Prodrugs of 2,4-pyrimidinediamine compounds and their uses

1. A compound according to structural formula (I):

or a salt and/or N-oxide thereof wherein:

Y is O;

Z 1 is CH and Z 2 is N;

R 2 is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more of the same or different R 8 groups, (C3-C8) cycloalkyl 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, and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R 8 groups;

R 5 is selected from the group consisting of halo, cyano, nitro, and trihalomethyl;

each R 8 is, independently of the others, 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—(CH2) 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 the group consisting of hydrogen, halogen, and lower alkyl 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 the group consisting of hydrogen, halogen, and lower alkyl 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 the group consisting of hydrogen and lower alkyl 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 the group consisting of hydrogen and lower alkyl 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 the group consisting of hydrogen, lower alkyl, lower cycloalkyl, (C4-C11) cycloalkylalkyl, (C6-C10) aryl, (C7-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;

each R b is independently selected from the group consisting of ═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 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 comprise 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 , R 22 and R 23 are each, independently of one another, selected from the group consisting of hydrogen and R p ;

R P has the formula —(CR d R d )-A-R 3 , where A is O or S; each R d is, independently of the others, selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted (C6-C14) aryl and optionally substituted (C7-C20) arylalkyl; where the optional substituents are, independently of one another, selected from the group consisting of hydroxyl, lower alkoxy, (C6-C14) aryloxy, lower alkoxyalkyl and halogen, or, alternatively, two R d bonded to the same carbon atom, taken together with the carbon atom to which they are bonded, form a cycloalkyl group containing from 3 to 8 carbon atoms; R 3 together with the heteroatom, A, to which it is bonded, is selected from the group consisting of an alcohol, an ether, a thioether, an ester, a thioester, an amide, a carbonate, a thiocarbonate, a carbamate, a thiocarbamate, a urea, a phosphate, a phosphate salt or a phosphate ester;

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 , and R 23 is R p .

2. The compound of claim 1 in which R 5 is fluoro.

3. The compound of claim 1 in which R 2 is a phenyl optionally substituted with one or more of the same or different R 8 groups.

4. The compound of claim 3 in which R 2 is 3,4,5 tri(lower alkoxy)phenyl.

5. The compound of claim 4 in which R 2 is 3,4,5-(trimethoxy)phenyl.

6. The compound of claim 1 in which R 17 and R 18 are each methyl and R 19 and R 20 are taken together to form an oxo group.

7. The compound of claim 6 in which R 2 is a phenyl optionally substituted with one or more of the same or different R 8 groups.

8. The compound of claim 7 in which R 2 is 3,4,5-tri(lower alkoxy)phenyl.

9. The compound of claim 8 in which R 2 is 3,4,5-(trimethoxy)phenyl.

10. The compound of claim 9 in which only R 21 is R P .

11. The compound of claim 10 in which R P is selected from the group consisting of an ester, a thioester, an ether, a thioether, a silyl ether, a thiosilyl ether, a carbonate, a thiourea, an amide, a thioamide, a carbamate and a urea linkage.

12. The compound of claim 10 in which R 3 , together with the heteroatom, A, to which it is bonded, is a phosphate group.

13. The compound of claim 12 in which R P has the formula —(CR d R d )—O—P(O)(OH) 2 , or a salt thereof, where each R d is, independently of the others, selected from the group consisting of optionally substituted lower alkyl, optionally substituted (C6-C14) aryl and optionally substituted (C7-C20) arylalkyl; where the optional substituents are, independently of one another, selected from hydroxyl, lower alkoxy, (C6-C14) aryloxy, lower alkoxyalkyl, and halogen, or, alternatively, two R d bonded to the same carbon atom are taken together with the carbon atom to which they are bonded to form a cycloalkyl group containing from 3 to 8 carbon atoms.

14. The compound of claim 10 in which R P comprises a phosphate ester group.

15. The compound of claim 14 in which R P is selected from the group consisting of —(CR d R d )—O—P(O)(OR e )(OH), —(CR d R d )—O—P(O)(OR e )(OR e ),

and salts thereof, wherein each R e is, independently of the others, selected from the group consisting of substituted or unsubstituted lower alkyl, substituted or unsubstituted (C6-C14) aryl, substituted or unsubstituted (C7-C20) arylalkyl, —(CR d R d ) y—OR f , —(CR d R d ) y —O—C(O)R d R d ) y —O—C(O)OR f , —(CR d R d ) y —S—C(O)R f , —(CR d R d ) y —S—C(O)OR f , —(CR d R d ) y —NH—C(O)R f , —(CR d R d ) y —NH—C(O)OR f and —Si(R d ) 3 , wherein each R f is, independently of the others, selected from the group consisting of unsubstituted or substituted lower alkyl, substituted or unsubstituted (C6-C14) aryl, and substituted or unsubstituted (C7-C20) arylalkyl;

each R g is, independently of the others, selected from the group consisting of hydrogen and lower alkyl; each R h is, independently of the others, selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloheteroalkyl, substituted or unsubstituted (C6-C14) aryl, substituted or unsubstituted (C7-C20) arylalkyl and substituted or unsubstituted 5-14 membered heteroaryl; y is an integer ranging from 1 to 3; z is an integer ranging from 0 to 2; and

each R d is independently of the others, selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted (C6-C14) aryl and optionally substituted (C7-C20) arylalkyl; where the optional substituents are, independently of one another, selected from hydroxyl, lower alkoxy, (C6-C14) aryloxy, lower alkoxyalkyl, and halogen, or, alternatively, two R d bonded to the same carbon atom are taken together with the carbon atom to which they are bonded to form a cycloalkyl group containing from 3 to 8 carbon atoms.

16. A method of treating an autoimmune disease in a subject, and/or one or more symptoms associated therewith, comprising administering to the subject an amount of a compound according to claim 1 effective to treat the autoimmune disease, in which the autoimmune disease is selected from 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, membranous glomerulopathy, systemic lupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid.

17. A method of treating rheumatoid arthritis in a subject, comprising administering to a subject suffering from rheumatoid arthritis an amount of the compound according to claim 1 effective to provide therapeutic benefit.

18. The method of claim 17 in which the amount of the compound administered is effective to achieve a serum concentration of the corresponding drug that is at or above the IC 50 of Syk inhibition of the drug, as measured in an in vitro assay.

19. The method of claim 17 in which the compound is according to structural formula (V), and/or a pharmaceutically-acceptable salt and/or N-oxide thereof: