Azabiphenylaminobenzoic acid derivatives as dhodh inhibitors

Abstract

The present disclosure relates to new azabiphenylaminobenzoic acid derivatives of formula (I); as well as processes for their preparation, pharmaceutical compositions comprising them, and their use in therapy as inhibitors of the dehydroorotate dihydrogenase (DHODH).

1 - 24 . (canceled) 
     
     
         25 . The compound according to  claim 26 , chosen from:
 5-cyclopropyl-2-(2-phenylpyrimidin-5-ylamino)benzoic acid,   2-(6-Cyclopropyl-5-methylpyridin-3-ylamino)-5-methylbenzoic acid,   5-(2-Carboxy-4-cyclopropylphenylamino)-3-methyl-2-phenylpyridine 1-oxide,   5-Methyl-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-ylamino)benzoic acid,   5-cyclopropyl-2-(6-hydroxy-5-phenylpyridin-3-ylamino)benzoic acid,   5-cyclopropyl-2-(2-(2,6-difluoro-4-hydroxyphenyl)pyrimidin-5-ylamino)benzoic acid,   5-Cyclopropyl-2-(6-methoxy-5-phenylpyridin-3-ylamino)benzoic acid,   2-(5-Fluoro-6-phenylpyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(Ethyl(methyl)amino)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid,   5-Cyclopropyl-2-(3′-fluoro-2,4′-bipyridin-5-ylamino)benzoic acid,   2-(6-(Diethylamino)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-((2-Methoxyethyl)(methyl)amino)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid,   2-(5-Chloro-6-phenylpyridin-3-ylamino)-5-methylbenzoic acid,   5-Cyclopropyl-2-(2-(2-cyclopropylphenyl)pyrimidin-5-ylamino)benzoic acid,   5-cyclopropyl-2-(5-phenylpyridin-3-ylamino)benzoic acid,   5-methyl-2-(quinolin-3-ylamine)benzoic acid,   5-methyl-2-(5,6,7,8-tetrahydroquinolin-3-ylamino)benzoic acid,   2-(5-Chloro-2-phenylpyridin-3-ylamino)-5-methylbenzoic acid,   5-Cyclopropyl-2-(5,6diphenylpyridin-3-ylamino)benzoic acid,   5-cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidin-5-ylamino)benzoic acid,   5-Cyclopropyl-2-(5-methylpyridin-3-ylamino)benzoic acid,   2-(2-(3-Cyclopropoxyphenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid,   5-Methyl-2-(6-morpholinopyridin-3-ylamino)benzoic acid,   5-Methyl-2-(5-methyl-6-morpholinopyridin-3-ylamino)benzoic acid,   5-cyclopropyl-2-(6cyclopropyl)-5-phenylpyridin-3-ylamino)benzoic acid,   2-(6-(2cyclopropylphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(2-Cyanophenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid,   2-(2-(3-Chlorophenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid,   5-Methyl-2-(6-phenyl-5-(trifluoromethyl)pyridin-3-ylamino)benzoic acid,   5-Methyl-2-(5-methyl-6-(piperidin-1-yl)pyridin-3-ylamino)benzoic acid,   2-(6-(Azepan-1-yl)-5-methylpyridin-3-ylamino)-5methylbenzoic acid,   2-(6-(3-Methoxyphenyl)-5-phenylpyridin-3-ylamino)-5-methylbenzoic acid,   2-(2,3′-bipyridin-5-ylamino)-5-cyclopropylbenzoic acid,   2-(3′-chloro-2,4′-bipyridin-5-ylamino)-5-methylbenzoic acid,   5-Methyl-2-(3-methyl-2,2′-bipyridin-5-ylamino)benzoic acid,   2-(5,6-Difluoropyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(3-Methoxyphenyl)pyridin-3-ylamino)benzoic acid,   2-(6-(3-Ethoxyphenyl)pyridin-3-ylamino)benzoic acid,   2-(6-(3-Ethoxyphenyl)pyridin-3-ylamino)-5-fluorobenzoic acid,   2-(6-(3-Ethoxyphenyl)-5-methylpyridin-3-ylamino)benzoic acid,   2-(6-(3-Ethoxyphenyl)pyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(3-Ethoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(3-Ethoxy-2-fluorophenyl)pyridin-3-ylamino)benzoic acid,   2-(6-(3-Ethoxyphenyl)-4-methylpyridin-3-ylamino)-5-ethylbenzoic acid,   2-(6-(3-Ethoxyphenyl)-4-methylpyridin-3-ylamino)benzoic acid,   5-Bromo-2-(6-(3-ethoxyphenyl)pyridin-3-ylamino)benzoic acid,   5-Chloro-2-(6-(3-ethoxyphenyl)pyridin-3-ylamino)benzoic acid,   2-(6-(5-Ethoxy-2-fluorophenyl)pyridin-3-ylamino)benzoic acid,   2-(6-(3-Ethoxyphenyl)-5-methylpyridin-3-ylamino)-5-(trifluoromethyl)benzoic acid,   2-(6-(3-Methoxyphenyl)-5-methylpyridin-3-ylamino)-5-(trifluoromethyl)benzoic