Compounds and methods for inhibiting histone demethylases

1. A compound being of Formula (I):

wherein:

Q is selected from CO 2 H, CO 2 R 20 , —CH═NR 12 , —W, —CH 2 NHR 13 , —CH═O and —CH(OR 17 ) 2 ;

M is CH or N;

A is selected from —C(R 2 ) 2 C(O)—, —C(R 2 ) 2 C(R 2 ) 2 C(O)—, C 3-10 alkyl, —Z—C 3-10 cycloalkylene, —Z-heterocyclylene, —Z-heteroarylene and —Z-arylene, wherein the C 3-10 alkyl, —Z-cycloalkylene, —Z-heterocyclylene, —Z-heteroarylene and —Z-arylene are optionally substituted with one or more R 3 , or A and Y form a C 3-10 cycloalkyl or heterocyclic ring;

Y is selected from —H, —NR 6 R 7 , —OR 7 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more R 3 ;

R 1 is selected from —H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents selected from —OH, aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —NR 6 R 7 , —F and C 3-6 cycloalkyl; or R 1 , together with A-Y and the nitrogen atom to which it is attached, forms a nitrogen-containing heterocyclic ring optionally substituted with one or more substituents independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents independently selected from —OH, aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —NR 6 R 7 , —F and C 3-6 cycloalkyl; or R 1 and R 18 , together with the atoms to which they are attached, form a nitrogen-containing heterocyclic ring optionally substituted with one or more substituents independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents independently selected from —OH, aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —NR 6 R 7 , —F and C 3-6 cycloalkyl;

Each R 2 is independently selected from —H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents independently selected from —OH, aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —F, C 3-6 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—OR 7 , halogen, —Z—SR 7 , —Z—SOR 7 , —Z—SO 2 R 7 , —Z—SO 2 NR 6 R 7 and —Z—COOR 7 ; or two R 2 substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a C 4-10 cycloalkyl or heterocyclic ring; or two R 2 substituents on the same carbon atom, together with the carbon atom to which they are attached, form a C 3-10 cycloalkyl or heterocyclic ring; or R 2 and Y, together with the carbon atoms to which they are attached, form a C 4-10 cycloalkyl or heterocyclic ring;

each R 3 is independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—OR 7 , halogen, —Z—SR 7 , —Z—SOR 7 , —Z—SO 2 R 7 , —Z—SO 2 NR 6 R 7 and —Z—COOR 7 , wherein the heterocyclyl is optionally substituted with one or more R 4 , and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 ; or two R 3 on the same carbon atom may, together with the carbon atom to which they are attached, form a C 3-10 cycloalkyl or heterocyclic ring;

Z is selected from a single bond, C 1-4 alkylene, heterocyclylene and C 3-6 cycloalkylene;

each R 4 is independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 3-10 cycloalkyl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—C(═O)—H, —OR 7 , halogen, —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 6 R 7 , and —COOR 7 ;

each R 5 is independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, —CN, —F, —Cl, —Br, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—C(═O)—H, —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 6 R 7 , and —COOR 7 ;

each R 6 and R 7 is independently selected from —H, C 1-8 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-heteroaryl and —Z-aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more R 8 ; or R 6 and R 7 may, together with the N-atom to which they are attached, form a heterocyclic ring optionally substituted with one or more R 8 ;

each R 8 is independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-heteroaryl, —Z-aryl, —Z—NR 10 R 11 , —Z—C(═O)—NR 10 R 11 , —Z—OR 9 , halogen, —CN, —Z—SR 9 , —Z—SOR 9 , —Z—SO 2 R 9 and —Z—COOR 9 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more substituents independently selected from C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, —Z-heterocyclyl, —Z-heteroaryl, —Z-aryl, —Z—NR 10 R 11 , —Z—C(═O)—NR 10 R 11 , —Z—OR 9 , halogen, —CN, —Z—SR 9 , —Z—SOR 9 , —Z—SO 2 R 9 and —Z—COOR 9 ; wherein the heterocyclyl is optionally substituted with one or more R 4 and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 ;

