Pyrimidine Compounds as Histamine Modulators

A compound of formula [1]:

• wherein:
• A represents a fully saturated or partially unsaturated ring of 5 to 7 atoms, at least one of which is a nitrogen atom;
• B represents aryl or heteroaryl ring of 5 to 6 atoms, wherein B is optionally substituted with one to three groups of formula R5, wherein R5 is selected from the group consisting of H, F, Cl, Br, I, C1-4-alkyl, C3-6-cycloalkyl, heterocycloalkyl, C1-4-alkoxy, C3-6-cycloalkoxy, OH, OCF3, CF3, cyano, and NR6R7, wherein R6 and R7 independently represent H or C1-4-alkyl;
• X represents O, NH, S, or CH2;
• R1 represents H or C1-4-alkyl;
• R2 is selected from the group consisting of H, optionally substituted C1-4-alkyl, optionally substituted C3-6-cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R3 and R4 independently represent H, or C1-2-alkyl;
• or R3 and R4 taken together represent a C1-4-alkylene group;
• and corresponding N-oxides, pharmaceutically acceptable salts, solvates, metabolites and prodrugs thereof,
• provided that at least one of the following prerequisites is fulfilled:
• a) R1 is H;
• b) R2 is not H or C1-4 alkyl;
• c) At least one of R3 and R4 is not H;
• d) X is not O or S;
• e) A is attached to the pyrimidine ring via a carbon ring atom;
• and
• f) B is not a phenyl ring.

A compound selected from the group consisting of:

• 8-Chloro-2-methyl-4-(4-methylpiperazin-1-yl)benzo[4,5]furo[3,2-d]pyrimidine;
• 8-Chloro-2-cyclopropyl-4-(4-methylpiperazin-1-yl)benzo[4,5]furo[3,2-d]pyrimidine;
• 8-Chloro-4-(4-methylpiperazin-1-yl)-2-trifluoromethylbenzo[4,5]furo[3,2-d]pyrimidine;
• 8-Chloro-4-(1-methylpiperidin-4-yl)benzo[4,5]furo[3,2-d]pyrimidine;
• 8-Chloro-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzo[4,5]furo[3,2-d]pyrimidine;
• 8-Chloro-4-(3-methylpiperazin-1-yl)benzo[4,5]furo[3,2-d]pyrimidine;
• 8-Chloro-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]benzo[4,5]furo[3,2-d]pyrimidine;
• 8-Chloro-4-(3,4-dimethylpiperazin-1-yl)benzo[4,5]furo[3,2-d]pyrimidine;
• 4-(piperazin-1-yl)benzo[4,5]thieno[3,2-d]pyrimidine;
• 4-(1,4-diazepan-1-yl)benzo[4,5]thieno[3,2-d]pyrimidine;
• 8-Chloro-4-(1-methylpyrrolidin-3-yl)benzo[4,5]furo[3,2-d]pyrimidine;
• 8-Chloro-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)benzo[4,5]furo[3,2-d]pyrimidine;
• 8-Chloro-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]benzo[4,5]furo[3,2-d]pyrimidine;
• 8-Chloro-4-[5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl]benzo[4,5]furo[3,2-d]pyrimidine;
• and
• 8-Chloro-4-[5-methyl-2,5-diazabicyclo[3.2.1]oct-2-yl]benzo[4,5]furo[3,2-d]pyrimidine.

A method of using a compound of formula [1]:

• as a medicament for the prevention, treatment, or suppression of a disease mediated by the H4 receptor alone or by the H1 and H4 receptors in combination, in a human subject in need thereof,
• wherein:
• A is selected from the group consisting of
• B represents aryl or heteroaryl ring of 6 atoms, wherein B is optionally substituted with one to three groups of formula R5, wherein R5 is selected from the group consisting of H, F, Cl, Br, I, C1-4-alkyl, C3-6-cycloalkyl, heterocycloalkyl, C1-4-alkoxy, C3-6-cycloalkoxy, OH, OCF3, CF3, cyano, and NR6R7, wherein R6 and R7 independently represent H or C1-4-alkyl;
• X represents O, NH, or S;
• R1 represents H, or C1-4-alkyl;
• R2 represents H, C1-4-alkyl optionally substituted with halo, or C3-6-cycloalkyl optionally substituted with halo;
• R3 and R4 independently represent H, or C1-2-alkyl;
• or R3 and R4 taken together represent a C1-4-alkylene group;
• and corresponding N-oxides, pharmaceutically acceptable salts, solvates, metabolites and prodrugs thereof.