COMPOSITIONS AND METHODS OF MODULATING SHORT-CHAIN DEHYDROGENASE ACTIVITY

1 . A compound of formula (IA):

or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

R 1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl;

R 2 is —NH 2 , CN, or —NHC(O)alkyl;

R 6 is 5- to 6-membered heteroaryl optionally substituted with one or more R 3 ;

R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl, or —C(O)NR 5 -alkyl, each of which is optionally substituted with one or more R 4 ;

R 3 is oxo, —OH, —O-alkylene-OH, —O-alkylene-N(R 5 ) 2 , —N(R 5 ) 2 , —N(R 5 )(alkylene-OH), —N(R 5 )(alkylene-O-alkyl), alkyl, -alkylene-OH, haloalkyl, cycloalkyl, heterocyclyl, —C(O)N(R 5 ) 2 , —C(O)N(R 5 )(alkylene-OH), —C(O)-alkyl, —C(O)O-alkyl, or —S(O) m -alkyl, wherein the cycloalkyl and the heterocyclyl is each optionally substituted with R 10 ;

R 4 is oxo, halogen, —CN, —N(R 5 ) 2 , —OH, —O-alkylene-OH, —S(O) m -alkyl, —C(O)-alkyl, —C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R 8 ;

each R 5 is independently, H, alkyl, -alkylene-OH optionally substituted with —OH, -alkylene-NH 2 , -alkylene-N(R 9 ) 2 , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 , —C(O)-alkyl, —C(O)O-alkyl, -alkylene-COOH, or —S(O) m -alkyl;

or alternatively, two R 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 ;

R 8 is halogen, alkyl, or alkoxy;

R 9 is H or alkyl, or two R 9 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S(O) t , or N;

R 10 is —OH, halogen, alkyl, or alkoxy;

X is N or CH;

in is 0, 1, or 2;

n is 0, 1, or 2; and

t is 0, 1, or 2;

wherein the compound is one not having a formula selected from the group consisting of:

2 . The compound, salt, or solvate of claim 1 , wherein R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, —(C 1 -C 6 alkylene)-(3- to 6-membered cycloalkyl), —(C 1 -C 6 alkylene)—(C 1 -C 6 alkoxy), 3- to 6-membered heterocyclyl, or —(C 1 -C 6 alkylene)-(3- to 6-membered heterocyclyl).

3 . The compound, salt, or solvate of claim 1 , wherein R 2 is —NH 2 .

4 . The compound, salt, or solvate of claim 1 , wherein R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —C(O)(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 alkyl), or —C(O)NR 5 (C 1 -C 6 alkyl), each of which is optionally substituted with one or more R 4 .

5 . The compound, salt, or solvate of claim 1 , wherein R 3 is —O—(C 1 -C 6 alkylene)-N(R 5 ) 2 , —N(R 5 ) 2 , —N(R 5 )(C 1 -C 6 alkylene-OH), —C(O)N(R 5 ) 2 , —C(O)N(R 5 )(C 1 -C 6 alkylene-OH), —C(O)(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 alkyl), or —S(O) m (C 1 -C 6 alkyl).

6 . The compound, salt, or solvate of claim 1 , wherein R 4 is halogen, —CN, —N(R 5 ) 2 , —OH, —O—(C 1 -C 6 alkylene)—OH, —S(O) m (C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), —C(O)-(3- to 6-membered cycloalkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl.

7 . The compound, salt, or solvate of claim 1 , wherein n is 1.

8 . The compound, salt, or solvate of claim 1 , wherein the compound has the structure of formula (II):

wherein:

R 1 is 3- to 6-membered cycloalkyl, —(C 1 -C 6 alkylene)-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocyclyl, or —(C 1 -C 6 alkylene)-(3- to 6-membered heterocyclyl);

R 2 is —NH 2 , CN, or —NHC(O)alkyl;

R 6 is 5- to 6-membered heteroaryl optionally substituted with one or more R 3 ;

R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl, or —C(O)NR 5 -alkyl, each of which is optionally substituted with one or more R 4 ;

R 3 is oxo, —OH, —O-alkylene-N(R 5 ) 2 , —N(R 5 ) 2 , —N(R 5 )(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclyl, —C(O)N(R 5 ) 2 , —C(O)N(R 5 )(alkylene-OH), —C(O)-alkyl, —C(O)O-alkyl, or —S(O) m -alkyl;

R 4 is oxo, halogen, —CN, —N(R 5 ) 2 , —OH, —O-alkylene-OH, —S(O) m -alkyl, —C(O)-alkyl, —C(O)-cycloalkyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R 8 ;

each R 5 is independently, H, alkyl, -alkylene-OH optionally substituted with —OH, -alkylene-NH 2 , -alkylene-N(R 9 ) 2 , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 , —C(O)-alkyl, —C(O)O-alkyl, -alkylene-COOH, or —S(O) m -alkyl;

or alternatively, two R 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 ;

R 8 is halogen, alkyl, or alkoxy;

R 9 is H or alkyl, or two R 9 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S(O) t , or N;

X is N or CH;

m is 0, 1, or 2; and

t is 0, 1, or 2.

