Alpha-amino boronic acid derivatives, selective immunoproteasome inhibitors

Patent metadata

Field	Value
Publication number	US-9688702-B2
Application number	US-201214366949-A
Country	US
Kind code	B2
Filing date	Dec 21, 2012
Priority date	Dec 22, 2011
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

Abstract

The present invention provides compounds of Formula (I) as inhibitors of LMP7 for the treatment of autoimmune and inflammatory diseases.

First claim

The invention claimed is:

1. A compound of Formula (I)

wherein
R b and R c are each independently H or C 1 -C 6 -alkyl; or R b and R c together with the atoms to which each is attached, form a 5 or 6 membered-ring;
Q denotes Ar, Het or cycloalkyl;
R 1 and R 2 are each independently H, OR a , Hal, or C 1 -C 6 -alkyl; wherein 1 to 5 H atoms may be independently substituted by OH or Hal;
Y denotes CR 3 R 4 ;
R 3 and R 4 are each independently H or C 1 -C 6 -alkyl;
L denotes L 1 , or L 2 ;
n is an integer selected from 1 to 3;
L 1 is

 wherein

Q 1 is Ar or Het, optionally substituted with 1 to 5 groups independently selected from ORa, Hal, phenyl, and C1-C6-alkyl, wherein 1 to 5 H atoms may be independently replaced by OH or Hal;
L 2 is

 wherein

Q 2 is a fused bicyclic system comprising 1 nitrogen atom and 1 to 3 additional groups independently selected from O, S, N, or CO, and wherein at least one of the rings is aromatic, wherein the fused bicyclic system is optionally substituted with 1 to 5 groups independently selected from OR a , Hal, phenyl, and C 1 -C 6 -alkyl, wherein 1 to 5 H atoms may be independently replaced by OH or Hal;
or
Q 2 is an unsaturated or aromatic 5 membered-ring system comprising 1 to 3 heteroatoms selected from N, O, S and CO, and optionally substituted with a phenyl ring or pyridine ring, wherein the phenyl ring and pyridine ring are optionally substituted with 1 to 4 groups independently selected from OR a , Hal, phenyl, and C 1 -C 6 -alkyl, wherein 1 to 5 H atoms may be independently replaced by OH or Hal;
each M is independently a linear or branched alkylene having 1 to 5 carbon atoms wherein 1 or 2 H atoms may be replaced by OR a or a phenyl ring, which is optionally substituted with 1 to 5 groups independently selected from Hal, OR a , and C 1 -C 6 -alkyl, each of which is optionally substituted with 1 to 5 groups independently selected from OH, and Hal; or
each M is independently a cycloalkylene having 3 to 7 carbon atoms; or
each M is independently a thiazolidinyl group;
each R a is independently H or C 1 -C 6 -alkyl wherein 1 to 5 H atom may be independently substituted by OH or Hal;
each Ar is independently a 6 membered-aromatic carbocyclic ring optionally fused with another carbocyclic saturated, unsaturated or aromatic ring having 5 to 8 carbon atoms;
Het denotes a 5- or 6-membered saturated, unsaturated or aromatic heterocyclic ring having 1 to 3 heteroatoms independently selected from N, N+O—, O, S, SO, and SO 2 , and optionally fused with another saturated, unsaturated or aromatic ring having 5 to 8 atoms and optionally comprising 1 to 3 heteroatoms selected from N, O, and S;
Hal denotes CI, Br, I of F;

and enantiomers, diastereoisomers, and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein L is selected from the following groups:

Or wherein L is selected from the following groups:

3. The compound of claim 1 wherein

is selected from the following:

4. The compound of claim 1 , selected from the following:

Ex
Formula

 1

 2

 3

 4

 5

 6

 7

 8

 9

 10

 11

 12

Assignees

• Ares Trading Sa
• Ares Trading

Inventors

• Swinnen Dominique
• Crosignani Stefano
• Seenisamy Jeyaprakashnarayanan
• Morandi Federica

Classifications

• A61P35/02

  specific for leukemia · CPC title

• 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

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title