Benzimidazole derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-9790188-B2
Application number	US-201414776184-A
Country	US
Kind code	B2
Filing date	Mar 17, 2014
Priority date	Mar 15, 2013
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof. The present invention also provides methods and kits using the inventive compounds and pharmaceutical compositions for treating and/or preventing diseases associated with protein aggregation, such as amyloidoses (e.g., Parkinson's disease and Alzheimer's disease), treating and/or preventing neurodegenerative diseases, treating and/or preventing diseases associated with Tar DNA binding protein 43 kDa, reducing or preventing protein aggregation, and/or modulating E3 ubiquitin ligase in a subject in need thereof.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof;
wherein:
Ring A is aryl;
Ring B is aryl;
X is —C(═O)—;
each instance of R A is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —N(R A1 ) 2 , —SR A1 , —CN, —SCN, —C(═NR A1 )R A1 , —C(═NR A1 )OR A1 , —C(═NR A1 )N(R A1 ) 2 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)N(R A1 ) 2 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(O)OR A1 , —NR A1 C(═O)N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , or —OC(═O)N(R A1 ) 2 , or two R A groups are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring;
each instance of R A1 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A1 groups are joined to form a substituted or unsubstituted heterocyclic ring;
R B is hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
R C is hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
each instance of R D is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR D1 , —N(R D1 ) 2 , —SR D1 , —CN, —SCN, —C(═NR D1 )R D1 , —C(═NR D1 )OR D1 , —C(═NR D1 )N(R D1 ) 2 , —C(═O)R D1 , —C(═O)OR D1 , —C(═O)N(R D1 ) 2 , —NO 2 , —NR D1 C(═O)R D1 , —NR D1 C(═O)OR D1 , —NR D1 C(═O)N(R D1 ) 2 , —OC(═O)R D1 , —OC(═O)OR D1 , or —OC(═O)N(R D1 ) 2 ;
each instance of R D1 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;
R E is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
each instance of R F is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR F1 , —N(R F1 ) 2 , —SR F1 , —CN, —SCN, —C(═NR F1 )R F1 , —C(═NR F1 )OR F1 , —C(═NR F1 )N(R F ) 2 , —C(═O)R F1 , —C(═O)OR F1 , —C(═O)N(R F1 ) 2 , —NO 2 , —NR F1 C(═O)R F1 , —NR F1 C(═O)OR F1 , —NR F1 C(═O)N(R F1 ) 2 , —OC(═O)R F1 , —OC(═O)OR F1 , or —OC(═O)N(R F1 ) 2 , or two R F groups are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring;
each instance of R F1 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R F1 groups are joined to form a substituted or unsubstituted heterocyclic ring;
k is 1, 2, 3, 4, or 5;
p is 1, 2, 3, 4, or 5; and
m is 0, 1, 2, or 3;
provided that at least one instance of R A or R D is not hydrogen; and
provided that the compound is not

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound of claim 1 or a compound of the formula:

or a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable excipient.

9. A method of treating a disease associated with protein aggregation in a subject in need thereof, wherein the disease is amyloidosis, Parkinson's disease, Alzheimer's disease, or a prion disease, the method comprising:
administering to the subject a therapeutically or prophylactically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

10. The method of claim 9 , wherein the subject is a human.

Assignees

• Whitehead Inst Biomedical Res
• Massachusetts Inst Technology

Inventors

• Lindquist Susan L
• Buchwald Stephen L
• Tardiff Daniel
• Jui Nathan

Classifications

• A61P25/16

  Anti-Parkinson drugs · 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

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P21/02

  Muscle relaxants, e.g. for tetanus or cramps · CPC title