ERK inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-12428416-B2
Application number	US-201917294225-A
Country	US
Kind code	B2
Filing date	Nov 15, 2019
Priority date	Nov 16, 2018
Publication date	Sep 30, 2025
Grant date	Sep 30, 2025

Abstract

The present disclosure provides compounds and compositions that are inhibitors of ERK1, ERK2, or both, and methods of use thereof.

First claim

We claim:

1. A compound having the structure of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is optionally substituted heterocyclyl, or optionally substituted heteroaryl;
L 1 is a bond;

is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, wherein any of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl can be optionally substituted with one or more substituents selected from halogen, optionally substituted C 1-3 alkyl and N(R 3 ) 2 ;
X in each occurrence is independently selected from CH and N;
L 2 is optionally substituted C 1-5 alkyl, C(O)N(R 4 )(C(R 4 ) 2 ) m , (C(R 4 ) 2 ) m C(O)N(R 4 ), C(O)heterocyclyl, heterocyclyl-C(O), N(R 4 ), S(O) 2 N(R 4 ), N(R 4 )S(O) 2 , S(O) 2 , or heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more optionally substituted aryl, optionally substituted C1-4alkyl or halogen;

is aryl or heteroaryl;
R 2 if present, in each instance is independently optionally substituted C 1-6 alkyl, alkoxy, optionally substituted cycloalkyl, CN, NR 1a R 1b , C(O)N(R 1a )(R 1b ), N(R 1a )C(O)R 1a , halogen or CF 3 ;
each of R 1a and R 1b is, in each instance, independently hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl; or R 1a and R 1b , together with the N to which they are bonded, form an optionally substituted heterocyclyl;
R 3 is, in each instance, independently hydrogen or optionally substituted C 1-4 alkyl;
R 4 is, in each instance, independently hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl;
m is 0, 1, 2 or 3; and
q is 0, 1, 2 or 3.

2. The compound of claim 1 , wherein L 2 is optionally substituted C 1-5 alkyl, optionally substituted heterocyclyl, C(O)N(R 4 )(C(R 4 R 4 )) m , or C(O) heterocyclyl.

3. The compound of claim 1 , wherein L 2 is hydroxy-substituted C 1-5 alkyl or methoxy-substituted C 1-5 alkyl.

4. The compound of claim 1 , wherein L 2 is unsubstituted oxazolinyl or unsubstituted imidazolinyl.

5. The compound of claim 2 , wherein L 2 is C(O)N(R 4 )(C(R 4 R 4 )) m ; and each instance of R 4 is independently hydrogen or C 1-4 alkyl; and m is 0, 1, or 2.

6. The compound of claim 1 , wherein the compound of Formula I has the structure of Formula Ia′:

or a pharmaceutically acceptable salt thereof,
the compound of Formula I has the structure of Formula Ib′:

or a pharmaceutically acceptable salt thereof,
the compound of Formula I has the structure of Formula Ic′:

or a pharmaceutically acceptable salt thereof.

7. A compound having the structure of Formula II:

or a pharmaceutically acceptable salt thereof,
wherein:

is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, wherein any of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl can be optionally substituted with one or more substituents selected from halogen, optionally substituted C 1-3 alkyl and N(R 3 ) 2 ;
X in each occurrence is independently selected from CH and N;

is aryl or heteroaryl;
R 2 if present, in each instance is independently optionally substituted C 1-6 alkyl, alkoxy, optionally substituted cycloalkyl, CN, NR 1a R 1b , C(O)N(R 1a )(R 1b ), N(R 1a )C(O)R 1a , halogen or CF 3 ;
each of R 1a and R 1b is, in each instance, independently hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl; or R 1a and R 1b , together with the N to which they are bonded, form an optionally substituted heterocyclyl;
R 3 is, in each instance, independently hydrogen or optionally substituted C 1-4 alkyl;
R 4 is, in each instance, independently hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl;
R 7 when present, is optionally substituted C 1-6 alkyl;
m is 0, 1, 2 or 3;
n is 0, 1, 2, 3 or 4; and
q is 0, 1, 2 or 3.

8. The compound of claim 7 , wherein the compound of Formula II has the structure of Formula IIa:

or a pharmaceutically acceptable salt thereof.

9. A compound having the structure of Formula III:

or a pharmaceutically acceptable salt thereof,
wherein:

is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, wherein any of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl can be optionally substituted with one or more substituents selected from halogen, optionally substituted C 1 -3alkyl and N(R 3 ) 2 ;
X in each occurrence is independently selected from CH and N;

is aryl or heteroaryl;

is heterocyclyl;
R 2 if present, in each instance is independently optionally substituted C 1-6 alkyl, alkoxy, optionally substituted cycloalkyl, CN, NR 1a R 1b , C(O)N(R 1a )(R 1b ), N(R 1a )C(O)R 1a , halogen or CF 3 ;
each of R 1a and R 1b is, in each instance, independently hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl; or R 1a and R 1b , together with the N to which they are bonded, form an optionally substituted heterocyclyl;
R 3 is, in each instance, independently hydrogen or optionally substituted C 1-4 alkyl;
R 4 is, in each instance, independently hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl;
R 7 when present, is optionally substituted C 1-6 alkyl;
n is 0, 1, 2, 3 or 4;
p is 0 or 1; and
q is, in each instance, independently 0, 1, 2 or 3.

10. The compound of claim 9 , wherein the compound of Formula III has the structure of Formula IIIa:

or a pharmaceutically acceptable salt thereof.

Assignees

• California Inst Of Techn
• 1200 Pharma Llc
• Univ California

Inventors

• Reeves Corey M
• O'Boyle Brendan M
• Hilf Justin A
• Conklin Dylan
• Mcdermott Martina S
• O'Brien Neil A
• Palazzolo Michael J
• Slamon Dennis
• Wittenberger Steven J
• Loson Oliver C
• Bartberger Michael D
• Stoltz Brian M

Classifications

• C12N9/1205

  Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title