9 . The compound, salt, or solvate of claim 8 , wherein R 1 is 3- to 5-membered cycloalkyl or —(C 1 -C 6 alkylene)-(3- to 5-membered cycloalkyl).

10 . The compound, salt, or solvate of claim 8 , wherein R 1 is cyclobutyl.

11 . The compound, salt, or solvate of claim 8 , wherein R 1 is a bicyclic 4- to 6-membered cycloalkyl.

12 . The compound, salt, or solvate of claim 8 , wherein R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —C(O)(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 alkyl), or —C(O)NR 5 (C 1 -C 6 alkyl), each of which is optionally substituted with one or more R 4 .

13 . The compound, salt, or solvate of claim 8 , wherein R 7 is C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R 4 .

14 . The compound, salt, or solvate of claim 8 , wherein R 3 is —O—(C 1 -C 6 alkylene)-N(R 5 ) 2 , —N(R 5 ) 2 , —N(R 5 )(C 1 -C 6 alkylene-OH), —C(O)N(R 5 ) 2 , —C(O)N(R 5 )(C 1 -C 6 alkylene-OH), —C(O)(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 alkyl), or —S(O) m (C 1 -C 6 alkyl).

15 . The compound, salt, or solvate of claim 1 , selected from the group consisting of:

16 . The compound of claim 1 .

17 . A pharmaceutical composition comprising the compound, solvate, or salt of claim 1 and a pharmaceutically acceptable excipient or a carrier.

18 . A method of treating inflammatory bowel disease, the method comprising administering to a human subject in need of treatment a therapeutic amount of the compound of claim 1 .

19 . A method of:

(i) treating a subject in need of cell therapy comprising administering to the subject a therapeutically effective amount of a preparation comprising human hematopoietic stem cells and the compound, salt, or solvate of claim 1 and/or a therapeutic composition comprising human hematopoietic stem cells and the compound, salt, or solvate of claim 1 ; or

(ii) treating a subject having at least one symptom associated with an ischemic tissue or a tissue damaged by ischemia comprising administering to the subject a therapeutically effective amount of a preparation comprising the compound, salt, or solvate of claim 1 and/or a therapeutic composition comprising human hematopoietic stem cells and the compound, salt, or solvate of claim 1 ; or

(iii) increasing neutrophils in a subject in need thereof, the method comprising administering to the subject the compound, salt, or solvate of claim 1 ; or

(iv) increasing numbers of and/or mobilizing peripheral blood hematopoietic stem cells in a subject in need thereof, the method comprising administering to the subject the compound, salt, or solvate of claim 1 ; or

(v) increasing numbers of hematopoietic stem cells in blood or bone marrow, the method comprising: administering to blood or bone marrow of the subject the compound, salt, or solvate of claim 1 ; or

(vi) treating or preventing a fibrotic disease, disorder or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, salt, or solvate of claim 1 ; or

(vii) treating intestinal, gastrointestinal, or bowel disorders in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, salt, or solvate of claim 1 alone or in combination with a corticosteroid and/or a tumor necrosis factor a (TNFα) inhibitor; or

(viii) treating intestinal, gastrointestinal, or bowel disorders in a subject in need thereof, the method comprising administering to the subject therapeutically effective amounts of the compound, salt, or solvate of claim 1 and a corticosteroid; or

(ix) treating inflammation and/or reducing the activity of the immune system in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, salt, or solvate of claim 1 and a corticosteroid; or

(x) the treatment of glucocorticoid insensitivity, restoring corticosteroid sensitivity, enhancing glucocorticoid sensitivity or reversing the glucocorticoid insensitivity in a subject experiencing corticosteroid dependence or corticoid resistance or unresponsiveness or intolerance to corticosteroids, comprising administering a pharmaceutical composition comprising the compound, salt, or solvate of claim 1 in combination with a corticosteroid to the subject exhibiting one or more glucocorticoid insensitivity related conditions, wherein the glucocorticoid insensitivity related conditions comprise a range of immune-inflammatory disorders/diseases treated with steroids when the therapy fails to achieve disease control or is not effective or intolerant or dependent to corticosteroids, and combinations thereof.