IP Library › Granted Patent US 9,834,518
Granted Patent B2
US 9,834,518 · App. 13/464,921 · Granted Dec 5, 2017

Compounds for inhibiting cell proliferation in EGFR-driven cancers

Inventors: David C. Dalgarno (Brookline, MA); Wei-Sheng Huang (Acton, MA); William C. Shakespeare (Southborough, MA); Yihan Wang (Newton, MA); Xiaotian Zhu (Newton, MA)
Assignee: ARIAD Pharmaceuticals, Inc.
C07D239/48A61K31/4025A61K31/444A61K31/4523A61K31/505A61K31/506A61K31/538A61K31/553C07D401/12C07D403/12C07D405/12C07D413/12
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Quick Facts
Patent No.
US 9,834,518
App. No.
13/464,921
Granted
Dec 5, 2017
Kind
B2
Abstract

The invention features compounds, pharmaceutical compositions and methods for treating patients who have an EGFR-driven cancer of formula I: wherein the variables are as defined herein.

Claims (72)

1. A compound that is:

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;

(E)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide;

(E)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-morpholinobut-2-enamide;

(E)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide;

(E)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)but-2-enamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-3-methylbut-2-enamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)methacrylamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acrylamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)propiolamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)but-2-ynamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)ethenesulfonamide;

N-(3-((5-chloro-2-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-methyloxirane-2-carboxamide;

N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;

N-(3-((5-bromo-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;

N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-3-methylphenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;

N-(3-((5-chloro-4-((2-(diethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;

methyl 2-(((3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)amino)methyl)acrylate;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((dimethylamino)methyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)acrylamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N-(3-(dimethylamino)propyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acetamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((tetrahydrofuran-3-yl)oxy)phenyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-methoxyethoxy)phenyl)acrylamide;

N-acryloyl-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(diethylamino)-3-methoxypropan-2-yl)oxy)-4-methoxyphenyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)-4-methoxyphenyl)acrylamide;

rac-(R)—N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(diethylamino)-3-methoxypropan-2-yl)oxy)-4-methoxyphenyl)acrylamide;

rac-(R)—N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(diethylamino)-3-methoxypropan-2-yl)oxy)-4-methoxyphenyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-2-methylpropoxy)-4-methoxyphenyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(diethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((3-(dimethylamino)propyl)(methyl)amino)-4-methoxyphenyl)acrylamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((diisopropylamino)methyl)acrylamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methylphenyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-3-methoxypropoxy)-4-methoxyphenyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((2-((2-methoxyethyl)(methyl)amino)ethyl)(methyl)amino)phenyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-((2-methoxyethyl)(methyl)amino)ethoxy)phenyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(diethylamino)propyl)-4-methoxyphenyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(diethylamino)ethyl)-4-methoxyphenyl)acrylamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N-methylacrylamide;

N-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)acrylamide;

1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-1H-pyrrole-2,5-dione;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-ethoxyphenyl)acrylamide;

N-(5-((5-chloro-4-((2-(diethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide;

N-(5-((5-chloro-4-((2-(diethylphosphoryl)-3-methylphenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide;

N-(3-((5-chloro-4-((2-(diethylphosphoryl)-3-methylphenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;

(E)-N-(3-((5-chloro-2-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide;

N-(5-((5-chloro-4-((2-(diethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)acrylamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-3-fluorophenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide;

(E)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide;

(E)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-methoxyethoxy)phenyl)-4-(dimethylamino)but-2-enamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)oxirane-2-carboxamide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)oxirane-2-carboxamide;

(2-((5-chloro-2-((2-methoxy-5-((methyl(vinyl)phosphoryl)methyl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide;

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(diethylamino)ethyl)(ethyl)amino)-4-methoxyphenyl)acrylamide;

N-(2-((2-(diethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-ethylpyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;

N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-ethylpyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;

N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;

N-(3-((5-cyclopropyl-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;

or a pharmaceutically acceptable salt thereof.

2. A compound that is:

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)cyclohexyl)acrylamide;

rac-N-((1R,3R)-3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)cyclohexyl)acrylamide;

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)cyclohexyl)acrylamide;

or a pharmaceutically acceptable salt thereof.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 23, 2021
From: ARIAD PHARMACEUTICALS, INC.
To: TAKEDA PHARMACEUTICAL COMPANY LIMITED
Reel/Frame 056637/0879 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 13, 2012
From: DALGARNO, DAVID C.; HUANG, WEI-SHENG; SHAKESPEARE, WILLIAM C.; WANG, YIHAN; ZHU, XIAOTIAN
To: ARIAD PHARMACEUTICALS, INC.
Reel/Frame 028392/0143 →
Continuity (2)
Provisional Application 61482433 · May 4, 2011
Related Publication 20120316135A1 · Dec 13, 2012