Novel Compounds

Abstract

This invention relates to a novel group of 8-Alkyl/Aryl-4-aryl-2-N-(alkylamino)-N″-substituted-N′-cyanoguanidino-8H-pyrido[2,3-d]pyrimidin-7-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 method of treating a CSBP/RK/p38 kinase mediated disease in a human in need thereof, which method comprises administering to said mammal an effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is an optionally substituted aryl or an optionally substituted heteroaryl ring; 
 R 2  and R 2′  are independently selected from hydrogen, C 1-10 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-10 alkyl, C 5-7 cycloalkenyl, C 5-7 cycloalkenyl-C 1-10 alkyl, aryl, arylC 1-10 alkyl, heteroaryl, heteroarylC 1-10 alkyl, heterocyclic, or a heterocyclylC 1-10 alkyl moiety, wherein all of the moieties are optionally substituted, or R 2  and R 2′  together with the nitrogen to which they are attached form a 5 to 7 membered optionally substituted ring, which ring may contain an additional heteroatom selected from O/N/S; 
 R a  is hydrogen, or an optionally substituted C 1-4 alkyl; 
 R g  is selected from an optionally substituted C 1-10 alkyl, —CH 2 —CH 2 —O—CH 2 —CH 2 —, —CH 2 —C(O)—CH 2 , CH 2 —C(O)N(R 12 )CH 2 —CH 2 —, CH 2 —N(R 12 )C(O)CH 2 —, CH 2 —CH(OR 12 )—CH 2 , CH 2 —C(O)O—CH 2 —CH 2 , or CH 2 —CH 2 —O—C(O)CH 2 —; 
 R 12  is hydrogen, or an optionally substituted C 1-4 alkyl; 
 R 3  is a C 1-10 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, aryl, arylC 1-10 alkyl, heteroaryl, heteroarylC 1-10 alkyl, heterocyclic, or a heterocyclylC 1-10 alkyl moiety, which moieties are all optionally substituted; or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The method according to  claim 1  wherein the compound is of Formula (I), or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method according to  claim 1  wherein the compound is of Formula (Ia), or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The method according to  claim 1  wherein R 1  is optionally substituted one or more times independently at each occurrence by substituents selected from halogen, C 1-4 alkyl, halo-substituted-C 1-4 alkyl, hydroxy, cyano, nitro, (CR 10 R 20 ) v NR 4 R 14 , (CR 10 R 20 ) v C(Z)NR 4 R 14 , (CR 10 R 20 ) v C(Z)OR 8 , (CR 10 R 20 ) v COR c , (CR 10 R 20 ) v C(O)H, SR 5 , S(O)R 5 , S(O) 2 R 5 , (CR 10 R 20 ) v OR 8 , ZC(Z)R 11 , N(R 10′ )C(Z)R 11 , or N(R 10′ )S(O) 2 R 7 ; and wherein
 R 4  and R 14  are each independently selected at each occurrence, by hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, optionally substituted aryl, or optionally substituted aryl-C 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic, or heterocyclic C 1-4 alkyl; or R 4  and R 14  together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9 ;   R 5  is independently selected, at each occurrence by hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or NR 4 R 14 , excluding the moieties SR 5  being SNR 4 R 14 , S(O) 2 R 5  being SO 2 H and S(O)R 5  being SOH;   R 7  is independently selected from C 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclic, heterocyclylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl; and wherein each of these moieties may be optionally substituted;   R 9  is hydrogen, C(Z)R 6  or optionally substituted C 1-10 alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4 alkyl;   R 10  and R 20  are independently selected at each occurrence, from hydrogen or C 1-4 alkyl;   R 10′  is independently selected at each occurrence, from hydrogen or C 1-4 alkyl;   R 11  is C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, aryl, arylC 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclyl, heterocyclylC 1-4 alkyl, (CR 10 R 20 ) t OR 7 , (CR 10 R 20 ) t S(O) m R 7 , (CR 10 R 20 ) t  N(R 10′ )S(O) 2 R 7 , or (CR 10 R 20 ) v NR 4 R 14 ; and wherein the aryl, arylalkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclyl, and heterocyclyl C 1-4 alkyl moieties may be optionally substituted;   R c  is C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, aryl, arylC 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclyl, heterocyclylC 1-4 alkyl, (CR 10 R 20 ) v OR 7 , (CR 10 R 20 ) v S(O) m R 7 , (CR 10 R 20 ) v  N(R 10′ )S(O) 2 R 7 , or (CR 10 R 20 ) v NR 4 R 14 ; and wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic and heterocyclic C 1-4 alkyl moieties may be optionally substituted;   m is independently selected at each occurrence from 0 or an integer having a value of 1 or 2;   t is an integer having a value of 1 to 3;   v is 0 or an integer having a value of 1 or 2; and   Z is independently selected from oxygen or sulfur.   
     
     
         5 . The method according to  claim 4  wherein R 1  is an optionally substituted phenyl or naphthyl. 
     
     
         6 . The method according to  claim 5  wherein the phenyl is substituted one or more times independently by halogen, C 1-4 alkyl, (CR 10 R 20 ) v OR 8 , (CR 10 R 20 ) v NR 4 R 14 , or halo-substituted-C 1-4 alkyl. 
     
     
         7 . The method according to  claim 6  wherein the substituent is halogen, hydroxy, alkoxy, amino, or halosubstituted alkyl. 
     
     
         8 . The method according to  claim 7  wherein the substituents are independently selected from fluorine, chlorine, methyl, or CF 3 . 
     
     
         9 . The method according to  claim 5  wherein R 1  is phenyl or a phenyl ring mono-substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2,4,6-position. 
     
     
         10 . The method according to  claim 9  wherein R 1  is phenyl, 2-methyl-4-fluorophenyl, 2-methylphenyl, 2-chlorophenyl, 2-fluorophenyl, or 2-methyl-3-fluorophenyl. 
     
     
         11 . The method according to  claim 1  wherein the R 3  moiety 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 1-10 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 N(R 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 N(R 10′ )C(Z)R 6 , (CR 10 R 20 ) n N(R 10′ )C(═N(R 10′ ))NR 4 R 14 , (CR 10 R 20 ) n OC(Z)NR 4 R 14 , (CR 10 R 20 ) n N(R 10′ )C(Z)NR 4 R 14 , or (CR 10 R 20 ) n N(R 10′ )C(Z)OR 7 ; and wherein
 R 4  and R 14  are each independently selected from hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, optionally substituted aryl, or optionally substituted aryl-C 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic, or heterocyclic C 1-4 alkyl; or R 4  and R 14  together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9 ;   R 6  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, wherein each of these moieties may be optionally substituted independently one or more times;   R 7  is C 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclic, heterocyclylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl; and wherein each of these moieties may be optionally substituted independently one or more times;   R 9  is hydrogen, C(Z)R 6  or optionally substituted C 1-10 alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4 alkyl, wherein the optional substituents are independently substituted;   R 10  and R 20  are independently selected from hydrogen or C 1-4 alkyl;   R 10′  is independently selected from hydrogen or C 1-4 alkyl;   m is independently selected at each occurrence from 0 or an integer having a value of 1 or 2;   n is 0 or an integer having a value of 1 to 10; and   Z is independently selected at each occurrence from oxygen or sulfur.   
     
     
         12 . The method according to  claim 11  wherein R 3  is an optionally substituted C 1-10 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylalkyl, or aryl. 
     
     
         13 . The method according to  claim 12  wherein the optional substituents are independently selected at each occurrence from halogen, C 1-10 alkyl, halo-substituted C 1-10 alkyl, (CR 10 R 20 ) n OR 6 , or (CR 10 R 20 ) n NR 4 R 14 . 
     
     
         14 . The method according to  claim 13  wherein the optional substituents are halogen, methyl, hydroxy, alkoxy, amino, or CF 3 . 
     
     
         15 . The method according to  claim 11  wherein R 3  is phenyl, 4-trifluoromethyl-phenyl, 2-fluorophenyl, 2,6-difluoro-phenyl, 2,4-difluoro-phenyl, 2-chlorophenyl, 2-methylphenyl, or 2,6-dimethylphenyl. 
     
     
         16 . The method according to  claim 1  wherein R 2  and R 2′  are independently hydrogen or C 1-10 alkyl, 
     
     
         17 . The method according to  claim 1  wherein R g  is an optionally substituted C 1-10 alkyl. 
     
     
         18 . The method according to  claim 1 , wherein the compound is: 
       N-cyano-N′-(2-{[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)guanidine; 
       N-cyano-N′-(2-{[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)-N″-methylguanidine; 
       N-cyano-N′-(2-{[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)-N″-ethylguanidine; 
       N-Cyano-N′-(2-{[4-(2,4-difluorophenyl)-8-(2-fluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)guanidine; 
       N-Cyano-N′-(2-{[8-(2,6-difluorophenyl)-4-(2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)guanidine; 
       N-Cyano-N′-(2-{[8-(2,6-difluorophenyl)-4-(4-fluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)guanidine; 
       N-cyano-N′-(2-{[4-(2,4-difluorophenyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)guanidine; or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method according to  claim 1  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, atheroschlerosis, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, neurodegenrative disease, muscle degeneration, atheroschlerosis, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic disease, influenza induced pneumonia, eczema, contact dermatitis, psoriasis, sunburn, or conjunctivitis. 
     
     
         20 . A method according to  claim 1  wherein the CSBP/RK/p38 kinase mediated disease is traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis or other arthritic condition. 
     
     
         21 . A method according to  claim 1  wherein the CSBP/RK/p38 kinase mediated disease is asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, or chronic obstructive pulmonary disease (COPD). 
     
     
         26 . A method according to  claim 1  wherein the CSBP/RK/p38 kinase mediated disease is atherosclerosis. 
     
     
         27 . A method of treating inflammation in a human in need thereof comprising administering to said human which method comprises administering to said mammal an effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is an optionally substituted aryl or an optionally substituted heteroaryl ring; 
 R 2  and R 2′  are independently selected from hydrogen, C 1-10 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-10 alkyl, C 5-7 cycloalkenyl, C 5-7 cycloalkenyl-C 1-10 alkyl, aryl, arylC 1-10 alkyl, heteroaryl, heteroarylC 1-10 alkyl, heterocyclic, or a heterocyclylC 1-10 alkyl moiety, wherein all of the moieties are optionally substituted, or R 2  and R 2′  together with the nitrogen to which they are attached form a 5 to 7 membered optionally substituted ring, which ring may contain an additional heteroatom selected from O/N/S; 
 R a  is hydrogen, or an optionally substituted C 1-4 alkyl; 
 R g  is selected from an optionally substituted C 1-10 alkyl, —CH 2 —CH 2 —O—CH 2 —CH 2 —, —CH 2 —C(O)—CH 2 , CH 2 —C(O)N(R 12 )CH 2 —CH 2 —, CH 2 —N(R 12 )C(O)CH 2 —, CH 2 —CH(OR 12 )—CH 2 , CH 2 —C(O)O—CH 2 —CH 2 , or CH 2 —CH 2 —O—C(O)CH 2 —; 
 R 12  is hydrogen, or an optionally substituted C 1-4 alkyl; 
 R 3  is a C 1-10 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, aryl, arylC 1-10 alkyl, heteroaryl, heteroarylC 1-10 alkyl, heterocyclic, or a heterocyclylC 1-10 alkyl moiety, which moieties are all optionally substituted; or a pharmaceutically acceptable salt thereof.