2,4-pyrimidinediamine compounds for treatment of inflammatory disorders

1. A compound according to the formula:

wherein:

X represents (CH 2 ) m wherein m is an integer from 1 to 4 , and one or more CH 2 are optionally replaced with O, S or N(R 01 ) wherein R 01 represents H, C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl;

Y represents (CH 2 ) n wherein n is an integer from 2 to 5 , and one or more CH 2 are optionally replaced with O, S or N(R 02 ) wherein R 02 represents H, C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl;

Z represents N(R 1 ), O or S, wherein R l represents H, C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl;

represents a bond having an endo-configuration, an exo-configuration, or a mixture thereof;

p is 0 or 1;

R 2 represents H, C 1 -C 7 alkyl or C 2 -C 8 alkanoyl;

R 3 represents F;

R 4 represents H, C 1 -C 7 alkyl or C 2 -C 8 alkanoyl; and

R 5 represents a substituted aryl or heteroaryl.

2. The compound of claim 1 , represented by the formula:

3. The compound of claim 1 , wherein R 5 represents substituted aryl or heteroaryl having 6 ring atoms.

4. The compound of claim 3 , wherein R 5 represents one of the following formulae:

wherein R 6 represents halogen, cyano, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 alkoxy or C 1 -C 7 haloalkoxy; and

R 7 represents H, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 - 7 alkoxy, C 1 -C 7 haloalkoxy, C 3 -C 8 cycloalkyl, —SO 2 —C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-SO 2 —R 8 , C 3 -C 8 cycloalkyl, —SO 2 —C 3 -C 8 cycloalkenyl, C 3 - C 8 cycloalkenyl-SO 2 —R 8 , aryl, —SO 2 -aryl, aryl-SO 2 —R 8 , a heterocyclic group, a —SO 2 -heterocyclic group, a heterocyclic-SO 2 —R 8 group, or —SO 2 —NR 9 R 10 , wherein R 8 and R 9 each independently represents C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl, and R l0 represents H, C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl; or

R 6 and R 7 are combined to form a ring together with the carbon atoms to which they are bonded,

provided that when R 6 is halogen, X is (CH 2 ) 2 , Y is (CH 2 ) 3 and Z is N(R 1 ), one or more of R l to R 4 and R 7 is not H.

5. The compound of claim 4 , wherein the heterocyclic group encompassed by R 7 : (a) is aromatic, aliphatic or unsaturated, spiro, fused or bridged; (b) has 3 to 14 carbon ring atoms, at least one of which is replaced with O, S or N(R 03 ) wherein R 03 represents H, C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl; (c) has 1 to 3 rings; and/or (d) is selected from the group consisting of aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyridyl, tetrahydroquinolyl, tetrahydroisoquinolyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxolanyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, pyrazolidinyl, 2H-pyrrolyl, pyrrolinyl, imidazolinyl, pyrazolinyl, dihydrofuryl, dihydrothienyl, dihydropyranyl, dihydrothiopyranyl, dihydropyridyl, dihydroquinolyl, dihydroisoquinolyl, indolinyl, isoindolinyl, furyl, furazanyl, pyranyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzopyranyl, benzofuranyl, indolyl, and quinolinyl.

6. The compound of claim 4 , represented by the formula:

7. The compound of claim 6 , wherein R 6 represents halogen or C 1 -C 7 haloalkyl.

8. The compound of claim 7 , wherein R 6 represents Cl or CF 3 .

9. The compound of claim 4 , represented by the formula:

10. The compound of claim 9 , wherein R 6 represents CF 3 .

11. The compound of claim 10 , wherein R 7 represents the following formula:

H, C 1 -C 7 alkoxy,

wherein q represents 0 or 1 , and R 11 represents H or C 1 -C 7 alkyl.

12. The compound of claim 11 , wherein R 8 represents methyl or cyclopropyl.

13. The compound of claim 1 , wherein: (a) R 3 represents F; (b) R 2 and/or R 4 represent H; and/or (c) X represents (CH 2 ) 2 , Y represents (CH 2 ) 3 , and Z represents N(R 1 ).

