(4-hydroxypyrrolidin-2-yl)-heterocyclic compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11242344-B2
Application number	US-202016858004-A
Country	US
Kind code	B2
Filing date	Apr 24, 2020
Priority date	Oct 24, 2017
Publication date	Feb 8, 2022
Grant date	Feb 8, 2022

Abstract

The present disclosure relates to bifunctional compounds, which can be used as modulators of targeted ubiquitination. In particular, the present disclosure is directed to compounds which contain on one end a VHL ligand moiety, which binds to the VHL E3 ubiquitin ligase, and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated. Also disclosed are VHL ligands.

First claim

What is claimed is:

1. A compound of Formula (III) or (IV)

or a pharmaceutically acceptable salt thereof, wherein:
X is selected from the group consisting of —C(O)—, O, S, —SO 2 —, —N(R 4 )—, and —C(R 5a )(R 5b )— wherein R 4 , R 5a , and R 5b are each independently selected from the group consisting of H, substituted or unsubstituted C 1 -C 3 alkyl, and substituted or unsubstituted aryl;
R 1 is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroaryl;
R 2 is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl;
or R 1 and R 2 are taken together with the carbon to which they are attached to form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is substituted or unsubstituted or fused with a ring selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R 3 is substituted or unsubstituted alkyl, or R 3 is taken together with R 6 , when present, and the atoms to which they are attached, to form a substituted or unsubstituted heterocyclylene;
Z is selected from the group consisting of —N(R 6 )R 6a , —OR 6a , —N(R 6 )—SO 2 —R 6b ,

 wherein
R 6 is selected from the group consisting of H and substituted or unsubstituted alkyl; or R 6 , when present, is taken together with R 3 and the atoms to which they are attached to form a substituted or unsubstituted heterocyclylene;
R 6a is selected from the group consisting of H, substituted or unsubstituted acyl, and substituted or unsubstituted alkyl;
R 6b is selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted aryl;
indicates the point of attachment to the remaining structure of the compound;
r is 0 or 1;
R 13 is selected from the group consisting of —OR 13a and substituted or unsubstituted alkyl;
R 13a is selected from the group consisting of H and substituted or unsubstituted alkyl; and
R 14 is selected from the group consisting of H and substituted or unsubstituted alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is selected from the group consisting of —C(O)—, O, —SO 2 , —N(R 4 )—, and C(R 5a )(R 5b );
R 1 is selected from the group consisting of H, unsubstituted alkyl, and substituted or unsubstituted aryl;
R 2 is selected from the group consisting of H, substituted or unsubstituted alkyl, and unsubstituted aryl;
or R 1 and R 2 are taken together with the carbon to which they are attached to form a cycloalkyl, wherein the cycloalkyl is unsubstituted or fused with a ring selected from the group consisting of substituted or unsubstituted aryl;
R 3 is t-butyl or isopropyl, or R 3 is taken together with R 6 , when present, and the atoms to which they are attached, to form a substituted or unsubstituted heterocyclylene;
R 4 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 3 alkyl, and unsubstituted aryl;
R 5a and R 5b are each independently unsubstituted C 1 -C 3 alkyl; and
Z is selected from the group consisting of —N(R 6 )R 6a , —N(R 6 )—SO 2 —R 6b ,

R 6 is H; or R 6 is taken together with R 3 and the atoms to which they are attached to form a substituted or unsubstituted heterocyclylene;
each R 6a is substituted or unsubstituted acyl;
R 6b is unsubstituted alkyl;
R 13 is selected from the group consisting of —OR 13a and unsubstituted alkyl;
R 13a is selected from the group consisting of H and unsubstituted alkyl; and
R 14 is unsubstituted alkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is —C(O)— or O;
R 1 is

wherein R 7 is selected from the group consisting of halo, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl;
R 2 is a substituted or unsubstituted C 1 -C 3 alkyl;
or R 1 and R 2 are taken together with the carbon to which they are attached to form a cycloalkyl, wherein the cycloalkyl is unsubstituted or fused with an unsubstituted aryl;
R 3 is t-butyl or isopropyl; and
Z is selected from the group consisting of —N(R 6 )R 6a

 wherein
R 6 is H;
R 6a is a substituted or unsubstituted acyl;
r is 1; and
R 13 is selected from the group consisting of —OR 13a and unsubstituted alkyl, wherein R 13a is selected from the group consisting of H and unsubstituted alkyl.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein:
R 7 is selected from the group consisting of

R 9b is halo; and
Z is selected from the group consisting of —N(R 6 )R 6a and

wherein R 13 is selected from the group consisting of —CH 3 and —OR 13a , wherein R 13a is H or —CH 3 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

Assignees

• Genentech Inc

Inventors

• Blaquiere Nicole
• DRAGOVICH Peter
• Gazzard Lewis J
• Pillow Thomas
• Staben Steven T
• Wei Binqing
• Xin Jianfeng

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D471/16 Primary

  Peri-condensed systems · CPC title