Immunoproteasome inhibitors

Patent metadata

Field	Value
Publication number	US-2019336515-A1
Application number	US-201816478788-A
Country	US
Kind code	A1
Filing date	Jan 16, 2018
Priority date	Jan 18, 2017
Publication date	Nov 7, 2019
Grant date	—

Abstract

Provided herein are compounds, such as a compound of Formula (I), as described herein, 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:
W is —O—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;
P is -alkyl-N(R)—, -alkyl-(C 3 -C 6 )cycloalkyl-N(R)—, -alkyl-O-alkyl-N(R)—,

Z and Z 1 are independently a covalent bond, -alkyl-, -alkyl-O—, -alkyl-N(R)—, or -alkyl-O-alkyl-, with the proviso that Z is connected to ring A at a carbon atom adjacent to the ring nitrogen atom;
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 a saturated 4 to 10 membered heterocyclyl;
Y 1 is C or N;
Z 2 is a covalent bond or N(R), with the proviso that when Y 1 in ring J is nitrogen, then Z 2 is a covalent bond;
each R is independently hydrogen, or alkyl;
Q is —C(═O)— or —S(═O) 2 —;
R 8a is hydrogen, halogen, or cyano;
R 8b is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; or
R 8a and R 8b are taken together to form a bond; and
R 8c is hydrogen or optionally substituted alkyl;
R b1 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; and
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.

2 . A compound and/or a pharmaceutically acceptable salt of claim 1 , wherein:
W is —O—P-Q-C(R 8a )═C(R 8b )(R 8c ) or a group of formula

A 1 is hydrogen;
P is

Z is -alkyl- or -alkyl-O-alkyl-, with the proviso that Z is connected to ring A at a carbon atom adjacent to the ring nitrogen atom;
ring A with the ring nitrogen atom shown is an optionally substituted saturated mono- or multicyclic 4 to 10 membered heterocyclyl;
Q is —C(═O)—;
R 8a is hydrogen, halogen, or cyano;
R 8b is hydrogen; alkyl which is optionally substituted with 1-2 substituents chosen from a —N(alkyl)(haloalkyl), —N(alkyl) 2 , and optionally substituted heterocyclyl; and heterocyclyl which is optionally substituted with 1-2 substituents chosen from halo, alkyl, alkoxy, haloalkyl, cyano, and —S(═O) 2 -alkyl; or
R 8a and R 8b are taken together to form a bond; and
R 8c is hydrogen or alkyl;
R b1 is alkyl which is optionally substituted with 1-2 substituents chosen from aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently chosen from halo, alkyl, alkoxy, haloalkyl, cyano, and —S(═O) 2 -alkyl; and
R b2 and R b3 are each hydrogen.

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

4 . The compound and/or a pharmaceutically acceptable salt of claim 3 , wherein A 1 is H.

5 . The compound and/or a pharmaceutically acceptable salt of claim 1 , wherein W is —O—P-Q-C(R 8a )═C(R 8b )(R 8c ).

6 . The compound and/or a pharmaceutically acceptable salt of claim 1 , wherein:
said -alkyl-N(R)— of P is:

said -alkyl-O-alkyl-N(R)— of P is:

said

of P is:

and
said

of P is:

7 . The compound and/or a pharmaceutically acceptable salt of claim 1 , wherein P is

8 . The compound and/or a pharmaceutically acceptable salt of claim 7 , wherein ring A of P with the ring nitrogen atom shown is:

9 . The compound and/or a pharmaceutically acceptable salt of claim 3 , wherein Z of P is -alkyl-O-alkyl- or -alkyl-.

10 . The compound and/or a pharmaceutically acceptable salt of claim 9 , wherein:
said -alkyl-O-alkyl- of Z is —(CH 2 ) 1-4 —O—(CH 2 ) 1-4 —; and said -alkyl- of Z is —(CH 2 ) 1-4 —.

11 . (canceled)

12 . The compound and/or a pharmaceutically acceptable salt of claim 5 , wherein Z of P is -alkyl-; and said -alkyl- of Z is —(CH 2 )—.

13 . (canceled)

14 . The compound and/or a pharmaceutically acceptable salt of claim 1 , wherein Q is —C(═O)—.

15 . The compound and/or a pharmaceutically acceptable salt of claim 1 , wherein R 8a is hydrogen or cyano; and
said optionally substituted alkyl of R 8b is chosen from:

and
said optionally substituted heterocyclyl of R 8b is chosen from:

16 . (canceled)

17 . The compound and/or a pharmaceutically acceptable salt of claim 1 , wherein:
R 8b is H, or an alkyl which is optionally substituted with 1-2 substituents chosen from —N(alkyl)(haloalkyl), —N(alkyl) 2 , and optionally substituted heterocyclyl; and R 8c is H.

18 . The compound and/or a pharmaceutically acceptable salt of claim 17 , wherein R 8b is an unsubstituted or substituted alkyl chosen from isopropyl, t-butyl, —C(CH 3 ) 2 —N(CH 3 )—CH 2 CF 3 , —CH 2 —N(CH 3 ) 2 , —C(CH 3 ) 2 —N(CH 3 )—CH 2 —CHF 2 ,

19 . The compound and/or a pharmaceutically acceptable salt of claim 16 , wherein R 8b is an optionally substituted heterocyclyl chosen from

Assignees

• Principia Biopharma Inc

Inventors

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

Classifications

• A61K47/00

  Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient · CPC title

• A61K31/69 Primary

  Boron compounds · CPC title

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title