each R 9 is independently selected from —H, C 1-8 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, and —Z-heteroaryl, wherein the heterocyclyl is optionally substituted with one or more R 4 and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 ;

each of R 10 and R 11 is independently selected from —H, C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, heterocyclyl, heteroaryl, and C 6-14 aryl, wherein the heterocyclyl is optionally substituted with one or more R 4 and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 ; or R 10 and R 11 may, together with the N-atom to which they are attached, form a 5- to 7-membered heterocyclic ring optionally substituted with one or more R 4 ;

when Q is —CH═NR 12 , R 12 is selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—OR 7 , —Z—SR 7 , —Z—SOR 7 , —Z—SO 2 R 7 and —Z—COOR 7 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more R 3 ;

when Q is —CH 2 NHR 13 , R 13 is selected from —H, —C(O)R 7 , —C(O)C(O)R 7 , —C(O)C(O)OR 7 , C 1-8 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, —Z—heterocyclyl, and —Z-monocyclic-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with one or more R 8 ; or R 13 is —CR 14 R 15 NR 6 R 7 , —CR 14 R 15 CN, or —CR 14 R 15 OR 7 , wherein each R 14 and R 15 is independently selected from —H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, heterocyclyl, heteroaryl, and C 6-14 aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more R 3 ; or wherein R 14 and R 15 together with the intervening carbon atom form a C 3-10 cycloalkyl or C 5-10 -cycloalkenyl ring optionally substituted with one or more R 3 ;

when Q is W, W is selected from a 1,3-diazacycloalk-2-yl group which is N-substituted with R 16 , optionally further substituted with one or more R 3 , and optionally containing one or two oxo groups; a 1,3-thiazacycloalk-2-yl group which is N-substituted with R 16 , optionally further substituted with one or more R 3 and optionally containing one or two oxo groups; and a 1,3-oxazacycloalk-2-yl group which is N-substituted with R 16 , optionally further substituted with one or more R 3 , and optionally containing one or two oxo groups, wherein in all three instances two R 3 on the same carbon atom may, together with the carbon atom to which they are attached, form a C 3-10 cycloalkyl or heterocyclic ring;

R 16 is selected from —H, —C(O)R 7 , —C(O)C(O)R 7 and —C(O)C(O)OR 7 ;

when Q is —CH(OR 17 ) 2 , each R 17 independently is R 3 ; or wherein two R 17 together with the intervening —O—CH—O— form a heterocyclic ring optionally substituted with one or more R 3 and optionally containing one to two oxo groups;

R 18 is selected from —H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 hydroxyalkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 3-7 oxyalkyl; or R 18 and A, together with the atoms to which they are attached, form a heterocyclic ring; or R 18 and Y, together with the atoms to which they are attached, form a heterocyclic ring; or R 18 and R 1 , together with the atoms to which they are attached, form a heterocyclic ring;

R 19 is selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents independently selected from aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, C 3-6 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—OR 7 , halogen, —Z—SR 7 , —Z—SOR 7 , —Z—SO 2 R 7 , —Z—SO 2 NR 6 R 7 and —Z—COOR 7 ; and may optionally form a cyclophane structure by attaching to Y or A; and

when Q is CO 2 R 20 , R 20 is selected from C 1-8 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, and —Z-heteroaryl, wherein the C 1-8 alkyl, C 3-10 cycloalkyl and heterocyclyl are optionally substituted with one or more R 4 , and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 as defined above;

or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1 , wherein A is selected from —Z-heterocyclylene, —Z-arylene, and —Z-heteroarylene.

