Prodrugs of 2,4-Pyrimidinediamine Compounds and Their Uses

Abstract

The present disclosure provides prodrugs of biologically active 2,4-pyrimidinediamine compounds, salts and hydrates of the prodrugs, compositions comprising the prodrugs, intermediates and methods for synthesizing the prodrugs and methods of using the prodrugs in a variety of applications.

1 . A method of treating an autoimmune disease in a mammal afflicted with the disease, the method comprising administering to the mammal an effective amount of a prodrug compound, or a salt, solvate, hydrate or N-oxide thereof, comprising a 2,4-pyrimidinediamine moiety and at least one progroup R p , said progroup R p  being covalently linked to a primary or secondary amino nitrogen atom of the 2,4-pyrimidinediamine moiety,
 wherein R p  is of the formula —CR d R d -AR 3 , where each R d  is, independently of the other, selected from hydrogen, cyano, optionally substituted (C1-C20) alkyl, (C1-C20) perfluoroalkyl, optionally substituted (C7-C30) arylalkyl and optionally substituted 6-30 membered heteroarylalkyl, where each optional substituent is, independently of the others, selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl and heteroalkyl, or, alternatively, the two R d  are taken together with the carbon atom to which they are bonded to form a cycloalkyl containing from 3 to 8 carbon atoms; A is selected from O, S and NR 50 , where R 50  is selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl, or alternatively is combined with R 3 , and, together with the nitrogen to which they are attached, form a three to seven membered ring; and R 3  represents a group that can be metabolized in vivo to yield a group of the formula —CR d R d -AH, and   R 3  is selected from R f , —C(O)R f , —C(O)OR f , —C(O)NR f R f  and —SiR f R f R f , where each R f  is, independently of the others, selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower heteroalkyl, optionally substituted lower cycloalkyl, optionally substituted lower heterocycloalkyl, optionally substituted (C6-C10) aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted (C7-C18) arylalkyl and optionally substituted 6-18 membered heteroarylalkyl   wherein the autoimmune disease is associated with nonanaphylactic hypersensitivity reactions (Type II, Type III and/or Type IV hypersensitivity reactions) or mediated, at least in part, by activation of the FcγR signaling cascade in monocyte cells.   
     
     
         2 . The method of  claim 1 , wherein the compound has structural formula (I): 
       
         
           
           
               
               
           
         
         or a salt, solvate, hydrate, or N-oxide thereof, wherein, 
         Y is selected from CH 2 , NR 24 , O, S, S(O) and S(O) 2 ; 
         Z 1  and Z 2  are each, independently of one another, selected from CH and N; 
         R 2  is selected from (C 1 -C 6 ) alkyl optionally substituted with one or more of the same or different R 8  groups, (C 3 -C 8 ) cycloalkyl optionally substituted with one or more of the same or different R 8  groups, cyclohexyl optionally substituted with one or more of the same or different R 8  groups, 3-8 membered cycloheteroalkyl optionally substituted with one or more of the same or different R 8  groups, (C 6 -C 14 ) 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 and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R 8  groups; 
         R 5  is selected from halo, fluoro, cyano, nitro, trihalomethyl and trifluoromethyl; 
         R 8  is selected from 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 ], —N[(CH 2 ) m R b ] 2 , —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 ; 
         R 17  is selected from hydrogen, halogen, fluoro, lower alkyl and methyl or, alternatively, R 17  may be taken together with R 8i  to form an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; 
         R 18  is selected from hydrogen, halogen, fluoro, lower alkyl and methyl or, alternatively, R 18  may be taken together with R 17  to form an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; 
         R 19  is selected from hydrogen, lower alkyl, and methyl or, alternatively, R 19  may be taken together with R 20  to form an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; 
         R 20  is selected from hydrogen, lower alkyl and methyl or, alternatively, R 20  may be taken together with R 19  to form an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; 
         each R a  is, independently of the others, selected from hydrogen, lower alkyl, lower cycloalkyl, cyclohexyl, (C 4 -C 11 ) cycloalkylalkyl, (C 6 -C 10 ) aryl, phenyl, (C 7 -C 16 ) 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 a suitable group independently selected from ═O, —OR a , (C 1 -C 3 ) haloalkyloxy, ═S, —SR a , ═NR a , ═NOR a , —NR C R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R a , —S(O) 2 R a , —S(O) 2 OR a , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R a , —OS(O) 2 R a , —OS(O) 2 OR a , —OS(O) 2 NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R a , —OC(O)OR a , —OC(O)NR c R c , —OC(NH)NR C R C , —OC(NR a )NR C R C , —[NHC(O)] n R a , —[NR a C(O)] n R a , —[NHC(O)] n OR a , —[NR a C(O)] n OR a , —[NHC(O)] n NR c R c , —[NR a C(O)] n NR c R c , —[NHC(NH)] n NR c R c  and —[NR a C(NR a )] n NR c R c ; 
         each R e  is, independently of the others, selected from a protecting group and R a , or, alternatively, the two R e  bonded to the same nitrogen atom are taken together with that nitrogen atom to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a  groups; 
         R 21  is a progroup R p ; 
         R 22  and R 23  are hydrogen or a progroup R p ; 
         R 24  is hydrogen, lower alkyl, or a progroup R p ; 
         each m is, independently of the others, an integer from 1 to 3; 
         and each n is, independently of the others, an integer from 0 to 3. 
       
     
     
         3 . The method according to  claim 1 , wherein the autoimmune 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. 
     
     
         4 . The method according to  claim 1 , wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid. 
     
     
         5 . The method according to  claim 1 , wherein the autoimmune disease is selected from the group consisting of autoimmune alopecia, Type I or juvenile onset diabetes, and thyroiditis. 
     
     
         6 . The method according to  claim 1 , wherein the autoimmune disease is rheumatoid arthritis or systemic lupus erythematosis. 
     
     
         7 . The method according to  claim 6 , wherein the mammal is a human. 
     
     
         8 . The method according to  claim 2 , wherein the autoimmune 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. 
     
     
         9 . The method according to  claim 2 , wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid. 
     
     
         10 . The method according to  claim 2 , wherein the autoimmune disease is selected from the group consisting of autoimmune alopecia, Type I or juvenile onset diabetes, and thyroiditis. 
     
     
         11 . The method according to  claim 2 , wherein the autoimmune disease is rheumatoid arthritis or systemic lupus erythematosis. 
     
     
         12 . The method according to  claim 11 , wherein the mammal is a human. 
     
     
         13 . The method according to  claim 2 , wherein the autoimmune disease is autoimmune hemolytic anemia. 
     
     
         14 . The method according to  claim 2 , wherein the autoimmune disease is autoimmune thrombocytopenia.