Activators of class I histone deacetlyases (HDACs) and uses thereof

Patent metadata

Field	Value
Publication number	US-10167277-B2
Application number	US-201514834587-A
Country	US
Kind code	B2
Filing date	Aug 25, 2015
Priority date	Jul 22, 2011
Publication date	Jan 1, 2019
Grant date	Jan 1, 2019

Abstract

The present invention provides compounds of Formulae (A), (B), (C), and (D), pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, pharmaceutical compositions thereof, and kits thereof. The present invention further provides methods of using the compounds to treat or prevent neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis), traumatic brain injury, ischemic brain injury, stroke, frontal temporal dementia, Pick's disease, corticobasal degeneration, supra cerebral palsy, prion diseases (e.g., Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia, and Kuru), Nieman Pick type C, spinal cerebellar ataxia, spinal muscular dystrophy, ataxia telangiectasia, hippocampal sclerosis, Cockayne syndrome, Werner syndrome, xeroderma pigmentosaum, and Bloom syndrome. In one aspect, the methods include administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of DAC-001, DAC-002, DAC-003, DAC-009, or DAC-012, or a compound of Formula (A), (B), (C), or (D).

First claim

What is claimed is:

1. A compound of Formula (B):

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein:
each of X B1 , X B3 , and X B4 is independently oxygen, sulfur, NR B4a , or C(R B4b ) 2 , wherein R B4a is hydrogen, a nitrogen protecting group, or optionally substituted C 1-6 alkyl, and each occurrence of R B4b is independently hydrogen, halogen, or optionally substituted C 1-6 alkyl, or two R B4b groups are joined to form an optionally substituted, carbocyclic or heterocyclic ring;
X B2 is nitrogen or CR B2a , wherein R B2a is hydrogen, halogen, or optionally substituted C 1-6 alkyl;
each instance of R B1 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR B1a , —N(R B1a ) 2 , —SR B1a , —C(═O)R B1a , —C(═O)OR B1a , —C(═O)SR B1a , —C(═O)N(R B1b ) 2 , —OC(═O)R B1a , OC(═O)OR B1a , —OC(═O)SR B1a , —OC(═O)N(R B1b ) 2 , —NR B1b C(═O)R B1b , —NR B1b C(═O)OR B1a , —NR B1b C(═O)SR B1a , —NR B1b C(═O)N(R B1b ) 2 , —SC(═O)R B1a , —SC(═O)OR B1a , —SC(═O)SR B1a SC(═O)N(R B1b ) 2 , —C(═NR B1b )R B1a , —C(═NR B1b )OR B1a , —C(═NR B1b )SR B1a , —C(═NR B1b )N(R B1b ) 2 , —OC(═NR Bb )R B1a , —OC(═NR B1b )OR B1a , —OC(═NR B1b )SR B1a , —OC(═NR B1b )N(R B1b ) 2 , —NR B1b C(═NR B1b )R B1b , —NR B1b C(═NR B1b )OR B1a , —NR B1b C(═NR B1b )SR B1a , NR B1b C(═NR B1b )N(R B1b ) 2 , —SC(═NR B1b )R B1a , —SC(═NR B1b )OR B1a , —SC(═NR B1b )SR B1a SC(═NR B1b )N(R B1b ) 2 , —C(═S)R B1a , —C(═S)OR B1a , —C(═S)SR B1a , —C(═S)N(R B1b ) 2 , —OC(═S)R B1a , OC(═S)OR B1a , —OC(═S)SR B1a , —OC(═S)N(R B1b ) 2 , —NR B1b C(═S)R B1b , —NR B1b C(═S)OR B1a , —NR B1b C(═S)SR B1a , —NR B1b C(═S)N(R B1b ) 2 , —SC(═S)R B1a , —SC(═S)OR B1a , —SC(═S)SR B1a , SC(═S)N(R B1b ) 2 , —S(═O)R B1a , —SO 2 R B1a , —NR B1b SO 2 R B1a , —SO 2 N(R B1b ) 2 , —CN, —SCN, or —NO 2 , wherein each occurrence of R B1a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R B1b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group when attached to a nitrogen atom, or two R B1b groups are joined to form an optionally substituted heterocyclic ring;
each of R B2 , R B3 , R B4 , and R B5 is independently hydrogen, halogen, or optionally substituted C 1-6 alkyl;
R B6 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —N(R B6b ) 2 , or —SR B6a , wherein R B6a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R B6b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R B6b groups are joined to form an optionally substituted heterocyclic ring; and
p is 0, 1, 2, 3, or 4;
provided that the compound is not of the formula:

2. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein X B1 is NH, and X B2 is nitrogen.

3. The compound of claim 2 , wherein the compound is of formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein X B3 is sulfur.

5. The compound of claim 1 , wherein the compound is of formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein X B4 is oxygen.

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

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof.

8. The compound of claim 7 , wherein the compound is of formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof.

9. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein R B2 and R B3 are hydrogen.

10. The compound of claim 9 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein R B4 and R B5 are optionally substituted C 1-6 alkyl.

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

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof.

12. The compound of claim 1 , wherein the compound is of formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof.

13. The compound of claim 1 , wherein the compound is of formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof.

14. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, wherein R B6 is unsubstituted ethyl.

15. The compound of claim 1 , wherein the compound is of formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof.

16. The compound of claim 1 , wherein the compound is of formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof.

17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.

18. A method for therapeutically treating a neurological

Assignees

• Massachusetts Inst Technology
• Massachusetts Gen Hospital

Inventors

• Tsai Li-Huei
• Pan Ling
• Haggarty Stephen J
• Patnaik Debasis

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

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

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P25/36

  Opioid-abuse · 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