Kras protein degraders, pharmaceutical compositions thereof, and their therapeutic applications

Patent metadata

Field	Value
Publication number	US-2024190883-A1
Application number	US-202318542629-A
Country	US
Kind code	A1
Filing date	Dec 16, 2023
Priority date	Jun 16, 2021
Publication date	Jun 13, 2024
Grant date	—

Abstract

Provided herein are KRAS protein degraders, for example, a compound of Formula (A), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a KRAS-mediated disorder, disease, or condition.

First claim

What is claimed is:

1 . A compound of Formula (I):

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, hydrate, or prodrug thereof; wherein:
R 4A is -A-L-R E and R 4B is R 4 ; or R 4A is R 4 and R 4B is -A-L-R E ;
A is a bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-10 cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene;
L is a linker;
R E is a moiety having the structure of

R 1 , R 3 , and R 4 are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(NR 1a )NR 1b R 1c —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1a R 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —N 1a C(NR 1d R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1e , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;
R 2 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, heterocyclyl, or C 1-6 alkyl-heterocyclylene;
each R 1a , R 1b , R 1c , and R 1d is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;
X E is C(R E2 ) or N;
Y E is a bond, C 1-6 alkylene, —O—, —S—, —S(O)—, —S(O 2 )—, or —N(R E3 )—;
Z E is C 6-14 arylene, heteroarylene, or C 6-14 arylene-heteroarylene;
R E1 is hydrogen or C 1-6 alkyl;
R E2 is hydrogen, deuterium, halo, or C 1-6 alkyl;
R E3 is hydrogen or C 1-6 alkyl; and
m is an integer of 0, 1, or 2;
wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) —C(O)R a , —C(O)OR a , —C(O)NR 1b R 1c , —C(O)SR a , —C(NR a )NR 1b R 1c , —C(S)R a , —C(S)OR a , —C(S)NR 1b R 1c , —OR, —OC(O)R a , —OC(O)OR a , —OC(O)NR 1b R 1c , —OC(O)SR a , —OC(NR a )NR 1b R 1c , —OC(S)R a , —OC(S)OR a , —OC(S)NR 1b R 1c , —OP(O)(OR b )OR c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R, —NR 1b R 1c , —NR a C(O)R 1d , —NR a C(O)OR, —NR a C(O)NR—R c , —NR a C(O)SR 1d , —NR a C(NR 1d )NR 1b R 1c , —NR a C(S)R 1d , —NR a C(S)OR 1d , —NR a C(S)NR 1b R 1c , —NR a S(O)R 1d , —NR a S(O) 2 R b , —NR a S(O)NR 1b R 1c , —NR a S(O) 2 NR 1b R 1c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR 1b R 1c , and —S(O) 2 NR 1b R 1c , wherein each R a , R b , R c , and R 1d is independently (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ;
wherein each Q a is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R c , —C(O)OR e , —C(O)NR f R g , —C(O)SR e , —C(NR c )NR f R g , —C(S)R e , —C(S)OR e , —C(S)NR f R g , —OR e , —OC(O)R e , —OC(O)OR e , —OC(O)NR f R g , —OC(O)SR c , —OC(NR e )—NR f R g , —OC(S)R e , —OC(S)OR e , —OC(S)NR f R g , —OP(O)(OR f )OR g , —OS(O)R e , —OS(O) 2 R, —OS(O)NR f R—, —OS(O) 2 NR f R g , —NR f R g , —NR e C(O)R h , —NR c C(O)OR f , —NR c C(O)NR f R g , —NR e C(O)SR f , —NR e C(NR h )NR f R g , —NR e C(S)R h , —NR e C(S)OR, —NR e C(S)NR f R g , —NR e S(O)R h , —NR e S(O) 2 R h , —NRS(O)NR f R g , —NR e S(O) 2 NR f R, —SW, —S(O)R, —S(O) 2 , —S(O)NR f R g , and —S(O) 2 NR f R g ; wherein each R e , R f , R g , and R h is independently (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl.

2 . The compound of claim 1 , having the structure of Formula (II):

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, hydrate, or prodrug thereof.

3 . The compound of claim 1 , having the structure 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, hydrate, or prodrug thereof.

4 . The compound of any one of claims 1 to 3 , wherein A is a bond, C 1-6 alkylene, C 3-10 cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; each of which is optionally substituted with one or more substituents Q.

5 . The compound of any one of claims 1 to 4 , wherein A is a bond or C 1-6 alkylene, optionally substituted with one or more substituents Q.

6 . The compound of any one of claims 1 to 5 , wherein A is a bond or methylene.

7 . The compound of any one of claims 1 to 4 , wherein A is C 6-14 arylene, optionally substituted with one or more substituents Q.

8 . The compound of any one of claims 1 to 4 and 7 , wherein A is phenylene, optionally substituted with one or more substituents Q.

9 . The compound of any one of claims 1 to 4, 7, and 8 , wherein A is phen-1,3-diyl or phen-1,4-diyl, each optionally substituted with one or more substituents Q.

10 . The compound of any one of claims 1 to 4 , wherein A is heterocyclylene, optionally substituted with one or more substituents Q.

11 . The compound of any one of claims 1 to 4 and 10 , wherein A is monocyclic heterocyclylene, optionally subs

Assignees

• Biotheryx Inc

Inventors

• Chan Kyle W H
• Chourasia Aparajita Hoskote
• Erdman Paul E
• Fung Leah M
• Hecht David Aaron
• Lam Imelda
• Papa Patrick
• Schoolmeesters Angela
• Torres Eduardo

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title