Modulators of methyl modifying enzymes, compositions and uses thereof

1. A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Z is ═C(R 2 )—;

each of X 1 , X 2 and X 3 is ═C(R 3 )—;

X 4 is ═C(R 3 )—;

X 5 is ═C—;

each R 1 CH 3 ;

R 2 is hydrogen;

each R 3 is independently selected from hydrogen, halo, —OH, —CN, C 1 -C 4 alkyl, C 2 -C 4 alkenyl or alkynyl, —O—(C 1 -C 4 alkyl), N(R 7 ) 2 , —(C 0 -C 4 alkylene)-aryl, —(C 0 -C 4 alkylene)-heteroaryl, —(C 0 -C 4 alkylene)-heterocyclyl, —(C 0 -C 4 alkylene)-carbocyclyl, —O—(C 0 -C 4 alkylene)-aryl, —O—(C 0 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-heterocyclyl, —O—(C 0 -C 4 alkylene)-carbocyclyl, —C(O)OR 9 , —C(O)N(R 9 ) 2 , —S(O)R 8 , —S(O) 2 R 8 and —S(O) 2 N(R 9 ) 2 ;

R 4 —H is selected from hydrogen and —CH 3 ;

R 5 —H is selected from —CH 3 , —CH(CH 3 ) 2 , —(CH 2 ) 2 CH 3 , —CH 2 CH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCH 3 , —OCH 2 CH(CH 3 ) 2 , —OH, —CH 2 OH, —(CH 2 ) 2 OH, —(CH 2 ) 2 —O—CH 3 , —NH—C(═O)—CH 3 , —(CH 2 ) 2 —NH—CH 3 , —(CH 2 ) 2 —NH—C(═O)—CH 3 , —CH 2 —C(═O)NH 2 , —NH—S(═O) 2 —CH 3 , and —NH—C(═O)—NH—CH 3 ;

R 5 is taken together with X 4 , and the intervening atoms to form an optionally substituted heterocyclyl selected from:

 wherein:

the heterocyclyl is optionally substituted with one or more substituents independently selected from —CH 3 —CH 2 CH 3 , and phenyl;

 represents a point of attachment to X 1 ; and

 represents a point of attachment to X 3 ;

R 6 is hydrogen or methyl;

each R 7 is independently selected from hydrogen, —(C 0— C 4 alkylene)-R 9 , —(C 2 -C 4 alkylene)-O—R 9 , C 2 -C 4 haloalkyl, —S(O) 2 —R 8 , —C(═O)—R 8 , —C(═O)—N(R 9 )(R 9 ), —(C 2 -C 4 alkylene)-O—C(═O)—R 8 and —(C 0 -C 4 alkylene)-C(═O)—O—R 9 ; or

two R 7 are taken together with the nitrogen atom to which they are commonly bound to form an optionally substituted heterocyclyl or heteroaryl;

R 8 is selected from C 1 -C 4 alkyl, aryl, heteroaryl, carbocyclyl and heterocyclyl;

each R 9 is independently selected from hydrogen and R 8 ;

represents a double bond;

wherein unless otherwise designated any alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, aryl, heteroaryl, heterocyclyl or carbocyclyl portion of the compound is optionally substituted;

wherein:

when each of X 1 , X 2 , X 3 and X 4 is ═C(H)—, X 5 is ═C— and each of R 4 and R 6 is hydrogen, then R 5 is other than —NH—C(═O)—(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —C 1 -C 4 straight alkyl, —O—CH 2 —CF 3 , or —OCH 3 ;

when each of X 1 , X 2 , X 3 and X 4 is ═C(H)—, X 5 is ═C— and R 4 is —CH 3 , then R 5 is other than —CH 3 ; and

the compound is other than:

2. The compound of claim 1 , wherein each R 3 is independently selected from hydrogen, halo, C 1 -C 4 alkyl and —O-phenyl.

3. The compound of claim 2 , wherein each R 3 is independently selected from hydrogen, chloro, —CH 3 and —O-phenyl.

4. The compound of claim 1 , wherein —R 5 —H is selected from —CH 3 , —CH(CH 3 ) 2 , —(CH 2 ) 2 CH 3 , —CH 2 CH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCH 3 , and —OCH 2 CH(CH 3 ) 2 .

5. The compound of claim 1 , wherein

R 6 is hydrogen.

6. A pharmaceutically acceptable composition comprising:

a) the compound of claim 1 ; and

b) a pharmaceutically acceptable carrier.

7. A compound selected from:

N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(pentan-2-yl)benzamide;

N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-isopropyl-2-methylbenzamide;

2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-isopropyl benzamide;

N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(2-hydroxypropan-2-yl)benzamide;

N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(2-methoxypropan-2-yl)benzamide;

N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-methoxyethyl)benzamide;

N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-isopropoxyethyl)benzamide;

4-(1-ethoxyethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide;

N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-isobutoxyethyl)benzamide;

N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(3-methylbutan-2-yl)benzamide;

N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-isopropyl-3-phenoxy benzamide;

N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-3-methyl-2,3-dihydrobenzofuran-6-carboxamide;

N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(pentan-2-yl)benzamide;

4-(1-acetamidoethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide;

N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(4-methoxybutan-2-yl)benzamide;

4-(4-acetamidobutan-2-yl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide; and

N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(4-hydroxybutan-2-yl)benzamide; or

a pharmaceutically acceptable salt thereof.