6-amino-pyrimidine-4-carboxamide derivatives and related compounds which bind to the sphingosine 1-phosphate (S1P) receptor for the treatment of multiple sclerosis

1. A compound according to formula (I):

wherein

X is NR a R b , SR b or Hal,

R a is H or A,

R b is A,

A is branched or linear alkyl having 1 to 12 C-atoms, wherein one or more H-atoms may be replaced by Hal, OR 3 , COOR 3 , CN or N(R 3 ) 2 and wherein one or more non-adjacent CH 2 -groups may be replaced by O, NR 3 , S or SO 2 and/or by —CH═CH— groups, or A is a cycloalkyl or cycloalkylalkylene having 3-7 ring C atoms

Hal is F, Cl, Br or I,

W is C═O, C═S, SO 2 or SO,

Q is NR 3 , —O— or —S—,

R is H, A, Ar, Het,

Ar denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic carbocyclic ring having 6 to 14 carbon atoms which may be unsubstituted, monosubstituted, disubstituted or trisubstituted by Hal, A, OR 3 , —[C(R 3 ) 2 ] n —OR 3 , N(R 3 ) 2 , —[C(R 3 ) 2 ] n —N(R 3 ) 2 , NO 2 , CN, COOR 3 , CF 3 , OCF 3 , CON(R 3 ) 2 , NR 3 COA, NR 3 CON(R 3 ) 2 , —[C(R 3 ) 2 ] n -Het, —[C(R 3 ) 2 ] n -Ar, —[C(R 3 ) 2 ] n -cycloalkyl, —[C(R 3 ) 2 ] n —CON(R 3 ) 2 , —[C(R 3 ) 2 ] n —COOR 3 , —[C(R 3 ) 2 ] n —NR 3 —[C(R 3 ) 2 ] n —CO 2 R 3 , —[C(R 3 ) 2 ] n —NR 3 —[C(R 3 ) 2 ] n —OR 3 , —SO 2 —[C(R 3 ) 2 ] n —CO 2 R 3 , —SO 2 —N(R 3 ) 2 —[C(R 3 ) 2 ] n —CO 2 R 3 , —[C(R 3 ) 2 ] n —SO 2 —[C(R 3 ) 2 ] n —CO 2 R 3 , —SO 2 —[C(R 3 ) 2 ] n —OR 3 , —SO 2 —N(R 3 ) 2 —[C(R 3 ) 2 ] n —OR 3 , —[C(R 3 ) 2 ] n —SO 2 —[C(R 3 ) 2 ] n —OR 3 , NR 3 CON(R 3 ) 2 , NR 3 SO 2 A, COR 3 , SO 2 N(R 3 ) 2 , SO 2 N(R 3 )A, SOA, SONR 3 A, or SO 2 A, and/or —O[C(R 3 ) 2 ] n —COOR 3 ,

Het denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 N, O and/or S atoms which may be unsubstituted, monosubstitutcd, disubstituted or trisubstituted by Hal, A, OR 3 , [C(R 3 ) 2 ] n —OR 3 , N(R 3 ) 2 , —[C(R 3 ) 2 ] n —N(R 3 ) 2 , NO 2 , CN, COOR 3 , CF 3 , OCF 3 , CON(R 3 ) 2 , NR 3 COA, NR 3 CON(R 3 ) 2 , —[C(R 3 ) 2 ] n -Het, —[C(R 3 ) 2 ] n -Ar, —[C(R 3 ) 2 ] n -cycloalkyl, —[C(R 3 ) 2 ] n —CON(R 3 ) 2 , —[C(R 3 ) 2 ] n —COOR 3 , —[C(R 3 ) 2 ] n —NR 3 —[C(R 3 ) 2 ] n —CO 2 R 3 , —[C(R 3 ) 2 ] n —NR 3 , —[C(R 3 ) 2 ] n —OR 3 , —SO 2 —[C(R 3 ) 2 ] n —CO 2 R 3 , —[SO 2 —N(R 3 ) 2 ]—[C(R 3 ) 2 ] n —CO 2 R 3 , —[C(R 3 ) 2 ] n —SO 2 —[C(R 3 ) 2 ] n —CO 2 R 3 , —SO 2 —[C(R 3 ) 2 ] n —OR 3 , —SO 2 —N(R 3 ) 2 —[C(R 3 ) 2] n —OR 3 , —[C(R 3 ) 2 ] n —SO 2 —[C(R 3 ) 2 ] n —OR 3 , NR 3 CON(R 3 ) 2 , NR 3 SO 2 A, COR 3 , SO 2 N(R 3 ) 2 , SO 2 N(R 3 )A, SOA, SONR 3 A, or SO 2 A, and/or —O[C(R 3 ) 2 ] n —COOR 3 ,

R 1 is H or A,

R 2 is H, A or Hal,

R 3 is H or A, and

N is 0, 1, 2, 3, 4, 5, 6, 7 or 8,

or pharmaceutically acceptable derivatives, solvates, tautomers, salts, stereoisomers or mixtures thereof.

2. The compound according to claim 1 , wherein X is NR a R b or OR b , W is CO, Q is NR 3 , R 1 and R 2 are H.

3. The compound according to claim 1 , wherein R is Ar or Het.

4. The compound according to claim 3 , wherein Ar is one of the following groups:

wherein m is 1, 2 or 3, n is 0, 1, 2 or 3, and R 3 and A are as defined in claim 1 .

5. The compound according to claim 3 , wherein Het denotes one of the following groups:

wherein m is 1, 2, or 3, n is 0, 1, 2 or 3, and R 3 is as defined in claim 1 .

6. The compound according to claim 1 , wherein said compound is:

or pharmaceutically acceptable derivatives, solvates, tautomers, salts, stereoisomers or mixtures thereof.

7. A process for the preparation of a compound according to claim 1 , wherein:

a) a compound of formula A

wherein R 1 , R 2 , W, Q, R are as defined in claim 1 and L is a leaving group, is reacted with a compound of formula XH, wherein X is as defined in claim 1 ,

or

b) a compound of formula B

wherein X, R 1 , R 2 and W are as defined as in claim 1 and T is OH, OA, Cl, Br or a leaving group,

is reacted with

HNR 3 R, HOR or HSR, wherein R is as defined in claim 11 ,

and/or

transforming the groups R 1 and/or R 2 in the compounds of formula (I) into different groups R 1 and R 2

and/or

a base or acid of the formula (I) is converted into one of its salts.

8. A process for the preparation of a compound according to claim 1 , wherein

a) a compound of formula C

wherein X, R 2 , W, Q, R are as defined in claim 1 , is hydrogenated in the presence of a suitable catalyst and a suitable base.

9. A pharmaceutical composition comprising at least one compound according to claim 1 and an excipient and/or adjuvant.

10. A set (kit) consisting of separate packs of:

(a) an effective amount of a compound according to claim 1 , and

(b) an effective amount of an additionally medicinally active ingredient.

11. The compound according to claim 7 , wherein said compound of Formula (I) is a pharmaceutically acceptable salt.

12. The compound according to claim 7 , wherein said compound is a pharmaceutically acceptable salt of said compound.