acid,   2-(6-(3-Methoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(3-Methoxyphenyl)-5-methylpyridin-3-ylamino)-6-methylbenzoic acid,   5-Fluoro-2-(6-(3-methoxyphenyl)-5-methylpyridin-3-ylamino)benzoic acid,   2-(6-(5-Ethoxy-2-fluorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(2-Fluoro-5-methoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid,   Ethyl 2-(6-(2-fluoro-5-methoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoate,   2-(6-(2-Fluorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(3-Methoxyphenyl)-5-phenylpyridin-3-ylamino)-5-methylbenzoic acid,   Ethyl 2-(6-(3-methoxyphenyl)-5-phenylpyridin-3-ylamino)-5-methylbenzoate,   5-Methyl-2-(5-methyl-6-phenylpyridin-3-ylamino)benzoic acid,   Ethyl 5-methyl-2-(5-methyl-6-phenylpyridin-3-ylamino)benzoate,   5-Methyl-2-(5-methyl-6-(3-(trifluoromethoxy)phenyl)pyridin-3-ylamino)benzoic acid,   Ethyl 5-methyl-2-(5-methyl-6-(3-(trifluoromethoxy)phenyl)pyridin-3-ylamino)benzoate,   2-(5-Cyclopropyl-6-(3-methoxyphenyl)pyridin-3-ylamino)-5-methylbenzoic acid,   Ethyl 2-(5-cyclopropyl-6-(3-methoxyphenyl)pyridin-3-ylamino)-5-methylbenzoate,   2-(6-(2-Fluoro-5-isopropoxyphenyl)pyridin-3-ylamino)-5-ethylbenzoic acid,   2-(6-(3-Isopropoxyphenyl)-5-methylpyridin-3-ylamino)-5-ethylbenzoic acid,   Ethyl 2-(6-(3-isopropoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoate,   2-(6-(3-Cyclopropoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid, tert-Butyl 2-(6-(3-cyclopropoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoate,   2-(6-(2-Chlorophenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid, tert-Butyl 2-(6-(2-chlorophenyl)-5-methylpyridin-3-ylamino)-5-ethylbenzoate,   2-(6-(3-Carbamoylphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid,   Ethyl 2-(6-(3-carbamoylphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoate,   2-(6-(2-Fluoro-5-methoxyphenyl)-4-methylpyridin-3-ylamino)-5-methylbenzoic acid,   Ethyl 2-(6-(2-fluoro-5-methoxyphenyl)-4-methylpyridin-3-ylamino)-5-methylbenzoate,   2-(6-(3-Methoxyphenyl)-5-(trifluoromethyl)pyridin-3-ylamino)-5-methylbenzoic acid,   Ethyl 2-(6-(3-methoxyphenyl)-5-(trifluoromethyl)pyridin-3-ylamino)-5-methylbenzoate,   2-(6-(3-(Dimethylcarbamoyl)phenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid,   Ethyl 2-(6-(3-(dimethylcarbamoyl)phenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoate,   2-(6-(3-Isopropoxyphenyl)-5-methylpyridin-3-ylamino)-3-methylbenzoic acid, tert-Butyl 2-(6-(3-isopropoxyphenyl)-5-methylpyridin-3-ylamino)-3-methylbenzoate,   3-Methyl-2-(5-methyl-6-phenylpyridin-3-ylamino)benzoic acid,   tert-Butyl 3-methyl-2-(5-methyl-6-phenylpyridin-3-ylamino)benzoate,   2-(6-(2-Chlorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid, tert-Butyl 2-(6-(2-chlorophenyl)pyridin-3-ylamino)-5-methylbenzoate,   3-Fluoro-2-(6-(3-methoxyphenyl)-5-methylpyridin-3-ylamino)benzoic acid, tert-Butyl 3-fluoro-2-(6-(3-methoxyphenyl)-5-methylpyridin-3-ylamino)benzoate,   5-Cyclopropyl-2-(5-methyl-6-(3-(trifluoromethoxy)phenyl)pyridin-3-ylamino)benzoic acid,   Ethyl 5-cyclopropyl-2-(5-methyl-6-(3-(trifluoromethoxy)phenyl)pyridin-3-ylamino)benzoate,   5-Cyclopropyl-2-(5-methyl-6-phenylpyridin-3-ylamino)benzoic acid,   Ethyl 5-cyclopropyl-2-(5-methyl-6-phenylpyridin-3-ylamino)benzoate,   5-Methyl-2-(5-methyl-6-(2-(trifluoromethyl)phenyl)pyridin-3-ylamino)benzoic acid,   tert-Butyl 5-methyl-2-(5-methyl-6-(2-(trifluoromethyl)phenyl)pyridin-3-ylamino)benzoate,   2-(6-(3-Chlorophenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid, tert-Butyl 2-(6-(3-chlorophenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoate,   2-(6-(2-Fluorophenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid, tert-Butyl 2-(6-(2-fluorophenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoate,   5-Methyl-2-(5-methyl-6-(quinolin-5-yl)pyridin-3-ylamino)benzoic