Compounds and methods for inhibiting histone demethylases

A compound being of Formula (I):

• wherein:
• Q is selected from CO2H, CO2R20, —CH═NR12, —W, —CH2NHR13, —CH═O and —CH(OR17)2;
• M is CH or N;
• A is selected from —C(R2)2C(O)—, —C(R2)2C(R2)2C(O)—, C3-10 alkyl, —Z—C3-10 cycloalkylene, —Z-heterocyclylene, —Z-heteroarylene and —Z-arylene, wherein the C3-10 alkyl, —Z-cycloalkylene, —Z-heterocyclylene, —Z-heteroarylene and —Z-arylene are optionally substituted with one or more R3, or A and Y form a C3-10 cycloalkyl or heterocyclic ring;
• Y is selected from —H, —NR6R7, —OR7, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more R3;
• R1 is selected from —H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, and C3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents selected from —OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —NR6R7, —F and C3-6 cycloalkyl;
• or R1, 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 C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, and C3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents independently selected from —OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —NR6R7, —F and C3-6 cycloalkyl;
• or R1 and R18, 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 C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, and C3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents independently selected from —OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —NR6R7, —F and C3-6 cycloalkyl;
• Each R2 is independently selected from —H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, and C3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents independently selected from —OH, aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —F, C3-6 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR6R7, —Z—C(═O)—NR6R7, —Z—NR6—C(═O)—R7, —Z—C(═O)—R7, —Z—OR7, halogen, —Z—SR7, —Z—SOR7, —Z—SO2R7, —Z—SO2NR6R7 and —Z—COOR7;
• or two R2 substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a C4-10 cycloalkyl or heterocyclic ring;
• or two R2 substituents on the same carbon atom, together with the carbon atom to which they are attached, form a C3-10 cycloalkyl or heterocyclic ring;
• or R2 and Y, together with the carbon atoms to which they are attached, form a C4-10 cycloalkyl or heterocyclic ring;
• each R3 is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR6R7, —Z—C(═O)—NR6R7, —Z—NR6—C(═O)—R7, —Z—C(═O)—R7, —Z—OR7, halogen, —Z—SR7, —Z—SOR7, —Z—SO2R7, —Z—SO2NR6R7 and —Z—COOR7, wherein the heterocyclyl is optionally substituted with one or more R4, and wherein the heteroaryl and aryl are optionally substituted with one or more R5;
• or two R3 on the same carbon atom may, together with the carbon atom to which they are attached, form a C3-10 cycloalkyl or heterocyclic ring;
• Z is selected from a single bond, C1-4 alkylene, heterocyclylene and C3-6 cycloalkylene;
• each R4 is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C3-10 cycloalkyl, —Z—NR6R7, —Z—C(═O)—NR6R7, —Z—NR6—C(═O)—R7, —Z—C(═O)—R7, —Z—C(═O)—H, —OR7, halogen, —SR7, —SOR7, —SO2R7, —SO2NR6R7, and —COOR7;
• each R5 is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C3-6 cycloalkyl, —CN, —F, —Cl, —Br, —Z—NR6R7, —Z—C(═O)—NR6R7, —Z—NR6—C(═O)—R7, —Z—C(═O)—R7, —Z—C(═O)—H, —SR7, —SOR7, —SO2R7, —SO2NR6R7, and —COOR7;
• each R6 and R7 is independently selected from —H, C1-8 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 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 R8;
• or R6 and R7 may, together with the N-atom to which they are attached, form a heterocyclic ring optionally substituted with one or more R8;
• each R8 is independently selected from C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, —Z-heterocyclyl, —Z-heteroaryl, —Z-aryl, —Z—NR10R11, —Z—C(═O)—NR10R11, —Z—OR9, halogen, —CN, —Z—SR9, —Z—SOR9, —Z—SO2R9 and —Z—COOR9, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more substituents independently selected from C1-4 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C3-6 cycloalkyl, —Z-heterocyclyl, —Z-heteroaryl, —Z-aryl, —Z—NR10R11, —Z—C(═O)—NR10R11, —Z—OR9, halogen, —CN, —Z—SR9, —Z—SOR9, —Z—SO2R9 and —Z—COOR9;
