Immunoproteasome inhibitors

Patent metadata

Field	Value
Publication number	US-2023133165-A1
Application number	US-201816764199-A
Country	US
Kind code	A1
Filing date	Nov 14, 2018
Priority date	Nov 16, 2017
Publication date	May 4, 2023
Grant date	—

Abstract

Provided herein are compounds, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof that are immunoproteasome (such as LMP2 and LMP7) inhibitors. The compounds described herein can be useful for the treatment of diseases treatable by inhibition of immunoproteasomes. Also provided herein are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

First claim

1 . A compound of Formula (I):

and/or a pharmaceutically acceptable salt thereof, wherein:
Y is —OR 2 , —N(R′)R 2 , or a group of formula

A 1 is hydrogen, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or —S(═O) 2 -alkyl, where said alkyl of said —S(═O) 2 -alkyl is optionally substituted;
R′ is H or optionally substituted alkyl;
each R 1 is H or optionally substituted alkyl;
each R 2 independently is a group of Formula (a) or (b):

wherein:
each X independently is -alkyl-, -alkyl-cycloalkyl-, -alkyl-aryl-, -alkyl-heteroaryl--alkyl-heterocyclyl-, -alkyl-heterocyclenyl-, -alkyl-O-alkyl-, -alkyl-O-cycloalkyl-, -alkyl-O-aryl-, -alkyl-O-heteroaryl-, -alkyl-O-heterocyclyl-, -alkyl-O-heterocyclenyl-, -alkyl-N(R)-alkyl-, -alkyl-N(R)-cycloalkyl-, -alkyl-N(R)-aryl-, -alkyl-N(R)-heteroaryl-, -alkyl-N(R)-heterocyclyl-, -alkyl-N(R)-heterocyclenyl-, -alkyl-O-alkyl-cycloalkyl-, -alkyl-O-alkyl-aryl-, -alkyl-O-alkyl-heteroaryl-, -alkyl-O-alkyl-heterocyclyl-, -alkyl-O-alkyl-heterocyclenyl-, -alkyl-N(R)-alkyl-cycloalkyl-, -alkyl-N(R)-alkyl-aryl-, -alkyl-N(R)-alkyl-heteroaryl-, -alkyl-N(R)-alkyl-heterocyclyl-, -alkyl-N(R)-alkyl-heterocyclenyl-, -cycloalkyl-aryl-, -heterocyclyl-alkyl-, -heterocyclyl-cycloalkyl-, -heterocyclyl-aryl-, -heterocyclyl-heteroaryl-, -heterocyclyl-heterocyclyl-, -heterocyclyl-heterocyclenyl-, —O-alkyl-, —O-cycloalkyl-, —O-aryl-, —O-heteroaryl-, —O-heterocyclyl-, —O-heterocyclenyl-, —N(R)-alkyl-, —N(R)-cycloalkyl-, —N(R)-aryl-, —N(R)-heteroaryl-, —N(R)-heterocyclyl-, —N(R)-heterocyclenyl-, —O-alkyl-cycloalkyl-, —O-alkyl-aryl-, —O-alkyl-heteroaryl-, —O— alkyl-heterocyclyl-, —O-alkyl-heterocyclenyl-, —N(R)-alkyl-cycloalkyl-, —N(R)-alkyl-aryl-, —N(R)-alkyl-heteroaryl-, —N(R)-alkyl-heterocyclyl-, —N(R)-alkyl-heterocyclenyl-, -aryl-aryl-, or

 wherein each instance of alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and heterocyclenyl is optionally substituted;
ring A with the ring nitrogen atom shown is an optionally substituted five- to six-membered heterocyclyl that is benzofused as shown, wherein said benzofused ring A is optionally substituted;
X 1 is —C(═O)— or —S(═O) 2 —;
R 6 is hydrogen, optionally substituted alkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;
R 7 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or
R 6 and R 7 together with the nitrogen atom to which they are shown attached form an optionally substituted heterocyclyl or optionally substituted heterocyclenyl;
Het is an optionally substituted aryl or optionally substituted heteroaryl;
each R independently is H or optionally substituted alkyl;
R b1 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl;
R b2 and R b3 are independently hydrogen or optionally substituted alkyl; or
R b2 and R b3 together with the boron atom to which they are shown attached form a cyclic boronic ester having 2 to 20 carbons, and optionally containing one or two additional cyclic heteroatoms chosen from N, O and S; and
m and n are independently 0 or 1.