acid,   tert-Butyl 5-methyl-2-(5-methyl-6-(quinolin-5-yl)pyridin-3-ylamino)benzoate,   2-(3′-Fluoro-3-methyl-2,4′-bipyridin-5-ylamino)-5-methylbenzoic acid,   tert-Butyl 2-(3′-fluoro-3-methyl-2,4′-bipyridin-5-ylamino)-5-methylbenzoate,   5-Methyl-2-(5-methyl-6-(pyrazin-2-yl)pyridin-3-ylamino)benzoic acid,   tert-Butyl 5-methyl-2-(5-methyl-6-(pyrazin-2-yl)pyridin-3-ylamino)benzoate,   5-Cyclopropyl-2-(6-phenyl-5-(trifluoromethyl)pyridin-3-ylamino)benzoic acid,   Ethyl 5-cyclopropyl-2-(6-phenyl-5-(trifluoromethyl)pyridin-3-ylamino)benzoate,   5-Cyclopropyl-2-(6-(3-methoxyphenyl)-5-(trifluoromethyl)pyridin-3-ylamino)benzoic acid,   Ethyl 5-cyclopropyl-2-(6-(3-methoxyphenyl)-5-(trifluoromethyl)pyridin-3-ylamino)benzoate,   5-Chloro-2-(6-(2-fluorophenyl)pyridin-3-ylamino)benzoic acid,   5-Chloro-2-(6-(2-chlorophenyl)pyridin-3-ylamino)benzoic acid,   5-Chloro-2-(6-(quinolin-5-yl)pyridin-3-ylamino)benzoic acid,   2-(6-(2-Chlorophenyl)pyridin-3-ylamino)-5-cyclopropylbenzoic acid,   Ethyl 2-(6-(2-chlorophenyl)pyridin-3-ylamino)-5-cyclopropylbenzoate,   5-Chloro-2-(6-(2-(trifluoromethyl)phenyl)pyridin-3-ylamino)benzoic acid,   5-Fluoro-2-(6-(2-(trifluoromethyl)phenyl)pyridin-3-ylamino)benzoic acid,   2-(3′-Fluoro-2,4′-bipyridin-5-ylamino)-5-methylbenzoic acid,   2-(2-(2-Fluorophenyl)pyrimidin-5-ylamino)-5-methylbenzoic acid, tert-Butyl 2-(2-(2-fluorophenyl)pyrimidin-5-ylamino)-5-methylbenzoate,   2-(6-(2,6-Difluorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid,   Ethyl 2-(6-(2,6-difluorophenyl)pyridin-3-ylamino)-5-methylbenzoate,   2-(2-(2-Chlorophenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid,   Methyl 2-(2-(2-chlorophenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoate,   2-(2-(2-Chlorophenyl)pyrimidin-5-ylamino)-5-methylbenzoic acid,   tert-Butyl 2-(2-(2-chlorophenyl)pyrimidin-5-ylamino)-5-methylbenzoate,   5-Methyl-2-(5-methyl-6-(3-(pyrrolidine-1-carbonyl)phenyl)pyridin-3-ylamino)benzoic acid,   2-(6-(3-(Cyclopropylcarbamoyl)phenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid,   5-Cyclopropyl-2-(2-(2-fluorophenyl)pyrimidin-5-ylamino)benzoic acid,   2-(2-(2-trifluoromethylphenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid,   2-(2-o-tolylpyrimidin-5-ylamino)-5-cyclopropylbenzoic acid,   2-(2-(2-cyclopropoxyphenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid,   2-(2-(2,5-difluorophenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid,   2-(2-(2,3-difluorophenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid,   2-(2-(2-fluoro-5-chlorophenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid,   2-(2-(2-trifluoromethylphenyl)pyrimidin-5-ylamino)-5-methylbenzoic acid,   2-(2-(2-fluoro-5-trifluoromethoxyphenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid,   2-(6-(2-trifluoromethylphenyl)pyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-phenylpyridin-3-ylamino)-5-cyclopropylbenzoic acid,   2-(6-(2-fluorophenyl)pyridin-3-ylamino)-5-cyclopropylbenzoic acid,   2-(6-(3,5-difluoropyridin-4-yl)pyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(3-cyclopropylcarbamoylphenyl)pyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(2,4-difluorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(2,5-difluorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(2-fluorophenyl)pyridin-3-ylamino)-5-cyclopropyl-3-fluorobenzoic acid,   2-(6-(2,3,6-trifluorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)pyridin-3-ylamino)-5-methylbenzoic acid,   2-(5-methyl-6-(pyrimidin-5-yl)pyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(2,3-difluorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(5-fluoro-2-methoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid,   2-(6-(4-carbamoylphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid,   
       or a pharmaceutically acceptable salt or N-oxide thereof. 
     