3. The compound of claim 1 , wherein Y is —H or C 1-8 alkyl.

4. The compound claim 1 , wherein R 3 is —Z-aryl.

5. The compound claim 1 , wherein Z is a single bond or C 1-4 alkylene.

6. The compound claim 1 , wherein R 1 is —H.

7. The compound claim 1 , wherein R 1 is —H.

8. The compound claim 1 , wherein R 19 is C 1-8 alkyl optionally substituted with one —Z—OR 7 .

9. The compound of claim 1 , wherein Q is CO 2 H.

10. The compound of claim 1 being of Formula (II),

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

D is Z-heteroarylene optionally substituted with one to three R 23 ;

E is Z-aryl or Z-heteroaryl optionally substituted with one to three R 24 ;

each R 23 is independently selected from —H, —NR 6 R 7 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, C 5-10 heterocyclyl, C 5-14 heteroaryl and C 6-14 aryl;

each R 24 is independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, —CN, —F, —Cl, —Br, carbamoyl and —OH; and

n is 0 to 3.

11. The compound of claim 10 , wherein D is imidazolyl optionally substituted with one to three R 23 .

12. The compound of claim 10 , wherein D is pyridinyl optionally substituted with one to three R 23 .

13. The compound of claim 10 , wherein D is triazolyl optionally substituted with one to three R 23 .

14. The compound of claim 10 , wherein E is Z-aryl optionally substituted with one to three R 24 .

15. The compound of claim 10 , wherein R 19 is —CH 2 OH.

16. The compound of claim 10 , wherein R 19 is methyl.

17. The compound of claim 10 , wherein Q is CO 2 H.

18. The compound of claim 1 being of Formula (III),

or a pharmaceutically acceptable salt or solvate thereof, wherein:

Z is N or CR Z ;

R N , R C , and R Z are each independently selected from —H, C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—OR 7 , halogen, —Z—SR 7 , —Z—SOR 7 , —Z—SO 2 R 7 , —Z—SO 2 NR 6 R 7 and —Z—COOR 7 , wherein the heterocyclyl is optionally substituted with one or more R 4 , and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 ; and

n is 1 or 2.

19. The compound of claim 18 , wherein Q is CO 2 H.

20. The compound of claim 1 being of Formula (IV),

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 30 and R 31 are independently selected from —H, C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—OR 7 , halogen, —Z—SR 7 , —Z—SOR 7 , —Z—SO 2 R 7 , —Z—SO 2 NR 6 R 7 and —Z—COOR 7 , wherein the heterocyclyl is optionally substituted with one or more R 4 , and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 ; and

n is 1 or 2.

21. The compound of claim 20 , wherein Q is CO 2 H.

22. The compound of claim 1 being of Formula (V),

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 32 , R 33 , and R 34 are independently selected from —H, C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—OR 7 , halogen, —Z—SR 7 , —Z—SOR 7 , —Z—SO 2 R 7 , —Z—SO 2 NR 6 R 7 and —Z—COOR 7 , wherein the heterocyclyl is optionally substituted with one or more R 4 , and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 .

23. The compound of claim 22 , wherein Q is CO 2 H.

24. A compound being of Formula (VI):

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

M is CH or N;

A is selected from —C(R 2 ) 2 C(O)—, —C(R 2 ) 2 C(R 2 ) 2 C(O)—, C 3-10 alkyl, —Z—C 3-10 cycloalkylene, —Z-heterocyclylene, —Z-heteroarylene and —Z-arylene, wherein the C 3-10 alkyl, —Z-cycloalkylene, —Z-heterocyclylene, —Z-heteroarylene and —Z-arylene are optionally substituted with one or more R 3 , or A and Y form a C 3-10 cycloalkyl or heterocyclic ring;

Y is selected from —H, —NR 6 R 7 , —OR 7 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more R 3 ;

R 1 is selected from —H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents selected from —OH, aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —NR 6 R 7 , —F and C 3-6 cycloalkyl; or R 1 , together with A-Y and the nitrogen atom to which it is attached, forms a nitrogen-containing heterocyclic ring optionally substituted with one or more substituents independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents independently selected from —OH, aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —NR 6 R 7 , —F and C 3-6 cycloalkyl; or R 1 and R 18 , together with the atoms to which they are attached, form a nitrogen-containing heterocyclic ring optionally substituted with one or more substituents independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents independently selected from —OH, aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —NR 6 R 7 , —F and C 3-6 cycloalkyl;

