COMPOUNDS, COMPOSITIONS AND METHODS FOR HISTONE LYSINE DEMETHYLASE INHIBITION

1 . A compound of formula I:

or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:

one of W or X is N and the other of W and X is CR 4 ; or W and X are CR 4 ;

R 1 is hydrogen, —P(O)(OR 20 ) 2 , —CH 2 P(O)(OR 20 ) 2 , —P(O)(R 20 )(OR 20 ), —CH 2 P(O)(R 20 )(OR 20 ), —P(O)(N(R 20 ) 2 )(OR 20 ), —CH 2 P(O)(N(R 20 ) 2 )(OR 20 ), —P(O)(R 20 )(N(R 20 ) 2 ), —CH 2 P(O)(R 20 )(N(R 20 ) 2 ), —C(O)R 20 , —C(O)N(R 2 )(R 22 ), —CH 2 P(O)(N(R 20 ) 2 ) 2 , or —P(O)(N(R 20 ) 2 ) 2 ;

R 2 is —OH, —OCH 2 P(O)(OR 20 ) 2 , —OCH 2 P(O)(R 20 )(N(R 20 ) 2 ), —OCH 2 P(O)(R 20 )(OR 20 ), —OCH 2 P(O)(N(R 20 ) 2 )(OR 20 ), —OCH 2 P(O)(N(R 20 ) 2 ) 2 , —N(R 21 )(R 22 ), —N(R 20 )C(O)R 20 , —N(R 20 )C(O)OR 20 , —N(R 20 )C(O)N(R 21 )(R 21 ), —N(R 20 )S(O) 2 (R 20 ), —NR 20 S(O) 2 N(R 2 )(R 22 ), or —NR 20 S(O) 2 O(R 20 )

R 3 is halo, cyano, or C 1-6 haloalkyl;

each R 4 is independently hydrogen, halo, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl of R 4 is independently optionally substituted with 1-5 R 14 ;

R 5 is halo, cyano, -L-C 1-6 alkyl, -L-C 1-6 haloalkyl, -L-C 3-10 cycloalkyl, -L-C 3-10 cycloalkenyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl of R 5 is independently optionally substituted with 1-5 R 15 ;

L is a bond, —C 1-6 alkylene, —C 1-6 heteroalkylene, —O—, —S—, —S(O)—, —S(O) 2 —, —NR 16 —, —C(O)NR 16 —, —NR 16 C(O)—, —OC(O)—, or —C(O)O—;

each of R 6 , R 7 , R 8 , and R 9 are independently hydrogen, deuterium, C 1-6 alkyl, or C 1-6 haloalkyl;

each of R 14 and R 15 are independently hydroxy, halo, cyano, —NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, heterocyclyl, —N(R 16 ) 2 , —C(O)R 16 , —C(O)OR 16 , —S—R 16 , S(O)R 16 , —NR 16 S(O)R 16 , —S(O)N(R 16 ) 2 , —NR 16 S(O)N(R 16 ) 2 , —S(O) 2 R 16 , —NR 16 S(O) 2 —R 16 , —S(O) 2 N(R 16 ) 2 , —NR 16 S(O) 2 N(R 16 ) 2 , —NR 16 C(O)N(R 16 ) 2 , —C(O)N(R 16 ) 2 , —NR 16 C(O)R 16 , —OC(O)N(R 16 ) 2 , or —NR 16 C(O)OR 16 ;

each R 16 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R 16 is independently optionally substituted with 1-5 halo, cyano, —NO 2 , oxo, —SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl;

each R 20 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently optionally substituted with 1-5 R 30 ;

each R 21 and R 22 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently optionally substituted with 1-5 R 30 groups, or R 20 and R 21 together with the nitrogen to which they are attached form a heterocyclyl; wherein said heterocyclyl is independently optionally substituted with 1-5 R 30 ;