     
         26 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is chosen from a hydrogen atom, halogen atoms, C 1-4  alkyl, C 3-4  cycloalkyl, —CF 3  and —OCF 3 , 
 R 2  is chosen from a hydrogen atom, halogen atoms and C 1-4  alkyl groups, 
 R 3  is chosen from —COOR 5 , —CONHR 5 , tetrazolyl, —SO 2 NHR 5  and —CONHSO 2 R 5  groups, wherein R 5  is chosen from a hydrogen atom and linear or branched C 1-4  alkyl groups, 
 R 4  is chosen from a hydrogen atom and C 1-4  alkyl groups, 
 R 9  is chosen from a hydrogen atom and phenyl groups, 
 G 1  represents a group chosen from N and CR 6 , wherein R 6  is chosen from a hydrogen atom, halogen atoms, C 1-4  alkyl groups, C 3-4  cycloalkyl groups, C 1-4  alkoxy groups, —CF 3 , —OCF 3 , monocyclic N-containing C 5-7  heteroaryl groups, monocyclic N-containing C 3-7  heterocyclyl groups and C 6-10  aryl groups which are optionally substituted with at least one substituent chosen from halogen atoms and C 1-4  alkyl groups, 
 G 2  represents a group chosen from:
 a hydrogen atom, hydroxy groups, halogen atoms, C 3-4  cycloalkyl groups, C 1-4  alkoxy groups and —NR a R b , wherein 
 R a  is chosen from C 1-4  alkyl groups, and R b  is chosen from C 1-4  alkyl groups and C 1-4  alkoxy-C 1-4  alkyl groups, or 
 R a  and R b  together with the nitrogen atom to which they are attached form a saturated 6 to 8 membered heterocyclic ring optionally containing one oxygen atom as an additional heteroatom, 
 a monocyclic or bicyclic 5 to 10 membered heteroaromatic ring containing one or more nitrogen atoms, which is optionally substituted by at least one substituent chosen from halogen atoms, C 1-4  alkyl groups, C 1-4  alkoxy groups, C 3-4  cycloalkyl groups, C 3-4  cycloalkoxy groups, —CF 3 , —OCF 3 , and —CONR 7 R 8 , wherein R 7  and R 8  are independently chosen from a hydrogen atom, linear or branched C 1-4  alkyl groups, C 3-7  cycloalkyl groups, or R 7  and R 8  together with the nitrogen atom to which they are attached form a group of formula 
 