Each R 2 is independently selected from —H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents independently selected from —OH, aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —F, C 3-6 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—OR 7 , halogen, —Z—SR 7 , —Z—SOR 7 , —Z—SO 2 R 7 , —Z—SO 2 NR 6 R 7 and —Z—COOR 7 ; or two R 2 substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a C 4-10 cycloalkyl or heterocyclic ring; or two R 2 substituents on the same carbon atom, together with the carbon atom to which they are attached, form a C 3-10 cycloalkyl or heterocyclic ring; or R 2 and Y, together with the carbon atoms to which they are attached, form a C 4-10 cycloalkyl or heterocyclic ring;

each R 3 is independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—OR 7 , halogen, —Z—SR 7 , —Z—SOR 7 , —Z—SO 2 R 7 , —Z—SO 2 NR 6 R 7 and —Z—COOR 7 , wherein the heterocyclyl is optionally substituted with one or more R 4 , and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 ; or two R 3 on the same carbon atom may, together with the carbon atom to which they are attached, form a C 3-10 cycloalkyl or heterocyclic ring;

Z is selected from a single bond, C 1-4 alkylene, heterocyclylene and C 3-6 cycloalkylene;

each R 4 is independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 3-10 cycloalkyl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—C(═O)—H,

—OR 7 , halogen, —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 6 R 7 , and —COOR 7 ;

each R 5 is independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, —CN, —F, —Cl, —Br, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—C(═O)—H, —OR 7 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 6 R 7 , and —COOR 7 ;

each R 6 and R 7 is independently selected from —H, C 1-8 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-heteroaryl and —Z—aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more R 8 ; or R 6 and R 7 may, together with the N-atom to which they are attached, form a heterocyclic ring optionally substituted with one or more R 8 ;

each R 8 is independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-heteroaryl, —Z-aryl, —Z—NR 10 R 11 , —Z—C(═O)—NR 10 R 11 , —Z—OR 9 , halogen, —CN, —Z—SR 9 , —Z—SOR 9 , —Z—SO 2 R 9 and —Z—COOR 9 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more substituents independently selected from C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, —Z-heterocyclyl, —Z-heteroaryl, —Z-aryl, —Z—NR 10 R 11 , —Z—C(═O)—NR 10 R 11 , —Z—OR 9 , halogen, —CN, —Z—SR 9 , —Z—SOR 9 , —Z—SO 2 R 9 and —Z—COOR 9 ; wherein the heterocyclyl is optionally substituted with one or more R 4 and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 ;

each R 9 is independently selected from —H, C 1-8 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, and —Z-heteroaryl, wherein the heterocyclyl is optionally substituted with one or more R 4 and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 ;

each of R 10 and R 11 is independently selected from —H, C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, heterocyclyl, heteroaryl, and C 6-14 aryl, wherein the heterocyclyl is optionally substituted with one or more R 4 and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 ; or R 10 and R 11 may, together with the N-atom to which they are attached, form a 5- to 7-membered heterocyclic ring optionally substituted with one or more R 4 ;

R 18 is selected from —H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 hydroxyalkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 3-7 oxyalkyl; or R 18 and A, together with the atoms to which they are attached, form a heterocyclic ring; or R 18 and Y, together with the atoms to which they are attached, form a heterocyclic ring; or R 18 and R 1 , together with the atoms to which they are attached, form a heterocyclic ring;

R 19 is selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents independently selected from aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, C 3-6 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—OR 7 , halogen, —Z—SR 7 , —Z—SOR 7 , —Z—SO 2 R 7 , —Z—SO 2 NR 6 R 7 and —Z—COOR 7 and may optionally form a cyclophane structure by attaching to Y or A; and

wherein:

R 21 is (R 22 ) 2 N— or R 22 O, wherein R 22 is C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, and aryloxy optionally substituted with one or more substituents independently selected from —OH, aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —F, a sulfonamide moiety, and C 3-6 cycloalkyl; wherein one R 22 in (R 22 ) 2 N—is optionally —H.

25. The compound of claim 24 , wherein:

M is CH;

A is selected from —Z-heterocyclylene, —Z-arylene, and —Z-heteroarylene;

Y is selected from —H and C 1-8 alkyl;

R 1 is H;

each R 3 is independently selected from —Z-heterocyclyl, —Z-aryl, and —Z-heteroaryl;

R 18 is H;

Z is selected from a single bond and C 1-4 alkylene; and

R 19 is methyl.

26. The compound of claim 24 , wherein:

M is CH;

A is selected from —Z-heterocyclylene, —Z-arylene, and —Z-heteroarylene;

Y is selected from —H and C 1-8 alkyl;

R 1 is H;

each R 3 is independently selected from —Z-heterocyclyl, —Z-aryl, and —Z-heteroaryl;

R 18 is H;

Z is selected from a single bond and C 1-4 alkylene; and

R 19 is —CH 2 OH.

27. The compound of claim 24 , wherein R 21 is (R 22 ) 2 N—.

28. The compound of claim 27 , wherein one R 22 is —H, and the other R 22 is C 1-8 alkyl or C 3-10 cycloalkyl.

29. The compound of claim 24 , wherein R 21 is R 22 O.

30. The compound of claim 29 , wherein R 22 is C 1-8 alkyl optionally substituted with one or more —F.

31. The compound of claim 1 being of Formula (IIIa),

or a pharmaceutically acceptable salt or solvate thereof.

32. The compound of claim 1 being of Formula (IIIb),

or a pharmaceutically acceptable salt or solvate thereof.

33. The compound of claim 1 being of Formula (IIIc),

or a pharmaceutically acceptable salt or solvate thereof.

34. The compound of claim 1 being of Formula (IIId),

or a pharmaceutically acceptable salt or solvate thereof.

35. The compound of claim 1 being of Formula (IIIe),

or a pharmaceutically acceptable salt or solvate thereof.

36. The compound of claim 1 being of Formula (IIIf),

or a pharmaceutically acceptable salt or solvate thereof.

37. The compound of claim 1 being of Formula (IIIg),

or a pharmaceutically acceptable salt or solvate thereof.

38. The compound of claim 1 , selected from any one of the following:

or a pharmaceutically acceptable salt or solvate thereof.

39. The compound of claim 1 , selected from any one of the following:

or a pharmaceutically acceptable salt or solvate thereof.

40. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and optionally one or more pharmaceutically acceptable excipients, diluents and/or carriers.

41. The pharmaceutical composition according to claim 40 , which comprises one or more further active substances.

42. A method of reversing, alleviating, or inhibiting the process of a HDME-dependent disease in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of at least one compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, to alleviate the symptoms of the HDME-dependent disease or to eliminate the HDME-dependent disease.

43. A method of inhibiting a HDME, comprising contacting a cell with a compound of claim 1 in an amount effective to produce a concentration sufficient to inhibit the demethylation of a histone in a cell.

44. The method of claim 43 , wherein the HDME is a member of the KDM7 family, PHF8 family, KDM6 family, KDM5 family, KDM4 family, or KDM2 family.

45. The method of claim 43 , wherein the HDME is KDM4C, KDM2B, PHF8, KDM6A, or KDM5B.

46. A pharmaceutical composition comprising at least one compound of claim 24 , or a pharmaceutically acceptable salt or solvate thereof, and optionally one or more pharmaceutically acceptable excipients, diluents and/or carriers.

47. A method of reversing, alleviating, or inhibiting the process of a HDME-dependent disease in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of at least one compound according to claim 24 , or a pharmaceutically acceptable salt or solvate thereof, to alleviate the symptoms of the HDME-dependent disease or to eliminate the HDME-dependent disease.