Prodrugs of 2,4-Pyrimidinediamine Compounds and Their Uses

Abstract

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

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         of 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 lower alkyl optionally substituted with one or more of the same or different R 8  groups, lower 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, (C6-C14) 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, for example, from one to four, 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 18  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, (C4-C11) cycloalkylalkyl, (C6-C10) aryl, phenyl, (C7-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 a suitable group independently selected from ═O, —OR a , (C1-C3) 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 c  is, independently of the others, selected from a protecting group and R a , or, alternatively, the two R c  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, for example, from one to four, of the same or different R a  groups; 
         R 21 , R 22  and R 23  are each, independently of one another, selected from hydrogen and a progroup R P ; 
         R 24  is selected from hydrogen, lower alkyl and 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, with the proviso that at least one of R 21 , R 22 , R 23  and R 24  is a progroup. 
       
     
     
         2 . A method of activating the Fc receptor signalling cascades in a cell, the method comprising contacting the cell with an effective amount of a compound according to  claim 1 . 
     
     
         3 . The method according to  claim 2 , wherein the Fc receptor signalling cascade is the FcεRI- and/or FcγRI-signaling cascades. 
     
     
         4 . The method according to  claim 2 , wherein the cell is a mast cell or basophil cell. 
     
     
         5 . The method of treating a disease or condition mediated by the FcεRI- and/or FcγRI-signaling cascades in a subject in need thereof, the method comprising administering to the subject an amount of a compound according to  claim 1  effective to ameliorate a symptom of the disease. 
     
     
         6 . The method according to  claim 5 , wherein the disease or condition is an anaphylactic reaction, an anaphylactoid reaction, hay fever, allergic conjunctivitis, allergic rhinitis, allergic asthma, atopic asthma, atopic dermatitis, eczema, urticaria, a mucosal disorders, a tissue disorder, or a gastrointestinal disorder. 
     
     
         7 . The method according to  claim 5 , wherein the disease or condition is allergic conjunctivitis, allergic rhinitis, atopic asthma, atopic dermatitis and food allergies, low grade scarring, scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion injury, post myocardial infarction, COPD, or cardiobronchitis. 
     
     
         8 . The method according to  claim 5 , wherein the disease or condition is inflammation, an inflammatory disease, low grade scarring, or sicca complex or syndrome. 
     
     
         9 . The method according to  claim 5 , wherein the disease or condition is a disease of the skin, a cardiac disease, a pulmonary disease, or a disease of the gut 
     
     
         10 . The method according to  claim 5 , wherein the disease or condition is osteoarthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, idiopathic inflammatory bowel disease, irritable bowel syndrome, spastic colon, scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion injury, post myocardial infarction, or acute mycloid leukemia (AML). 
     
     
         11 . The method according to  claim 5 , wherein the disease or condition is immune thrombocytopenic purpura. 
     
     
         12 . The method according to  claim 5 , wherein the disease is rheumatoid arthritis. 
     
     
         13 . The method according to  claim 5 , wherein the disease is an autoimmune disease. 
     
     
         14 . The method according to  claim 13 , wherein the autoimmune disease is single organ or single cell-type autoimmune disorders or systemic autoimmune disorder. 
     
     
         15 . The method according to  claim 13 , wherein the autoimmune disease is Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, erythroblastosis fetalis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis or membranous glomerulopathy. 
     
     
         16 . The method according to  claim 13 , wherein the autoimmune disease is systemic lupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis or bullous pemphigoid. 
     
     
         17 . The method according to  claim 13 , wherein the autoimmune disease is autoimmune alopecia, Type I or juvenile onset diabetes, or thyroiditis. 
     
     
         18 . The method according to  claim 13 , wherein the autoimmune disease is contact dermatitis and allograft rejection