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

Patent metadata

Field	Value
Publication number	US-10183934-B2
Application number	US-201615013811-A
Country	US
Kind code	B2
Filing date	Feb 2, 2016
Priority date	Feb 2, 2015
Publication date	Jan 22, 2019
Grant date	Jan 22, 2019

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

The invention claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt, hydrate, tautomer or isomer thereof, wherein:
X 1 is O;
X 2 is CR 1 R 2
X 3 is CR 1 R 2 ;
X 4 and X 5 are each CR 1 R 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 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 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 N, S, P, or O;
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 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 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 N(C 1 -C 6 alkyl) 2 ; and
n is independently, and at each occurrence, an integer from 0 to 6.

2. The compound of claim 1 , wherein Y 1 , Y 3 , and Y 4 are each CR 1 and Y 2 is C.

3. The compound of claim 1 , wherein Y 1 , Y 2 , and Y 4 are each CR 1 and Y 3 is C.

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

5. The compound of claim 4 , wherein R is —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

6. The compound of claim 5 , wherein R is aryl.

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

8. The compound of claim 7 , wherein R is —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

9. The compound of claim 8 , wherein R is aryl.

10. The compound of claim 8 , wherein R is heterocyclyl.

11. The compound of claim 1 , wherein L is —S(O) 2 —.

12. The compound of claim 11 , wherein R is —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

13. The compound of claim 12 , wherein R is aryl.

14. The compound of claim 1 , wherein L is —C(O)NR 3 —.

15. The compound of claim 14 , wherein R is —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

16. The compound of claim 15 , wherein R is aryl.

17. The compound of claim 1 , wherein L is —S(O) 2 NR 3 —.

18. The compound of claim 17 , wherein R is —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

19. The compound of claim 18 , wherein R is aryl.

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

21. The compound of claim 20 , wherein R is hydrogen, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

22. The compound of claim 21 , wherein R is aryl.

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

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

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

26. The compound of claim 1 selected from:
N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine-9-carboxamide;
N-hydroxy-5-(tetrahydro-2H-pyran-4-carbonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine-9-carboxamide;
N-hydroxy-5-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine-9-carboxamide;
N-hydroxy-5-phenyl-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine-9-carboxamide;
5-benzyl-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine-9-carboxamide;
5-benzoyl-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine-9-carboxamide;
5-(cyclohexanecarbonyl)-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine-9-carboxamide;
N-hydroxy-5-(phenylsulfonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine-9-carboxamide;
N9-hydroxy-N5-phenyl-3,4-dihydro-2H-benzo[b][1,5]oxazocine-5,9(6H)-dicarboxamide;
N-hydroxy-5-(N-phenylsulfamoyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine-9-carboxamide;
N-hydroxy-5-phenyl-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine-8-carboxamide;
5-benzyl-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine-8-carboxamide;
5-benzoyl-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine-8-carboxamide;
5-(cyclohexanecarbonyl)-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine-8-carboxamide;
N-hydroxy-5-(tetrahydro-2H-pyran-4-

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

• C07D413/06 Primary

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

• C07D267/22

  Eight-membered rings · CPC title