Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors

Patent metadata

Field	Value
Publication number	US-9796664-B2
Application number	US-201614993621-A
Country	US
Kind code	B2
Filing date	Jan 12, 2016
Priority date	Sep 3, 2008
Publication date	Oct 24, 2017
Grant date	Oct 24, 2017

Abstract

This invention relates to compounds of Formula (I) wherein Cy 1 , L 1 , Y, R 1 , L 2 , and Ar2 are defined herein, for the treatment of cancers, inflammatory disorders, and neurological conditions.

First claim

What is claimed is:

1. A method of treating a disorder selected from cutaneous T cell lymphoma, B cell lymphoma, colorectal cancer, psoriasis, rheumatoid arthritis, osteoarthritis, Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, and Alzheimer's disease in a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a compound having a structure of Formula (I):

wherein
Ar 2 is selected from C 6-10 aryl and benzo[d][1,3]dioxolyl; wherein said C 6-10 aryl and benzo[d][1,3]dioxolyl are each substituted at one ortho position by NH 2 and by m independently selected R z groups;
L 2 is selected from straight chain C 4-6 alkylene and straight chain C 4-6 alkenylene; wherein 1 or 2 carbon atoms of said straight chain C 4-6 alkylene, or straight chain C 4-6 alkenylene is optionally replaced by a group independently selected from —O—, —S—, —S(═O)—, —S(═O) 2 —, —C(═O)—, and —NR a —;
each R a is independently selected from H and C 1-3 alkyl;
Cy 1 is selected from C 6-10 aryl and C 1-9 heteroaryl; each of which is substituted with n independently selected R y groups;
R 1 is H or C 1-4 alkyl;
each R y is independently selected from halogen, cyano, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, C 1-6 haloalkylcarbonyl, C 6-10 arylcarbonyl, C 1-6 alkylsulfonyl, sulfonamido, C 1-6 alkylthio, carbamyl, C 1-6 alkylcarbamyl, di-C 1-6 alkylcarbamyl, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonyl-(C 1-4 -alkyl)amino, C 1-6 alkoxycarbonylamino, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, C 3-7 cycloalkyl, C 2-6 heterocycloalkyl, phenyl, C 1-6 heteroaryl, C 3-7 cycloalkyl-C 1-4 -alkyl, C 2-6 heterocycloalkyl-C 1-4 -alkyl, phenyl-C 1-4 -alkyl, and C 1-6 heteroaryl-C 1-4 -alkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbamyl, di-C 1-6 alkylcarbamyl, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonyl-(C 1-4 -alkyl)amino, C 1-6 alkoxycarbonylamino, C 1-6 alkylamino, di-C 1-6 alkylamino are each optionally substituted by 1, 2, or 3 independently selected R y′ groups; and wherein said C 3-7 cycloalkyl, C 2-6 heterocycloalkyl, phenyl, C 1-6 heteroaryl, C 3-7 cycloalkyl-C 1-4 -alkyl, C 2-6 heterocycloalkyl-C 1-4 -alkyl, phenyl-C 1-4 -alkyl, and C 1-6 heteroaryl-C 1-4 -alkyl are each optionally substituted by 1, 2, or 3 independently selected R y″ groups;
provided that only one R y is selected from the optionally substituted groups C 3-7 cycloalkyl, C 2-6 heterocycloalkyl, phenyl, C 1-6 heteroaryl, C 3-7 cycloalkyl-C 1-4 -alkyl, C 2-6 heterocycloalkyl-C 1-4 -alkyl, phenyl-C 1-4 -alkyl, and C 1-6 heteroaryl-C 1-4 -alkyl;
each R z is independently selected from halogen, cyano, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryloxy, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, carbamyl, C 1-6 alkylcarbamyl, di-C 1-6 alkylcarbamyl, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonyl-(C 1-4 -alkyl)amino, C 1-6 alkoxycarbonylamino, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, C 3-7 cycloalkyl, C 2-6 heterocycloalkyl, phenyl, C 1-6 heteroaryl, C 3-7 cycloalkyl-C 1-4 -alkyl, C 2-6 heterocycloalkyl-C 1-4 -alkyl, phenyl-C 1-4 -alkyl, and C 1-6 heteroaryl-C 1-4 -alkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbamyl, di-C 1-6 alkylcarbamyl, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonyl-(C 1-4 -alkyl)amino, C 1-6 alkoxycarbonylamino, C 1-6 alkylamino, di-C 1-6 alkylamino are each optionally substituted by 1, 2, or 3 independently selected R z′ groups; and wherein said C 3-7 cycloalkyl, C 2-6 heterocycloalkyl, phenyl, C 1-6 heteroaryl, C 3-7 cycloalkyl-C 1-4 -alkyl, C 2-6 heterocycloalkyl-C 1-4 -alkyl, phenyl-C 1-4 -alkyl, and C 1-6 heteroaryl-C 1-4 -alkyl are each optionally substituted by 1, 2, or 3 independently selected R z″ groups;
provided that only one R z is selected from the optionally substituted groups C 3-7 cycloalkyl, C 2-6 heterocycloalkyl, phenyl, C 1-6 heteroaryl, C 3-7 cycloalkyl-C 1-4 -alkyl, C 2-6 heterocycloalkyl-C 1-4 -alkyl, phenyl-C 1-4 -alkyl, and C 1-6 heteroaryl-C 1-4 -alkyl;
each R y′ and R z′ is independently selected from hydroxyl, cyano, nitro, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, and di-C 1-4 -alkylamino;
each R y″ and R z″ is independently selected from halogen, hydroxyl, cyano, nitro, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, and di-C 1-4 -alkylamino;
n is an integer selected from 0, 1, 2, 3, and 4 when Cy 1 is C 1-9 heteroaryl and n is an integer selected from 1, 2, 3, and 4 when Cy 1 is C 6-10 aryl; and
m is an integer selected from 0, 1, 2, and 3;

or pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein Cy 1 is selected from C 6-10 aryl, which is substituted with n independently selected R y groups.

3. The method of claim 1 , wherein Cy 1 is selected from C 2-9 heteroaryl, which is substituted with n independently selected R y groups.

4. The method of claim 3 , wherein Cy 1 is indolyl or indazolyl, each of which is substituted with n independently selected R y groups.

5. The method of claim 1 , wherein Cy 1 is phenyl, which is optionally substituted with n independently selected R y groups.

6. The method of claim 1 , wherein Cy 1 is C 1-6 heteroaryl, which is optionally substituted with n independently selected R y groups.

7. The method of claim 1 , wherein Ar 2 is phenyl, and said phenyl is substituted at one ortho position by NH 2 and by m independently selected R z groups.

8. The method of claim 7 , wherein R z is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

9. The method of claim 8 , wherein R z is halogen.

10. The method of claim 4 , wherein L 2 is straight chain C 4-6 alkenylene.

11. The method of claim 10 , wherein L 2 is straight chain C 4-6 alkenylene having one double bond.

12. The method of claim 1 , wherein R 1 is hydrogen.

13. The method of claim 1 , wherein Ar 2 is phenyl; which is substituted at one ortho position by NH 2 and by m independently selected R z groups;
Cy 1 is C 6-10 aryl; which is substituted with n independently selected R y groups;
each R y is independently selected from halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 2-6 heterocycloalkyl, phenyl, C 1-6 heteroaryl, C 3-7 cycloalkyl-C 1-4 -alkyl, C 2-6 heterocycloalkyl-C 1-4 -alkyl, phenyl-C 1-4 -alkyl, and C 1-6 heteroaryl-C 1-4 -alkyl; wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy are each optionally substituted by 1, 2, or 3 independently selected R y′ groups; and wherein said C 3-7 cycloalkyl, C 2-6 heterocycloalkyl, phenyl, C 1-6 heteroaryl, C 3-7 cycloalkyl-C 1-4 -alkyl, C 2-6 heterocycloalkyl-C 1-4 -alkyl, phenyl-C 1-4 -alkyl, and C 1-6 heteroaryl-C 1-4 -alkyl are each optionally substituted by 1 or 2 independently selected R y″ groups;

Assignees

• Biomarin Pharm Inc

Inventors

• Rusche James R
• Peet Norton P
• Hopper Allen

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · 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