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

Patent metadata

Field	Value
Publication number	US-10407418-B2
Application number	US-201816199489-A
Country	US
Kind code	B2
Filing date	Nov 26, 2018
Priority date	Feb 2, 2015
Publication date	Sep 10, 2019
Grant date	Sep 10, 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 thereof, wherein:
X 1 is CR 1 R 2 ;
X 2 is NR 3 ;
X 3 , 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 spirocyclyl, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from N, S, P, or O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocyclyl, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from —OH, halogen, oxo, —NO 2 , —CN, —R 1 , —R 2 , —OR 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, 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, —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 )—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 , heterocyclyl, aryl, and 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 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, and —(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 , heterocyclyl, aryl, and heteroaryl containing 1-5 heteroatoms selected from N, S, P, or O;
R 5 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, heterocyclyl, aryl, heteroaryl, —OH, halogen, —NO 2 , —CN, —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 X 1 , X 3 , X 4 , and X 5 are each CH 2 .

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

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 1 selected from:
N-hydroxy-5-methyl-2-phenyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;
2-benzyl-N-hydroxy-5-methyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;
2-benzoyl-N-hydroxy-5-methyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;
2-(cyclohexanecarbonyl)-N-hydroxy-5-methyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;
N-hydroxy-5-methyl-2-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;
N8-hydroxy-5-methyl-N2-phenyl-3,4,5,6-tetrahydrobenzo[f][1,4]diazocine-2,8(1H)-dicarboxamide;
N-hydroxy-5-methyl-2-(N-phenylsulfamoyl)-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;
N-hydroxy-2-methyl-5-phenyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;
5-benzyl-N-hydroxy-2-methyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;
5-benzoyl-N-hydroxy-2-methyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;
5-(cyclohexanecarbonyl)-N-hydroxy-2-methyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;
N-hydroxy-2-methyl-5-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;
N9-hydroxy-5-methyl-N2-phenyl-3,4,5,6-tetrahydrobenzo[f][1,4]diazocine-2,9(1H)-dicarboxamide; or
N-hydroxy-2-methyl-5-(N-phenylsulfamoyl)-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide.

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

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

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

9. The compound of claim 1 , wherein X 2 is N(CH 3 ).

10. The compound of claim 9 , wherein R is —C 3 -C 8 cycloalkyl, heterocyclyl, or aryl.

11. The compound of claim 10 , wherein R is aryl.

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

13. The compound of claim 10 , wherein R is —C 3 -C 8 cycloalkyl.

14. The compound of claim 10 , wherein L is a bond, —CH 2 —, —C(O)—, —C(O)NH—, or —S(O) 2 NH—.

15. The compound of claim 14 , wherein L is a bond.

16. The compound of claim 14 , wherein L is —CH 2 —.

17. The compound of claim 14 , wherein L is —C(O)—.

18. The compound of claim 14 , wherein L is —C(O)NH—.

19. The compound of claim 14 , wherein L is —S(O) 2 NH—.

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