ISOINDOLINES AS HDAC INHIBITORS

1 . A compound of the Formula I:

and pharmaceutically acceptable salts thereof, wherein:

Z is N, C or CH;

X 1 and X 2 are each independently, at each occurrence, —CR 1 R 2 —, ═CR 1 —, —NR 3 —, or —C(O)—, as valency permits, provided that only one of X 1 and X 2 is —C(O)—;

the dotted line between z x 1 and z x 2 is absent or represents a bond, provided that, at most, only one of the dotted lines represents a bond;

i) one of Y 1 , Y 2 , and Y 3 is N and the other two of Y 1 , Y 2 , and Y 3 are CR 1 , or

ii) two of Y 1 , Y 2 , and Y 3 are N and the other one of Y 1 , Y 2 , and Y 3 is CR 1 ;

L is a bond, —(CR 1 R 2 ) p —, —C(O)NR 3 —, —NR 3 C(O)—, —O(CR 1 R 2 ) p C(O)—, —C(O)(CR 1 R 2 ) p O—, —(CR 1 R 2 ) p C(O)—, or —C(O)(CR 1 R 2 ) p —;

R is —C 4 -C 8 cycloalkenyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of —OH, halogen, oxo, —NO 2 , —CN, —R 1 , —R 2 , —SR 3 , —OR 3 , —NHR 3 , —NR 3 R 4 , —S(O) 2 NR 3 R 4 , —S(O) 2 R 1 , —C(O)R 1 , —C(O)OR 1 , —NR 3 S(O) 2 R 1 , —S(O)R 1 , —S(O)NR 3 R 4 , and —NR 3 S(O)R 1 ;

R 1 and R 2 are independently, at each occurrence, —H, —R 3 , —R 4 , —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, —OH, halogen, —NO 2 , —CN, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O) 2 R 5 , —S(O) 2 (C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)S(O) 2 R 5 , —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, or —(CHR 5 ) p NR 3 R 4 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —OR 3 , —NHR 3 , —NR 3 R 4 , —S(O) 2 N(R 3 ) 2 —, —S(O) 2 R 5 , —C(O)R 5 , —C(O)OR 5 , —NR 3 S(O) 2 R 5 , —S(O)R 5 , —S(O)NR 3 R 4 , —NR 3 S(O)R 5 , heterocyclyl, aryl, and heteroaryl;

or R 1 and R 2 can combine with the carbon atom to which they are both attached to form a spirocycle, spiroheterocycle, or spirocycloalkenyl, each optionally substituted with one or more independent occurrences of R 3 and R 4 ;

or R 1 and R 2 , when on adjacent atoms, can combine to form a cycloalkyl, a heterocycle, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or a cycloalkenyl, each optionally substituted with one or more independent occurrences of R 3 and R 4 ;

or R 1 and R 2 , when on non-adjacent atoms, can combine to form an optionally bridging cycloalkyl, an optionally bridging heterocycle, or an optionally bridging cycloalkenyl, each optionally substituted with one or more independent occurrences of R 3 and R 4 ;

R 3 and R 4 are independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from N, S, P, and O, —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 (C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)S(O) 2 R 5 , —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, or —(CHR 5 ) p N(C 1 -C 6 alkyl) 2 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —O(C 1 -C 6 )alkyl, —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 NHC 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, —S(O)R 5 , —S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)R 5 , heterocyclyl, aryl, and heteroaryl;

R 5 is independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from N, S, P and O, —OH, halogen, —NO 2 , —CN, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 C 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)SO 2 C 1 -C 6 alkyl, —S(O)(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)(C 1 -C 6 alkyl) or —(CH 2 ) p N(C 1 -C 6 alkyl) 2 ; and

p is 0, 1, 2, 3, 4, 5, or 6;

provided that when X 2 is —C(O)—, X 1 is CH 2 , Y 1 , Y 2 and Y 3 are each CH, and L is a bond, then R is a group other than substituted or unsubstituted phenyl; and

provided that X 1 and X 2 are not both nitrogen.

2 . The compound of claim 1 , wherein the compound is selected from one of:

3 . The compound of claim 1 , wherein one of Y 1 , Y 2 , and Y 3 is N and the other two of Y 1 , Y 2 , and Y 3 are CR 1 .

4 . The compound of claim 1 , wherein two of Y 1 , Y 2 , and Y 3 are N and the other one of Y 1 , Y 2 , and Y 3 is CR 1 .

5 . (canceled)

6 . The compound of claim 1 , wherein L is a bond.

7 . The compound of claim 1 , wherein L is —C(O)—.

8 . The compound of claim 1 , wherein L is —(CR 1 R 2 ) p —, —C(O)NR 3 —, —NR 3 C(O)—, —C(O)(CR 1 R 2 ) p O—, or —(CR 1 R 2 ) p C(O)—, wherein p is 1 or 2.

