WO2022170052A1 - Dérivés de quinazoline, dérivés de pyridopyrimidine, dérivés de pyrimidopyrimidine et leurs utilisations - Google Patents

Dérivés de quinazoline, dérivés de pyridopyrimidine, dérivés de pyrimidopyrimidine et leurs utilisations Download PDF

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Publication number
WO2022170052A1
WO2022170052A1 PCT/US2022/015249 US2022015249W WO2022170052A1 WO 2022170052 A1 WO2022170052 A1 WO 2022170052A1 US 2022015249 W US2022015249 W US 2022015249W WO 2022170052 A1 WO2022170052 A1 WO 2022170052A1
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alkyl
compound
cancer
subject
present disclosure
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PCT/US2022/015249
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English (en)
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Luca Arista
Alexander Flohr
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Black Diamond Therapeutics, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the HER family receptor tyrosine kinases are mediators of cell growth, differentiation and survival. They include the four distinct members EGFR (epidermal growth factor receptor, also HER1), HER2, HER3 and HER4. Upon ligand binding the receptors form homo- and heterodimers and subsequent activation of the intrinsic tyrosine kinase activity leads to receptor auto-phosphorylation and the activation of downstream signaling molecules. De-regulation of EGFR by overexpression or mutation has been implicated in many types of human cancer including colorectal, pancreatic, gliomas, head and neck, and lung cancer, in particular non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • Tyrosine kinase inhibitors (TKIs) against EGFR have been developed over the past three decades and have become standard treatment in the clinic for subjects with advanced EGFR mutant NSCLC.
  • First-generation EGFR TKIs e.g. gefitinib and erlotinib, bind competitively and reversibly to the ATP -binding site of the EGFR tyrosine kinase domain and have resulted in a significant improvement in outcome for patients having NSCLC with activating EGFR mutations (L858R and Dell9).
  • L858R and Dell9 activating EGFR mutations
  • the present disclosure provides a compound of formula I: or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:
  • X 1 is -O-, -S-, or -NR 2 -; each R a independently is -H or -Ci-4 alkyl; each R b independently is -H or -Ci-4 alkyl; each R c independently is -H or -Ci-4 alkyl; each R d independently is -H or -Ci-4 alkyl; R 1 is -H or -Ci-4 alkyl;
  • R 2 is -H or -Ci-4 alkyl
  • R 3 is -H or -O-Ci-4 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and
  • Ar 1 is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH 2 , -NH(CI-6 alkyl), -N(CI-C 6 alkyl) 2 , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH 2 , - NH(CI-C 6 alkyl), or -N(CI-C 6 alkyl) 2 .
  • the compound is not 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methox- yquinazolin-6-yl]oxypiperidin-l-yl]-7V-methylacetamide or 2-(3-((4-((3-chloro-2-fluoro- phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)-N-methylacetamide.
  • the compound is not 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methox- yquinazolin-6-yl]oxypiperidin-l-yl]-7V-methylacetamide.
  • the compound is not 2-(3-((4-((3-chloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin-l-yl)-N-methylacetamide.
  • the present disclosure provides an isotopic derivative of a compound disclosed herein.
  • the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein and one or more pharmaceutically acceptable carriers or excipients.
  • the present disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound disclosed herein.
  • the present disclosure provides a compound disclosed herein for treating or preventing cancer in a subject.
  • the present disclosure provides a use of a compound disclosed herein in the manufacture of a medicament for treating or preventing cancer in a subject.
  • the cancer is characterized by an EGFR mutation C797.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.
  • the present disclosure provides a compound of formula I: or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:
  • X 1 is -O-, -S-, or -NR 2 -; each R a independently is -H or -Ci-4 alkyl; each R b independently is -H or -Ci-4 alkyl; each R c independently is -H or -Ci-4 alkyl; each R d independently is -H or -Ci-4 alkyl;
  • R 1 is -H or -Ci-4 alkyl
  • R 2 is -H or -Ci-4 alkyl
  • R 3 is -H or -O-Ci-4 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and
  • Ar 1 is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH 2 , -NH(CI-6 alkyl), -N(CI-C 6 alkyl) 2 , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH 2 , - NH(CI-C 6 alkyl), or -N(CI-C 6 alkyl) 2 .
  • the compound is not 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methox- yquinazolin-6-yl]oxypiperidin-l-yl]-A-methylacetamide or 2-(3-((4-((3-chloro-2-fluoro- phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)-N-methylacetamide.
  • the compound is not 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methox- yquinazolin-6-yl]oxypiperidin-l-yl]-A-methylacetamide or 2-(3-((4-((3-chloro-2-fluoro- phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)-N-methylacetamide or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • the compound is not 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methox- yquinazolin-6-yl]oxypiperidin-l-yl]-A-methylacetamide.
  • the compound is not 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methox- yquinazolin-6-yl]oxypiperidin-l-yl]-A-methylacetamide, or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • the compound is not 2-(3-((4-((3-chloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin-l-yl)-N-methylacetamide.
  • the compound is not 2-(3-((4-((3-chloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin-l-yl)-N-methylacetamide or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of formula I: or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:
  • X 1 is -O-, -S-, or -NR 2 -; each R a independently is -H or -Ci-4 alkyl; each R b independently is -H or -Ci-4 alkyl; each R c independently is -H or -Ci-4 alkyl; each R d independently is -H or -Ci-4 alkyl;
  • R 1 is -H or -Ci-4 alkyl
  • R 2 is -H or -Ci-4 alkyl
  • R 3 is -H or -O-Ci-4 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and
  • Ar 1 is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH 2 , -NH(CI-6 alkyl), -N(CI-C 6 alkyl) 2 , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH 2 , - NH(CI-C 6 alkyl), or -N(CI-C 6 alkyl) 2 ; provided that the compound is not 2-[4-[4-(3-chloro-2-fluoroan
  • the present disclosure provides a compound of formula I: (I) or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:
  • X 1 is -O-, -S-, or -NR 2 -; each R a independently is -H or -Ci-4 alkyl; each R b independently is -H or -Ci-4 alkyl; each R c independently is -H or -Ci-4 alkyl; each R d independently is -H or -Ci-4 alkyl;
  • R 1 is -H or -Ci-4 alkyl
  • R 2 is -H or -Ci-4 alkyl
  • R 3 is -H or -O-Ci-4 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and
  • Ar 1 is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH 2 , -NH(CI-6 alkyl), -N(CI-C 6 alkyl) 2 , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH 2 , - NH(CI-C 6 alkyl), or -N(CI-C 6 alkyl) 2 ; provided that when X 1 is -O-, R 3 is -OMe, R 1 , R
  • X 1 is -O-, -S-, or -NR 2 -.
