3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors

Inventors: Xiaozhang Zheng (Lexington, MA); Pui Yee Ng (Lexington, MA); Bingsong Han (Westwood, MA); Jennifer R. Thomason (Clinton, MA); Mary-Margaret Zablocki (Revere, MA); Cuixian Liu (Madison, CT); Aleksandra Rudnitskaya (Roslindale, MA); David R. Lancia, Jr. (Boston, MA); David S. Millan (Watertown, MA); Matthew W. Martin (Arlington, MA)

Assignee: VALO HEALTH, INC.

C07D267/14 C07D243/14 C07D267/12 C07D291/08 C07D401/06 C07D401/10 C07D403/06 C07D403/10 C07D405/06 C07D413/04 C07D413/06 C07D413/08 C07D413/12 C07D413/14 C07D417/04 C07D471/04 C07D491/107 C07D493/08 C07D495/10 C07D498/04 C07D498/08

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Quick Facts

Patent No.: US 12,264,137
App. No.: 17/691,186
Granted: Apr 1, 2025
Kind: B2

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Abstract

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.

Claims (129)

1. A method of treating breast cancer, lung cancer, ovarian cancer, or multiple myeloma in a subject in need thereof, comprising administering to the subject an effective amount of a compound is of Formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

X 1 is O;

X 2 and X 4 are each CR 1 R 2 ;

X 3 is CR 1′ R 2′ ;

Y 1 and Y 4 are not bonded to —C(O)NHOH and are CR 1 ; Y 2 and Y 3 are each CR 1 when not bonded to —C(O)NHOH, and Y 2 and Y 3 are C when bonded to —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 bonded 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 bonded 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 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 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;

or R 1 and R 2 can combine with the atom to which they are both attached to form a spirocycle, spiroheterocycle, or a spirocycloalkenyl;

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

or R 1 and R 2 , when on non-adjacent atoms, can combine to form a bridging cycloalkyl, cycloalkenyl, or heterocycloalkyl;

each R 1′ and R 2′ is independently, at each occurrence, 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 ;

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 method of claim 1 , wherein the compound is of the Formula IA: