Immunoproteasome Inhibitors

Patent metadata

Field	Value
Publication number	US-2024199655-A1
Application number	US-202318380962-A
Country	US
Kind code	A1
Filing date	Oct 17, 2023
Priority date	Nov 16, 2017
Publication date	Jun 20, 2024
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 method of treating a disease chosen from an autoimmune disorder, an inflammatory disorder, and a hematological disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
W is —O—P-Q-C(R 8a )═C(R 8b )(R 8c ), —N(R′)—P-Q-C(R 8a )═C(R 8b )(R 8c ), 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, wherein 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;
P is -alkyl-, -alkyl-O-alkyl-, -alkyl-N(R)—, -alkyl-aryl-N(R)—, -alkyl-N(R)-aryl-N(R)—, -alkyl-O-aryl-N(R)—, -alkyl-aryl-alkyl-N(R)—, -alkyl-heteroaryl-N(R)—, -alkyl-cycloalkyl-N(R)—, -alkyl-O-cycloalkyl-N(R)—, -alkyl-N(R)-cycloalkyl-N(R)—, -alkyl-O-alkyl-N(R)—, -alkyl-N(R)— alkyl-N(R)—,

 wherein each instance of alkyl, aryl, heteroaryl, and cycloalkyl is optionally substituted;
Z and Z 1 are independently a covalent bond, -alkyl-, -alkyl-O—, -alkyl-N(R)—, or -alkyl-O-alkyl-, wherein each instance of alkyl is optionally substituted;
ring A with the ring nitrogen atom shown is an optionally substituted saturated mono- or multicyclic 4 to 10 membered heterocyclyl;
ring J with the ring nitrogen atom and ring Y 1 atom shown is an optionally substituted saturated 4 to 10 membered heterocyclyl;
Y 1 is C or N;
Z 2 is a covalent bond or N(R);
each R is independently hydrogen or optionally substituted alkyl;
Q is —C(═O)— or —S(═O) 2 —;
each R 8a independently is hydrogen, halogen, or cyano;
each R 8b independently is hydrogen or optionally substituted alkyl; or
each R 8a and R 8b independently are taken together to form a bond; and
each R 8c independently is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
R b1 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or optionally substituted heterocyclyl;
R b2 and R b3 are independently hydrogen or optionally substituted C 1-6 alkyl; or
R b2 and R b3 together with the boron atom to which they are shown attached form an optionally substituted 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;
provided that when W is —O—P-Q-C(R 8a )═C(R 8b )(R 8c ), or a group of formula

wherein m and n are each 0, then P is not -alkyl-N(R)—, -alkyl-(C 3 -C 6 ) cycloalkyl-N(R)—, alkyl-O-alkyl-N(R)—, or

 wherein each instance of alkyl, and cycloalkyl is optionally substituted, ring A with the ring nitrogen atom as shown is an optionally substituted saturated monocyclic five- to seven-membered heterocyclyl with only the one nitrogen shown as the ring heteroatom, and wherein Z is connected to ring A at a carbon atom adjacent to the ring nitrogen atom; and
provided that when W is —O—P-Q-C(R 8a )═C(R 8b )(R 8c ), or a group of formula

wherein m and n are each 0, and P is

 wherein Y 1 in ring J is nitrogen, then Z 2 is a covalent bond.

2 . A method of treating a disease chosen from an autoimmune disorder, an inflammatory disorder, and a hematological disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I′):

or a pharmaceutically acceptable salt thereof, wherein:
W is —O—P-Q-C(R 8a )═C(R 8b )(R 8c ), —N(R 8a )—P-Q-C(R 8a )═C(R 8b )(R 8c ), or a group of formula

wherein:
A 1 is hydrogen; hydroxy; alkyl which is optionally substituted with 1-2 substituents chosen from halo, hydroxy, and —N(H)—C(═O)-alkyl; —S(═O) 2 -alkyl; heterocycyl; aryl; or heteroaryl; wherein each of said heterocyclyl, aryl and heteroaryl is independently 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;
R 1 is H or alkyl;
P is -alkyl-N(R)—, -alkyl-aryl-N(R)—, or

Z is a covalent bond, -alkyl-, or -alkyl-O-alkyl-;
ring A with the ring nitrogen atom shown is an optionally substituted saturated mono- or multicyclic 4 to 10 membered heterocyclyl;
each R independently is hydrogen or alkyl;
Q is —C(═O)— or —S(═O) 2 —;
R 8a is hydrogen or cyano;
R 8b is hydrogen or alkyl; or
R 8a and R 8b are taken together to form a bond; and
R 8c is hydrogen or alkyl which is optionally substituted with 1-2 substituents chosen from cycloalkyl and heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 substituents chosen from halo, alkyl, and heterocyclyl;
R b1 is alkyl which is optionally substituted with 1-2 substituents chosen from cycloalkenyl, aryl and heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with 1-2 substituents chosen from alkyl, halo, hydroxy, alkoxy, cyano, haloalkyl, —NH 2 , —NH(alkyl), and —N(alkyl) 2 ;
R b2 and R b3 are independently hydrogen or C 1-6 alkyl; or
R b2 and R b3 together with the boron atom to which they are shown attached form an optionally substituted 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;
provided that when W is —O—P-Q-C(R 8a )═C(R 8b )(R 8c ), or a group of formula

wherein m and n are each 0, then P is not -alkyl-N(R)— or

 wherein ring A with the ring nitrogen atom as shown is an optionally substituted saturated monocyclic five- to seven-membered heterocyclyl with only the one nitrogen shown as the ring heteroatom, and wherein Z is connected to ring A at a carbon atom adjacent to th

Assignees

• Principia Biopharma Inc

Inventors

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

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61K31/69

  Boron compounds · CPC title

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title