Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds

Abstract

The present invention provides methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds, as well as methods of treating, preventing or ameliorating symptoms associated with such diseases. Specific examples of autoimmune diseases that can be treated or prevented with the compounds include rheumatoid arthritis and/or its associated symptoms, systemic lupus erythematosus and/or its associated symptoms and multiple sclerosis and/or its associated symptoms.

We claim: 
     
         1 . A compound of the formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 L 1  and L 2  are each, independently of one another, selected from the group consisting of a direct bond and a linker selected from (C1-C6) alkyldiyl, (C1-C6) alkano or (C1-C6) heteroalkyldiyl; 
 R 2  is a phenyl group trisubstituted with three R b  groups; 
 R 4  is 
 
       
         
           
           
               
               
           
         
         R 5  is selected from the group consisting of R 6 , (C1-C6) alkyl optionally substituted with one or more of the same or different R 8  groups, (C1-C4) alkanyl optionally substituted with one or more of the same or different R 8  groups, (C2-C4) alkenyl optionally substituted with one or more of the same or different R 8  groups and (C2-C4) alkynyl optionally substituted with one or more of the same or different R 8  groups; 
         each R 6  independently is selected from the group consisting of hydrogen, an electronegative group, —OR d , —SR d , (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, —NR c R c , halogen, (C1-C3) haloalkyl,(C1-C3) 
       
       perhaloalkyl, —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS(O) 2 R d , —OS(O) 2 OR d , —OS(O)NR c R c , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —OC(O)R d , —SC(O)R d , —OC(O)OR d , —SC(O)OR d , —OC(O)NR c R c , —SC(O)NR c R c , —OC(NH)NR c R c , —SC(NH)NR c R c , —[NHC(O)] n R d , —[NHC(O)] n OR d , —[NHC(O)] n NR c R c    
       and —[NHC(NH)] n NR c R c , (C5-C10) aryl optionally substituted with one or more of the same or different R 8  groups, phenyl optionally substituted with one or more of the same or different R 8  groups, (C6-C16) arylalkyl optionally substituted with one or more of the same or different R 8  groups, 5-10 membered heteroaryl optionally substituted with one or more of the same or different R 8  groups and 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different R 8  groups;
 R 8  is selected from the group consisting of R a , R b , R a  substituted with one or more of the same or different R a  or R b , —OR a  substituted with one or more of the same or different R a  or R b , —B(OR a ) 2 , —B(NR c R c ) 2 , —(CH 2 ) m —R b , —(CHR a ) m —R b , —O—(CH 2 ) m —R b , 
 
       —S—(CH 2 ) m —R b , —O—CHR a R b , —O—CR a (R b ) 2 , —O—(CHR a ) m —R b , —O—(CH 2 ) m CH[(CH 2 ) m R b ]R b , —S—(CHR a ) m —R b , —C(O)NH—(CH 2 ) m —R b , —C(O)NH—(CHR a ) m —R b , —O—(CH 2 ) m —C(O)NH—(CH 2 ) m —R b , —S—(CH 2 ) m —C(O)NH—(CH 2 ) m —R b , —O—(CHR a ) m —C(O)NH—(CHR a ) m —R b , —S—(CHR a ) m —C(O)NH—(CHR a ) m —R b , —NH—(CH 2 ) m —R b , —NH—(CHR a ) m —R b , —NH—[(CH 2 ) m R b ], —NH—(CH 2 ) m —R b , —NH—C(O)—NH—(CH 2 ) m —R b , —NH—C(O)—(CH 2 ) m —CHR b R b  and —NH—(CH 2 ) m —C(O)—NH—(CH 2 ) m —R b ;
 each R a  is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; 
 each R b  is independently selected from —OR d , 
 
       (C 1 -C 3 )haloalkyloxy, —OCF 3 , —SR d , —NR c R c , halogen, —CF 3 , —CN, —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS(O) 2 R d , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NR a )NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c , —OC(NH)NR c R c , —OC(NR a )NR c R c , —[NHC(O)] n R d , —[NR a C(O)] n R d , —[NHC(O)] n OR d , [NR a C(O)] n OR d , —[NHC(O)] n NR c R c , and —[NR a C(O)] n NR c R c ;
 each R c  is independently (C1-C6) alkyl, or, alternatively, each R c  is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl 
 each R d  is independently (C1-C6) alkyl; 
 Y is O; 
 Z is NH; and 
 X is N; 
 
       wherein the compound is not
 N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine; 
 N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine; or 
 N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine. 
 
     
     
         2 . The compound according to  claim 1 , wherein the substitution about the R 2  phenyl is at the 2,3,4, 2,3,5, 2,3,6, 2,4,5, 2,4,6, 2,5,6, 3,4,5, 3,4,6, 3,5,6, or 4,5,6 positions. 
     
     
         3 . The compound according to  claim 1 , wherein the substitution about the R 2  phenyl is at the 2,3,4. 
     
     
         4 . The compound according to  claim 1 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
       and each R 31 , independently of the others, is (C1-C6) alkyl. 
     
     
         5 . The compound according to  claim 1 , wherein R 5  is halogen. 
     
     
         6 . The compound according to  claim 1 , wherein R 5  is F. 
     
     
         7 . The compound according to  claim 1 , wherein R 6  is hydrogen. 
     
     
         8 . The compound according to  claim 1 , wherein L 1  and L 2  are each a direct bond. 
     
     
         9 . The compound according to  claim 1 , wherein L 1  and L 2  are each (C1-C6) alkyldiyl. 
     
     
         10 . The compound of  claim 1 , wherein the compound is in the form of a salt. 
     
     
         11 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         12 . A method of treating an autoimmune diseases or symptom thereof in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         13 . The method of  claim 12 , wherein the disease is a Type II, Type III and/or Type IV nonanaphylactic hypersensitivity reaction. 
     
     
         14 . The method of  claim 12 , wherein the disease is mediated, at least in part, by activation of the FcγR signaling cascade in monocyte cells. 
     
     
         15 . The method of  claim 12 , wherein the disease is selected from the group consisting of Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy. 
     
     
         16 . The method of  claim 12 , wherein the disease is selected from the group consisting of systemic lupus erythematosis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis  nodosa , multiple sclerosis and bullous pemphigoid. 
     
     
         17 . The method of  claim 12 , wherein the disease is autoimmune hemolytic anemia. 
     
     
         18 . The method of  claim 12 , wherein the disease is autoimmune thrombocytopenia.