Irreversible covalent inhibitors of the GTPase K-Ras G12C

• US 9,745,319 B2
• Filed: 03/14/2014
• Issued: 08/29/2017
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Araxes Pharma LLC
• Original Assignee: Araxes Pharma LLC
• Inventors: Ren, Pingda, Liu, Yi, Li, Liansheng, Feng, Jun
• Primary Examiner(s): Neagu, Irina
• Application Number:
  US14/777,334
• Publication Number:
  US 20160031898A1
• Time in Patent Office: 1,264 Days
• Field of Search: 514469, 514470, 549464
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/34 having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 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 Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 311/11 of an acyclic unsaturated carbon skeleton
• CPC Class Codes: C07C 311/17 to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 311/18 to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
• CPC Class Codes: C07D 493/04 Ortho-condensed systems

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.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein R₂ is —

CH₂—

R₄.

3. The compound of claim 2, wherein R₄ is OH.

4. The compound of claim 1, wherein R₂ is —

O—

CH₂—

.

5. The compound of claim 4, wherein R₄ is C₆H₅.

6. The compound of claim 1, wherein R₁ is an alkyl, unsubstituted or substituted with one or more R₃ groups.

7. The compound of claim 1, wherein R₁ is an alkyl substituted with one or more R₃ groups, and wherein R₃ is aryl.

8. The compound of claim 1, wherein R₁ is —

CH₂—

C₆H₅.

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.