 
       
         
           
           
               
               
           
         
       
       wherein n is an integer from 0 to 3, and
 a phenyl group, which is optionally substituted by at least one substituent chosen from halogen atoms, C 1-4  alkyl groups, hydroxyl, C 1-4  alkoxy groups, C 3-4  cycloalkyl groups, C 3-4  cycloalkoxy groups, cyano groups, —CF 3 , —OCF 3 , —CONR 7 R 8 , oxadiazolyl groups, triazolyl groups, pyrazolyl groups and imidazolyl groups, wherein the oxadiazolyl, triazolyl, pyrazolyl and imidazolyl groups are optionally substituted by C 1-4  alkyl group or C 3-7  cycloalkyl groups and wherein R 7  and R 8  are independently chosen from a hydrogen atom, linear or branched C 1-4  alkyl groups, and C 3-7  cycloalkyl groups, or R 7  and R 8  together with the nitrogen atom to which they are attached form a group of formula 
 
       
         
           
           
               
               
           
         
         wherein n is an integer from 0 to 3, 
         or, G 2  together with R 6  forms a non-aromatic C 5-10  carbocyclic group or a C 6-10  aryl group, 
       
       or a pharmaceutically acceptable salt or N-oxide thereof, 
       with the proviso that when G 2  is a hydrogen or chlorine atom, a methoxy or butoxy group or together with R 6  forms a phenyl group, then R 1  is not a hydrogen atom or a chlorine atom. 
     
     
         27 . (canceled) 
     
     
         28 . A pharmaceutical composition comprising a compound as defined in  claim 26 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . A composition comprising (i) a compound according to  claim 26 ; and (ii) at least one compound chosen from:
 a) Anti-TNF-alpha monoclonal antibodies,   b) TNF-alpha Antagonists;   c) Calcineurin (PP-2B) Inhibitors/INS Expression Inhibitors;   d) IL-1 Receptor Antagonists:   e) Anti-CD20 monoclonal antibodies;   f) p38 Inhibitors;   g) NF-kappaB (NFKB) Activation Inhibitors; and   h) Dihydrofolate Reductase (DHFR) Inhibitors.   
     