  • X 1 is -O-. In some embodiments, X 1 is -S-.
  • X 1 is -NR 2 -.
  • X 1 is -NH-. In some embodiments, X 1 is -N(CI-4 alkyl)-.
  • X 1 is -N(CH3)-.
  • R 1 is -H or -Ci-4 alkyl.
  • R 1 is -H. In some embodiments, R 1 is -C1-4 alkyl.
  • R 1 is methyl, ethyl, n-propyl, or n-butyl. [038] In some embodiments, R 1 is methyl.
  • R 2 is -H or -Ci-4 alkyl.
  • R 2 is -H. In some embodiments, R 2 is -C1-4 alkyl.
  • R 2 is methyl, ethyl, n-propyl, or n-butyl.
  • R 2 is methyl
  • R 3 is -H or -O(Ci-6 alkyl).
  • R 3 is -H or -OMe.
  • R 3 is -H. In some embodiments, R 3 is -OMe.
  • At least one R a is -H or -Ci-4 alkyl.
  • At least one R a is -H. In some embodiments, at least one R a is -Ci-4 alkyl.
  • At least one R a is methyl, ethyl, n-propyl or n-butyl.
  • At least one R b is -H or -Ci-4 alkyl.
  • At least one R b is -H. In some embodiments, at least one R b is -Ci-4 alkyl.
  • At least one R b is methyl, ethyl, n-propyl or n-butyl.
  • At least one R c is -H or -Ci-4 alkyl.
  • At least one R c is -H. In some embodiments, at least one R c is -Ci-4 alkyl.
  • At least one R c is methyl, ethyl, n-propyl or n-butyl.
  • At least one R d is -H or -Ci-4 alkyl.
  • At least one R d is -H. In some embodiments, at least one R d is -Ci-4 alkyl.
  • At least one R d is methyl, ethyl, n-propyl or n-butyl.
  • m is 0, 1, or 2.
  • m is 0. In some embodiments, m is 1. In some embodiments, m is 2.
  • n is 1, 2, or 3.
  • n is 1. In some embodiments, n is 2. In some embodiments, n is 3. [062] In some embodiments, m is 1 and n is 1.
  • n 2
  • Ar 1 is Ce-io aryl optionally substituted with one or more halogen, - CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI-6 alkyl), -N(Ci-Ce alkyl)2, -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, - C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH2, -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl)2.
  • Ar 1 is phenyl optionally substituted with one or more halogen, - CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI-6 alkyl), -N(Ci-Ce alkyl)2, -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, - C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH2, -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl)2.
  • Ar 1 is Ce-io aryl.
  • Ar 1 is phenyl
  • Ar 1 is Ce-io aryl optionally substituted with one or more halogen, - CF3, or C1-6 alkyl.
  • Ar 1 is phenyl optionally substituted with one or more halogen, - CF3, or C1-6 alkyl.
  • Ar 1 is Ce-io aryl substituted with one or more halogen, -CF3, or Ci- 6 alkyl.
  • Ar 1 is phenyl substituted with one or more halogen, -CF3, or C1-6 alkyl.
  • Ar 1 is Ce-io aryl optionally substituted with one or more halogen.
  • Ar 1 is phenyl optionally substituted with one or more halogen.
  • Ar 1 is Ce-io aryl substituted with one or more halogen.
  • Ar 1 is phenyl optionally substituted with F and Cl.
  • Ar 1 is phenyl substituted with one or more halogen.
  • Ar 1 is phenyl substituted with F and Cl. [078] In some embodiments,
  • Ar 1 is not F
  • R 4 is halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI-6 alkyl), -N(Ci-Ce alkyl)2, -
  • R 5 is halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI-6 alkyl), -N(Ci-Ce alkyl)2, - C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH2, -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl)2;
  • R 5 ’ is halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI-6 alkyl), -N(Ci-Ce alkyl)2, - C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH2, -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl)2;
  • R 6 is halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI-6 alkyl), -N(Ci-Ce alkyl)2, - C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH2, -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl)2; and
  • R 6 ’ is halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI-6 alkyl), -N(Ci-Ce alkyl)2, - C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH2, -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl)2.
  • R 4 is halogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, hydroxy C1-5 alkyl, Ci-6 alkoxy-Ci-6 alkyl, amino Ci-4 alkyl, Ci-6 alkylamino, Ci-6 alkoxycarbonyl, or Ci-6 alkoxyaminocarbonyl.
  • R 4 is -H.
  • R 4 is Ci-6 haloalkyl. In some embodiments, R 4 is -CF3.
  • R 4 is halogen. In some embodiments, R 4 is -F, -Cl, -Br, or -I.
  • R 4 is -F. In some embodiments, R 4 is -Cl.
  • R 5 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy C1-5 alkyl, C1-6 alkoxy-Ci-6 alkyl, amino Ci-4 alkyl, C1-6 alkylamino, C1-6 alkoxycarbonyl, or C1-6 alkoxyaminocarbonyl.
  • R 5 is -H.
  • R 5 is C1-6 haloalkyl. In some embodiments, R 5 is -CF3.
  • R 5 is halogen. In some embodiments, R 5 is -F, -Cl, -Br, or -I.
  • R 5 is -F. In some embodiments, R 5 is -Cl.
  • R 5 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy C1-5 alkyl, C1-6 alkoxy-Ci-6 alkyl, amino Ci-4 alkyl, C1-6 alkylamino, C1-6 alkoxycarbonyl, or C1-6 alkoxyaminocarbonyl.
  • R 5 is -H.
  • R 5 is C1-6 haloalkyl. In some embodiments, R 5 is -CF3.