14. The compound of claim 13 , wherein R 1 represents CH 3 .

15. The compound of claim 1 , represented by one of the following formulae:

16. A composition comprising one or more compounds of claim 1 .

17. A method for preparing the compound of claim 1 , comprising:

(a) reacting a substituted or unsubstituted uracil with a halogenating agent, to obtain a 2,4-dichloropyrimidine compound;

(b) reacting the 2,4-dichloropyrimidine compound with

 to obtain a 4N- substituted-4-pyrimidineamine derivative;

(c) reacting the 4N-substituted-4-pyrimidineamine derivative with R 5 NH 2 , to obtain a 2,4-pyrimidinediamine derivative; and

(d) reacting the 2,4-pyrimidinediamine derivative with R 2 -LG, wherein R 2 is not H and LG represents a leaving group, to thereby obtain the compound of claim 1 , wherein R 4 is H.

18. A method for preparing the compound of claim 1 , comprising:

(a) converting a substituted or unsubstituted cytosine into a N4-protected cytosine;

(b) reacting the N4-protected cytosine with a halogenating agent, to obtain a 2-chloro-4N-protected-4-pyrimidine amine;

(c) reacting the 2-chloro-4N-protected-4-pyrimidine amine with R 5 NH 2 , to obtain a 4N-protected -2,4-pyrimidinediamine derivative;

(d) deprotecting the 4N-protected-2,4-pyrimidinediamine derivative, to obtain a 2,4-pyrimidinediamine derivative; and

(e) reacting the 2,4-pyrimidinediamine derivative with

 to obtain the compound of claim 1 , wherein R 2 and R 4 are H.

19. A method for preparing the compound of claim 1 , comprising:

(a) reacting a substituted or unsubstituted cytosine with unprotected

 to obtain a N4-substituted cytosine derivative;

(b) reacting the N4-substituted cytosine derivative with a halogenating agent, to obtain a 2-chloro-N4-substituted-pyrimidineamine derivative; and

(c) reacting the 2-chloro-N4-substituted-pyrimidineamine derivative with R 5 NH 2 , to thereby obtain the compound of claim 1 , wherein R 2 and R 4 are H.

20. A method for preparing the compound of claim 1 , comprising:

(a) reacting a substituted or unsubstituted cytosine with protected

 to obtain a protected N4-substituted cytosine derivative;

(b) reacting the protected N4-substituted cytosine derivative with a halogenating agent, to obtain a protected 2-chloro-N4-substituted-pyrimidineamine derivative;

(c) reacting the protected 2-chloro-N4-substituted-pyrimidineamine derivative with R 5 NH 2 , to obtain a protected 2,4-pyrimidinediamine compound; and

(d) deprotecting the protected 2,4-pyrimidinediamine compound to thereby obtain the compound of claim 1 , wherein R 2 and R 4 are H.

21. A method for preparing the compound of claim 1 , comprising:

(a) reacting a substituted 2-amino-4-pyrimidinol with R 5 -LG, wherein LG represents a leaving group, to obtain a N2-substituted-4-pyrimidinol;

(b) reacting the N2-substituted-4-pyrimidinol with a halogenating agent, to obtain a N2-substituted 4-halo-2-pyrimidine amine; and

(c) reacting the N2-substituted 4-halo-2-pyrimidine amine with

 to obtain the compound of claim 1 , wherein R 2 and R 4 are H.

22. A method for inhibiting production of IL-23 , comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds according to the formula:

wherein:

X represents (CH 2 ) m wherein m is an integer from 1 to 4 , and one or more CH 2 are optionally replaced with O, S or N(R 01 ) wherein R 01 represents H, C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl;

Y represents (CH 2 ) n wherein n is an integer from 2 to 5 , and one or more CH 2 are optionally replaced with O, S or N(R 02 ) wherein R 02 represents H, C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl;

Z,represents N(R 1 ), O or S, wherein R 1 represents H, C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl;

represents a bond having an endo-configuration, an exo-configuration, or a mixture thereof;

p is 0 or 1;

R 2 represents H, C 1 -C 7 alkyl or C 2 -C 8 alkanoyl;

R 3 represents F;

R 4 represents H, C 1 -C 7 alkyl or C 2 -C 8 alkanoyl; and

R 5 represents a substituted aryl or heteroaryl.