     
         32 . The composition according to  claim 31 , wherein:
 a) the Anti-TNF-alpha monoclonal antibodies are chosen from Infliximab, Certolizumab pegol, Golimumab, Adalimumab and AME-527;   b) the TNF-alpha Antagonists are chosen from Etanercept, Lenercept, Onercept and Pegsunercept:   c) the Calcineurin (PP-28) Inhibitors/INS Expression Inhibitors are chosen from cyclosporine A, Tacrolimus and ISA-247;   d) the IL-1 Receptor Antagonists are chosen from Anakinra and AMG-719;   e) the Anti-CD20 monoclonal antibodies are chosen from Rituximab, Ofatumumab, Oc elizumab, Veltuzumab and TRU-015;   f) the p38 Inhibitors are chosen from AMG-548, ARRY-797, Chlormethiazole edisylate, Doramapimod, PS-540446, BMS-582949 SB-203580, SB-242235, SB-235699, SB-281832, SB-681323, SB-856553, KC-706, LEO-1606, LEO-15520, SC-80036, SD-06, PH-797804, RWJ-67657, RO-3201195, RO-4402257, AVE-9940, SCIO-323, SCIO-469, TA-5493, and VX-745 and VX-702;   g) the NF-kappaB (NFKB) Activation Inhibitors are chosen from Sulfasalazine and Iguratimod; and   h) the Dihydrofolate Reductase (DHFR) Inhibitors are chosen from Methotrexate, Aminopterin and CH-1504.   
     
     
         33 . The compound according to  claim 25 , chosen from
 5-cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidin-5-ylamino)benzoic acid,   2-(2-(2-trifluoromethylphenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid, or   2-(6-(2,3-difluorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid.   
     
     
         34 . The compound according to  claim 25 , wherein the compound is 5-cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidin-5-ylamino)benzoic acid. 
     
     
         35 . A pharmaceutical composition comprising a compound as defined in  claim 25 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         36 . A composition comprising (i) a compound according to  claim 25 ; and (ii) at least one compound chosen from:
 a) Anti-TNF-alpha monoclonal antibodies;   b) TNF-alpha Antagonists;   c) Calcineurin (PP-2B) Inhibitors/INS Expression Inhibitors;   d) IL-1 Receptor Antagonists;   e) Anti-CD 2 O monoclonal antibodies;   f) p38 Inhibitors;   g) NF-kappaB (NFKB) Activation Inhibitors; and   h) Dihydrofolate Reductase (DHFR) Inhibitors.   
     
     
         37 . The composition according to  claim 36 , wherein:
 a) the Anti-TNF-alpha monoclonal antibodies are chosen from Infliximab, Certolizumab pegol, Golimumab, Adalimumab and AME-527;   b) the TNF-alpha Antagonists are chosen from Etanercept, Lenercept, Onercept and Pegsunercept;   the Calcineurin (PP-28) Inhibitors/INS Expression Inhibitors are chosen from cyclosporine A, Tacrolimus and ISA-247;   d) the IL-1 Receptor Antagonists are chosen from Anakinra and AMG-719;   e) the Anti-CD20 monoclonal antibodies are chosen from Rituximab, Ofatumumab, Ocrelizumab, Veltuzumab and TRU-015;   f) the p38 Inhibitors are chosen from AMG-548, ARRY-797, Chlormethiazole edisylate, Doramapimod, PS-540446, BMS-582949 SB-203580, SB-242235, SB-235699, SB-281832, SB-681323, SB-856553, KC-706, LEO-1606, LEO-15520, SC-80036, SD-06, PH-797804, RWJ-67657, RO-3201195, RO-4402257, AVE-9940, SCIO-323, SCIO-469, TA-5493, and VX-745 and VX-702;   g) the NF-kappaB (NFKB) Activation Inhibitors are chosen from Sulfasalazine and Iguratimod; and   h) the Dihydrofolate Reductase (DHFR) Inhibitors are chosen from Methotrexate, Aminopterin and CH-1504.   
     
