Chemical compounds
The invention relates to pyrazole derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. More particularly the invention relates to HbS modulators of formula (I) or tautomers thereof, or pharmaceutically acceptable salts of said modulators or tautomers thereof, wherein X, Y, R 2 and R 3 are as defined in the description. HbS modulators are potentially useful in the treatment of a wide range of disorders, including sickle cell disease (SCD).
1. A compound of formula (I)
or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein
X is an amino substituted naphthyridine or quinoline selected from
wherein the right-hand-side ring of said naphthyridine is optionally substituted by R 1 , and wherein the right-hand-side ring of said quinoline is optionally independently substituted by one or two R 1 ;
Y is CH or N;
each R 1 is independently halogen; CN; (C 1 -C 4 )alkyl, optionally substituted by OH; or CONR 4 R 5 ;
R 2 and R 3 together with the carbon atoms to which they are attached form a 5-membered heteroaryl containing one or two N, optionally substituted by R 6 ; or
R 2 is H; OH; (C 1 -C 4 )alkyl, optionally substituted by OH or CO 2 R 4 ; (C 1 -C 4 )alkyloxy, optionally substituted by OH or CO 2 R 4 ; CO 2 R 4 ; CONR 4 R 5 ; SO 2 NR 4 R 4 ; NR 4 SO 2 (C 1 -C 4 )alkyl; or oxadiazolone;
R 3 is H or halogen;
each R 4 is independently H or (C 1 -C 4 )alkyl;
each R 5 is independently H; (C 1 -C 4 )alkyl, optionally substituted by OH, O(C 1 -C 4 )alkyl or CO 2 R 4 ; SO 2 (C 1 -C 4 )alkyl; or (C 3 -C 6 )cycloalkyl, optionally substituted by OH; and
R 6 is (C 1 -C 4 )alkyl, optionally substituted by OH, CO 2 R 4 or CONR 4 R 5 .
2. A compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein X is an amino substituted quinoline selected from
3. A compound of claim 2 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein X is an amino substituted quinoline selected from
4. A compound of claim 3 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein X is the amino substituted quinoline
5. A compound of claim 3 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein X is the amino substituted quinoline
6. A compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein X is an amino substituted naphthyridine selected from
7. A compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein each R 1 is independently F, C, Br, CN, CH 3 or CONH 2 .
8. A compound of claim 7 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein each R 1 is independently F, Cl or CONH 2 .
9. A compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein Y is CH.
10. A compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein Y is N.
11. A compound of claim 9 or claim 10 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein R 2 and R 3 together with the carbon atoms to which they are attached form a 5-membered heteroaryl selected from
12. A compound of claim 11 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein R 2 and R 3 together with the carbon atoms to which they are attached form a pyrazolyl selected from
13. A compound of claim 9 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein R 2 is (C 1 -C 4 )alkyl substituted by CO 2 R 4 ; (C 1 -C 4 )alkyloxy substituted by CO 2 R 4 ; CO 2 R 4 ; CONR 4 R 5 ; SO 2 NR 4 R 4 ; or oxadiazolone.
14. A compound of claim 10 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein R 2 is H; OH; (C 1 -C 4 )alkyl substituted by OH; (C 1 -C 4 )alkyloxy; (C 1 -C 4 )alkyloxy substituted by OH or CO 2 R 4 ; CO 2 R 4 ; or CONR 4 R 5 .
15. A compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein R 3 is H or F.
16. A compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein R 4 is H or methyl.
17. A compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein R 5 is H or methyl.
18. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from:
3-{(1S)-1-[(2-amino-6,8-difluoroquinolin-3-yl)oxy]ethyl}-4-(1H-pyrazol-1-yl)benzoic acid;
6-{(1S)-1-[(2-amino-6-fluoroquinolin-3-yl)oxy]ethyl}-5-(1H-pyrazol-1-yl)pyridin-2-ol;
(S)-6-(1-((2-amino-6-fluoroquinolin-3-yl)oxy)ethyl)-5-(1H-pyrazol-1-yl)pyridin-2(1H)-one; and
2-amino-7-fluoro-3-{(1S)-1-[5-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]ethoxy}quinoline-6-carboxamide.
19. A compound that is (S)-6-(1-((2-amino-6-fluoroquinolin-3-yl)oxy)ethyl)-5-(1H-pyrazol-1-yl)pyridin-2(1H)-one or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof.
20. A compound that is (S)-6-(1-((2-amino-6-fluoroquinolin-3-yl)oxy)ethyl)-5-(1H-pyrazol-1-yl)pyridin-2(1H)-one or a tautomer thereof.
21. A compound that is (S)-6-(1-((2-amino-6-fluoroquinolin-3-yl)oxy)ethyl)-5-(1H-pyrazol-1-yl(pyridin-2(1H)-one or a pharmaceutically acceptable salt thereof.
22. A compound that is (S)-6-(1-((2-amino-6-fluoroquinolin-3-yl)oxy)ethyl)-5-(1H-pyrazol-1-yl)pyridin-2(1H)-one.
23. A pharmaceutical composition comprising a compound according to claim 19 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, and a pharmaceutically acceptable excipient.
24. The pharmaceutical composition according to claim 23 further comprising one or more additional therapeutic agents.
25. A method of treating sickle cell disease in a human or animal, comprising administering to said human or animal a therapeutically effective amount of a compound according to claim 19 or a tautomer thereof, or a pharmaceutically acceptable salt thereof of said compound or tautomer.
26. A pharmaceutical composition comprising a compound according to claim 18 , or a pharmaceutically acceptable salt thereof, in combination with pharmaceutically acceptable excipient.
27. The compound 6-{(1S)-1-[(2-amino-6-fluoroquinolin-3-yl)oxy]ethyl}-5-(1H-pyrazol-1-yl)pyridin-2-ol, or a pharmaceutically acceptable salt thereof.
28. The compound 6-{(1S)-1-[(2-amino-6-fluoroquinolin-3-yl)oxy]ethyl}-5-(1H-pyrazol-1-yl)pyridin-2-ol.