  • R 5 is halogen. In some embodiments, R 5 is -F, -Cl, -Br, or -I.
  • R 5 is -F. In some embodiments, R 5 is -Cl.
  • R 6 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy C1-5 alkyl, C1-6 alkoxy-Ci-6 alkyl, amino Ci-4 alkyl, C1-6 alkylamino, C1-6 alkoxycarbonyl, or C1-6 alkoxyaminocarbonyl.
  • R 6 is -H.
  • R 6 is C1-6 haloalkyl. In some embodiments, R 6 is -CF3.
  • R 6 is halogen. In some embodiments, R 6 is -F, -Cl, -Br, or -I. [0100] In some embodiments, R 6 is -F. In some embodiments, R 6 is -Cl.
  • R 6 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy C1-5 alkyl, C1-6 alkoxy-Ci-6 alkyl, amino Ci-4 alkyl, C1-6 alkylamino, C1-6 alkoxycarbonyl, or C1-6 alkoxyaminocarbonyl. [0102] In some embodiments, R 6 is -H.
  • R 6 is Ci-6 haloalkyl. In some embodiments, R 6 is -CF3.
  • R 6 is halogen. In some embodiments, R 6 is -F, -Cl, -Br, or -I.
  • R 6 is -F. In some embodiments, R 6 is -Cl.
  • the compound is of any one of Formulae (la), (lb), (Ic), (Id), (le),
  • the compound is of Formula (II): or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • the compound is of any one of Formulae (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), or (IIh):
  • the compound is of Formula (III) or (IV): or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • the compound is of any one of Formulae (Illa), (Illb), (IIIc), (Hid), (IVa), (IVb), (IVc), or (IVd): wo 2022/170052
  • the compound is a compound described in Table I, or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • the compound is a compound described in Table I or pharmaceutically acceptable salt thereof.
  • the compound is a compounds described in Table I.
  • the compound is selected from Compound Nos. 2-10 and 12-15, or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • the compound is selected from Compound Nos. 2-10 and 12-15, or a pharmaceutically acceptable salt thereof.
  • the compound is selected from Compound Nos. 2-10 and 12-15.
  • the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds disclosed herein.
  • the compound is an isotopic derivative of any one of the compounds described in Table I and pharmaceutically acceptable salts thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table I.
  • the isotopic derivative can be prepared using any of a variety of art- recognized techniques.
  • the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the isotopic derivative is a deuterium labeled compound.
  • the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.
  • the compound is a deuterium labeled compound of any one of the compounds described in Table I and pharmaceutically acceptable salts thereof.
  • the compound is a deuterium labeled compound of any one of the compounds described in Table I.
  • the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.
  • the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium.
  • the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques.
  • the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a deuterium labeled reagent for a non-deuterium labeled reagent.
  • a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the present disclosure. Further, substitution with deuterium (/. ⁇ ., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. [0129] For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.
  • a suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, formic, citric methane sulphonate or maleic acid.
  • an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, formic, citric methane sulphonate or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxy- ethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxy- ethyl)amine.
  • the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”
  • chiral center refers to a carbon atom bonded to four nonidentical substituents.
  • chiral isomer means a compound with at least one chiral center.
  • Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.”
  • a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center.
  • Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • the substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.
  • geometric isomer means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.
  • atropic isomers are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.
  • tautomer is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed.
  • keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.
  • Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (- OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-su- perimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • the compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • Some of the compounds of the disclosure may have geometric isomeric centers (E- and Z- isomers).
  • present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess inflammasome inhibitory activity. [0143] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.
  • any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable.
  • a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein.
  • Suitable anions include chloride, bromide, iodide, sulphate, bisulphate, sulphamate, nitrate, phosphate, citrate, methanesulphonate, trifluoroacetate, glutamate, glu- curonate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulphonate, and acetate (e.g., trifluoroacetate).
  • the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt.
  • a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion.
  • the substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.
  • the compounds of the present disclosure can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • Nonlimiting examples of hydrates include monohydrates, dihydrates, etc.
  • Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
  • solvate means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.
  • analog refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • derivative refers to compounds that have a common core structure and are substituted with various groups as described herein.
  • bioisostere refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms.
  • the objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound.
  • the bioisosteric replacement may be physicochemically or topologically based.
  • Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulphonamides, tetrazoles, sulphonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.
  • solvated forms such as, for example, hydrated forms.
  • a suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a dihydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess inflammasome inhibitory activity.
  • crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy.
  • DRIFT Diffuse Reflectance Infrared Fourier Transform
  • NIR Near Infrared
  • solution and/or solid state nuclear magnetic resonance spectroscopy The water content of such crystalline materials may be determined by Karl Fischer analysis.
  • tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, ni- troso/oxime, thioketone/enethiol, and nitro/aci -nitro. keto enol enolate
  • N-ox- ides Compounds of the present disclosure containing an amine function may also form N-ox- ides.
  • a reference herein to a compound disclosed herein that contains an amine function also includes the N-oxide.
  • one or more than one nitrogen atom may be oxidised to form an N-oxide.
  • Particular examples of N-oxides are the N- oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g.
  • N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.
  • mCPBA meta-chloroperoxybenzoic acid
  • the compounds of the present disclosure may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure.
  • a prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure.
  • a prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached.
  • Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the sulphonylurea group in a compound of the any one of the Formulae disclosed herein.
  • the present disclosure includes those compounds of the present disclosure as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of the present disclosure that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the present disclosure may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically acceptable prodrug of a compound of the present disclosure is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.
  • Bundgaard Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “ProDrugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.
  • a suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the present disclosure containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include Ci-Cio alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci-Cio alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(Ci-Ce alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Ci-Cio alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups
  • Ci-Cio alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(Ci-Ce alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a Ci-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or di ethylamine, a C1-C4 alkoxy-C2- C4 alkylamine such as 2 -methoxy ethylamine, a phenyl-Ci-C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a Ci-4alkylamine such as methylamine
  • a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or di ethylamine
  • a suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with Ci-Cio alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl, and 4-(CI-C4 alkyl)piperazin-l-ylmethyl.
  • the in vivo effects of a compound of the present disclosure may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the present disclosure. As stated hereinbefore, the in vivo effects of a compound of the present disclosure may also be exerted by way of metabolism of a precursor compound (a prodrug).
  • the present disclosure provides a method of preparing a compound disclosed herein.
  • the present disclosure provides a method of preparing a compound, comprising one or more steps as described herein.
  • the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound described herein.
  • the present disclosure provides an intermediate being suitable for use in a method for preparing a compound described herein.
  • the compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxy carbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxy carbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(tri- fluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
  • a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.
  • a base such as sodium hydroxide
  • a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.
  • the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of the present disclosure into another compound of the present disclosure; (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof.
  • the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions.
  • suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as tri chlorethylene, 1,2-di chloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as
  • Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.
  • Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity.
  • the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.
  • high-throughput screening can be used to speed up analysis using such assays.
  • it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art.
  • General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263.
  • High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.
  • in vitro or in vivo biological assays are may be suitable for detecting the effect of the compounds of the present disclosure.
  • These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.
  • the biological assay is a retrovirus production assay.
  • the EGFR mutants are subcloned I and the retroviral expression vector is produced by transient transfection (e.g., of HEK 293T cells with a retroviral EGFR mutant expression vector).
  • the cells may be plated and incubated (e.g., overnight) and the retroviral plasmids may be mixed in serum (e.g., Optimem).
  • the mixture may be incubated (e.g., at room temperature for a period of time) and then added to serum comprising transfection reagent (e.g., Lipofectamine) and incubated for a period of time (e.g., 20 minutes).
  • serum comprising transfection reagent e.g., Lipofectamine
  • the mixture may be added to the cells and the medium replaced with fresh culture medium and the retrovirus may be harvested.
  • the biological assay is the generation of EGFR mutant stable cell lines.
  • the cells e.g., BaF3 cells
  • the cells may be infected with a viral supernatant, centrifuged, and incubated for a period of time (e.g., overnight).
  • the cells may then be spun to pellet the cells and the supernatant removed.
  • the cells may be re-infected a fresh viral supernatant, centrifuges, and incubated for a period of time (e.g., overnight).
  • the cells may then be maintained in IL-3, followed by the cells being selected for retroviral infection.
  • the blasticidin resistant populations may be washed buffered saline prior to plating in media lacking IL-3 to select for IL-3 independent growth.
  • the biological assay is an assay for cell proliferation.
  • the cell lines e.g., BaF3 cell lines
  • the cells may be incubated in the presence of vehicle control or test drug at varying concentrations.
  • the inhibition of cell growth may be determined by luminescent quantification of intracellular ATP content (e.g., using Cell Titer Gio).
  • the comparison of cell number on different days may be used to plot dose-response curves.
  • inhibition of proliferation, relative to vehicle-treated controls was expressed as a fraction of 1 and graphed using PRISM® software, as well as ECso values determined utilizing the same application
  • a cell line e.g., the A431 lung cancer cell line, which natively expresses WT-EGFR
  • WT-EGFR inhibition may be used to assess WT-EGFR inhibition.
  • a cell line (e.g., the BT474, which natively expresses WT-HER2) may be used to assess WT-HER2 inhibition.
  • cells may be plated in well plates and subjected to various doses of compound to generate a dose-response curve for each cell line to be assessed (e.g., by using a Cell Titer Gio cell proliferation kit).
  • doseresponse curves may be generated for each cell line and ICso values generated.
  • the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient.
  • the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table I.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • composition can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
  • the compounds of present disclosure on can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle.
  • the aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient.
  • Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/ suspending agent, buffer, and pH modifying agent, and a mixture thereof.
  • solubility enhancing agent examples include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-P- cyclodextrin, methyl-P-cyclodextrin, randomly methylated-P-cyclodextrin, ethylated-P- cyclodextrin, triacetyl-P-cyclodextrin, peracetylated-P-cyclodextrin, carboxymethyl-P- cyclodextrin, hydroxy ethyl-P-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-P- cyclodextrin, glucosyl-P-cyclodextrin, sulphated P-cyclodextrin (S-P-CD), maltosyl-P- cyclodextrin, P-cyclodextrin sulphobutyl ether,
  • cyclodextrin such as those selected from the
  • Any suitable chelating agent can be used.
  • a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, di sodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.
  • any suitable preservative can be used.
  • a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hy- droxybenzoate, and sorbic acid, and mixtures thereof.
  • quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride
  • the aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure).
  • the tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.
  • the aqueous vehicle may also contain a viscosity/ suspending agent.
  • Suitable viscosity/sus- pending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.
  • the formulation may contain a pH modifying agent.
  • the pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid.
  • the aqueous vehicle may also contain a buffering agent to stabilize the pH.
  • the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and 8-aminocaproic acid, and mixtures thereof.
  • the formulation may further comprise a wetting agent.
  • wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxy ethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
  • compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent an inflammasome related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the present disclosure will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
  • compounds of the present disclosure could be highly selective inhibitors and specifically inhibit C797 (i.e. C797S/G) containing EGFR mutants.
  • the compounds of the present disclosure could therefore be useful and effective in the therapeutic treatment in patients suffering from cancer comprising such mutation ⁇ ), and specifically in patients who have acquired resistance to treatment with EGFR TKIs and show a reduced response or are not or no longer responding to therapies with EGFR TKIs.
  • the present disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of at least one compound of the present disclosure.
  • the present disclosure provides a method of treating cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of at least one compound of the present disclosure.
  • the present disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject at least one compound of the present disclosure.
  • the present disclosure provides a method of treating cancer in a subject, comprising administering to the subject at least one compound of the present disclosure.
  • the present disclosure provides at least one compound of the present disclosure for treating or preventing cancer in a subject.
  • the present disclosure provides at least one compound of the present disclosure for treating cancer in a subject.
  • the present disclosure provides use of at least one compound of the present disclosure in the manufacture of a medicament for treating or preventing cancer in a subject.
  • the present disclosure provides use of at least one compound of the present disclosure in the manufacture of a medicament for treating cancer in a subject.
  • the present disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure.
  • the present disclosure provides a method of treating cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure.