     
         38 . A pharmaceutical composition comprising a compound as defined in  claim 33 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         39 . A composition comprising (i) a compound according to  claim 33 ; and (ii) at least one compound chosen from:
 a) Anti-TNF-alpha monoclonal antibodies;   b) TNF-alpha Antagonists;   c) Calcineurin (PP-2B) Inhibitors I INS Expression Inhibitors;   d) IL-1 Receptor Antagonists;   e) Anti-CD20 monoclonal antibodies;   f) p38 Inhibitors:   g) NF-kappaB (NFKB) Activation Inhibitors; and   h) Dihydrofolate Reductase (DHFR) Inhibitors.   
     
     
         40 . The composition according to  claim 39 , wherein:
 a) the Anti-TNF-alpha monoclonal antibodies are chosen from Infliximab, Certolizumab pegol, Golimumab, Adalimumab and AME-527;   the TNF alpha Antagonists are chosen from Etaner ept, Lenercept, Onercept and Pegsunercept;   c) the Calcineurin (PP-28) Inhibitors/INS Expression Inhibitors are chosen from cyclosporine A, Tacrolimus and ISA-247;   d) the IL-1 Receptor Antagonists are chosen from Anakinra and AMG-719;   e) the Anti-CD20 monoclonal antibodies are chosen from Rituximab, Ofatumumab, Ocrelizumab, Veltuzumab and TRU-015:   f) the p38 Inhibitors are chosen from AMG-548, ARRY-797, Chlormethiazole edisylate, Doramapimod, PS-540446, BMS-582949 SB-203580, SB-242235, SB-235699, SB-281832, SB-681323, SB-856553, KC-706, LEO-1606, LEO-15520, SC-80036, SD-06, PH-797804, RWJ-67657, RO-3201195, RO-4402257, AVE-9940, SCIO-323, SCIO-469, TA-5493, and VX-745 and VX-702;   g) the NF-kappaB (NFKB) Activation inhibitors are chosen from Sulfasalazine andiguratimod; and   h) the Dihydrofolate Reductase (DHFR) Inhibitors are chosen from Methotrexate, Aminopterin and CH-1504.   
     
     
         41 . A pharmaceutical composition comprising a compound as defined in  claim 34 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         42 . A composition comprising (i) a compound according to  claim 34 ; and (ii) at least one compound chosen from:
 a) Anti-TNF-alpha monoclonal antibodies;   b) TNF-alpha Antagonists;   c) Calcineurin (PP-2B) Inhibitors/INS Expression Inhibitors;   d) IL-1 Receptor Antagonists;   e) Anti-CD20 monoclonal antibodies;   f) p38 Inhibitors;   g) NF-kappaB (NFKB) Activation Inhibitors; and   h) Dihydrofolate Reductase (DHFR) Inhibitors.   
     
     
         43 . The composition according to  claim 42 , wherein:
 a) the Anti-TNF-alpha monoclonal antibodies are chosen from Infliximab, Certolizumab pegol, Golimumab, Adalimumab and AME-527;   b) the TNF-alpha Antagonists are chosen from Etanercept, Lenercept, Onercept and Pegsunercept;   c) the Calcineurin (PP-28) Inhibitors/INS Expression Inhibitors are chosen from cyclosporine A, Tacrolimus and ISA-247;   d) the IL-1 Receptor Antagonists are chosen from Anakinra and AMG-719;   e) the Anti-CD20 monoclonal antibodies are chosen from Rituximab, Ofatumumab, Ocrelizumab, Veltuzumab and TRU-015;   f) the p38 Inhibitors are chosen from AMG-548, ARRY-797, Chlormethiazole edisylate, Doramapimod, PS-540446, BMS-582949 SB-203580, SB-242235, SB-235699, SB-281832, SB-681323, SB-856553, KC-706, LEO-1606, LEO-15520, SC-80036, SD-06, PH-797804, RWJ-67657, RO-3201195, RO-4402257, AVE-9940, SCIO-323, SCIO-469, TA-5493, and VX-745 and VX-702;   g) the NF-kappaB (NFKB) Activation Inhibitors are chosen from Sulfasalazine and Iguratimod; and   h) the Dihydrofolate Reductase (DHFR) Inhibitors are chosen from Methotrexate, Aminopterin and CH-1504.