4-Phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives
View Patent ↗Disclosed herein are 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives having Formula I, wherein each of the substituents is given the definition as set forth in the specification and claims; or a pharmaceutically acceptable salt thereof. Also disclosed are pharmaceutical compositions comprising these 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives and use of these 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives 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.
1. A 4-phenyl-6-substituted-pyrimidine-2-carbonitrile compound having the general formula I
wherein
R represents 1-3 optional substituents independently selected from (C 1-4 )alkyl optionally substituted with one or more halogens, (C 1-4 )alkyloxy optionally substituted with one or more halogens and halogen;
X is NR 1 , O or S;
R 1 is H or (C 1-4 )alkyl;
Y is (C 1-4 )alkyl, benzyl or (C 2-6 )alkyl, substituted with a group selected from OH,
(C 1-4 )alkyloxy, NR 2 R 3 , a 4-8 membered saturated heterocyclic ring comprising 1 or 2 heteroatoms selected from O, S and NR 4 , and a 5 or 6-membered aromatic heterocyclic group comprising 1-4 N atoms; or
R 1 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 4 and NO; the ring being optionally substituted with NR 2 R 3 or with 1 to 4 (C 1-3 )alkyl groups;
R 2 and R 3 are independently H or (C 1-4 )alkyl; or
R 2 and R 3 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 4 ;
R 4 is H, (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 3-6 )cycloalkyl(C 1-4 )alkyl, (C 1-4 )alkyloxy(C 1-4 )alkyl, benzyl, amido(C 1-4 )alkyl, (C 1-6 )alkyloxycarbonyl(C 1-4 )alkyl or carboxy(C 1-4 )alkyl; or a pharmaceutically acceptable salt thereof.
2. The 4-phenyl-6-substituted-pyrimidine-2-carbonitrile compound according to claim 1 , wherein R represents a trifluoromethyl substituent at the meta position of the 4-phenyl group.
3. The 4-phenyl-6-substituted-pyrimidine-2-carbonitrile compound according to claim 1 , wherein X is NR 1 .
4. The 4-phenyl-6-substituted-pyrimidine-2-carbonitrile compound according to claim 2 , wherein X is NR 1 .
5. The 4-phenyl-6-substituted-pyrimidine-2-carbonitrile compound of formula I which is selected from:
4-(piperazin-1-yl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
4-(4-cyclopropyl-piperazin-1-yl)-6-(trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
4-[1,4]diazepan-1-yl-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
4-[methyl-(1-methyl-piperidin-4-yl)-amino]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
4-[(1H-tetrazol-5-ylmethyl)-amino]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
4-(4-methoxy-3-trifluoromethylphenyl)-6-piperazin-1-yl-pyrimidine-2-carbonitrile;
4-(2-piperidin-1-yl-ethoxy)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
4-(4-carbamoylmethyl-piperazin-1-yl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
4-(4-isopropyl-piperazin-1-yl)-6-(trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
4-[4-(2-carboxy-ethyl)-piperazin-1-yl]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
4-(4-cyclopropylmethyl-piperazin-1-yl)-6-(trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
4-(3,3,4-trimethyl-piperazin-1-yl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
4-(4-methyl-[1,4]diazepan-1-yl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
4-(carboxymethyl-amino)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
4-(2-morpholin-4-yl-ethoxy)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
4-(2-diethylamino-ethoxy)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile.
6. A pharmaceutical composition comprising a 4-phenyl-6-substituted-pyrimidine-2-carbonitrile compound according to claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable auxilliaries.
7. A method of treating a cathepsin K and cathepsin S dependent disorder selected from the group consisting of osteoporosis, atherosclerosis, rheumatoid arthritis, osteoarthritis and chronic pain in a subject, the method comprising administering to the subject an effective amount of a 4-phenyl-6-substituted-pyrimidine-2-carbonitrile compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
8. The method of claim 7 , wherein the disorder is osteoporosis.
9. The method of claim 7 , wherein the disorder is atherosclerosis.
10. The method of claim 7 , wherein the disorder is rheumatoid arthritis.
11. The method of claim 7 , wherein the disorder is osteoarthritis.
12. The method of claim 7 , wherein the disorder is chronic pain.