  • the present disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject a compound of the present disclosure.
  • the present disclosure provides a method of treating cancer in a subject, comprising administering to the subject a compound of the present disclosure.
  • the present disclosure provides a compound of the present disclosure for treating or preventing cancer in a subject.
  • the present disclosure provides a compound of the present disclosure for treating cancer in a subject.
  • the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating or preventing cancer in a subject.
  • the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating cancer in a subject.
  • the cancer is characterized by an EGFR mutation C797.
  • an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides a method of treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of at least one compound of the present disclosure.
  • the present disclosure provides a method of treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of at least one compound of the present disclosure.
  • the present disclosure provides a method of treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject at least one compound of the present disclosure.
  • the present disclosure provides a method of treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject at least one compound of the present disclosure.
  • the present disclosure provides a method of treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure.
  • the present disclosure provides a method of treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure.
  • the present disclosure provides a method of treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject a compound of the present disclosure.
  • the present disclosure provides a method of treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject a compound of the present disclosure.
  • the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of at least one compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of at least one compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject at least one compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject at least one compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject a compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject a compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides at least one compound of the present disclosure for use in treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof.
  • the present disclosure provides at least one compound of the present disclosure for use in treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof.
  • the present disclosure provides a compound of the present disclosure for use in treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof.
  • the present disclosure provides a compound of the present disclosure for use in treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof.
  • the present disclosure provides at least one compound of the present disclosure for use in treating or preventing a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides at least one compound of the present disclosure for use in treating a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides a compound of the present disclosure for use in treating or preventing a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides a compound of the present disclosure for use in treating a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides use of at least one compound of the present disclosure in the manufacture of a medicament for treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof.
  • the present disclosure provides use of at least one compound of the present disclosure in the manufacture of a medicament for treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof.
  • the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof.
  • the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof.
  • the present disclosure provides use of at least one compound of the present disclosure for treating or preventing a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides use of at least one compound of the present disclosure for treating a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides use of a compound of the present disclosure for treating or preventing a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides use of a compound of the present disclosure for treating a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure for treating or preventing cancer in a subject.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure for treating cancer in a subject.
  • the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure for treating or preventing cancer in a subject.
  • the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure for treating cancer in a subject.
  • the present disclosure provides a pharmaceutical kit comprising at least one compound of the present disclosure for treating or preventing cancer in a subject.
  • the present disclosure provides a pharmaceutical kit comprising at least one compound of the present disclosure for treating cancer in a subject.
  • the present disclosure provides a pharmaceutical kit comprising a compound of the present disclosure for treating or preventing cancer in a subject.
  • the present disclosure provides a pharmaceutical kit comprising a compound of the present disclosure for treating cancer in a subject.
  • the present disclosure provides a method of providing therapy recommendation for a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) recommending the administration of at least one therapeutically effective amount of at least one compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified.
  • the present disclosure provides a method of providing therapy recommendation for a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) recommending the administration of a therapeutically effective amount of a compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified.
  • the present disclosure provides a method of providing therapy recommendation for a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) recommending the administration of at least one compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified.
  • the present disclosure provides a method of providing therapy recommendation for a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) recommending the administration of a compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified.
  • the present disclosure provides a method of treating a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) administrating to the subject at least one therapeutically effective amount of at least one compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified.
  • the present disclosure provides a method of treating a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) administrating to the subject a therapeutically effective amount of a compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified.
  • the present disclosure provides a method of treating a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) administrating to the subject at least one compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified.
  • the present disclosure provides a method of treating a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) administrating to the subject a compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified.
  • the preceding methods can further comprise administering at least one therapeutically effective amount of at least a second anticancer therapy to the subject.
  • the preceding methods can further comprise administering a therapeutically effective amount of a second anticancer therapy to the subject.
  • the preceding methods can further comprise administering at least one second anticancer therapy to the subject.
  • the preceding methods can further comprise administering a second anticancer therapy to the subject.
  • the preceding uses can further comprise administering at least one therapeutically effective amount of at least a second anticancer therapy to the patient.
  • the preceding uses can further comprise administering a therapeutically effective amount of a second anticancer therapy to the patient.
  • the preceding uses can further comprise administering at least one second anticancer therapy to the patient.
  • the preceding uses can further comprise administering a second anticancer therapy to the patient.
  • the second anticancer therapy is a surgical therapy, chemotherapy, radiation therapy, cryotherapy, hormonal therapy, toxin therapy, immunotherapy, or cytokine therapy.
  • the present disclosure provides a method of selecting a drug therapy for a patient having cancer comprising: (a) obtaining a sample of the cancer; (b) determining the presence or absence of an EGFR mutation C797 in the cancer; and (c) if the EGFR mutation C797 is present selecting and administering a therapeutically effective amount of a compound of the present disclosure to the subject.
  • the present disclosure provides a method of selecting a drug therapy for a patient having cancer comprising: (a) obtaining a sample of the cancer; (b) determining the presence or absence of an EGFR mutation C797 in the cancer; and (c) if the EGFR mutation C797 is present selecting and administering a compound of the present disclosure to the subject.
  • the subject is a mammal.
  • the subject is a human.
  • the subject has previously undergone at least one round of anticancer therapy. In some embodiments, the subject has previously undergone at least one round of anti-cancer therapy and has acquired resistance to treatment with the anti-cancer therapy. In some embodiments, the anti-cancer therapy can comprise the administration of EGFR TKIs.
  • the subject is a non-human mammal.
  • the subject has previously undergone at least one round of anticancer therapy.
  • the subject has previously undergone one round of anti-cancer therapy.
  • the subject has previously undergone two rounds of anti-cancer therapy.
  • the subject has previously undergone three rounds of anti-cancer therapy.
  • the subject is treated at least a second time.
  • the subject is treated over a period of 1 week to 6 months.
  • the subject has been shown to be resistant to selected first-generation inhibitors and/or selected second-generation inhibitors.
  • the treatment results in one or more of: (a) inhibition of tumor growth; (b) reduction in tumor size; (c) reduction in the number of tumors, and (d) decreased tumor burden in the subject.
  • the cancer is characterized by at least one oncogenic variant of at least one ErbB protein.
  • the at least one ErbB protein is EGFR.
  • the cancer is characterized by at least one oncogenic variant of EGFR.
  • a cancer that is characterized by at least one oncogenic variant of at least one ErbB protein is a cancer that is typically associated with the at least one oncogenic variant of the at least one ErbB protein, including, but not limited to, cancers whose primary oncogenic activity is thought to be driven by the at least one oncogenic variant in the at least one ErbB protein.
  • an oncogenic variant of an ErbB protein e.g. EGFR
  • an ErbB protein e.g. EGFR
  • an oncogenic mutation can include, but is not limited to, a mutation that results in the substitution of one amino acid for another at a specific position within an ErbB protein (e.g. EGFR), an insertion of one or more amino acids between two positions within an ErbB protein (e.g. EGFR), a deletion of one more amino acids between two positions within an ErbB protein (e.g. EGFR).
  • an oncogenic mutation can include, but is not limited to, a missense mutation, a nonsynonymous mutation, an insertion of one or more nucleotides, a deletion of one or more nucleotides, an inversion and a deletion-insertion.
  • an oncogenic mutation in the context of a protein (e.g. EGFR), is not limited to, the substitution of one amino acid for another at a specific position within EGFR, an insertion of one or more amino acids between two positions within EGFR, a deletion of one more amino acids between two positions within EGFR, and a fusion of EGFR, or portion thereof, with another protein, or portion thereof.
  • a protein e.g. EGFR
  • an oncogenic mutation is not limited to, the substitution of one amino acid for another at a specific position within EGFR, an insertion of one or more amino acids between two positions within EGFR, a deletion of one more amino acids between two positions within EGFR, and a fusion of EGFR, or portion thereof, with another protein, or portion thereof.
  • a wild type EGFR sequence of the disclosure may comprise or consist of the amino acid sequence of:
  • the ErbB protein has at least one deletion in Exon 19. Accordingly, in aspects wherein the ErbB protein is EGFR, the oncogenic variant of EGFR has at least one deletion in Exon 19 (EGFR-A19).
  • the oncogenic variant of EGFR can have an oncogenic mutation which is a substitution of the Cysteine residue at position 797 for another amino acid. That is, in some embodiments, the oncogenic variant of EGFR has an amino acid substitution of the Cysteine residue at position 797, herein referred to as "EGFR-C797X,” “C797 mutation” or "EGFR mutation C797.”
  • an amino acid substitution of the Cysteine residue at position 797 of EGFR can be a substitution of Serine for the Cysteine (C797S). Accordingly, the oncogenic variant of EGFR can be EGFR-C797S.
  • an amino acid substitution of the Cysteine residue at position 797 of EGFR can be a substitution of Glycine for the Cysteine (C797G). Accordingly, the oncogenic variant of EGFR can be EGFR-C797S.
  • the oncogenic variant of EGFR can have a first and an at least second oncogenic mutations, wherein the first oncogenic mutation is a substitution of the Cysteine residue at position 797 for another amino acid, and wherein the at least second oncogenic mutation is a deletion of one more amino acids, wherein the deletion is in Exon 19. Accordingly, the oncogenic variant of EGFR can be EGFR-C797X-A19.
  • the subject is a subject who has been shown to have developed an oncogenic variant of EGFR as the result of a previous anti-cancer treatment.
  • the subject is a subject who has an oncogenic variant of at least one ErbB protein. In some embodiments, the subject is a subject who has an oncogenic variant of EGFR.
  • the cancer is a carcinoma, a lymphoma, a blastoma, a sarcoma, a leukemia, a brain cancer, a breast cancer, a blood cancer, a bone cancer, a lung cancer, a skin cancer, a liver cancer, an ovarian cancer, a bladder cancer, a renal cancer, a kidney cancer, a gastric cancer, a thyroid cancer, a pancreatic cancer, an esophageal cancer, a prostate cancer, a cervical cancer, a uterine cancer, a stomach cancer, a soft tissue cancer, a laryngeal cancer, a small intestine cancer, a testicular cancer, an anal cancer, a vulvar cancer, a joint cancer, an oral cancer, a pharynx cancer, a renal pelvis cancer, intrahepatic bile duct cancer, bronchus cancer or a colorectal cancer.
  • the cancer is metastatic
  • the cancer comprises malignant primary cancer tumors.
  • the cancer comprises metastatic secondary cancer tumors.
  • the cancer is non-small cell lung cancer (NSCLC), glioblastoma, breast, head or neck, colon, gastric, pancreatic, bladder cancer.
  • NSCLC non-small cell lung cancer
  • glioblastoma breast, head or neck, colon, gastric, pancreatic, bladder cancer.
  • the cancer is NSCLC.
  • the NSCLC is an metastatic NSCLC tumor in the brain.
  • the NSCLC is in the brain.
  • the cancer is resistant to treatment with EGFR TKIs.
  • EGFR TKIs can include, but are not limited to, gefitinib, erlotinib, osimertinib, rociletinib, olmutinib, naquotinib, josartinib an any other EGFR TKI known in the art.
  • the compound of the present disclosure to be administered contains asymmetric centers and thus - without designation of the stereochemistry - it is to be understood to include all the optical isomers (e.g., diastereomers, enantiomers, etc) in pure or substantially pure form, as well as mixtures thereof (e.g. a racemic mixture, or an enantiomerically enriched mixture). It is well known in the art how to prepare such optically active forms (e.g. by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by chromatographic separation using a chiral stationary phase, and other methods).
  • optically active forms e.g. by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by chromatographic separation using a chiral stationary phase, and other methods).
  • the compounds can be isotopically-labeled compounds, for example, compounds including various isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, or chlorine.
  • the compound of the present disclosure to be administered also includes any pharmaceutically acceptable salts and stereoisomers thereof, see e.g. Berge et al, "Pharmaceutical Salts," J. Pharm. Sci, 1977:66: 1-19. It may exist in solid, i.e. crystalline or noncrystalline form (optionally as solvates) or liquid form. In the solid state, it may exist in, or as a mixture thereof. In crystalline solvates, solvent molecules are incorporated into the crystalline lattice during crystallization.