each R 30 is independently oxo, thioxo, hydroxy, halo, —NO 2 , —N 3 , cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-6 haloalkyl, aryl, heteroaryl, heterocyclyl, —O(C 1-6 alkyl), —O(C 2-6 alkenyl), —O(C 2-6 alkynyl), —O(C 3-10 cycloalkyl), —O(C 1-6 haloalkyl), —O(aryl), —O(heteroaryl), —O(heterocyclyl), —NH 2 , —NH(C 1-6 alkyl), —NH(C 2-6 alkenyl), —NH(C 2-6 alkynyl), —NH(C 3-10 cycloalkyl), —NH(C 1-6 haloalkyl), —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C 1-6 alkyl) 2 , —N(C 3-10 cycloalkyl) 2 , —N(C 2-6 alkenyl) 2 , —N(C 2-6 alkynyl) 2 , —N(C 3-10 cycloalkyl) 2 , —N(C 1-6 haloalkyl) 2 , —N(aryl) 2 , —N(heteroaryl) 2 , —N(heterocyclyl) 2 , —N(C 1-6 alkyl)(C 3-10 cycloalkyl), —N(C 1-6 alkyl)(C 2-6 alkenyl), —N(C 1-6 alkyl)(C 2-6 alkynyl), —N(C 1-6 alkyl)(C 3-10 cycloalkyl), —N(C 1-6 alkyl)(C 1-6 haloalkyl), —N(C 1-6 alkyl)(aryl), —N(C 1-6 alkyl)(heteroaryl), —N(C 1-6 alkyl)(heterocyclyl), —C(O)(C 1-6 alkyl), —C(O)(C 2-6 alkenyl), —C(O)(C 2-6 alkynyl), —C(O)(C 3-10 cycloalkyl), —C(O)(C 1-6 haloalkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl), —C(O)O(C 1-6 alkyl), —C(O)O(C 2-6 alkenyl), —C(O)O(C 2-6 alkynyl), —C(O)O(C 3-10 cycloalkyl), —C(O)O(C 1-6 haloalkyl), —C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)NH(C 2-6 alkenyl), —C(O)NH(C 2-6 alkynyl), —C(O)NH(C 3-10 cycloalkyl), —C(O)NH(C 1-6 haloalkyl), —C(O)NH(aryl), —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C 1-6 alkyl) 2 , —C(O)N(C 3-10 cycloalkyl) 2 , —C(O)N(C 2-6 alkenyl) 2 , —C(O)N(C 2-6 alkynyl) 2 , —C(O)N(C 3-10 cycloalkyl) 2 , —C(O)N(C 1-6 haloalkyl) 2 , —C(O)N(aryl) 2 , —C(O)N(heteroaryl) 2 , —C(O)N(heterocyclyl) 2 , —NHC(O)(C 1-6 alkyl), —NHC(O)(C 2-6 alkenyl), —NHC(O)(C 2-6 alkynyl), —NHC(O)(C 3-10 cycloalkyl), —NHC(O)(C 1-6 haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C 1-6 alkyl), —NHC(O)O(C 2-6 alkenyl), —NHC(O)O(C 2-6 alkynyl), —NHC(O)O(C 3-10 cycloalkyl), —NHC(O)O(C 1-6 haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C 1-6 alkyl), —NHC(O)NH(C 2-6 alkenyl), —NHC(O)NH(C 2-6 alkynyl), —NHC(O)NH(C 3-10 cycloalkyl), —NHC(O)NH(C 1-6 haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl), —NHC(O)NH(heterocyclyl), —SH, —S(C 1-6 alkyl), —S(C 2-6 alkenyl), —S(C 2-6 alkynyl), —S(C 3-10 cycloalkyl), —S(C 1-6 haloalkyl), —S(aryl), —S(heteroaryl), —S(heterocyclyl), —NHS(O)(C 1-6 alkyl), —N(C 1-6 alkyl)(S(O)(C 1-6 alkyl), —S(O)N(C 1-6 alkyl) 2 , —S(O)(C 1-6 alkyl), —S(O)(NH)(C 1-6 alkyl), —S(O)(C 2-6 alkenyl), —S(O)(C 2-6 alkynyl), —S(O)(C 3-10 cycloalkyl), —S(O)(C 1-6 haloalkyl), —S(O)(aryl), —S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O) 2 (C 1-6 alkyl), —S(O) 2 (C 2-6 alkenyl), —S(O) 2 (C 2-6 alkynyl), —S(O) 2 (C 3-10 cycloalkyl), —S(O) 2 (C 1-6 haloalkyl), —S(O) 2 (aryl), —S(O) 2 (heteroaryl), —S(O) 2 (heterocyclyl), —S(O) 2 NH(C 1-6 alkyl), or —S(O) 2 N(C 1-6 alkyl) 2 ; wherein each alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R 30 is optionally substituted with one to four halo, C 1-6 alkyl, C 1-6 haloalkyl, —OH, —NH 2 , —NH(C 1-6 alkyl), —NH(C 3-10 cycloalkyl), —NH(C 1-6 haloalkyl), —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C 1-6 alkyl) 2 , —N(C 3-10 cycloalkyl) 2 , —NHC(O)(C 3-10 cycloalkyl), —NHC(O)(C 1-6 haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C 1-6 alkyl), —NHC(O)O(C 2-6 alkynyl), —NHC(O)O(C 3-10 cycloalkyl), —NHC(O)O(C 1-6 haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C 1-6 alkyl), —S(O)(NH)(C 1-6 alkyl), S(O) 2 (C 1-6 alkyl), —S(O) 2 (C 3-10 cycloalkyl), —S(O) 2 (C 1-6 haloalkyl), —S(O) 2 (aryl), —S(O) 2 (heteroaryl), —S(O) 2 (heterocyclyl), —S(O) 2 NH(C 1-6 alkyl), —S(O) 2 N(C 1-6 alkyl) 2 , —O(C 3-10 cycloalkyl), —O(C 1-6 haloalkyl), —O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C 1-6 alkyl);