23. The method of claim 22 , wherein: (a) the method further comprises stimulating production of IL-10 ; and/or (b) the subject is a human.

24. A method for stimulating production of IL-10 , comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds according to the formula:

wherein:

X represents (CH 2 ) m wherein m is an integer from 1 to 4 , and one or more CH 2 are optionally replaced with O, S or N(R 01 ) wherein R 01 represents H, C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl;

Y represents (CH 2 ) n wherein n is an integer from 2 to 5 , and one or more CH 2 are optionally replaced with O, S or N(R 02 ) wherein R 02 represents H, C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl;

Z represents N(R 1 ), O or S, wherein R l represents H, C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl;

represents a bond having an endo-configuration, an exo-configuration, or a mixture thereof;

p is 0 or 1;

R 2 represents H, C 1 -C 7 alkyl or C 2 -C 8 alkanoyl;

R 3 represents F;

R 4 represents H, C 1 -C 7 alkyl or C 2 -C 8 alkanoyl; and

R 5 represents a substituted aryl or heteroaryl.

25. A compound of formula (VI):

wherein

R 1 represents H, C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl;

R 2 represents H, C 1 -C 7 alkyl or C 2 -C 8 alkanoyl;

R 3 represents F;

R 4 represents H, C 1 -C 7 alkyl or C 2 -C 8 alkanoyl;

p is 0 or 1;

Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are independently selected from C and N;

R 6 , R 7 , R 100 , R 101 , and R 102 are independently selected from H, halogen, cyano, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, C 3 -C 8 cycloalkyl, —SO 2 —C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-SO 2 —R 8 , C 3 -C 8 cycloalkyl, —SO 2 —C 3 -C 8 cycloalkenyl, C 3 -C 8 cycloalkenyl-SO 2 —R 8 , aryl, —SO 2 -aryl, aryl-SO 2 —R 8 , a heterocyclic group, a —SO 2 -heterocyclic group, a heterocyclic-SO 2 —R 8 group, or —SO 2 —NR 9 R 10 ; or

any two of R 6 , R 7 , R 100 , R 101 , and R 102 that are vicinal are combined to form a ring together with the carbon atoms to which they are bonded; and

any of R 6 , R 7 , R 100 , R 101 , and R 102 is absent to satisfy valence requirements;

wherein R 8 and R 9 each independently represents C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl, and R 10 represents H, C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl.

26. A compound of formula (VII):

wherein R l represents H, C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl;

R 2 represents H, C 1 -C 7 alkyl or C 2 -C 8 alkanoyl;

R 3 represents F;

R 4 represents H, C 1 -C 7 alkyl or C 2 -C 8 alkanoyl;

Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are independently selected from C and N;

R 6 , R 7 , R 100 , R 101 , and R 102 are independently selected from H, halogen, cyano, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, C 3 -C 8 cycloalkyl, —SO 2 —C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-SO 2 —R 8 , C 3 -C 8 cycloalkyl, —SO 2 —C 3 -C 8 cycloalkenyl, C 3 -C 8 cycloalkenyl-SO 2 —R 8 , aryl, —SO 2 -aryl, aryl-SO 2 —R 8 , a heterocyclic group, a —SO 2 -heterocyclic group, a heterocyclic-SO 2 —R 8 group, or —SO 2 —NR 9 R 10 ; or

any two of R 6 , R 7 , R 100 , R 101 , and R 102 that are vicinal are combined to form a ring together with the carbon atoms to which they are bonded; and

any of R 6 , R 7 , R 100 , R 101 , and R 102 is absent to satisfy valence requirements;

wherein R 8 and R 9 each independently represents C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl, and R l0 represents H, C 1 -C 7 alkyl or C 3 -C 8 cycloalkyl.