  • solvates may include non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or aqueous solvents such as water (also called “hydrates”).
  • non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate
  • aqueous solvents such as water (also called “hydrates”).
  • crystalline forms (and solvates thereof) may exhibit polymorphism, i.e. exist in different crystalline structures known as "polymorphs”, that have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state.
  • Polymorphs may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties, and may display different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • Such different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, during preparation of the compound of the present disclosure.
  • Administration of compound of Formula I may be in form of a pharmaceutical composition.
  • compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.
  • composition is intended to encompass a composition comprising the specified pharmaceutically active compound(s) in the specified amounts in combination with one or more pharmaceutically acceptable carriers and/or excipients for the administration route of choice.
  • the amount of pharmaceutically active compound in each case should be in amounts which are sufficient to achieve the dosage ranges given below.
  • the disclosure further provides a pharmaceutical composition comprising a therapeutically-effective amount of a compound of the present disclosure or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or excipients.
  • the excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).
  • terapéuticaally-effective amount refers to the amount of a compound of the present disclosure that results in a beneficial effect for at least a statistically significant fraction of patients, such as an improvement of symptoms, a cure, a reduction in disease load, reduction in tumor mass or cell numbers, extension of life, improvement in quality of life, or other effect generally recognized as positive by medical doctors familiar with treating the particular type of disease or condition.
  • compositions of a compound of the present disclosure may be in unit dose form containing a predetermined amount of a compound of the present disclosure per unit dose.
  • a unit may contain a therapeutically effective dose of a compound of the present disclosure or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of a compound of the present disclosure or salt thereof.
  • the cancer to be treated comprising an EGFR mutation C797 is metastatic, recurrent, or multi-drug resistant. In other embodiments the cancer to be treated comprising an EGFR mutation C797 comprises malignant primary cancer tumors and/or metastatic secondary cancer tumors.
  • the compound of the present disclosure may be administered by any acceptable means in solid or liquid form, including (1) oral administration, for example, drenches (aqueous or nonaqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) nasally; (9) pulmonary; or (10) intrathecally.
  • oral administration for example, drenches (aqueous or nonaqueous solutions or suspension
  • pharmaceutically-acceptable carrier means a pharmaceuti- cally-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • compositions may contain further components conventional in pharmaceutical preparations, e.g. wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants, pH modifiers, bulking agents, and further active agents.
  • wetting agents e.g. sodium lauryl sulfate and magnesium stearate
  • coloring agents e.g., coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants, pH modifiers, bulking agents, and further active agents.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • compositions may be prepared by any method known in the art, for example, by bringing into association the active ingredient with one or more carriers and/or excipients.
  • Different compositions and examples of carriers and/or excipients are well known to the skilled person and are described in detail in, e.g., Remington: The Science and Practice of Pharmacy. Pharmaceutical Press, 2013; Rowe, Sheskey, Quinn: Handbook of Pharmaceutical Excipients. Pharmaceutical Press, 2009.
  • Excipients that may be used in the preparation of the pharmaceutical compositions may include one or more of buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide a composition suitable for an administration of choice.
  • the compounds of the present disclosure may be in solid or liquid form and administered by various routes in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • a compound is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants,
  • pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lacto
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present disclosure such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the present disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • An oral composition can also include adjuvants such as wetting agents, emulsifying and suspending agents,
  • a compound may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Dosage forms for rectal or vaginal administration of a compound of the present disclosure include a suppository, which may be prepared by mixing one or more compounds of the present disclosure with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable forms include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically- acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • Such ointments, pastes, creams and gels may contain, in addition to a compound of the present disclosure, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Dosage forms such as powders and sprays for administration of a compound of the present disclosure, may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Dosage forms such as transdermal patches for administration of a compound of the present disclosure may include absorption enhancers or retarders to increase or decrease the flux of the compound across the skin.
  • the rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Other dosage forms contemplated include ophthalmic formulations, eye ointments, powders, solutions and the like. It is understood that all contemplated compositions must be stable under the conditions of manufacture and storage, and preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the dosage levels of a compound of the present disclosure in the pharmaceutical compositions of the present disclosure may be adjusted in order to obtain an amount of a compound of the present disclosure which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being deleterious to the subject.
  • the dosage of choice will depend upon a variety of factors including the nature of the particular compound of the present disclosure used, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound used, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts.
  • a medical practitioner having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • a suitable daily dose of a compound of the present disclosure will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this present disclosure for a subject, when used for the indicated analgesic effects, will range from about 0.1 to 100 mg/kg per kilogram of body weight of recipient (subject, mammal) per day.
  • the effective dose of a compound of the present disclosure may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout a specified period (per day or per week or per month), optionally, in unit dosage forms. Preferred dosing also depends on factors as indicated above, e.g. on the administration, and can be readily arrived at by one skilled in medicine or the pharmacy art.
  • the compounds of the present disclosure may be used in a combination treatment with at least a second anticancer therapy, such as a surgical therapy, chemotherapy, radiation therapy, cryotherapy, hormonal therapy, toxin therapy, immunotherapy, or cytokine therapy.
  • a second anticancer therapy such as a surgical therapy, chemotherapy, radiation therapy, cryotherapy, hormonal therapy, toxin therapy, immunotherapy, or cytokine therapy.
  • treatment is intended to encompass prophylaxis, therapy and cure.
  • the compound of the present disclosure and further therapeutically active agent may be administered separately (which implies that they are formulated separately) or together (which implies that they are formulated together). Hence, the administration of compound of the present disclosure may be prior to, concurrent to, or subsequent to the administration of the other active agent of the combination.
  • the method of treatment enabled by the present disclosure comprises administration of therapeutically effective amount of the compound of the present disclosure, optionally in combination with the administration of a further therapeutically active agent, to a subject in need thereof.
  • the compound of the present disclosure is administered intermittent or in a daily dosage such that the plasma level of the active substance preferably lies between 10 and 5000 nM for at least 12 hours of the dosing interval.
  • the compound of the present disclosure may be administered to the subject in a daily dose of 0.01-4 mg/kg of body weight (bw).
