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

1. A 2,4 pyrimidinediamine compound according to structure:

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

X is selected from the group consisting of N and CH;

Y is selected from the group consisting of O, S, SO, SO 2 , S(O)NR 36 , NH and NR 35 ;

Z is selected from the group consisting of O, S, SO, SO 2 , S(O)NR 36 , NH and NR 35 ;

R 5 is fluoro;

each R 6 independently is selected from the group consisting of hydrogen, —OR d , —SR d , (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, —NR c R c , halogen, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, —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, (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 e , R b , R e 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 , —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 ;

each R a is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-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 d , (C1-C3) haloalkyloxy, ═S, —SR d , ═NR d , ═NOR d , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 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) 2 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 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 , —[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 a protecting group or R a , or, alternatively, two R c are taken together with the nitrogen atom to which they are bonded 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 or R b groups;

each R d is independently a protecting group or R a wherein protecting group is:

an amino protecting group selected from the group consisting of formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl, tert-butoxycarbonyl, trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl, substituted trityl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, and nitro-veratryloxycarbonyl; or

a hydroxyl protecting group selected from the group consisting of benzyl ether, trityl ether, alkyl ether, tetrahydropyranyl ether, trialkylsilyl ether and allyl ether;

each R e is independently selected from the group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-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 31 , independently of the others, is (C1-C6) alkyl;

each R 35 is, independently of the others, selected from the group consisting of hydrogen and R 8 , or, alternatively, two R 35 bonded to the same carbon atom are taken together to form an oxo (═O), (═NH) or (═NR 38 ) group;

each R 36 is independently selected from the group consisting of hydrogen and (C1-C6) alkyl;

each R 38 is selected from the group consisting of (C1-C6) alkyl and (C5-C14) aryl;

each m is independently an integer from 1 to 3; and

each n is independently an integer from 0 to 3.

2. The compound of claim 1 in which R 6 is hydrogen.

3. The compound of claim 2 in which Y and Z are each, independently of one another, selected from the group consisting of O and NH.

4. The compound of claim 3 in which X is N.

5. The compound of claim 4 in which Y is O and Z is NH.

6. The compound of claim 5 in which two of R 35 are (C1-C6) alkyl and two R 35 bonded to the same carbon atom are taken together to form an oxo (═O).

7. A 2,4pyrimidinediamine compound according to structure:

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

X is selected from the group consisting of N and CH;

Y is selected from the group consisting of O, S, SO and SO 2 ;

Z is selected from the group consisting of NH and NR 35 ;

R 5 is fluoro;

each R 31 , independently of the others, is (C1-C6) alkyl; and each R 35 , independently of the others, is (C1- C6) alkyl.

8. The compound of claim 7 in which Y is O.

9. The compound of claim 8 in which Z is NH.

10. The compound of claim 9 in which X is N.

11. The compound of claim 9 in which X is CH.