US2022062242A1PendingUtilityA1

Methods and compositions for inhibiting mutant EGFR signaling

Assignee: GOVERNING COUNCIL UNIV TORONTOPriority: Sep 28, 2017Filed: Sep 8, 2021Published: Mar 3, 2022

Est. expirySep 28, 2037(~11.1 yrs left)· nominal 20-yr term from priority

Inventors:Igor Stagljar Jamie Snider Punit Saraon

A61K 31/553A61K 31/423A61K 31/497A61P 35/00A61K 31/4535A61K 39/3955

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References

Claims

Abstract

Methods of inhibiting mutant EGFR and methods of treating a subject afflicted with a lung cancer having a mutant EGFR, having for example a C797 mutation, are described. The methods comprise administering to a cell or a subject in need thereof a therapeutically effective amount of a compound selected from 3-(1,3-benzoxazol-2-yl)-7-(diethylamino)-2H-chromen-2-one and a structurally related analog thereof; midostaurin; and AZD7622 and a structurally related analog thereof; and mixtures thereof. Compositions and combinations comprising the compounds of the disclosure as well as uses are also provided.

Claims

exact text as granted — not AI-modified

1 .- 29 . (canceled) 
     
     
         30 . A composition or combination comprising at least two compounds selected from:
 3-(1,3-benzoxazol-2-yl)-7-(diethylamino)-2H-chromen-2-one and/or structurally related analog thereof, the structurally related analog thereof selected from benzoxazolyl and/or chromenone containing compounds, substituted versions thereof or a salt or solvate of any of the foregoing;   midostaurin or a salt or solvate thereof;   gilteritinib or a salt or solvate thereof;   3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide; and   an anti-EGFR therapeutic antibody.   
     
     
         31 . The composition or combination of  claim 30 , wherein the composition or combination comprises:
 a) i) 3-(1,3-benzoxazol-2-yl)-7-(diethylamino)-2H-chromen-2-one, a structurally related analog thereof, the structurally related analog thereof selected from benzoxazolyl and/or chromenone containing compounds, substituted versions thereof or a salt or solvate of any of the foregoing, ii) midostaurin or a salt or solvate thereof, iii) gilteritinib or a salt or solvate thereof, or iv) 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide; and   b) an anti-EGFR therapeutic antibody.   
     
     
         32 . The composition or combination of  claim 30 , wherein the composition is a pharmaceutical composition. 
     
     
         33 . The composition or combination of  claim 32 , wherein the composition is in a dosage form selected from a solid dosage form and a liquid dosage form. 
     
     
         34 . The composition or combination of  claim 32 , wherein the composition is an injectable dosage form. 
     
     
         35 . The composition or combination of  claim 32 , wherein the composition is formulated for administration by parenteral, intravenous, subcutaneous, intracardial, intramuscular, or oral administration. 
     
     
         36 .- 43 . (canceled) 
     
     
         44 . The composition or combination of  claim 30 , wherein the structurally related analog thereof is a halogen substituted benzoxazolyl analog or chlorine substituted analog thereof. 
     
     
         45 . The composition or combination of claim  37 , wherein the chlorine substituted analog is 3-(5-chloro-1,3-benzoxazol-2-yl)-7-(diethylamino)-2H-chromen-2-one. 
     
     
         46 . The composition or combination of  claim 30 , wherein the chromenone containing compound is selected from the following chromen-2-one derivatives: 7-Methoxy-3-(2-methyl-thiazol-4-yl)-chro-men-2-one; 7-Ethoxy-3-(2-methyl-thiazol-4-yl)-chro-men-2-one; 3-(2-[4-(Chromen-2-one-3-yl)tiazol-2-yl]thia-zol-4-yl)-chromen-2-one; 7-Methoxy-3-(2-methyl-thiazol-4-yl)-chro-men-2-one; 7-Hydroxy-3-(2-phenyl-thiazol-4-yl)-chro-men-2-one; 6-Methoxy-3[4(4-methoxy-phenyl)thia-zol-2-yl]-chromen-2-one; 7-Hydroxy-3-[4-(4-methoxy-phenyl)-thia-zol-2-yl]-chromen-2-one; 7-Diethylamino-3-[2-(4-dimethylamino-phenyl)-thiazol-4-yl]-chromen-2-one; 3-[4-(4-Chloro-phenyl)-thiazol-2-yl]-6-hexyl-7-hydroxy-chromen-2-one; 6-Hexyl-7-hydroxy-3-[4-(4-phenoxy-phe-nyl)-thiazol-2-yl]-chromen-2-one; 7-Hydroxy-3-[4-(4-phenoxy-phenyl)-thia-zol-2-yl]-chromen-2-one; 6-Hexyl-7-hydroxy-3-[4-(4-methoxy-phe-nyl)-thiazol-2-yl]-chromen-2-one; 7-Diethylamino-3-(4-methyl-thiazol-2-yl)-chro-men-2-one; 3-[4-(4-Bromo-phenyl)-thiazol-2-yl]-6-hex-yl-7-hydroxy-chromen-2-one; 6-Hexyl-7-hydroxy-3-(2-phenyl-thia-zol-4-yl)-chromen-2-one, 6-Hexyl-7-hydroxy-3-(4-phenyl-thiazol-2-yl)-chromen-2-one; 7-Hydroxy-3-(4-phenyl-thiazol-2-yl)-chromen-2-one; 6-Hexyl-7-hydroxy-3-(4-methyl-thiazol-2-yl)-chromen-2-one; 7-Hydroxy-3-(5-methyl-4-phenyl-thiazo-2-yl)-chromen-2-one; 3-[4-(4-Chloro-4-phenyl)-5-methyl-thiazol-2-yl]-7-hydroxy-chromen-2-one; 7-Hydroxy-3-(5-methyl-4-p-tolyl-thiazol-2-yl)-chromen-2-one; 6-Bromo-3-[4-(4-ethoxy-phenyl)-thia-zol-2-yl]-chromen-2-one; 3-[4-(4-Ethyl-phenyl)-5-methyl-thiazol-2-yl]-7-hydroxy-chromen-2-one; 3-[4-(4-Chloro-phenyl)-thiazol-2-yl]-6-meth-oxy-chromen-2-one; 3-[2-(3,4-Dimethoxy-phenyl)-thiazol-4-yl]-chro-men-2-one; 3-[4-(4-Bromo-phenyl)-5-ethyl-thiazol-2-yl]-7-hydroxy-chromen-2-one; 3-(4,5-Dihydro-naphtho[1,2-d]thiazol-2-yl)-7-hy-droxy-chromen-2-one; 7-Diethylamino-3-(4-phenyl-thiazol-2-yl)-chro-men-2-one; 3-[4-(3,4-Dichloro-phenyl)-5-methyl-thiazol-2-yl]-7-hydroxy-chromen-2-one; 3-[4-(4-Chloro-phenyl)-5-ethyl-thia-zol-2-yl]-7-hydroxy-chromen-2-one, 3-(5-Ethyl-4-p-tolyl-thiazol-2-yl)-7-hy-droxy-chromen-2-one; 7-Diethylamine-3-(2-phenyl-thiazol-4-yl)-chro-men-2-one; 3-[4-(2,5-Dimethyl-phenyl)-5-ethyl-thiazol-2-yl]-7-hydroxy-chromen-2-one; 3-[2-(4-Hydroxy-phenyl)-thiazol-4-yl]-chro-men-2-one; 3-(5-Ethyl-4-phenyl-thiazol-2-yl)-7-hy-droxy-chromen-2-one; 3-[2-(2,4-Dimethyl-phenyl)-thiazol-4-yl]-7-hy-droxy-chromen-2-one; 3-[4-(3-Bromo-phenyl)-thazol-2-yl]-8-meth-oxy-chromen-2-one; 7-Hydroxy-3-[4-(3-methoxy-phenyl)-thia-zol-2-yl]-chromen-2-one; 3-Benzothiazol-2-yl-7-hydroxy-chro-men-2-one; 3-(5-Chloro-1H--benzoimidazol-2-yl)-8-meth-oxy-chromen-2-one; 3-[5-(3-Fluoro-phenyl)-[1,3,4]oxa-diazol-2-yl]-8-methoxy-chromen-2-one; 3-Benzo[d]imidazo[2,1-b]thiazol-2-yl-chro-men-2-one; 3-(7-Methoxy-benzo[d]imidazo[2,1-b]thia-zol-2-yl)-chromen-2-one; 6-Chloro-3-(7-fluoro-benzo[d]imi-dazo[2,1-b]thiazol-2-yl)-chromen-2-one; 3-Benzo[d]imidazo[2,1-b]thiazol-2-yl-6-hex-yl-7-hydroxy-chromen-2-one; 6,8-Dichloro-3-(5-p-tolylamino-[1,3,4]thia-diazol-2-yl)-chromen-2-one; 3-[5-(3-Chloro-phenyl)-[1,3,4]oxa-diazol-2-yl]-6-hexyl-7-hydroxy-chro-men-2-one; 6-Hexyl-7-hydroxy-3-[5-(3-methoxy-phe-nyl)-[1,3,4]oxadiazol-2-yl]-chro-men-2-one; 6-Hexyl-7-hydroxy-3-(7-methyl-imidazo[1,2-a]pyridin-2-yl)-chromen-2-one; 6-Methoxy-3-[2-(4-methoxy-phenyl-amino)-thiazol-5-yl]-chromen-2-one; and 6-hexyl-7-hydroxy-3-[5-(3,4,5-trimeth-oxy-phenyl)-[1,3,4]oxadiazol-2-yl]-chro-men-2-one. 
     
     
         47 . The composition or combination of  claim 30 , wherein the anti-EGFR therapeutic antibody is cetuximab or an antigen-binding fragment thereof or panitumumab or an antigen-binding fragment thereof. 
     
     
         48 . The composition or combination of  claim 31 , wherein the composition is a pharmaceutical composition. 
     
     
         49 . The composition or combination of claim  41 , wherein the composition is in a dosage form selected from a solid dosage form and a liquid dosage form. 
     
     
         50 . The composition or combination of claim  41 , wherein the composition is an injectable dosage form. 
     
     
         51 . The composition or combination of claim  41 , wherein the composition is formulated for administration by parenteral, intravenous, subcutaneous, intracardial, intramuscular, or oral administration. 
     
     
         52 . The composition or combination of claim  41 , wherein the structurally related analog thereof is a halogen substituted benzoxazolyl analog or chlorine substituted analog thereof. 
     
     
         53 . The composition or combination of  claim 45 , wherein the chlorine substituted analog is 3-(5-chloro-1,3-benzoxazol-2-yl)-7-(diethylamino)-2H-chromen-2-one. 
     
     
         54 . The composition or combination of  claim 31 , wherein the chromenone containing compound is selected from the following chromen-2-one derivatives: 7-Methoxy-3-(2-methyl-thiazol-4-yl)-chro-men-2-one; 7-Ethoxy-3-(2-methyl-thiazol-4-yl)-chro-men-2-one; 3-(2-[4-(Chromen-2-one-3-yl)tiazol-2-yl]thia-zol-4-yl)-chromen-2-one; 7-Methoxy-3-(2-methyl-thiazol-4-yl)-chro-men-2-one; 7-Hydroxy-3-(2-phenyl-thiazol-4-yl)-chro-men-2-one; 6-Methoxy-3-[4-(4-methoxy-phenyl)-thia-zol-2-yl]-chromen-2-one; 7-Hydroxy-3-[4-(4-methoxy-phenyl)-thia-zol-2-yl]-chromen-2-one; 7-Diethylamino-3-[2-(4-dimethylamino-phenyl)-thiazol-4-yl]-chromen-2-one; 3-[4-(4-Chloro-phenyl)-thiazol-2-yl]-6-hexyl-7-hydroxy-chromen-2-one; 6-Hexyl-7-hydroxy-3-[4-(4-phenoxy-phe-nyl)-thiazol-2-yl]-chromen-2-one; 7-Hydroxy-3-[4-(4-phenoxy-phenyl)-thia-zol-2-yl]-chromen-2-one; 6-Hexyl-7-hydroxy-3-[4-(4-methoxy-phe-nyl)-thiazol-2-yl]-chromen-2-one; 7-Diethylamino-3-(4-methyl-thiazol-2-yl)-chro-men-2-one; 3-[4-(4-Bromo-phenyl)-thiazol-2-yl]-6-hex-yl-7-hydroxy-chromen-2-one; 6-Hexyl-7-hydroxy-3-(2-phenyl-thia-zol-4-yl)-chromen-2-one, 6-Hexyl-7-hydroxy-3-(4-phenyl-thiazol-2-yl)-chromen-2-one; 7-Hydroxy-3-(4-phenyl-thiazol-2-yl)-chro-men-2-one; 6-Hexyl-7-hydroxy-3-(4-methyl-thiazol-2-yl)-chromen-2-one; 7-Hydroxy-3-(5-methyl-4-phenyl-thiazol-2-yl)-chromen-2-one; 3-[4-(4-Chloro-4-phenyl)-5-methyl-thiazol-2-yl]-7-hydroxy-chromen-2-one; 7-Hydroxy-3-(5-methyl-4-p-tolyl-thiazol-2-yl)-chromen-2-one; 6-Bromo-3-[4-(4-ethoxy-phenyl)-thia-zol-2-yl]-chromen-2-one; 3-[4-(4-Ethyl-phenyl)-5-methyl-thiazol-2-yl]-7-hydroxy-chromen-2-one; 3-[4-(4-Chloro-phenyl)-thiazol-2-yl]-6-meth-oxy-chromen-2-one; 3-[2-(3,4-Dimethoxy-phenyl)-thiazol-4-yl]-chro-men-2-one; 3-[4-(4-Bromo-phenyl)-5-ethyl-thiazol-2-yl]-7-hydroxy-chromen-2-one; 3-(4,5-Dihydro-naphtho[1,2-d]thiazol-2-yl)-7-hy-droxy-chromen-2-one; 7-Diethylamino-3-(4-phenyl-thiazol-2-yl)-chro-men-2-one; 3-[4-(3,4-Dichloro-phenyl)-5-methyl-thiazol-2-yl]-7-hydroxy-chromen-2-one; 3-[4-(4-Chloro-phenyl)-5-ethyl-thia-zol-2-yl]-7-hydroxy-chromen-2-one; 3-(5-Ethyl-4-p-tolyl-thiazol-2-yl)-7-hy-droxy-chromen-2-one; 7-Diethylamino-3-(2-phenyl-thiazol-4-yl)-chro-men-2-one; 3-[4-(2,5-Dimethyl-phenyl)-5-ethyl-thiazol-2-yl]-7-hydroxy-chromen-2-one; 3-[2-(4-Hydroxy-phenyl)-thiazol-4-yl]-chro-men-2-one; 3-(5-Ethyl-4-phenyl-thiazol-2-yl)-7-hy-droxy-chromen-2-one; 3-[2-(2,4-Dimethyl-phenyl)-thiazol-4-yl]-7-hy-droxy-chromen-2-one; 3-[4-(3-Bromo-phenyl)-thiazol-2-yl]-8-meth-oxy-chromen-2-one; 7-Hydroxy-3-[4-(3-methoxy-phenyl)-thia-zol-2-yl]-chromen-2-one; 3-Benzothiazol-2-yl-7-hydroxy-chro-men-2-one; 3-(5-Chloro-1H-benzoimidazol-2-yl)-8-meth-oxy-chromen-2-one; 3-[5-(3-Fluoro-phenyl)[1,3,4]oxa-diazol-2-yl]-8-methoxy-chromen-2-one; 3-Benzo[d]imidazo[2,1-b]thiazol-2-yl-chro-men-2-one; 3-(7-Methoxy-benzo[d]imidazo[2,1-b]thia-zol-2-yl)-chromen-2-one; 6-Chloro-3-(7-fluoro-benzo[d]imi-dazo[2,1-b]thiazol-2-yl)-chromen-2-one; 3-Benzo[d]imidazo[2,1-b]thiazol-2-yl-6-hex-yl-7-hydroxy-chromen-2-one; 6,8-Dichloro-3-(5-p-tolylamino-[1,3,4]thia-diazol-2-yl)-chromen-2-one; 3-[5-(3-Chloro-phenyl)-[1,3,4]oxa-diazol-2-yl]-6-hexyl-7-hydroxy-chro-men-2-one; 6-Hexyl-7-hydroxy-3-[5-(3-methoxy-phe-nyl)-[1,3,4]oxadiazol-2-yl]-chro-men-2-one; 6-Hexyl-7-hydroxy-3-(7-methyl-imidazo[1,2-a]pyridin-2-yl)-chromen-2-one; 6-Methoxy-3-[2-(4-methoxy-phenyl-amino)-thiazol-5-yl]-chromen-2-one; and 6-Hexyl-7-hydroxy-3-[5-(3,4,5-trimeth-oxy-phenyl)-[1,3,4]oxadiazol-2-yl]-chromen-2-one. 
     
     
         55 . The composition or combination of  claim 31 , wherein the anti-EGFR therapeutic antibody is cetuximab or an antigen-binding fragment thereof or panitumumab or an antigen-binding fragment thereof. 
     
     
         56 . The composition or combination of claim  1 , wherein the composition or combination comprises:
 a) i) 3-(1,3-benzoxazol-2-yl)-7-(diethylamino)-2H-chromen-2-one, ii) midostaurin or a salt or solvate thereof, iii) gilteritinib or a salt or solvate thereof, or iv) 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide; and   b) an anti-EGFR therapeutic antibody.   
     
     
         57 . The composition or combination of  claim 49 , wherein the anti-EGFR therapeutic antibody is cetuximab or an antigen-binding fragment thereof or panitumumab or an antigen-binding fragment thereof.

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