Irreversible covalent inhibitors of the GTPase K-Ras G12C

Patent metadata

Field	Value
Publication number	US-9745319-B2
Application number	US-201414777334-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

Irreversible inhibitors of K-Ras, H-Ras or N-ras protein comprising a G12C mutation are provided. Also disclosed are methods to regulate the activity of K-Ras, H-Ras or N-ras protein comprising G12C mutation and methods to disease mediated by K-Ras, H-Ras or N-ras G12C.

First claim

The invention claimed is:

1. A compound of Formula I:

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, each of which is either unsubstituted or substituted with one or more R 3 groups;
R 2 is hydrogen, halogen, alkoxy, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, wherein each of the alkoxy, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl is either unsubstituted or substituted with one or more R 4 groups;
R 3 is hydrogen, halogen, OR 5 , NR 6 R 7 , cyano, oxo, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, wherein each of the OR 5 , NR 6 R 7 , alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl is either unsubstituted or substituted with one or more R 8 groups;
R 5 , R 6 and R 7 are independently hydrogen, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, wherein each of the alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl is either unsubstituted or substituted with one or more R 9 groups;
R 4 , R 8 and R 9 are independently hydrogen, cyano, halogen, hydroxy, alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, wherein each of the alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl is either unsubstituted or substituted with one or more R 10 groups;
each R 10 is independently halogen, hydroxy, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl; and
E is an electrophile capable of forming a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-ras G12C mutant protein and having one of the following structures:

wherein:
R 21 is alkyl;
R 22 is CN or alkyl;
R 23 is alkyl;
or R 23 joins with R 22 to form a cycloalkene or aryl ring.

2. The compound of claim 1 , wherein R 2 is —CH 2 —R 4 .

3. The compound of claim 2 , wherein R 4 is OH.

4. The compound of claim 1 , wherein R 2 is —O—CH 2 —.

5. The compound of claim 4 , wherein R 4 is C 6 H 5 .

6. The compound of claim 1 , wherein R 1 is an alkyl, unsubstituted or substituted with one or more R 3 groups.

7. The compound of claim 1 , wherein R 1 is an alkyl substituted with one or more R 3 groups, and wherein R 3 is aryl.

8. The compound of claim 1 , wherein R 1 is —CH 2 —C 6 H 5 .

9. The compound of claim 1 , wherein E is

10. The compound of claim 1 , wherein the compound has one of the following structures:

11. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

Assignees

• Araxes Pharma Llc

Inventors

• Ren Pingda
• Liu Yi
• Li Liansheng
• Feng Jun

Classifications

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• C07C311/11

  of an acyclic unsaturated carbon skeleton · CPC title

• A61K31/18

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

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