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

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

or a salt thereof, wherein

R is hydrogen, halo, methyl or trifluoromethyl;

Y is O, S, SO, SO 2 , SONR 36 , NH, NR 37 , or NR 35 ;

R 4 is a 3-8 membered cycloheteroalkyl optionally substituted with one or more of the same or different R 8 groups;

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 , —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, (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 a suitable group 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(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 , —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 selected from the group consisting of formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl, tert-butoxycarbonyl, trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, and nitro-veratryloxycarbonyl, or 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 an R a ;

each m is independently an integer from 1 to 3;

each n is independently an integer from 0 to 3;

R 35 is hydrogen or R 8 ;

R 36 is hydrogen or alkyl; and

R 37 is selected from the group consisting of hydrogen and a progroup selected from the group consisting of aryl, arylalkyl, heteroaryl, R a , R b , —CR a R b —O—C(O)R 8 , —CR a R b —O—PO(OR 8 ) 2 , —CH 2 —O—PO(OR 8 ) 2 , —CH 2 —PO(OR 8 ) 2 , —C(O)—CR a R b —N(CH 3 ) 2 , —CR a R b —O— C(O)—CR a R b —N(CH 3 ) 2 , —C(O)R 8 , —C(O)CF 3 and —C(O)—NR 8 —C(O)R 8 .

2. The compound of claim 1 in which R 4 is piperidin-4-yl optionally substituted with one or more of the same or different R 8 groups.

3. The compound of claim 2 in which R 8 is (C1-C6) alkyl.

4. The compound of claim 3 in which R 4 is 1,2,2,6,6-pentamethylpiperidin-4-yl.

5. The compound of claim 1 in which R a is (C3-C8) cycloalkyl.

6. The compound of claim 5 in which R a is cyclohexyl.

7. The compound of claim 1 in which R a is (C5-C 10) aryl.

8. The compound of claim 7 in which R a is phenyl.

9. The compound of claim 1 in which R a is (C6-C 16) arylalkyl.

10. The compound of claim 9 in which R a is benzyl.

11. The compound of claim 1 in which R a is a 3-8 membered cycloheteroalkyl.

12. The compound of claim 11 in which R a is selected from the group consisting of morpholinyl, piperazinyl, homopiperazinyl and piperadinyl.

13. A compound selected from the group consisting of:

N4-(1-tert-Butoxycarbonylazetidin-3-yl)-5-fluoro-N2-(4-morpholinophenyl)-2,4-pyrimidinediamine (1118);

N2-[4-(4-Acetylpiperazino)phenyl]-N4-(1-tert-butoxycarbonylazetidin-3-yl)-5-fluoro-2,4-pyrimidinediamine (1119);

N2-[3-(4-Acetylpiperazino)phenyl]-N4-(1-tert-butoxycarbonylazetidin-3-yl)-5-fluoro-2,4-pyrimidinediamine (1120);

N4-(1-tert-Butoxycarbonylazetidin-3-yl)-N2-[4-(4-ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine (1122);

N4-(Azetidin-3-yl)-5-fluoro-N2-(4-morpholinophenyl)-2,4-pyrimidinediamine (1123);

N2-[4-(4-Acetylpiperazino)phenyl]-N4-(azetidin-3-yl)-5-fluoro-2,4-pyrimidinediamine (1124);

N4-(Azetidin-3-yl)-N2-[4-(4-ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine (1125);

N4-(Azetidin-3-yl)-5-fluoro-N2-(3-morpholinophenyl)-2,4-pyrimidinediamine (1126);

N2-[3-(4-Acetylpiperazino)phenyl]-N4-(azetidin-3-yl)-5-fluoro-2,4-pyrimidinediamine (1127);

N4-(1-tert-Butoxycarbonylazetidin-3-yl)-N2-[3-(4-ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine (1129);

N4-(Azetidin-3-yl)-N2-[3-(4-ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine (1130);

N4-(Azetidin-3-yl)-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine (1131);

(S)-N4-(1-Benzylpyrrolidin-3-yl)-5-fluoro-N2-(4-morpholinophenyl)-2,4-pyrimidinediamine (1180);

(S)-N2-[4-(4-Acetylpiperazino)phenyl]-N4-(1-benzylpyrrolidin-3-yl)-5-fluoro-2,4-pyrimidinediamine (1181);

(S)-N4-(1-Benzylpyrrolidin-3-yl)-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine (1182);

(S)-N4-(1-Benzylpyrrolidin-3-yl)-N2-[4-(4-ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine (1183);

(S)-N4-(1-Benzylpyrrolidin-3-yl)-5-fluoro-N2-(3-morpholinophenyl)-2,4-pynmidinediamine (1184);

(S)-N2-[3-(4-Acetylpiperazino)phenyl]-N4-(benzylpyrrolidin-3-yl)-5-fluoro-2,4-pyrimidinediamine (1185);

(S)-N4-(1-Benzylpyrrolidin-3-yl)-5-fluoro-N2-[3-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine (1186);

(S)-N4-(1-Benzylpyrrolidin-3-yl)-N2-[3-(4-ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine (1187);

5-Fluoro-N2-[4-(4-methylpiperazino)phenyl]-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine (1219);

5-Fluoro-N2-[3-(4-methylpiperazino)phenyl]-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine (1221);

N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-5-fluoro-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediarnine (1222);

5-Fluoro-N2-[3-methyl-4-(4-methylpiperazino)phenyl]-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine (1223);

5-Fluoro-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-N2-[3-trifluoromethyl-4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine (1224);

N4-(1-Ethoxycarbonylpiperidin-4-yl)-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine (1225);

N4-(1-Ethoxycarbonylpiperidin-4-yl)-5-fluoro-N2-[3-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine (1226);

N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-N4-(1-ethoxycarbonylpiperidin-4-yl)-5-fluoro-2,4-pyrimidinediamine (1227);

N4-(1-Ethoxycarbonylpiperidin-4-yl)-5-fluoro-N2-[3-methyl-4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine (1228);

N4-(1-Ethoxycarbonylpiperidin-4-yl)-5-fluoro-N2-[4-(4-methylpiperazino)-3-trifluoromethylphenyl]-2,4-pyrimidinediamine (1229);

N2-[2-(4-Ethylpiperazino)pyrid-5-yl]-5-fluoro-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine (1237);

N4-(1-Ethoxycarbonylpiperidin-4-yl)-N2-[2-(4-ethylpiperazino)pyrid-5-yl]-5-fluoro-2,4-pyrimidinediamine (1238);

5-Fluoro-N2-[2-(4-methylpiperazino)-3-methylpyrid-5-yl]-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine (1244); and

5-Fluoro-N2-[2-(4-methylpiperazino)-4-methylpyrid-5-yl]-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine (1249)

or a salt thereof.