provided that:

when W and X are both CH, then R 5 and R 3 are not both halo; and

the compound is not 3-bromo-2-hydroxy-5-methoxy-y-oxo-benzenebutanoic acid.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, represented by formula II:

3 . The compound of claim 1 , wherein X is N and W is CR 4 .

4 . The compound of claim 1 , wherein W is N and X is CR 4 .

5 . The compound of claim 1 , wherein X is N and W is CH.

6 . The compound of claim 1 , wherein W is N and X is CH.

7 . The compound of claim 1 , wherein W and X are CH.

8 . The compound of claim 1 , or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, represented by formula III:

9 . The compound of claim 1 , wherein R 6 , R 7 , R 8 , and R 9 are hydrogen.

10 . The compound of claim 1 , or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, represented by formula IV:

11 . The compound of claim 1 , or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, represented by formula V:

12 . The compound of claim 1 , wherein R 1 is H.

13 . The compound of claim 1 , wherein R 2 is —OH.

14 . The compound of claim 1 , wherein R 5 is -L-C 3-10 cycloalkyl, -L-C 3-10 cycloalkenyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl of R 5 is optionally substituted with 1-3 R 5 .

15 . The compound of claim 1 , wherein R 5 is -L-aryl or -L-heteroaryl; wherein each aryl and heteroaryl of R is optionally substituted with 1-3 R 5 .

16 . The compound of claim 1 , wherein L is a bond, —C 1-5 alkylene, —C 1-5 heteroalkylene, —O—, —S—, —NR 16 —, or —C(O)NR 16 —; or L is a bond, —C 1-5 alkylene, —C 1-5 heteroalkylene, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)NR 16 —, —NR 16 C(O)—, —OC(O)—, or —C(O)O—.

17 . The compound of claim 1 , wherein L is a bond, methylene, or —O—.

18 . The compound according to claim 1 , wherein R 5 is bromo, cyano, —CF 3 , —S—CH 3 , methyl, phenyl, —O—CH 3 , benzyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-methoxy-phenyl, phenethyl, 1-methyl-1H-pyrazol-4-yl, 4-chloro-benzyl, 3-chloro-benzyl, 4-fluoro-phenyl, 3-fluoro-phenyl, 2-chloro-benzyl, 4-chloro-phenyl, 3-chloro-phenyl, naphthalen-2-ylmethyl, cyclohexyl, 4-trifluoromethyl-phenyl, 4-methoxy-benzyl, 3-trifluoromethyl-phenyl, 3-trifluoromethyl-benzyl, 2-chloro-6-fluoro-benzyl, 3,5-dichloro-benzyl, 2,6-dichloro-benzyl, cyclohexylmethyl, naphthalen-1-ylmethyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl, 4-trifluoromethyl-benzyl, 4-fluoro-benzyl, 2-trifluoromethyl-benzyl, 3-fluoro-benzyl, 2-fluoro-benzyl, 4-cyano-benzyl, 3-cyano-benzyl, 2-cyano-benzyl, 4-trifluoromethoxy-benzyl, 3-trifluoromethoxy-benzyl, 2-trifluoromethoxy-benzyl, biphenyl-4-ylmethyl, biphenyl-3-ylmethyl, biphenyl-2-ylmethyl, 2,6-difluoro-benzyl, 2,6-dimethyl-benzyl, 2,4,6-trifluoro-benzyl, 3-chloro-2,6-difluoro-benzyl, 2,3,6-trifluoro-benzyl, 2-chloro-6-cyano-benzyl, 2-chloro-6-trifluoromethyl-benzyl, 2-fluoro-6-trifluoromethyl-benzyl, 2-methoxy-6-trifluoromethyl-benzyl, 2-methyl-6-trifluoromethyl-benzyl, 2,5-dichloro-benzyl, 2,4-dichloro-benzyl, 2,3-dichloro-benzyl, 3-trifluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, naphthalen-1-yl, 2-fluoro-phenyl, 2-chloro-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, biphenyl-3-yl, biphenyl-4-yl, phenoxy, naphthalen-2-yl, phenylsulfanyl, 4-fluoro-phenoxy, 3-fluoro-2-methyl-phenyl, 2-chloro-4-methoxy-phenyl, 5-fluoro-2-methyl-phenyl, 2-chloro-4-fluoro-phenyl, 2-chloro-4-methyl-phenyl, 2-ethyl-phenyl, 4-fluoro-2-methyl-phenyl, 2-cyano-4-fluoro-phenyl, 2-fluoro-6-methyl-phenyl, 3-chloro-2-methyl-phenyl, 4-chloro-2-methyl-phenyl, 5-chloro-2-methyl-phenyl, 2,3-dimethyl-phenyl, 2,4-dimethyl-phenyl, 2,5-dimethyl-phenyl, 2-methyl-3-trifluoromethyl-phenyl, 2-methyl-4-trifluoromethyl-phenyl, 2-methyl-5-trifluoromethyl-phenyl, 3-cyano-2-methyl-phenyl, 4-cyano-2-methyl-phenyl, 5-cyano-2-methyl-phenyl, 2-chloro-3-methyl-phenyl, 2-chloro-5-methyl-phenyl, 2-chloro-3-trifluoromethyl-phenyl, 2-cyano-5-trifluoromethyl-phenyl, 2-chloro-5-methoxy-phenyl, 2-chloro-3-fluoro-phenyl, 2-chloro-5-fluoro-phenyl, 4-fluoro-naphthalen-1-yl, 4-chloro-naphthalen-1-yl, 4-phenyl-naphthalen-1-yl, quinolin-5-yl, 4-methyl-naphthalen-1-yl, 2-chloro-3-methoxy-phenyl, 2-chloro-4-trifluoromethyl-phenyl, quinolin-8-yl, 2-chloro-phenyl, 2-chloro-6-methyl-benzyl, 2,4,6-trimethyl-benzyl, 2-chloro-6-methoxy-benzyl, 2,6-dichloro-4-fluoro-benzyl, 2,6-dichloro-4-methyl-benzyl, 2,4,6-trichloro-benzyl, 2,6-dichloro-3-fluoro-benzyl, 2-chloro-phenoxy, 4-chloro-phenoxy, 3-chloro-phenoxy, p-tolyloxy-phenyl, o-tolyloxy-phenyl, 4-methoxy-phenoxy, 2,6-dichloro-4-trifluoromethoxy-benzyl, 2,6-dichloro-4-trifluoromethyl-benzyl, 2-benzyl-benzyl, 2,6-dichloro-4-methoxy-benzyl, 2-fluoro-6-methyl-benzyl, 2,6-dichloro-3-fluoro-benzyl, 2-fluoro-6-methoxy-benzyl, 4-fluoro-2,6-dimethyl-benzyl, 4-chloro-2,6-dimethyl-benzyl, 4-cyano-2,6-dimethyl-benzyl, 3,5-dimethyl-isoxazol-4-ylmethyl, 2,6-dichloro-3-methyl-benzyl, 2,3,6-trichloro-benzyl, benzoylamino, benzoyl-methyl-amino, (2,6-dimethyl-benzoyl)-methyl-amino, 2,6-dimethyl-benzoylamino, or 2,6-dichloro-benzoylamino.

19 . The compound of claim 1 , wherein:

one of W or X is N and the other of W and X is CR 4 ;

R 1 is H;

R 2 is H;

R 3 is halo, cyano, C 1-6 alkyl, or C 1-6 haloalkyl;

R 5 is -L- 3-10 cycloalkyl, -L-C 3-10 cycloalkenyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl of R 5 is optionally substituted with 1-3 R 15 ;

each of R 6 , R 7 , R 8 , and R 9 is hydrogen; and

L is a bond, —C 1-5 alkylene, —C 1-5 heteroalkylene, —O—, —S—, —NR 16 —, or —C(O)NR 16 —.

20 . The compound of claim 1 , wherein:

X is N and W is CR 4 ;

R 1 is H;

R 2 is H;

R 3 is halo, cyano, C 1-6 alkyl, or C 1-6 haloalkyl;

R 5 is -L-C 3-10 cycloalkyl, -L-C 3-10 cycloalkenyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl of R 5 is optionally substituted with 1-3 R 15 ;

each of R 6 , R 7 , R 8 , and R 9 is hydrogen; and

L is a bond, —C 1-5 alkylene, —C 1-5 heteroalkylene, —O—, —S—, —NR 16 —, or —C(O)NR 16 —.

21 . The compound of claim 1 , wherein:

X is N and W is CH;

R 1 is H;

R 2 is H;

R 3 is halo, cyano, methyl, or —CF 3 ;

R 5 is -L-C 3-10 cycloalkyl, -L-C 3-10 cycloalkenyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl of R 5 is optionally substituted with 1-3 R 15 ;

each of R 6 , R 7 , R 8 , and R 9 is hydrogen; and

L is a bond, methylene, or —O—.

22 . The compound of claim 1 , wherein:

X and W are CH;

R 1 is H;

R 2 is H;

R 3 is halo, cyano, methyl, or —CF 3 ;

R 5 is -L-C 3-10 cycloalkyl, -L-C 3-10 cycloalkenyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl of R 5 is optionally substituted with 1-3 R 15 ;

each of R 6 , R 7 , R 8 , and R 9 is hydrogen; and

L is a bond, methylene, or —O—.

23 . A compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, selected from:

24 . A pharmaceutical composition comprising one or more compounds of claim 1 and a pharmaceutically acceptable excipient.

25 . The pharmaceutical composition of claim 24 , further comprising at least one additional therapeutic agent.

26 . A method of inhibiting the activity of histone lysine demethylase, the method comprising bringing into contact histone lysine demethylase and an inhibitory-effective amount of a pharmaceutical composition of claim 24 .

27 - 40 . (canceled)