9 . The compound of claim 1 , wherein the compound has Formula II-A-i, II-A-ii, II-B-i, II-B-ii, II-C-i, II-C-ii, II-D-i, II-D-ii, II-E-i, II-E-ii, II-F-i, or II-F-ii:

10 . The compound of claim 1 , wherein R is heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, wherein each heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —OH, halogen, oxo, —NO 2 , —CN, —R 1 , —R 2 , —SR 3 , —OR 3 , —NHR 3 , —NR 3 R 4 , —S(O) 2 NR 3 R 4 , —S(O) 2 R 1 , —C(O)R 1 , —C(O)OR 1 , —NR 3 S(O) 2 R 1 , —S(O)R 1 , —S(O)NR 3 R 4 , —NR 3 S(O)R 1 , heterocyclyl, aryl, or heteroaryl.

11 . The compound of claim 1 , wherein R is heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, wherein the heteroaryl is optionally substituted with one or more —OH, halogen, oxo, —NO 2 , —CN, —R 1 , —R 2 , —SR 3 , —OR 3 , —NHR 3 , —NR 3 R 4 , —S(O) 2 NR 3 R 4 , —S(O) 2 R 1 , —C(O)R 1 , —C(O)OR 1 , —NR 3 S(O) 2 R 1 , —S(O)R 1 , —S(O)NR 3 R 4 , —NR 3 S(O)R 1 , heterocyclyl, aryl, or heteroaryl.

12 . The compound of claim 1 , wherein R is aryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, wherein the aryl is optionally substituted with one or more —OH, halogen, oxo, —NO 2 , —CN, —R 1 , —R 2 , —SR 3 , —OR 3 , —NHR 3 , —NR 3 R 4 , —S(O) 2 NR 3 R 4 , —S(O) 2 R 1 , —C(O)R 1 , —C(O)OR 1 , —NR 3 S(O) 2 R 1 , —S(O)R 1 , —S(O)NR 3 R 4 , —NR 3 S(O)R 1 , heterocyclyl, aryl, or heteroaryl.

13 . The compound of claim 1 , wherein R is phenyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, wherein the phenyl is optionally substituted with one or more —OH, halogen, oxo, —NO 2 , —CN, —R 1 , —R 2 , —SR 3 , —OR 3 , —NHR 3 , —NR 3 R 4 , —S(O) 2 NR 3 R 4 , —S(O) 2 R 1 , —C(O)R 1 , —C(O)OR 1 , —NR 3 S(O) 2 R 1 , —S(O)R 1 , —S(O)NR 3 R 4 , —NR 3 S(O)R 1 , heterocyclyl, aryl, or heteroaryl.

14 . The compound of claim 1 , wherein R is a group selected from:

15 . The compound of claim 1 , wherein:

Z is N, C, or CH;

X 1 and X 2 are each independently, at each occurrence, —CR 1 R 2 —, ═CR 1 —, —NR 3 —, or —C(O)—, as valency permits, provided that only one of X 1 and X 2 is —C(O)—;

the dotted line between z x 1 and z x 2 is absent or represents a bond, provided that, at most, only one of the dotted lines represents a bond;

Y 1 and Y 2 are each CR 1 , and Y 3 is N;

L is a bond, —(CR 1 R 2 ) p —, —C(O)NR 3 —, —NR 3 C(O)—, —(CR 1 R 2 ) p C(O)—, or —C(O)(CR 1 R 2 ) p —;

R is —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of —OH, —R 1 , —R 2 , and —OR 3 ;

R 1 and R 2 are independently, at each occurrence, —H, —C 1 -C 6 alkyl, or aryl, wherein each alkyl or aryl is optionally substituted with one or more substituents selected from the group consisting of halogen and —OR 3 ;

or R 1 and R 2 , when on adjacent atoms, can combine to form a cycloalkyl or a heterocycle, each optionally substituted with one or more independent occurrences of R 3 and R 4 ;

R 3 and R 4 are independently, at each occurrence, —H, —C 1 -C 6 alkyl, or —C(O)C 1 -C 6 alkyl, wherein each alkyl is optionally substituted with one or more halogen; and

p is 0 or 1.

16 . The compound of claim 1 , wherein

Y 1 is N, and Y 2 and Y 3 are each CR 1 .

17 . The compound of claim 1 having the structure:

Example

Structure

Name

33-1

N-hydroxy-1,1-dimethyl-2-(5- (trifluoromethyl)pyridin-2-yl)-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide

or a pharmaceutically acceptable salt thereof.

18 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

19 . A method of treating a disease or disorder associated with HDAC11 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 .

20 . The method of claim 19 , wherein the disease or disorder is selected from a cancer, a neurodegenerative disease, a neurodevelopmental disorder, an inflammatory disease, an autoimmune disease, infection, a metabolic disease, a hematologic disease, and a cardiovascular disease.

21 . A method of inhibiting a histone deacetylase comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .