US2022135571A1PendingUtilityA1
Therapeutic egfr inhibitors

Assignee: HOFFMANN LA ROCHEPriority: Jun 21, 2019Filed: Dec 21, 2021Published: May 5, 2022
Est. expiryJun 21, 2039(~12.9 yrs left)· nominal 20-yr term from priority
Inventors:Cosimo Dolente Annick Goergler Georg Jaeschke Bernd Kuhn Christa Ulrike Obst-Sander Antonio Ricci Daniel Rueher Sandra Steiner David Stephen Hewings Yvonne Alice Nagel
A61P 35/00A61K 31/5377C07D 487/04C07D 519/00A61K 47/12A61K 47/10A61K 9/4866A61K 9/4858A61K 9/485A61K 9/2054A61K 9/2018A61K 9/2013A61K 9/08
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Claims
Abstract

The invention provides novel compounds as described herein, compositions including the compounds and methods of using the compounds.
Claims

exact text as granted — not AI-modified
We claim: 
     
         1 . A compound selected from the group consisting of
 2-(4-chloro-6-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride;   2-(6-(4-(4-acetylpiperazin-1-yl)phenyl)-4-chloro-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-(4-chloro-6-(3-chloro-4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride;   2-(4-chloro-6-(3-chloro-4-(4-ethylpiperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-(6-(3-chloro-4-(piperazin-1-yl)phenyl)-4-fluoro-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride;   2-(6-(4-(4-acetylpiperazin-1-yl)-3-chlorophenyl)-4-fluoro-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-(6-(3-chloro-4-(4-ethylpiperazin-1-yl)phenyl)-4-fluoro-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-(4,7-dichloro-6-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride;   2-(6-(4-(4-acetylpiperazin-1-yl)phenyl)-4,7-dichloro-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-(4,7-dichloro-6-(4-(4-ethylpiperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-(4-chloro-7-fluoro-6-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride;   2-(4-chloro-6-(4-(4-ethylpiperazin-1-yl)phenyl)-7-fluoro-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-(4-chloro-7-fluoro-6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-[4-chloro-7-methoxy-6-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)indazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide;   2-[4-chloro-6-[4-(4-ethylpiperazin-1-yl)phenyl]-7-methoxyindazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide;   2-[4-chloro-6-[4-(1-cyclopropylpiperidin-4-yl)phenyl]-7-methoxyindazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide; and   2-(4-chloro-7-fluoro-6-(1-isopropyl-2-oxo-1,2-dihydropyridin-4-yl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   or a pharmaceutically acceptable salt thereof.   
     
     
         2 . The compound of  claim 1  selected from the group consisting of
 2-(4-chloro-6-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride; 
 2-(6-(4-(4-acetylpiperazin-1-yl)phenyl)-4-chloro-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-(4-chloro-6-(3-chloro-4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride; 
 2-(4-chloro-6-(3-chloro-4-(4-ethylpiperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-(6-(3-chloro-4-(piperazin-1-yl)phenyl)-4-fluoro-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride; 
 2-(6-(4-(4-acetylpiperazin-1-yl)-3-chlorophenyl)-4-fluoro-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-(6-(3-chloro-4-(4-ethylpiperazin-1-yl)phenyl)-4-fluoro-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-(4,7-dichloro-6-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride; 
 2-(6-(4-(4-acetylpiperazin-1-yl)phenyl)-4,7-dichloro-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-(4,7-dichloro-6-(4-(4-ethylpiperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-(4-chloro-7-fluoro-6-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride; 
 2-(4-chloro-6-(4-(4-ethylpiperazin-1-yl)phenyl)-7-fluoro-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-(4-chloro-7-fluoro-6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-[4-chloro-7-methoxy-6-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)indazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide; 
 2-[4-chloro-6-[4-(4-ethylpiperazin-1-yl)phenyl]-7-methoxyindazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide; 
 2-[4-chloro-6-[4-(1-cyclopropylpiperidin-4-yl)phenyl]-7-methoxyindazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide; and 
 2-(4-chloro-7-fluoro-6-(1-isopropyl-2-oxo-1,2-dihydropyridin-4-yl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide. 
 
     
     
         3 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the compound is selected from the group consisting of
 2-(4-chloro-6-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride;   2-(6-(4-(4-acetylpiperazin-1-yl)phenyl)-4-chloro-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-(4-chloro-6-(3-chloro-4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride;   2-(4-chloro-6-(3-chloro-4-(4-ethylpiperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-(6-(3-chloro-4-(piperazin-1-yl)phenyl)-4-fluoro-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride;   2-(6-(4-(4-acetylpiperazin-1-yl)-3-chlorophenyl)-4-fluoro-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-(6-(3-chloro-4-(4-ethylpiperazin-1-yl)phenyl)-4-fluoro-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-(4,7-dichloro-6-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride;   2-(6-(4-(4-acetylpiperazin-1-yl)phenyl)-4,7-dichloro-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-(4,7-dichloro-6-(4-(4-ethylpiperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-(4-chloro-7-fluoro-6-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride;   2-(4-chloro-6-(4-(4-ethylpiperazin-1-yl)phenyl)-7-fluoro-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-(4-chloro-7-fluoro-6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide;   2-[4-chloro-7-methoxy-6-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)indazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide;   2-[4-chloro-6-[4-(4-ethylpiperazin-1-yl)phenyl]-7-methoxyindazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide;   2-[4-chloro-6-[4-(1-cyclopropylpiperidin-4-yl)phenyl]-7-methoxyindazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide; and   2-(4-chloro-7-fluoro-6-(1-isopropyl-2-oxo-1,2-dihydropyridin-4-yl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide.   
     
     
         5 . A method for the treatment or prophylaxis of cancer, which method comprises administering an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The method of  claim 5  wherein the compound is selected from the group consisting of
 2-(4-chloro-6-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride; 
 2-(6-(4-(4-acetylpiperazin-1-yl)phenyl)-4-chloro-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-(4-chloro-6-(3-chloro-4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride; 
 2-(4-chloro-6-(3-chloro-4-(4-ethylpiperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-(6-(3-chloro-4-(piperazin-1-yl)phenyl)-4-fluoro-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride; 
 2-(6-(4-(4-acetylpiperazin-1-yl)-3-chlorophenyl)-4-fluoro-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-(6-(3-chloro-4-(4-ethylpiperazin-1-yl)phenyl)-4-fluoro-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-(4,7-dichloro-6-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride; 
 2-(6-(4-(4-acetylpiperazin-1-yl)phenyl)-4,7-dichloro-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-(4,7-dichloro-6-(4-(4-ethylpiperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-(4-chloro-7-fluoro-6-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide hydrochloride; 
 2-(4-chloro-6-(4-(4-ethylpiperazin-1-yl)phenyl)-7-fluoro-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-(4-chloro-7-fluoro-6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 
 2-[4-chloro-7-methoxy-6-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)indazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide; 
 2-[4-chloro-6-[4-(4-ethylpiperazin-1-yl)phenyl]-7-methoxyindazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide; 
 2-[4-chloro-6-[4-(1-cyclopropylpiperidin-4-yl)phenyl]-7-methoxyindazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide; and 
 2-(4-chloro-7-fluoro-6-(1-isopropyl-2-oxo-1,2-dihydropyridin-4-yl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide. 
 
     
     
         7 . The method of  claim 5 , wherein the cancer is a non-small cell lung cancer. 
     
     
         8 . The method of  claim 6 , wherein the cancer is a non-small cell lung cancer.
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