HER2 mutation inhibitors

Inventors

ELLIS, Bryan Daniel • Hicken, Erik James • Laird, Ellen Ruth • LAZZARA, Nicholas Charles • NEWHOUSE, Bradley Jon • PAJK, Spencer Phillip • Rosen, Rachel Zoe • Shelp, Russell Andrew

Assignees

Pfizer Inc

Abstract

This invention relates to compounds of Formula (I): and enantiomers thereof, and to pharmaceutically acceptable salts of Formula (I) and said enantiomers, wherein A, L2, R1, R2, R3, R4, and n are as defined herein. The invention further relates to pharmaceutical compositions comprising such compounds and salts, and to methods and uses of such compounds, salts, and compositions for the treatment of abnormal cell growth, including cancer, in a subject in need thereof.

Core Innovation

The invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, and compounds of Formula (III) and pharmaceutically acceptable salts thereof. The compound definition specifies A selected from carbon and nitrogen, R1 selected from -L1-R5, —NR6R7, N-methyl-3-acrylamide, and prop-1-en-2-yl, each R3 independently selected from halogen, methyl, difluoromethyl and trifluoromethyl, and R4 selected from hydrogen, Cl or methoxy.

L1 is selected from a bond, CHR8, O, NR8 and S, L2 is selected from NH and O, and R5 is a 4 to 10 membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, substituted by R6 and optionally substituted by 1 or 2 groups from a defined list. In Formula (III), each R3 is independently selected from halogen and methyl, R5 is a 4 to 9 membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, and R6 is selected from 1-prop-2-en-1-one, 1-(2-fluoroprop-2-en-1-one), 1-(2-methylprop-2-en-1-one), and 1-but-2-yn-1-one, with n being 1 or 2.

The invention further provides pharmaceutical compositions comprising the compound or pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable excipient. The disclosure also includes methods for treating cancer, including HER2 positive cancer selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer, esophageal cancer, liver cancer, pancreatic cancer, or stomach cancer, and treatment contexts involving HER2 mutation-associated cancers and brain metastases.

Claims Coverage

The consolidated claim coverage includes four independent claim groups: Formula (I) compounds, Formula (III) compounds, a compound and pharmaceutical composition, and a method for treating HER2 positive cancer. The inventive features are centered on constrained heterocyclic scaffolds, defined linker and substituent selections, pharmaceutical composition coverage, and treatment of specified HER2 positive cancer types.

Overall, the claims define Formula (I) and Formula (III) compounds through constrained substituent, linker, heterocycle, and n selections, extend coverage to pharmaceutical compositions containing the compound and excipient, and include treatment methods limited to HER2 positive cancers from a specified list.

Stated Advantages

Documented Applications