2 . A compound of Formula (I′):

and/or a pharmaceutically acceptable salt thereof, wherein:
Y is —OR 2 , —N(R′)R 2 , or a group of formula

A 1 is hydrogen, hydroxy, alkyl, aryl, heteroaryl, heterocyclyl, or —S(═O) 2 -alkyl, wherein each of said alkyl, aryl, heteroaryl, and heterocyclyl, and the “alkyl” portion of said —S(═O) 2 -alkyl is optionally substituted with 1-3 substituents independently chosen from halo, hydroxy, alkyl, alkoxy, cyano, haloalkyl, —NH 2 , —NH(alkyl), —N(alkyl) 2 , heterocyclyl, aryl, and heteroaryl;
R′ is H or alkyl;
each R 1 is H or alkyl;
each R 2 independently is a group of Formula (a) or (b):

wherein:
each X independently is -alkyl-aryl-, -alkyl-O-aryl-, or

 wherein the “aryl” portion of each of said -alkyl-aryl- and -alkyl-O-aryl- is optionally independently substituted with 1-2 substituents chosen from halo, alkoxy, hydoxyalkyl, and cyano;
ring A with the ring nitrogen atom shown is a five- to six-membered heterocyclyl that is benzofused as shown;
X 1 is —C(═O)— or —S(═O) 2 —;
R 6 is hydrogen, alkyl, or heterocyclyl;
R 7 is alkyl which is optionally substituted with 1-2 substituents chosen from halo and alkoxy; heterocyclyl; or aryl; or
R 6 and R 7 together with the nitrogen atom to which they are shown attached form a heterocyclyl which is optionally substituted with 1-2 substituents chosen from alkyl and heterocyclyl;
Het is a heteroaryl which is optionally substituted with 1-2 substituents chosen from halo, haloalkyl, alkoxy, and cyano;
R b1 is alkyl which is optionally substituted with an aryl or heteroaryl, wherein each of said aryl or heteroaryl is optionally substituted with 1-2 substituents chosen from halo, hydroxy, alkyl, alkoxy, cyano, haloalkyl, —NH 2 , —NH(alkyl), and —N(alkyl) 2 ;
R b2 and R b3 are independently hydrogen; and
m and n are independently 0 or 1.

3 . The compound and/or pharmaceutically acceptable salt of claim 1 , wherein Y is

4 . The compound and/or pharmaceutically acceptable salt of claim 1 , wherein Y is OR 2 or —N(R′)R 2 .

5 . (canceled)

6 . The compound and/or pharmaceutically acceptable salt of claim 3 , wherein m and n are each 0.

7 . The compound and/or pharmaceutically acceptable salt of claim 3 , wherein m and n are each 1; or m is 0 and n is 1.

8 . (canceled)

9 . The compound and/or pharmaceutically acceptable salt of claim 6 , wherein A 1 is H.

10 . The compound and/or pharmaceutically acceptable salt of claim 7 , wherein A 1 is alkyl, aryl or heteroaryl, each of which is optionally independently substituted with 1-3 substituents independently chosen from halo, hydroxy, alkyl, alkoxy, cyano, haloalkyl, —NH 2 , —NH(alkyl), —N(alkyl) 2 , optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

11 . (canceled)

12 . (canceled)

13 . (canceled)

14 . (canceled)

15 . The compound and/or pharmaceutically acceptable salt of claim 1 , wherein R 2 is a group of Formula (a); each X independently is -alkyl-O-aryl-, -alkyl-aryl-, -alkyl-O-alkyl-aryl-, -alkyl-O-heteroaryl-, -alkyl-heteroaryl-, -alkyl-O-alkyl-heteroaryl-, -alkyl-N(R)-aryl-, -alkyl-N(R)-alkyl-aryl-, -alkyl-N(R)-heteroaryl

Assignees

• Principia Biopharma Inc

Inventors

• Lou Yan
• Owens Timothy Duncan
• Brameld Kenneth Albert
• Goldstein David Michael

Classifications

• A61P9/00 Primary

  Drugs for disorders of the cardiovascular system · CPC title

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title

• A61P29/00

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

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title