Inhibitors of histone demethylases
The present application discloses compounds capable of modulating the activity of histone demethylases (HDMEs), which are useful for prevention and/or treatment of diseases in which genomic dysregulation is involved in the pathogenesis, such as e.g. cancer. The present application also discloses pharmaceutical compositions comprising said compounds and the use of such compounds as a medicament. The compounds take the form (I)
1. A compound according to the formula:
wherein:
R 12 is R 13 O—, wherein R 13 is C 1-4 alkyl;
A is —CHR 2 C(O)—;
Y is —NR 6 R 7 ;
R 1 is —H or methyl;
R 2 is —H, methyl or hydroxymethyl;
Z is a single bond;
each of R 6 and R 7 is independently selected from —H, C 1-8 alkyl, C 1-4 fluoroalkyl, and C 1-4 hydroxyalkyl, wherein alkyl may optionally be substituted with one or more independently selected R 8 ;
each R 8 is independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, —Z—NR 10 R 11 , —Z—C(═O)—NR 10 R 11 , —Z—OR 9 , halogen, and —Z—COOR 9 ; and
each R 9 is independently selected from —H and C 1-8 alkyl; and
each R 10 and R 11 is independently selected from —H and C 1-6 alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 13 is selected from methyl, ethyl, and propyl.
3. The compound of claim 1 , wherein Y is
wherein n is from 1 to 3.
4. The compound of claim 3 , wherein Y is
wherein n is from 1 to 3 and each m independently is from 0 to 2.
5. A compound having the structure
or a pharmaceutically acceptable salt thereof.
6. A compound having the structure
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising at least one compound as defined in claim 1 and one or more pharmaceutically acceptable excipients, diluents or carriers.
8. The pharmaceutical composition of claim 7 , comprising one or more further active substances.
9. The compound of claim 1 , wherein R 13 is selected from the group consisting of methyl, ethyl, propyl, and butyl.
10. The compound of claim 1 , wherein R 13 is methyl.
11. The compound of claim 1 , wherein R 13 is ethyl.
12. The compound of claim 1 , wherein R 1 is —H and R 2 is —H.
13. The compound of claim 1 , wherein each of R 6 and R 7 is independently C 1-8 alkyl optionally substituted with one or more independently selected R 8 .
14. The compound of claim 1 , wherein each R 8 is independently —Z—NR 10 R 11 and each R 10 and R 11 is independently C 1-6 alkyl.
15. The pharmaceutically acceptable salt of the compound of claim 6 , wherein the pharmaceutically acceptable salt is selected from a succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, trifluoroacetic, malic, lactic, formic, propionic, glycolic, gluconic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic, benzenesulfonic, p-toluenesulfonic, oxalic, methanesulfonic and naphthalenesulfonic acid salt.
16. The pharmaceutically acceptable salt of claim 15 , wherein the pharmaceutically acceptable salt is the oxalic acid salt.
17. The pharmaceutically acceptable salt of the compound of claim 5 , wherein the pharmaceutically acceptable salt is selected from a succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, trifluoroacetic, malic, lactic, formic, propionic, glycolic, gluconic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic, benzenesulfonic, p-toluenesulfonic, oxalic, methanesulfonic and naphthalenesulfonic acid salt.
18. The pharmaceutically acceptable salt of claim 17 , wherein the pharmaceutically acceptable salt is the oxalic acid salt.
19. A pharmaceutical composition comprising a compound having the structure:
or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising a compound having the structure:
or a pharmaceutically acceptable salt thereof.