4-PHENYL-6-SUBSTITUTED-PYRIMIDINE-2-CARBONITRILE DERIVATIVES

摘要

The invention relates to 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives having Formula (I) wherein R represents 1-3 optional substituents independently selected from (C<SUB>1-4</SUB>)- alkyl (optionally substituted with one or more halogens), (C<SUB>1-4</SUB>)alkyloxy (optionally substituted with one or more halogens) and halogen; X is NR<SUB>1</SUB>, O or S; R<SUB>1</SUB> is H or (C<SUB>1-4</SUB>)alkyl; Y is (C<SUB>1-4</SUB>)alkyl, benzyl or (C<SUB>2-6</SUB>)alkyl, substituted with a group selected from OH, (C<SUB>1-4</SUB>)alkyloxy, NR<SUB>2</SUB>R<SUB>3</SUB>, a 4-8 membered saturated heterocyclic ring comprising 1 or 2 heteroatoms selected from O, S and NR<SUB>4</SUB>, and a 5 or 6-membered aromatic heterocyclic group comprising 1-4 N atoms; or R<SUB>1</SUB> and Y form together with the nitrogen to which they are bonded a 5-8 membered saturated heterocyclic ring, optionally comprising a further heteroatom selected from O, S, NR<SUB>4</SUB> and NO; the ring being optionally substituted with NR<SUB>2</SUB>R<SUB>3</SUB> or with 1 to 4 (C<SUB>1-3</SUB>)alkyl groups; R<SUB>2</SUB> and R<SUB>3</SUB> are independently H or (C<SUB>1-4</SUB>)alkyl; or R<SUB>2</SUB> and R<SUB>3</SUB> form together with the nitrogen to which they are bonded a 4-8 membered saturated heterocyclic ring, optionally comprising a further heteroatom selected from O, S and NR<SUB>4</SUB>; R<SUB>4</SUB> is H, (C<SUB>1-6</SUB>)alkyl,(C<SUB>3-6</SUB>) cycloalkyl, (C<SUB>3-6</SUB>)cycloalkyl(C<SUB>1-4</SUB>)alkyl, (C<SUB>1-4</SUB>)alkyloxy-(C<SUB>1-4</SUB>)alkyl, benzyl, amido- (C<SUB>1-4</SUB>)alkyl, (C<SUB>1-6</SUB>)alkyloxycarbonyl(C<SUB>1-4</SUB>)alkyl or carboxy(C<SUB>1-4</SUB>)alkyl; or a pharmaceutically acceptable salt thereof, to pharmaceutical compositions comprising the same, as well as to the use of these 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives for the preparation of a medicament for the treatment of cathepsin K and cathepsin S related disorders, e.g. osteoporosis, atherosclerosis, inflammation and immune disorders such as rheumatoid arthritis and chronic pain.