Pyridine methylene azolidinones and use thereof phosphoinositide inhibitors
View Patent ↗The present invention relates to pyridine methylene azolidinone compounds of Formula (I) for the treatment and/or prophylaxis of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, allergy, asthma, pancreatitis, multi-organ failure, kidney diseases, platelet aggregation, cancer, sperm motility, graft rejection or lung injuries. Specifically, the present invention is related to pyridine methylene azolidinone derivatives for the modulation, notably the inhibition of the activity or function of the phosphoinositide-3-kinases, PI3Ks.
1. A pyridine methylene azolidinone compound according to Formula (I),
wherein
R 1 is selected from the group consisting of H, a halogen, a C 1 -C 6 -alkyl group, a C 2 -C 6 -alkenyl group, a C 2 -C 6 -alkynyl group, a C 1 -C 6 -alkyl group having an alkoxy substituent, an alkoxycarbonyl group, an acyl group, a sulfonyl group, a sulfanyl group, a sulfinyl group, an alkoxy group, and an amino group;
R 2 is selected from the group consisting of H, a halogen, a C 1 -C 6 -alkyl group, a C 2 -C 6 -alkenyl group, a C 2 -C 6 -alkynyl group, an aryl group, a heteroaryl group, a C 3 -C 8 -cycloalkyl group, a C 3 -C 8 -heterocycloalkyl group, an aryl C 1 -C 6 -alkyl group, a heteroaryl C 1 -C 6 -alkyl group, a C 3 -C 8 -cycloalkyl C 1 -C 6 -alkyl group, a C 3 -C 8 -heterocycloalkyl C 1 -C 6 -alkyl group, a C 1 -C 6 -alkyl alkoxy group, an alkoxycarbonyl group, an acyl group, a sulfonyl group, a sulfanyl group, a sulfinyl group, an alkoxy group and an amino group;
X is selected from the group consisting of S, NH and O;
Y is selected from the group consisting of O, S and NR 3 , wherein R 3 is selected from the group consisting of H, a C 1 -C 6 -alkoxy group, a substituted C 1 -C 6 -alkoxy group, a C 1 -C 6 -alkyl group, a substituted C 1 -C 6 -alkyl group, a C 2 -C 6 -alkenyl group, a substituted C 2 -C 6 -alkenyl group, a C 2 -C 6 -alkynyl group, a substituted C 2 -C 6 -alkynyl group, a C 1 -C 6 -alkyl aryl group, a substituted C 1 -C 6 -alkyl aryl group, a cyano group, a sulfonyl group, and a substituted sulfonyl group;
A together with the pyridine ring forms a group represented by formula (Ia):
n is 1 or 2;
or pharmaceutically acceptable salts thereof.
2. The pyridine methylene azolidinone compound according to claim 1 , wherein R 1 is H.
3. The pyridine methylene azolidinone compound according to claim 1 , wherein R 2 is H.
4. The pyridine methylene azolidinone compound according to claim 1 , wherein R 2 is C 3 -C 8 -heterocycloalkyl.
5. The pyridine methylene azolidinone compound according to claim 1 , wherein R 2 is an aryl group or a heteroaryl group.
6. The pyridine methylene azolidinone compound according to claim 1 , wherein X is S.
7. The pyridine methylene azolidinone compound according to claim 1 , wherein Y is O.
8. The pyridine methylene azolidinone compound according to claim 1 , wherein Y is S.
9. The pyridine methylene azolidinone compound according to claim 1 , wherein n is 1.
10. The pyridine methylene azolidinone compound according to claim 1 , wherein
R 1 is H;
R 2 is C 3 -C 8 -heterocycloalkyl;
X is S; and
Y is O or S.
11. The pyridine methylene azolidinone compound according to claim 1 , selected from the group consisting of:
(5Z)-5-{[4-(1-piperidinyl)pyrido[3,2-d]pyrimidin-6-yl]methylene}-1,3-thiazolidine-2,4-dione;
(5Z)-5-{[4-(4-fluoro-1-piperidinyl)pyrido[3,2-d]pyrimidin-6-yl]methylene}-1,3-thiazolidine-2,4-dione;
(5Z)-5-{4-[4-(trifluoromethyl)-1-piperidinyl]pyrido[3,2-d]pyrimidin-6-yl}methylene)-1,3-thiazolidine-2,4-dione; and
5-[4-(4-Fluoro-piperidin-1-yl)-pyrido[3,2-d]pyrimidin-6-ylmethylene]-2-thioxo-thiazolidin-4-one.
12. A pharmaceutical composition comprising pyridine methylene azolidinone compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient thereof.
13. A process for the preparation of pyridine methylene azolidinone compound according to claim 1 , comprising
reacting a compound of Formula (II) with a compound of Formula (III) in presence of a base:
wherein R 1 , R 2 , A, X, Y and n are as defined in claim 1 .