3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
The present disclosure relates to inhibitors of zinc-dependent histone deacetylases (HDACs) useful in the treatment of diseases or disorders associated with an HDAC, e.g., HDAC6, having a Formula I: where R, L, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , and Y 4 are described herein.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
X 1 is O;
X 2 is CR 1 R 2 , and X 4 is C═O;
X 3 is CR 1′ R 2′ ;
Y 1 and Y 4 are not bonded to —C(O)NHOH and are each CR 1 ;
one of Y 2 and Y 3 is CR 1 , and the other of Y 2 and Y 3 is C—C(O)NHOH;
L is selected from the group consisting of —C(O)—, —C(O)(CR 1 R 2 ) m —, and —C(O)(CR 1 R 2 ) m O—, wherein L is bound to the ring nitrogen through the carbonyl group;
R is independently, and at each occurrence, selected from the group consisting of —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, —C 5 -C 12 spirocyclyl, heterocyclyl, spiroheterocyclyl, aryl, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocyclyl, heterocyclyl, spiroheterocyclyl, 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 , —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, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, with the proviso that R is not bound to L via a nitrogen atom;
each R 1 and R 2 is independently, at each occurrence, selected from the group consisting of —H, —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 to 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, —CO 2 C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, and —(CHR 5 ) n 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 , —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, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O;
each of R 1′ and R 2′ is independently selected from the group consisting of H, aryl, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of —OH, halogen, —NO 2 , oxo, —CN, —R 3 , —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 , heterocycle, aryl, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, wherein at least one of R 1′ or R 2′ is not H;
each R 3 and R 4 is independently, at each occurrence, selected from the group consisting of —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 to 5 heteroatoms selected from the group consisting of 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, and —(CHR 5 ) n 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, —NHC 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, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O;
R 5 is independently, at each occurrence, selected from the group consisting of —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 to 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 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)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) and —(CH 2 ) n N(C 1 -C 6 alkyl) 2 ; and
each n is independently and at each occurrence an integer from 0 to 6; and
each m is independently and at each occurrence an integer from 1 to 6.
2. The compound of claim 1 , wherein the compound is of the Formula IA:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , wherein the compound is of the Formula IA-10:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein the compound is of the Formula IB:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4 , wherein the compound is of Formula IB-4:
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein one of R 1′ and R 2′ is optionally substituted aryl and the other of R 1′ and R 2′ is H.
7. The compound of claim 6 , wherein L is —C(O)— and R is an optionally substituted group selected from the group consisting of —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, and heteroaryl.
8. The compound of claim 7 , wherein R is optionally substituted heterocyclyl.
9. The compound of claim 1 , wherein one of R″ and R 2′ is optionally substituted heteroaryl and the other of R 1′ and R 2′ is H.
10. The compound of claim 9 , wherein L is —C(O)— and R is an optionally substituted group selected from the group consisting of —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.
11. The compound of claim 10 , wherein R is optionally substituted heterocyclyl.
12. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.