• wherein the heterocyclyl is optionally substituted with one or more R4 and wherein the heteroaryl and aryl are optionally substituted with one or more R5;
• each R9 is independently selected from —H, C1-8 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, and —Z-heteroaryl, wherein the heterocyclyl is optionally substituted with one or more R4 and wherein the heteroaryl and aryl are optionally substituted with one or more R5;
• each of R10 and R11 is independently selected from —H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and C6-14 aryl, wherein the heterocyclyl is optionally substituted with one or more R4 and wherein the heteroaryl and aryl are optionally substituted with one or more R5;
• or R10 and R11 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 R4;
• when Q is —CH═NR12, R12 is selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR6R7, —Z—C(═O)—NR6R7, —Z—NR6—C(═O)—R7, —Z—C(═O)—R7, —Z—OR7, —Z—SR7, —Z—SOR7, —Z—SO2R7 and —Z—COOR7, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more R3;
• when Q is —CH2NHR13, R13 is selected from —H, —C(O)R7, —C(O)C(O)R7, —C(O)C(O)OR7, C1-8 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, —Z—heterocyclyl, and —Z-monocyclic-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with one or more R8;
• or R13 is —CR14R15NR6R7, —CR14R15CN, or —CR14R15OR7, wherein each R14 and R15 is independently selected from —H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and C6-14 aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more R3;
• or wherein R14 and R15 together with the intervening carbon atom form a C3-10 cycloalkyl or C5-10-cycloalkenyl ring optionally substituted with one or more R3;
• when Q is W, W is selected from a 1,3-diazacycloalk-2-yl group which is N-substituted with R16, optionally further substituted with one or more R3, and optionally containing one or two oxo groups;
• a 1,3-thiazacycloalk-2-yl group which is N-substituted with R16, optionally further substituted with one or more R3 and optionally containing one or two oxo groups;
• and a 1,3-oxazacycloalk-2-yl group which is N-substituted with R16, optionally further substituted with one or more R3, and optionally containing one or two oxo groups, wherein in all three instances two R3 on the same carbon atom may, together with the carbon atom to which they are attached, form a C3-10 cycloalkyl or heterocyclic ring;
• R16 is selected from —H, —C(O)R7, —C(O)C(O)R7 and —C(O)C(O)OR7;
• when Q is —CH(OR17)2, each R17 independently is R3;
• or wherein two R17 together with the intervening —O—CH—O— form a heterocyclic ring optionally substituted with one or more R3 and optionally containing one to two oxo groups;
• R18 is selected from —H, C1-6 alkyl, C1-6 fluoroalkyl, C1-6 hydroxyalkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C3-7 oxyalkyl;
• or R18 and A, together with the atoms to which they are attached, form a heterocyclic ring;
• or R18 and Y, together with the atoms to which they are attached, form a heterocyclic ring;
• or R18 and R1, together with the atoms to which they are attached, form a heterocyclic ring;
• R19 is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, and C3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents independently selected from aryl, C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, C3-6 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR6R7, —Z—C(═O)—NR6R7, —Z—NR6—C(═O)—R7, —Z—C(═O)—R7, —Z—OR7, halogen, —Z—SR7, —Z—SOR7, —Z—SO2R7, —Z—SO2NR6R7 and —Z—COOR7;
• and may optionally form a cyclophane structure by attaching to Y or A;
• and
• when Q is CO2R20, R20 is selected from C1-8 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, and —Z-heteroaryl, wherein the C1-8 alkyl, C3-10 cycloalkyl and heterocyclyl are optionally substituted with one or more R4, and wherein the heteroaryl and aryl are optionally substituted with one or more R5 as defined above;
• or a pharmaceutically acceptable salt or solvate thereof.