Protein-targeting compounds and pharmaceutical compositions thereof, and their therapeutic applications

Patent metadata

Field	Value
Publication number	US-11345712-B2
Application number	US-202016882750-A
Country	US
Kind code	B2
Filing date	May 26, 2020
Priority date	May 24, 2019
Publication date	May 31, 2022
Grant date	May 31, 2022

Abstract

The present disclosure provides compounds, for example, a compound of Formula (I), that modulate a protein function and/or restore protein homeostasis. The disclosure provides a method of modulating a protein-mediated disease, disorder, condition, or response. Compositions, including in combination with other therapeutic agents, are provided.

First claim

What is claimed is:

1. A compound of Formula (III):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:
R 1 is selected from the group consisting of

each X is independently CH 2 or C(═O);
R Z is —NR 7a R 8a or ring A; and ring A is C 6 -C 10 aryl, 5 to 10 membered heteroaryl, C 3 -C 8 carbocyclyl, or 3 to 10 membered heterocyclyl, each optionally substituted with one or more R A ;
R 2 is H, deuterium, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 carbocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;
R 3a , R 3b , R 3c , R 3d , R 3e , and R 3f are each independently H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —(CH 2 ) t —NR 7a R 8a , —O(CH 2 ) t —NR 7a R 8a , —C(O)NR 7b R 8b , —S(O) 2 NR 7c R 8c , —OR 9 , —SR 10a , —C(O)OR 10b , —C(O)R 11a , —NR 7d C(O)R 11b , —S(O) 2 R 11c , —NR 7e S(O) 2 R 11d , (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted C 3 -C 8 carbocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;
each R 3g is independently deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —(CH 2 ) t —NR 7a R 8a , —O(CH 2 ) t —NR 7a R 8a , —C(O)NR 7b R 8b , —S(O) 2 NR 7c R 8c , —OR 9 , —SR 10a , —C(O)OR 10b , —C(O)R 11a , —NR 7d C(O)R 11b , —S(O) 2 R 11c , —NR 7e S(O) 2 R 11d , (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted C 3 -C 8 carbocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;
each R 4 is independently H, deuterium, halogen, or optionally substituted C 1 -C 6 alkyl;
each R 5 is independently H, deuterium, C 1 -C 6 alkyl,

each R 6a , R 6b , R 14 , and R 15 is independently H, substituted or unsubstituted amino, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or C 3 -C 8 carbocyclyl; or R 6a and R 6b together with the carbon atom to which they are attached form a C 3 -C 8 carbocyclyl; wherein each C 3 -C 8 carbocyclyl is optionally substituted with one or more R B ;
each R 7a , R 7b , R 7c , R 7d , R 7e , R 8a , R 8b , R 8c , R 16 , and R 17 is independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 7 -C 14 aralkyl, or optionally substituted C 3 -C 8 carbocyclyl; or R 7a and R 8a together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl; or R 7b and R 8b together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl; or R 7c and R 8c together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl; or R 16 and R 17 together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl; wherein each of C 6 -C 10 aryl, C 7 -C 14 aralkyl, C 3 -C 8 carbocyclyl, and 3 to 7 membered heterocyclyl is optionally substituted with one or more R B ;
each R 9 is independently optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 7 -C 14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C 3 -C 8 carbocyclyl;
each of R 10a , R 11b , R 12 , and R 13 is independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 7 -C 14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C 3 -C 8 carbocyclyl;
each R 11a , R 11b , R 11c , and R 11d is independently optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 7 -C 14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C 3 -C 8 carbocyclyl;
each R A is independently halogen, cyano, nitro, hydroxyl, optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —(CH 2 ) t —NR 7a R 8a , —O(CH 2 ) t —NR 7a R 8a , —C(O)NR 7b R 8b , —S(O) 2 NR 7c R 8c , —OR 9 , —SR 10a , —C(O)OR 10b , —C(O)R 11a , —NR 7d C(O)R 11b , —S(O) 2 R 11c , —NR 7e S(O) 2 R 11d , (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, phenyl, 5 to 10 membered heteroaryl, C 3 -C 8 carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5 to 10 membered heteroaryl, C 3 -C 8 carbocyclyl, and 3 to 10 membered heterocyclyl is optionally substituted with one or more R B ;
each R B is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, halogen, or cyano; or two geminal R B form oxo;
m is an integer of 0, 1, 2, 3, 4, or 5;
n1 is an integer of 0, 1, 2, or 3;
each p is independently an integer of 0, 1, or 2; and
each t is independently an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8.

2. The compound of claim 1 , being a compound of Formula (IIIa):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate, thereof.

3. The compound of claim 1 , being a compound of Formula (IIIb):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

4. The compound of claim 1 , being a compound of Formula (IIIc):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

5

Assignees

• Biotheryx Inc

Inventors

• Chan Kyle W H
• Erdman Paul E
• Fung Leah
• Hecht David Aaron
• Lam Imelda
• Sullivan Robert
• Torres Eduardo

Classifications

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P29/00

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

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title