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

1. A compound for formula (1a)

or a salt thereof wherein

R 5 is selected from the group consisting of halo, —F, —CN, —NO 2 , —C(O)R a , —C(O)OR a , —C(O)CF 3 , —C(O)OCF 3 , (C1-C3) haloalkyl, (C1-C3) perhaloalkyl (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, —OCF 3 and —CF 3

R 6 is hydrogen or halogen;

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 ], —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, 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 a suitable group independently selected from the group consisting of ═O, —OR d , (C1-C3) haloalkyloxy, —OCF 3 , ═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(O)R d , —C(O)OR d , —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 d , —OC(O)OR d , —OC(O)NR c R c , —C(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 R a , 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 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 suitable R b groups;

each R d is independently a protecting group or R a ;

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

each n is independently an integer from 0 to 3;

R 2 is phenyl optionally substituted with one or more of the same or different R 8 groups; and

R 4 is selected from the group consisting of

wherein each Y 1 is independently selected from the group consisting of O, S, SO, SO 2 , SONR 36 , and NH, and R 36 is hydrogen or alkyl.

2. The compound of claim 1 wherein R 8 is R a or R a substituted with one or more of the same or different R a or R b .

3. The compound of claim 2 wherein R 8 is morpholinyl or piperazinyl optionally substituted with one or more of the same or different R a or R b .

4. The compound according to claim 1 , wherein R 2 is mono substituted with an R 8 group.

5. The compound according to claim 2 , wherein the R 8 group is at the para position.

6. The compound according to claim 1 wherein NR c R c is a 5-6 membered saturated cycloheteroalkyl ring which optionally includes one or more of the same or different heteroatoms.

7. The compound according to claim 6 wherein the cycloheteroalkyl is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl.

8. The compound according to claim 1 wherein R 5 is fluoro and R 6 is H.

9. The compound according to claim 8 , wherein R 8 is independently selected from the group consisting of R d , —NR c R c , —(CH 2 ) m —NR c R c , —C(O)NR c R c , —(CH 2 ) m —C(O)NR c R c , —C(O)OR d , —(CH 2 ) m —C(O)OR d and —(CH 2 ) m —OR d .

10. The compound according to claim 8 , wherein R 4 is

wherein R 2 is phenyl substituted with one or more R 8 .

11. A compound according of formula

wherein:

R x and R 3 ′ independently are either both H or both methyl; and

R z is (a) piperizin-1-yl substituted on the N at the 4 position with methoxycarbonyl, methylcarbonyl, or methyl, or (b) morpholinyl.

12. A compound that is

5-Fluoro-N2-(4-morpholinophenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;

N4-(2,2-Dimethyl-2H-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl]-5-fluoro-N2-[4-(4-methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine;

N2-[4-(4-Acetylpiperazino)phenyl]-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;

N4-(2,2-Dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(4-morpholinophenyl)-2,4-pyrimidinediamine;

5-Fluoro-N2-[4-(4-methylpiperazino)phenyl]-N4-(2H-3-oxo-4H-5-pyrid [1,4]oxazin-6-yl)-2,4-pyrimidinediamine;

N4-(2,2-Dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine; or

a pharmaceutically acceptable salt of one of the foregoing.

13. A compound that is N4-(2,2-Dimethyl-2H-3-oxo-4H-5-pyrid [1,4]oxazin-6-yl) -5-fluoro-N2-(4-morpholinophenyl)-2,4-pyrimidinediamine; or a pharmaceutically acceptable salt thereof.

14. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, excipient or diluent.