2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors

1. A compound of the Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are each independently, at each occurrence, —CR 1 R 2 — or —C(O)—;

Y 1 , Y 2 , Y 3 , and Y 4 are each independently, at each occurrence, N or CR 1 , wherein —C(O)NHOH is attached at Y 2 or Y 3 , and Y 2 or Y 3 is a carbon atom when attached to —C(O)NHOH;

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

R is —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 cycloallkyl, —C 5 -C 12 spirocycloalkyl, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocycloalkyl, heterocyclyl, spiroheterocyclyl, 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 , —CO 2 R 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;

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, —NH(C 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, —CO 2 C 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 —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 , —CO 2 R 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, or heteroaryl;

or R 1 and R 2 , when on the same atom, can combine with the carbon atom to which they are attached to form a cycloalkyl, hetercyclyl, spirocycloalkyl, spiroheterocyclyl, or spirocycloalkenyl;

or R 1 and R 2 , when on adjacent or non-adjacent atoms, can combine to form a hetercyclyl, cycloalkyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or cycloalkenyl;

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 alkyl, —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, —CO 2 C 1 -C 6 alkyl, or —(CHR 5 ) p N(C 1 -C 6 alkyl) 2 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from —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 NH(C 1 -C 6 alkyl), —C(O)C 1 -C 6 alkyl, —CO 2 C 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, or 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, —NH(C 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, —CO 2 C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 allkyl) 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 ;

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

n is 0 or 1;

m is 0 or 1; and

wherein the sum m+n=1.

2. The compound of claim 1 , wherein n is 0.

3. The compound of claim 2 , wherein m is 1.

4. The compound of claim 1 , wherein n is 1.

5. The compound of claim 1 , wherein X 1 is —CH 2 — and X 2 is —CH 2 —.

6. The compound of claim 1 , wherein X 5 is —C(O)—.

7. The compound of claim 5 , wherein Y 1 and Y 4 are each CR 1 , wherein —C(O)NHOH is attached at Y 2 or Y 3 , and Y 2 or Y 3 is a carbon atom when attached to —C(O)NHOH.

8. The compound of claim 7 , wherein L is a bond, —(CR 1 R 2 ) p —, or —C(O)(CR 1 R 2 ) p —.

9. The compound of claim 8 , wherein p is 0 or 1.

10. The compound of claim 9 , wherein R is —H or an optionally substituted group selected from —C 1 -C 6 alkyl, aryl, and heteroaryl.

11. The compound of claim 10 , wherein R is an optionally substituted group selected from aryl or heteroaryl.

12. The compound of claim 1 , wherein the compound is of the Formula IA-1:

13. The compound of claim 1 , wherein the compound is of the Formula IA-2:

14. The compound of claim 1 , wherein the compound is of the Formula IA-4:

15. The compound of claim 1 , wherein the compound is of the Formula IB-1, Formula IB-2, or Formula IB-4:

16. A compound of claim 1 selected from:

(R)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-1);

(S)-N-hydroxy-1′-methyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-2);

(R)-N-hydroxy-1′-isopropyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine] -5-carboxamide (I-3);

(S)-N-hydroxy-1′-isopropyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrroldine] -5-carboxamide (I-4);

(R)-1′-ethyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolid ine]-5-carboxamide (I-5);

(S)-1′-ethyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-6);

(R)-N-hydroxy-1′-isobutyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-7);

(S)-N-hydroxy-1′-isobutyl-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-8);

(R)-N-hydroxy-1′-(2-methylbenzyl)-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine] -5-carboxamide (I-9);

(S)-N-hydroxy-1′-(2-methylbenzyl)-2′-oxo-1,3-dihydrospiro [indene-2,3′-pyrrolidine] -5-carboxamide (I-10);

(R)-1′-benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-11);

(S)-1′-benzyl-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-12);

(R)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-13);

(S)-N-hydroxy-2′-oxo-1′-phenyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-14);

(R)-1′-(4-fluorophenyl)-N-hydroxy-2′-oxo-1,3-dihydrospiro[ indene-2,3′-pyrrolidine]-5-carboxamide (I-15);

(S)-1′-(4-fluorophenyl)-N-hydroxy-2′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-16);

(R)-N-hydroxy-2′-oxo-1′-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-17);

(S)-N-hydroxy-2′-oxo-1′-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-18);

(R)-N-hydroxy-2′-oxo-1′-(pyridin-2-yl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-19);

(S)-N-hydroxy-2′-oxo-1′-(pyridin-2-yl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-20);

(R)-N-hydroxy-2′-oxo-1′-(pyridin-4-yl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-21);

(S)-N-hydroxy-2′-oxo-1′-(pyridin-4-yl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-22);

(R)-N-hydroxy-2′-oxo-1′-(pyridin-3-ylmethyl)-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-23);

(R)-N-hydroxy-1′-methyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-24);

(S)-N-hydroxy-1′-methyl-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-25);

(R)1′-benzyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-26);

(S)1′-benzyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-27);

(R)1′-acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-28);

(S)1′-acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-29);

(R)1′-benzoyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-30);

(S)1′-benzoyl-N-hydroxy-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-31); and

N-hydroxy-1′-methyl-5′-oxo-1,3-dihydrospiro[indene-2,3′-pyrrolidine]-5-carboxamide (I-38).

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