Cysteine protease inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9403843-B2
Application number	US-201314376361-A
Country	US
Kind code	B2
Filing date	Feb 1, 2013
Priority date	Feb 1, 2012
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

The invention provides for novel cysteine protease inhibitors and compositions comprising novel cysteine protease derivatives. The invention further provides for methods for treatment of neurodegenerative diseases comprising administration novel cysteine protease inhibitors or compositions comprising novel cysteine protease inhibitors. In some embodiments, the cysteine protease inhibitors are calpain inhibitors.

First claim

What is claimed is:

1. A compound of formula (I-a),

wherein,
R 1 is —CO 2 H or —CO 2 (C 1 -C 4 )-alkyl;
R 2 is hydrogen or —(C 1 -C 4 )-alkyl;
R 4 is —(CH 2 )-thiazolyl;
R 5 is —(C 1 -C 6 )-alkyl-R 6 , —(C 2 -C 5 )-alkenyl, —(C 2 -C 5 )-alkynyl, —(CH 2 ) n -aryl, or —(CH 2 ) n -heteroaryl, wherein said aryl or heteroaryl are substituted with one or more R 7 groups;
R 6 is —N(R 10 )C(O)R 8 or —N(R 10 )S(O) 2 R 8 ;
R 7 is independently halogen, —(C 1 -C 3 )-alkyl, aryl, methylenedioxyphenyl, —S(O) 2 N(R 10 ) 2 , or —S(O) 2 N(R 10 ) 2 , wherein said aryl is optionally substituted with one or more R 9 groups;
R 8 is —(C 1 -C 6 )-alkyl-R 11 or aryl, wherein aryl is optionally substituted with one or more R 9 groups;
R 9 is independently hydrogen, halogen, —(C 1 -C 4 )-alkyl, —(C 1 -C 4 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or

R 10 is independently hydrogen or —(C 1 -C 4 )-alkyl;
R 11 is hydrogen or

n is an integer from 0-4; and
p is an integer from 0-3.

2. The compound of claim 1 , wherein
R 1 is —CO 2 H or —CO 2 (C 1 -C 4 )-alkyl;
R 2 is hydrogen or —(C 1 -C 4 )-alkyl;
R 4 is

R 5 is —(C 1 -C 4 )-alkyl-R 6 , —(CH 2 ) n -aryl, or —(CH 2 ) n -heteroaryl, wherein said aryl or heteroaryl are substituted with one or more R 7 groups;
R 6 is —N(R 10 )C(O)R 8 or —N(R 10 )S(O) 2 R 8 ;
R 7 is independently halogen, —(C 1 -C 3 )-alkyl, aryl, methylenedioxyphenyl, —S(O) 2 N(R 10 ) 2 , or —S(O) 2 N(R 10 ) 2 , wherein said aryl is optionally substituted with one or more R 9 groups;
R 8 is —(C 1 -C 6 )-alkyl-R 11 or aryl, wherein aryl is optionally substituted with one or more R 9 groups;
R 9 is independently hydrogen, halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or

R 10 is independently hydrogen or —(C 1 -C 4 )-alkyl;
R 11 is hydrogen or

n is an integer from 0-2; and
p is an integer from 0-1.

3. The compound of claim 1 , wherein
R 1 is —CO 2 H or —CO 2 (C 1 -C 4 )-alkyl;
R 2 is hydrogen or —(C 1 -C 4 )-alkyl;
R 5 is —(CH 2 ) n -aryl, or —(CH 2 ) n -heteroaryl, wherein said aryl or heteroaryl are substituted with one or more R 7 groups;
R 7 is independently halogen, —(C 1 -C 3 )-alkyl, aryl, methylenedioxyphenyl, —S(O) 2 N(R 10 ) 2 , or —S(O) 2 N(R 10 ) 2 , wherein said aryl is optionally substituted with one or more R 9 groups;
R 9 is independently hydrogen, halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or

R 10 is independently hydrogen or —(C 1 -C 4 )-alkyl;
n is an integer from 0-2; and
p is an integer from 0-1.

4. The compound of claim 1 , wherein
R 1 is —CO 2 H or —CO 2 (C 1 -C 2 )-alkyl;
R 2 is hydrogen or —(C 1 -C 2 )-alkyl;
R 5 is —(CH 2 ) n -phenyl, or —(CH 2 ) n -heteroaryl, wherein said phenyl or heteroaryl are substituted with one or more R 7 groups;
R 7 is independently halogen, —(C 1 -C 3 )-alkyl, phenyl, methylenedioxyphenyl, —S(O) 2 N(R 10 ) 2 , or —S(O) 2 N(R 10 ) 2 , wherein said phenyl is optionally substituted with one or more R 9 groups;
R 9 is independently hydrogen, halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or

R 10 is independently hydrogen or —(C 1 -C 2 )-alkyl;
n is an integer from 0-2; and
p is an integer from 0-1.

5. The compound of claim 1 , wherein
R 1 is —CO 2 H or —CO 2 (C 1 -C 2 )-alkyl;
R 2 is hydrogen or —(C 1 -C 2 )-alkyl;
R 5 is thiazolyl or —(CH 2 )-triazolyl, wherein said thiazolyl or triazolyl are substituted with an R 7 group;
R 7 is phenyl optionally substituted with one or more R 9 groups;
R 9 is independently halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or

R 10 is independently hydrogen or —(C 1 -C 2 )-alkyl; and
p is an integer from 0-1.

6. The compound of claim 1 , wherein
R 1 is —CO 2 H or —CO 2 (C 1 -C 2 )-alkyl;
R 2 is hydrogen or —(C 1 -C 2 )-alkyl;
R 5 is thiazolyl or —(CH 2 )-triazolyl, wherein said thiazolyl or triazolyl are substituted with an R 7 group;
R 7 is phenyl optionally substituted with one or more R 9 groups;
R 9 is independently halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or

R 10 is independently hydrogen or methyl; and
p is an integer from 0-1.

7. The compound of claim 1 , wherein
R 1 is —CO 2 H or —CO 2 (C 1 -C 2 )-alkyl;
R 2 is hydrogen;
R 5 is

R 7 is phenyl optionally substituted with one or more R 9 groups;
R 9 is independently halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 3 )-alkynyl, NO 2 , —S(O) 2 NH 2 , or

 and
p is an integer from 0-1.

8. The compound of claim 1 , wherein the compound is selected from
(2S,3S)-3-((S)-1-(4-(4-fluorophenyl)thiazol-2-ylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid;
(2S,3S)-3-((S)-1-(4-(4-ethynylphenyl)thiazol-2-ylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid;
(2S,3S)-3-((S)-1-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid; and
(2S,3S)-3-((S)-1-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid.

9. The compound of claim 1 , wherein the compound is selected from
(2S,3S)-3-((S)-1-(4-(4-fluorophenyl)thiazol-2-ylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid;
(2S,3S)-3-((S)-1-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid; and
(2S,3S)-3-((S)-1-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methylamino)-1-oxo-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid.

Assignees

• Univ Columbia
• Univ Illinois

Inventors

• Thatcher Gregory R J
• Schiefer Isaac Thomas
• Arancio Ottavio
• Fa Mauro

Classifications

• A61P43/00

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D405/12

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

• C07D403/12

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