5,7-disubstituted thiazolo[4,5-d]pyrimidines for the selective inhibition of chemokine receptors
There are disclosed novel 5,7-disubstituted [1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one derivatives of formula (I) wherein R 1 , R 2 , R 3 , R 4 and n are as defined in the specification, and pharmaceutically acceptable salts thereof, together with processes for their preparation, pharmaceutical compositions comprising them and their use in therapy. The compounds of formula (I) are CX 3 CR1 receptor antagonists and are thereby particularly useful in the treatment or prophylaxis of neurodegenerative disorders, demyelinating disease, cardio- and cerebrovascular atherosclerotic disorders, peripheral artery disease, rheumatoid arthritis, pulmonary diseases such as COPD, asthma or pain.
1. A compound of formula (I)
wherein:
R 1 is CH 3 or CF 3 ;
R 2 is halo, CN or C 1-6 alkyl;
R 3 is H or CH 3 ;
R 4 is H or CH 3 ; and
n is 0, 1 or 2;
as a free base or a pharmaceutically acceptable salt.
2. A compound of claim 1 , as a free base or a pharmaceutically acceptable salt.
3. A compound of claim 1 , as a free base or a pharmaceutically acceptable salt.
4. A compound of claim 1 , as a free base or a pharmaceutically acceptable salt.
5. A compound of claim 1 , as a free base or a pharmaceutically acceptable salt.
6. A compound of claim 1 , as a free base or a pharmaceutically acceptable salt, wherein R 2 is CN.
7. A compound of claim 1 , as a free base or a pharmaceutically acceptable salt, wherein n is 1; R 1 is CH 3 ; and R 2 is F, Cl or CN.
8. A compound of claim 1 , as a free base or a pharmaceutically acceptable salt, wherein the pyridine is attached at the 5 position and has Cl in the 2-position.
9. A compound of claim 1 , as a free base or a pharmaceutically acceptable salt, wherein the pyridine is attached at the 2 position and has CN in the 4-position.
10. A compound of claim 1 , as a free base or a pharmaceutically acceptable salt, wherein the pyridine is attached at the 2 position and has F in the 5-position.
11. A compound of claim 1 , as a free base or a pharmaceutically acceptable salt, wherein the pyridine is attached at the 2 position and has Cl in the 5-position.
12. A compound of claim 1 , as a free base or a pharmaceutically acceptable salt, wherein the pyridine is attached at the 2 position and has F in the 3-position.
13. A compound of claim 1 , as a free base or a pharmaceutically acceptable salt, wherein the pyridine is attached at the 4 position and has F in the 3-position.
14. A compound of claim 1 , as a free base or a pharmaceutically acceptable salt, wherein R 3 is H.
15. A compound of claim 1 , as a free base or a pharmaceutically acceptable salt, wherein R 4 is CH 3 .
16. A compound selected from:
5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one;
5-{[(1S)-1-(5-fluoropyridin-2-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one;
5-{[1-(3-fluoropyridin-4-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one;
5-{[(1S)-1-(3-Fluoropyridin-4-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one;
5-{[(1R)-1-(3-Fluoropyridin-4-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one;
5-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one;
2-{(1S)-1-[(7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-2-oxo-2,3-dihydro [1,3]thiazolo [4,5-d]pyrimidin-5-yl)thio]ethyl}isonicotinonitrile;
5-{[(1S)-1-(6-chloropyridin-3-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)butyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one; and
5-{[(1S)-1-(6-chloropyridin-3-yl)ethyl]thio}-7-[[(1R)-1-(hydroxymethyl)butyl](methyl)amino][1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one;
as a free base or a pharmaceutically acceptable salt.
17. A pharmaceutical composition comprising a compound according to claim 1 as a free base or a pharmaceutically acceptable salt, thereof in admixture with a pharmaceutically acceptable diluent or carrier.
18. 5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]thio}-7-{[(1R)-1(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a compound according to claim 18 , or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.
20. A pharmaceutical composition comprising a compound according to claim 16 as a free base or a pharmaceutically acceptable salt, in admixture with a pharmaceutically acceptable diluent or carrier.