IP Library › Patent Application 13442480

Patent Application

App. No. 13/442,480

Methods of Treating or Preventing Autoimmune Diseases with 2,4-Pyrimidinediamine Compounds

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Patent No.: US None
App. No.: 13/442,480

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Abstract

The present invention provides methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds, as well as methods of treating, preventing or ameliorating symptoms associated with such diseases. Specific examples of autoimmune diseases that can be treated or prevented with the compounds include rheumatoid arthritis and/or its associated symptoms, systemic lupus erythematosis and/or its associated symptoms and multiple sclerosis and/or its associated symptoms.

Claims (147)

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

including salts, hydrates, solvates and N-oxides thereof, wherein:

L 1 is a direct bond or a linker;

L 2 is a direct bond or a linker;

R 2 is

R 4 is

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

Y is selected from the group consisting of O, S, SO, SO 2 , SONR 36 , NH, NR 35 and NR 37 ;

Z is selected from the group consisting of O, S, SO, SO 2 , SONR 36 , NH, NR 35 and NR 37 ;

R 5 is selected from the group consisting of R 6 , (C1-C6)alkyl optionally substituted with one or more of the same or different R 8 groups, (C1-C4)alkanyl optionally substituted with one or more of the same or different R 8 groups, (C2-C4)alkenyl optionally substituted with one or more of the same or different R 8 groups and (C2-C4)alkynyl optionally substituted with one or more of the same or different R 8 groups;

each R 6 independently is selected from the group consisting of hydrogen, an electronegative group, —OR d , —SR d , (C1-C3)haloalkyloxy, (C1-C3)perhaloalkyloxy, —NR c R c , halogen, (C1-C3)haloalkyl, (C1-C3)perhaloalkyl, —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , —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, phenyl 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 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 31 , independently of the others, is methyl or (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 and the other two R 35 are each, independently of one another, selected from the group consisting of hydrogen and R 8 ;

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

each R 37 is independently selected from the group consisting of hydrogen and a progroup;

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

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 , —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, 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;

each n is independently an integer from 0 to 3; and

yy is 1 through 6.

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

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

4 . The compound of claim 1 in which Y and Z are each, independently of one another, selected from the group consisting of O and NH.

5 . The compound of claim 4 in which X is CH.

6 . The compound of claim 5 in which Y and Z are each O.

7 . The compound of claim 6 in which each R 35 is hydrogen.

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

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

including salts, hydrates, solvates and N-oxides thereof, wherein:

L 1 is a direct bond or a linker;

L 2 is a direct bond or a linker;

R 2 is a disubstituted phenyl group with two R b groups or R 2 is a trisubstituted phenyl group with three R b groups;

R 4 is

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

Y is selected from the group consisting of O, S, SO, SO 2 , SONR 36 , NH, NR 35 and NR 37 ;

Z is selected from the group consisting of O, S, SO, SO 2 , SONR 36 , NH, NR 35 and NR 37 ;

each R 6 independently is selected from the group consisting of hydrogen, an electronegative group, —OR d , —SR d , (C1-C3)haloalkyloxy, (C1-C3)perhaloalkyloxy, —NR c R c , halogen, (C1-C3)haloalkyl, (C1-C3)perhaloalkyl, —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , —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, phenyl 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;

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

each R 37 is independently selected from the group consisting of hydrogen and a progroup;

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

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; with the proviso that

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

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

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

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

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

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

N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;

N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine; and

N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine are not included.

10 . A compound according to the structural formula:

and salts, hydrates, solvates, N-oxides and prodrugs thereof, wherein:

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, 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, (C5-C15)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 4 is

R 6a is (C5-C10)aryl optionally substituted with one or more of the same or different R 8 groups or phenyl optionally substituted with one or more of the same or different R 8 groups;

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 is optionally substituted with one or more of the same or different R a or suitable R b groups;

each R d is independently 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 a hydrogen or a suitable R 8 ; and

R 45 is a (C3-C8)cycloalkyl optionally substituted with one or more of the same or different R 8 groups.

11 . A compound according to the structural formula:

and salts, hydrates, solvates and N-oxides thereof, wherein:

R 2 is selected from the group consisting of

wherein each R 21 is independently a halogen atom or an alkyl optionally substituted with one or more of the same or different halo groups, R 22 and R 23 are each, independently of one another, a hydrogen atom, methyl or ethyl optionally substituted with one or more of the same or different halo groups;

R 4 is a (C3-C8)cycloalkyl optionally substituted with one or more of the same or different R 8 groups; and

each R d is independently R a ;

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

each n is independently an integer from 0 to 3.

12 . A compound according to the structural formula:

and salts, hydrates, solvates and N-oxides thereof, wherein:

R 4 is selected from the group consisting of hydrogen, (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, 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, (C5-C15)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; and

each R d is independently R a ;

each m is independently an integer from 1 to 3;

each n is independently an integer from 0 to 3; and

R 55 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, 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, (C5-C15)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.

13 . A compound according to the structural formula:

and salts, hydrates, solvates and N-oxides thereof, wherein:

R 2 is

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 ) n 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 d is independently R a ;

each m is independently an integer from 1 to 3;

each n is independently an integer from 0 to 3; and

each R 35 individually is a hydrogen or R 8 .

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

and salts, hydrates, solvates and N-oxides thereof, wherein

R 2 is a phenyl group or indazole group, substituted with one or more of the same R 8 groups;

R 4 is

R 5 is a fluorine atom;

R 6 is a hydrogen atom;

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 d is independently an R a ;

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

each n is independently an integer from 0 to 3.

15 . The compound of claim 14 in which R 2 is a di or tri substituted phenyl group.

16 . The compound of claim 15 in which one or more of the R 8 groups are selected from the group consisting of halogens and alkoxy groups.

17 . The compound of claim 16 in which the 2,4-pyrimidinediamine compound is 1256, 1257, 1258, 1259 or 1260.

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

and salts, hydrates, solvates and N-oxides thereof, wherein

R 2 is

or phenyl substituted with one or more R 8 groups;

R 4 is

R 5 is a fluorine atom;

R 6 is a hydrogen atom;

R 11 and R 12 are each, independently of one another, selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl;

R 35 is hydrogen or R 8 ; and

each R d is independently an R a ;

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

each n is independently an integer from 0 to 3.

19 . The compound of claim 18 in which R 35 is not a methyl group.

20 . The compound of claim 18 in which the 2,4-pyrimidinediamine compound is 1000, 1001 or 1002.

21 - 50 . (canceled)

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 11, 2012

From: SINGH, RAJINDER; ARGADE, ANKUSH; LI, HUI; BHAMIDIPATI, SOMASEKHAR; CARROLL, DAVID; SYLVAIN, CATHERINE; CLOUGH, JEFFREY; KEIM, HOLGER

To: RIGEL PHARMACEUTICALS, INC.

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