Bicyclic [4,6,0] hydroxamic acids as hdac inhibitors

Patent metadata

Field	Value
Publication number	US-2016221997-A1
Application number	US-201615013811-A
Country	US
Kind code	A1
Filing date	Feb 2, 2016
Priority date	Feb 2, 2015
Publication date	Aug 4, 2016
Grant date	—

Abstract

The present invention relates to inhibitors of zinc-dependent histone deacetylases (HDACs) useful in the treatment of diseases or disorders associated with HDAC6, having a Formulae I or Formula II:

where R, L, X 1 , X 2 , X 3 , X 4 , X 5 , Y 1 , Y 2 , Y 3 , and Y 4 are described herein.

First claim

1 . A compound of Formula I:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, wherein:
X 1 and X 2 are each independently CR 1 R 2 , NR 3 , O, C═O, SO 2 , S(O) or S;
X 3 , X 4 and X 5 are each independently CR 1 R 2 , C═O, S(O) or SO 2 ;
Y 1 and Y 4 are each independently N or CR 1 ;
Y 2 and Y 3 are each independently N or 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 a bond, —(CR 1 R 2 ) n —, —C(O)—, —C(O)O—, —C(O)NR 3 —, —S(O) 2 —, —S(O) 2 NR 3 —, —S(O)—, —S(O)NR 3 —, —C(O)(CR 1 R 2 ) n O—, or —C(O)(CR 1 R 2 ) n —;
R is independently, and 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, —C 5 -C 12 spirocycle, 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, spirocycle, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —OH, halogen, oxo, —NO 2 , —CN, —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 , heterocycle, aryl, or heteroaryl, with the proviso that when L is —C(O)— the spiroheterocyclyl is not bound to L via a nitrogen atom;
R 1 and R 2 are independently, and 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, or 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, or (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 —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 , heterocycle, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O;
or R 1 and R 2 may combine with the carbon 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, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, or cycloalkenyl;
or R 1 and R 2 , when on non-adjacent atoms, can combine to form a bridging cycloalkyl or heterocycloalkyl wherein the bridge between X 1 and X 4 cannot contain exactly one carbon;
R 3 and R 4 are independently, and 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 the group consisting of N, S, P, or 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 ) n 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 NHC 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 , heterocycle, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O;
R 5 is independently, and at each occurrence —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 3 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, —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) or (CH 2 ), N(C 1 -C 6 alkyl) 2 ; and
n is independently, and at each occurrence, an integer from 0 to 6;
provided that X 1 , X 2 , X 3 , X 4 and X 5 are not all CR 1 R 2 at the same time.

2 . The compound of claim 1 , wherein X 5 is CR 1 R 2 .

3 . The compound of claim 1 , wherein X 1 is NR 3 , O, C═O, SO 2 , or S.

4 . The compound of claim 1 , wherein X 1 is O and X 5 is CR 1 R 2 .

5 . The compound of claim 1 , wherein L is CH 2 .

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

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

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

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

10 . The compound of claim 1 , wherein the compound is of the Formula IA-3:

11 . The compound of claim 1 , wherein the compound is of the Formula IB:

12 . A compound of Formula II:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, wherein:
X 1 is independently CR 1 R 2 , NR 3 , O, C═O, SO 2 , S(O) or S;
X 2 , X 3 , X 4 and X 5 are each independently CR 1 R 2 , C═O, S(O) or SO 2 ;
Y 1 and Y 4 are each independently N or CR 1 ;
Y 2 and Y 3 are each independently N or 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 a bond, —(CR 1 R 2 ) n —, —C(O)—, —C(O)O—, —C(O)NR 3 —, —S(O) 2 —, —S(O) 2 NR 3 —, —S(O)—, —S(O)NR 3 —, —C(O)(CR 1 R 2 ) n O—, or —C(O)(CR 1 R 2 ) n —;
R is independently, and at each occurrence —H, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 5 -C 12 spirocycle, 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, spirocycle, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —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 , or —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 , heterocycle, aryl, or heteroaryl, with the proviso that when L is —C(O)— the spiroheterocyclyl is not bound to L via a nitrogen atom;

Assignees

• Forma Therapeutics Inc

Inventors

• Zheng Xiaozhang
• Ng Pui Yee
• Rudnitskaya Aleksandra
• Lancia Jr David R

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• C07D267/22

  Eight-membered rings · CPC title

• C07D413/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title