INDUCTION OF GATA2 BY HDAC1 AND HDAC2 INHIBITORS

1 . A method for treating a disease or disorder associated with GATA binding protein 2 (Gata2) deficiency comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or any of the compounds presented in Table 1, Table 2, Table 3, or Table 4, or a pharmaceutically salt thereof.

2 . The method of claim 1 , wherein the disease or disorder is selected from the group consisting of: acute myeloid leukemia, familial myelodysplastic syndrome, leukemia, sickle-cell anemia, and beta-thalassemia.

3 . The method of claim 1 , wherein the compound has the chemical structure of Formula I:

or a pharmaceutically acceptable salt thereof,

wherein

Y 1 is CR 7 or NR 7 ;

Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are each independently CH, CH 2 , N, or C(O), wherein at least one of Y 2 , Y 3 , Y 4 , and Y 5 are CH;

R 1 is mono-, bi-, or tri-cyclic aryl or heteroaryl, wherein the mono-, bi-, or tri-cyclic aryl or heteroaryl is optionally substituted with one or more groups selected from halo, C 1-4 -alkyl, CO 2 R 6 , C(O)R 6 , or C 1-6 -alkyl-OR 6 ;

R 2 and R 3 are each independently selected from C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkyl-C 3-6 -cycloalkyl, heterocycloalkyl, C 1-6 -alkyl-heterocycloalkyl, NR 4 R 5 , O—C 1-6 -alkyl-OR 6 , C 1-6 -alkyl-OR 6 , aryl, heteroaryl, C(O)N(H)-heteroaryl, C(O)-heteroaryl, C(O)-heterocycloalkyl, C(O)-aryl, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, or C(O)—C 1-6 -alkyl-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally, independently substituted one or more times with C 1-4 -alkyl, CO 2 R 6 , C(O)R 6 , or C 1-6 -alkyl-OR 6 ;

R 4 is H, C 1-6 -alkyl, or C 1-6 -alkyl-OR 6 ;

R 5 is CO 2 R 6 , C 1 -C 6 -alkyl-aryl, or C 1-6 -alkyl-OR 6 ;

R 6 is H or C 1-6 -alkyl;

R 7 is null, H, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkyl-C 3-6 -cyclo alkyl, heterocycloalkyl, or C 1-6 -alkyl-heterocycloalkyl;

a line denotes an optionally double bond;

m is 0 or 1; and

n is 0 or 1, provided at least one of m or n is 1.

4 . The method of claim 3 , wherein

R 1 is mono-, bi-, or tri-cyclic aryl or heteroaryl, wherein the mono-, bi-, or tri-cyclic aryl or heteroaryl is optionally substituted with halo, C 1-4 -alkyl, CO 2 R 6 , C(O)R 6 , or C 1-6 -alkyl-OR 6 ; and

R 2 and R 3 are each independently selected from C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkyl-C 3-6 -cycloalkyl, heterocycloalkyl, C 1-6 -alkyl-heterocycloalkyl, NR 4 R 5 , O—C 1-6 -alkyl-OR 6 , C 1-6 -alkyl-OR 6 , aryl, heteroaryl, C(O)N(H)-heteroaryl, C(O)-heteroaryl, C(O)-heterocycloalkyl, C(O)-aryl, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, and C(O)—C 1-6 -alkyl-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally, independently substituted one or more times with C 1-4 -alkyl, CO 2 R 6 , C(O)R 6 , or C 1-6 -alkyl-OR 6 .

5 . The method of claim 3 , wherein

R 1 is monocyclic aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with halo;

R 2 and R 3 are each independently selected from C 2-6 -alkenyl, C 3-6 -cycloalkyl, C 1-6 -alkyl-C 3-6 -cycloalkyl, heterocycloalkyl, C 1-6 -alkyl-heterocycloalkyl, NR 4 R 5 , O—C 1-6 -alkyl-OR 6 , or C 1-6 -alkyl-OR 6 ;

R 4 is H or C 1-6 -alkyl;

R 5 is CO 2 R 6 or C 1-6 -alkyl-OR 6 ; and

R 6 is C 1-6 -alkyl.

6 . The method of claim 3 , wherein

m is 1; n is 1; Y 1 is N; and Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are each CH;

m is 0; n is 1; Y 2 is N; Y 1 is CR 7 ; and Y 3 , Y 4 , and Y 6 are each CH;

m is 0; n is 1; Y 1 is CR 7 ; Y 2 is N; Y 3 is C(O); Y 4 is CH 2 ; and Y 6 is CH;

m is 1; n is 1; Y 1 is CR 7 ; Y 2 is N, and Y 3 , Y 4 , Y 5 , and Y 6 are each CH;

m is 0; n is 1; Y 1 is CR 7 ; Y 2 and Y 3 are each N; and Y 4 and Y 6 are each CH;

m is 0; n is 1; Y 1 and Y 2 are N; Y 3 , Y 4 , and Y 6 are each CH; or

m is 1; n is 1; and Y1, Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are each CH.

7 . The method of claim 3 , wherein the compound of Formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

8 . The method of claim 1 , wherein the compound has the chemical structure of Formula II:

or a pharmaceutically acceptable salt thereof;

wherein

R 1 and R 2 are independently H, mono-, bi-, or tri-cyclic aryl or heteroaryl, wherein the mono-, bi-, or tri-cyclic aryl or heteroaryl is optionally substituted with halo, C 1-4 -alkyl, CO 2 R 7 , C(O)R 7 , or C 1-6 -alkyl-OR 7 ;

or R 1 and R 2 are linked together to form a group of Formula:

R 3 and R 4 are independently selected from H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkyl-C 3-6 -cycloalkyl, heterocycloalkyl, C 1-6 -alkyl-heterocycloalkyl, NR 5 R 6 , O—C 1-6 -alkyl-OR 7 , aryl, heteroaryl, C(O)N(H)-heteroaryl, C(O)-heteroaryl, C(O)-heterocycloalkyl, C(O)-aryl, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, or C(O)—C 1-6 -alkyl-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with halo, C 1-4 -alkyl, CO 2 R 7 , C(O)R 7 , or C 1-6 -alkyl-OR 7 ;

R 5 is H, C 1-6 -alkyl, CO 2 R 7 or C 1-6 -alkyl-OR 7 ;

R 6 is H, C 1-6 -alkyl, CO 2 R 7 or C 1-6 -alkyl-OR 7 ;

R 7 is H or C 1-6 -alkyl;

X 1 , X 2 , and X 3 are each independently CH, N, or S, wherein at least one of X 1 or X 2 is N or S;

a line denotes an optionally double bond; and

p is 0 or 1.

9 . The method of claim 8 , wherein

R 1 is mono-, bi-, or tri-cyclic aryl or heteroaryl, wherein the mono-, bi-, or tri-cyclic aryl or heteroaryl is optionally substituted with halo, C 1-4 -alkyl, CO 2 R 7 , C(O)R 7 , or C 1-6 -alkyl-OR 7 ;

R 2 is H;

or R 1 and R 2 are linked together to form the following fused ring:

and

R 3 and R 4 are independently selected from H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkyl-C 3-6 -cycloalkyl, heterocycloalkyl, C 1-6 -alkyl-heterocycloalkyl, NR 5 R 6 , O—C 1-6 -alkyl-OR 7 , aryl, heteroaryl, C(O)N(H)-heteroaryl, C(O)-heteroaryl, C(O)-heterocycloalkyl, C(O)-aryl, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, or C(O)—C 1-6 -alkyl-heterocycloalkyl.

10 . (canceled)

11 . The method of claim 1 , wherein the compound of Table 1 is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

12 . The method of claim 1 , wherein the compound has the chemical structure of Formula IV:

or a pharmaceutically acceptable salt thereof,

wherein,

R x is selected from the group consisting of C 1-6 -alkyl, C 1-6 -alkoxy, halo, —OH, —C(O)R 1 , —CO 2 R 1 , —C(O)N(R 1 ) 2 , aryl, —C(S)N(R 1 ) 2 , and S(O) 2 R 1 , wherein aryl is optionally substituted with one or more groups selected from C 1-6 -alkyl, C 1-6 -alkoxy, —OH, halo, and haloalkyl;

R y is selected from the group consisting of H, C 1-6 -alkyl, C 1-6 -alkoxy, halo, —OH, —C(O)R 1 , —CO 2 R 1 , and —C(O)N(R 1 ) 2 ;

R z is selected from the group consisting of C 1-6 -alkyl, C 1-6 -alkenyl, C 1-6 -alkynyl, C 3-8 -cycloalkyl, C 3-7 -heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with C 1-6 -alkyl, C 1-6 -alkoxy, halo, or —OH; and

each R 1 is, independently for each occurrence, selected from the group consisting of H, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-7 -heterocycloalkyl, aryl, heteroaryl, C 1-6 -alkyl-cycloalkyl, C 1-6 -alkyl-heterocycloalkyl, C 1-6 -alkyl-aryl, and C 1-6 -alkyl-heteroaryl, wherein C 3-8 -cycloalkyl, C 3-7 -heterocycloalkyl, aryl, heteroaryl, C 1-6 -alkyl-cycloalkyl, C 1-6 -alkyl-heterocycloalkyl, C 1-6 -alkyl-aryl, and C 1-6 -alkyl-heteroaryl is optionally substituted with one or more groups selected from C 1-6 -alkyl, C 1-6 -alkoxy, —OH, halo, and haloalkyl.

13 . The method of claim 12 , wherein the compound has the structure of Formula V:

or a pharmaceutically acceptable salt thereof,

wherein,

R x is independently selected from the group consisting of aryl, —C(O)R′, —CO 2 R 1 , —C(O)N(R 1 ) 2 , —C(S)N(R 1 ) 2 , and S(O) 2 R 1 ;

R y is selected from the group consisting of H, C 1-6 -alkyl, or, halo; and

R z is selected from the group consisting of C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-7 -heterocycloalkyl, aryl, and heteroaryl.

14 . The method of claim 12 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

15 . The method of claim 1 , wherein the subject is a human.

16 - 32 . (canceled)

33 . A compound of Formula VII:

or a pharmaceutically acceptable salt thereof;

wherein

R 1 is phenyl or a 5-membered heteroaryl ring; and

R 2 is C 3-7 -cycloalkyl.

34 . A compound of Formula VIII:

or a pharmaceutically acceptable salt thereof;

wherein

R 1 is C 1-4 -alkyl; and

R 2 is a 5- or 6-membered heterocycloalkyl ring optionally substituted with C 1-4 -alkyl.

35 - 41 . (canceled)