therapy as CSBP/p38 kinase inhibitors.

What is claimed is:  
     
         1 . A compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is a 4-pyridyl, 4-pyrimidinyl, 4-pyridazinyl, 1,2,4-triazin-5-yl, quinolyl, isoquinolinyl, or quinazolin-4-yl ring which ring is optionally substituted independently by C 1-4  alkyl, halogen, hydroxyl, C 1-4  alkoxy, C 1-4  alkylthio, C 1-4  alkylsulfinyl, CH 2 OR 12 , amino, mono and di-C 1-6  alkyl substituted amino, N(R 10 )C(O)R c  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 ;  
 R 4  is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl ring, which ring is optionally substituted by one or two 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 ;  
 Z is oxygen or sulfur;  
 v is 0, or an integer having a value of 1 or 2;  
 n is an integer having a value of 1 to 10;  
 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;  
 R 2  is —C(H)(A)(R 22 );  
 A is an optionally substituted C 3-7  cycloalkyl, aryl, heterocyclyl, or heteroaryl ring, or A is a substituted C 1-10  alkyl;  
 R 22  is an optionally substituted C 1-10  alkyl;  
 R c  is hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, aryl, arylC 1-4  alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclyl, or heterocyclylC 1-4 alkyl C 1-4  alkyl;  
 R 3  is heterocyclyl, heterocyclylC 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 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, arylC 1-10  alkyl, heteroaryl, heteroarylC 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, arylC 1-10  alkyl, heteroaryl or heteroarylC 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 R 10  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 1-10 alkyl, heterocyclyl, heterocyclyl-C 1-10 alkyl, heteroaryl or heteroaryl 1-10 alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound according to  claim 1  wherein R 1  is a 4-pyridyl or 4-pyrimindyl substituted with an isopropoxy, ethoxy, methoxy, or methylthio group.  
     
     
         3 . The compound according to  claim 1  wherein R 4  is an optionally substituted phenyl.  
     
     
         4 . The compound according to  claim 3  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.  
     
     
         5 . The compound according to  claim 1  wherein R 22  is a C 1-6  alkyl or is a hydroxy substituted C 1-6  alkyl.  
     
     
         6 . The compound according to  claim 1  wherein A is an optionally substituted phenyl, or C 3-6  cycloalkyl.  
     
     
         7 . The compound according to  claim 1  wherein A is a substituted C 1-10  alkyl.  
     
     
         8 . The compound according to  claim 7  wherein A is a C 1-6  alkyl substituted by OR 11 , NR 13 R 14 , C(Z)OR 11 , or OC(Z)R 11 .  
     
     
         9 . The compound according to  claim 1  which is: 
 1-(1-Hydroxy-2-pheneth-2-yl))14-(4-fluorophenyl)-5-[2-(-propylthio)pyrimidin-4-yl]imidazole  
 1-(-Hydroxy-2-phenyleth-2-yl)-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole  
 1-(1-Hydroxyprop-2-yl))-4-(4-fluorophenyl)-5-[2-(1-propylthio)pyrimidin-4-yl]imidazole  
 1-(1-Hydroxybut-2-yl))-4-(4-fluorophenyl)-5-[2-(1-propylthio)pyrimidin-4-yl]imidazole  
 1-(1-Hydroxybut-2-yl))-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)i-idazole  
 1-(1,3-Dihydroxyprop-2-yl) 4 -(4-fluorophenyl)-5-[2-(1-propylthio)pyrimidin-4-yl]imidazole  
 1-(1-(1,3-Dihydroxyprop-2-yl)-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole  
 1-(1-Dimethylamino-prop-2-yl)-4-(4-fluorophenyl)-5-[2-(1-propylthio)pyrimidin-4-yl]imidazole  
 1-(1-Dimethylamino-prop-2-yl)-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole  
 1-(-(Carbomethoxy)prop-2-yl)-4-(4-fluorophenyl)-5-[2-(-propylthio)pyrimidin-4-yl]imidazole  
 1-(1-Phenoxyprop-2-yl)-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole  
 1-(1-Hydroxyprop-2-yl)-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole  
 1-(1-Hydroxy-3-phenylprop-2-yl)-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole  
 1-(1-Hydroxy-2-phenyleth-2-yl)-4-(4-fluorophenyl)-5-[(2-[N-(methyl)-amino]-pyrimidin-4-yl]imidazole  
 1-(1-Hydroxybut-2-yl) 4 -(4-fluorophenyl)-5-[(2-[N-(methyl)amino]pyrimidin-4-yl]imidazole  
 1-(-Hydroxyprop-2-yl)-4-(4-fluorophenyl)-5-[2-(N-methyl)amino]pyrimidin-4-yl]imidazole  
 1-(1-Hydroxyprop-2-yl)-4-(4-fluorophenyl)-5-(pyrimidin-4-yl)imidazole;  
 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 inflammation 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 . A method of treating a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a compound of Formula (I) according to any of  claims 1  to  9 .  
     
     
         13 . The method according to  claim 12  wherein the mammal is afflicted with a CSBP/RK/p38 kinase mediated disease which is psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, gouty arthritis, 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, angiogenesis related process, cancer, thrombosis, glomerularnephritis, diabetes, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, muscle degeneration, eczema, contact dermatitis, psoriasis, sunburn, and conjunctivitis.  
     
     
         14 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is a 4-pyridyl, 4-pyrimidinyl, 4-quinolyl, 6-isoquinolinyl, or 4-quinazolinyl ring which ring is substituted by NHR a , and which ring may be additionally substituted by C 1-4  alkyl, halogen, hydroxyl, C 1-4  alkoxy, C 1-4  alkylthio, 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  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 ;  
 R 4  is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, which is optionally substituted by one or two 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 ;  
 Z is oxygen or sulfur;  
 n is an integer having a value of 1 to 10;  
 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;  
 v is 0, or an integer having a value of 1 or 2;  
 R 2  is —C(H)(A)(R 22 );  
 A is an optionally substituted C 3-7  cycloalkyl, aryl, heterocyclyl, or heteroaryl ring, or A is a substituted C 1-10  alkyl;  
 R 22  is an optionally substituted C 1-10  alkyl;  
 R a  is aryl, arylC 1-6 alkyl, heterocyclic, heterocyclylC 1-6  alkyl, heteroaryl, heteroarylC 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, arylC 1-4  alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclyl, or heterocyclylC 1-4  alkyl, wherein each of these moieties may be optionally substituted;  
 R 3  is heterocyclyl, heterocyclylC 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 SORs being —SOH;  
 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, arylC 1-10  alkyl, heteroaryl, heteroarylC 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, arylC 1-10  alkyl, heteroaryl or heteroarylC 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 R 10  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 1-10 alkyl, heterocyclyl, heterocyclyl-C 1-10 alkyl, heteroaryl or heteroaryl 1-10 alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         15 . The compound according to  claim 14  wherein R 1  is a 4-pyridyl or 4-pyrimindyl.  
     
     
         16 . The compound according to  claim 15  wherein R a  is an optionally substituted aryl, or an optionally substituted arylalkyl.  
     
     
         17 . The compound according to  claim 14  wherein R 4  is an optionally substituted phenyl.  
     
     
         18 . The compound according to  claim 17  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.  
     
     
         19 . The compound according to  claim 14  wherein R 22  is a hydroxy substituted alkyl.  
     
     
         20 . The compound according to  claim 14  wherein A is an optionally substituted phenyl.  
     
     
         21 . The compound according to  claim 14  wherein A is a substituted C 1-10  alkyl.  
     
     
         22 . The compound according to  claim 14  wherein A is a C 1-6  alkyl substituted by OR 11 , NR 13 R 14 , C(Z)OR 11 , or OC(Z)R 11 .  
     
     
         23 . The compound according to  claim 14  which is 4-(4-Fluorophenyl)-1-(1-hydroxyprop-2-yl)-5-[2-[(N-phenyl)amino]pyrimidin-4-yl]imidazole; or a pharmaceutically acceptable salt thereof.  
     
     
         24 . A pharmaceutical composition comprising a compound according to any of  claims 14  to  23  and a pharmaceutically acceptable carrier or diluent.  
     
     
         25 . 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 (II), according to any of  claims 17  to  23 .  
     
     
         26 . The method according to  claim 25  wherein the mammal is afflicted with a CSBP/RK/p38 kinase mediated disease which is psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, gouty arthritis, 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, angiogenesis, cancer, thrombosis, glomerularonephritis, diabetes, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, muscle degeneration, eczema, contact dermatitis, psoriasis, sunburn, and conjunctivitis.  
     
     
         27 . A process for producing a compound of Formula (I) according to  claim 1  or a compound of Formula (II) according to  claim 17  which process comprises reacting a compound of the Formula (IIa):  
       
         
           
           
               
               
           
         
       
       with a compound of the Formula (III):  
       
         
           
           
               
               
           
         
       
       wherein p is 0 or 2; and a base strong enough to deprotonate the isonitrile moiety of Formula (II); and R 1 , R 2  and R 4  are as defined in Formula (I) or are precursors of the groups R 1 , R 2  and R 4  and Ar is an optionally substituted phenyl group, and thereafter if necessary, converting a precursor of R 1 , R 2  and R 4  to a group R 1 , R 2  and R 4 .  
     
     
         31 . The process according to claim  30  wherein p=2.  
     
     
         32 . The process according to  claim 31  wherein the imine of Formula (III), is isolated prior to reaction with Formula (IIa).  
     
     
         33 . The process according to  claim 31  wherein the imine of Formula (III), is formed in situ prior to reaction with Formula (IIa).  
     
     
         34 . The process according to  claim 33  wherein the imine is formed in situ by reacting an aldehyde of the formula R 1 CHO, wherein R 1  is as defined for Formula (I) or (II), with a primary amine of the formula R 2 NH 2 , wherein R 2  is as defined for Formula (I) or (II).  
     
     
         35 . The process according to  claim 34  wherein formation of the imine in situ utilizes dehydrating conditions.  
     
     
         36 . The process according to claim  30  or  35  wherein the solvent is N,N-dimethylformamide (DMF), a halogenated solvent, tetrahydrofuran (THF), dimethylsulfoxide (DMSO), an alcohol, benzene, toluene, MeCN, or DME.  
     
     
         37 . The process according to claim  30  wherein the base is an amine, a carbonate, a hydride, or an alkyl or aryl lithium reagent, or a mixture thereof.  
     
     
         38 . The process according to claim  30  wherein R 4  is a phenyl or a phenyl 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.  
     
     
         39 . The process according to claim  30  or  34  wherein R 1  is a pyrimidin-4-yl moiety.  
     
     
         40 . The process according to claim  30  or  34  wherein R 1  is a pyrid-4-yl moiety.