  • the compounds of formula (I) may be administered daily in a total dose of about 0.1 mg to about 1000 mg, optionally divided into multiple doses, e.g. 1 to 3 doses to be administered through the day.
  • the oral daily dose is administered only once.
  • treatment could follow a "7 day on - 7 day off, a " 14 day on - 14 day off, a "21 day on 7 day off or a continuous dosing schedule.
  • On-off time periods can be chosen shorter, especially if higher doses are administered, or individually adapted to the needs of the subject.
  • the skilled person will know it may be necessary to deviate from the amounts specified, depending on the body weight or method of administration, the individual response to the medication, the nature of the formulation used and the time or interval over which it is administered. Thus, in some cases, it may be sufficient to use less than the minimum quantity specified above, while in other cases the upper limit specified will have to be exceeded. When large amounts are administered it may be advisable to spread them over the day in a number of single doses.
  • Dosages and treatment schedules for the optionally included further therapeutically active agent are known in the art and may be applied analogously for the present disclosure.
  • the dosage of the therapeutically active agent(s) in a combination may be reduced, e.g. may vary in the range of 1/1 to 1/20 of the dosages described in the prior art.
  • a compound of the present disclosure may be depicted in a neutral form, a cationic form (e.g., carrying one or more positive charges), or an anionic form (e.g., carrying one or more negative charges), all of which are intended to be included in the scope of the present disclosure.
  • a compound of the present disclosure when depicted in an anionic form, such depiction also refers to the various neutral forms, cationic forms, and anionic forms of the compound.
  • a compound the present disclosure when a compound the present disclosure is depicted in an anionic form, such depiction also refers to various salts (e.g., sodium salt) of the anionic form of the compound.
  • the amine of a compound of the present disclosure is protonated.
  • compound of the present disclosure refers to any of the compound of formula I to IV including all their forms, such as polymorphs, hydrates, solvates or pharmaceutically acceptable salt.
  • halogen or "hal” as used herein may be fluoro, chloro, bromo or iodo preferably fluoro, chloro.
  • alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety.
  • Ci-6 alkyl and Ci-4alkyl refer to a fully saturated branched or unbranched hydrocarbon moiety having 1, 2, 3, 4, 5 or 6 carbon atoms and 1, 2, 3 or 4 carbon atoms, respectively.
  • Representative examples of Ci-4alkyl include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl.
  • aryl includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure.
  • aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. Conveniently, an aryl is phenyl, the term “aryl” includes multicyclic aryl, e.g., tricyclic, bicyclic, e.g., naphthalene,
  • substituted means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogen atoms on the atom are replaced.
  • Keto substituents are not present on aromatic moieties.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • any variable e.g., R
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R e.g., R
  • the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R.
  • substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • hydroxy or “hydroxyl” includes groups with an -OH or -O'.
  • alkoxy or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom.
  • alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups.
  • substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkyl- carbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, s
  • the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.
  • a biological sample refers to any biological material isolated from a subject.
  • a biological sample can comprise blood, plasma, serum, urine, breast milk, cerebrospinal fluid, mucus, gastric juice, peritoneal fluid, pleural fluid, saliva, sebum, semen, sweat, tears, vaginal secretion, vomit, endolymph, perilymph or any combination thereof.
  • a biological sample can comprise a tissue sample, wherein the tissue sample comprises cancerous tissue, non-cancerous tissue or a combination thereof.
  • anti-cancer therapy can include, but is not limited to, a surgical therapy, chemotherapy, radiation therapy, cryotherapy, hormonal therapy, toxin therapy, immunotherapy, cytokine therapy or any combination thereof.
  • chemotherapy may include administration of a further therapeutically active agent such as for example:
  • Tyrosine kinase inhibitors Erlotinib hydrochloride (e.g. Tarceva® by Genentech/Roche), Linifanib (or ABT 869, by Genentech), sunitinib malate (e.g. Sutent® by Pfizer), bosutinib (or SKI-606, described in US 6,780,996), dasatinib (e.g. Sprycel® by Bristol-Myers Squibb), armala (e.g. pazopanib, e.g. Votrient® by GlaxoSmithKline), imatinib and imatinib mesylate (e.g.
  • Erlotinib hydrochloride e.g. Tarceva® by Genentech/Roche
  • Linifanib or ABT 869, by Genentech
  • sunitinib malate e.g. Sutent® by Pfizer
  • bosutinib or SKI-606, described in US 6,7
  • Gil- vec® and Gleevec® by Novartis ascular Endothelial Growth Factor (VEGF) receptor inhibitors: Bevacizumab, or Avastin® (by Genentech/Roche), axitinib, (or AG013736, described in WO 01/002369), Brivanib Alaninate (or BMS-582664), motesanib (or AMG-706, described in PCT WO 02/066470), pasireotide (e.g. SOM230, described in WO 02/010192), sorafenib (e.g. Nexavar®);
  • VEGF ascular Endothelial Growth Factor
  • HER2 receptor inhibitors Trastuzumab (e.g. Herceptin® by Genentech/Roche), neratinib (or HKI-272, described WO 05/028443), lapatinib or lapatinib ditosylate (e.g. Tykerb® by GlaxoSmithKline); CD20 antibodies: Rituximab (e.g. Riuxan® and Mab Thera® by Genentech/Roche), tositumomab (e.g. Bexxar® by GlaxoSmithKline), ofatumumab (e.g. Arzerra® by GlaxoSmithKline);
  • trastuzumab e.g. Herceptin® by Genentech/Roche
  • neratinib or HKI-272, described WO 05/028443
  • lapatinib or lapatinib ditosylate e.g. Tykerb® by GlaxoSmithKline
  • CD20 antibodies Rit
  • Bcr/Abl kinase inhibitors nilotinib hydrochloride (e.g. Tasigna® by Novartis); DNA Synthesis inhibitors: Capecitabine (e.g. Xeloda® by Roche), gemcitabine hydrochloride (e.g. Gemzar® by Eli Lilly and Company), nelarabine (or Arranon® and Atriance® by GlaxoSmithKline); Antineoplastic agents: oxaliplatin (e.g. Eloxatin® ay Sanofi-Aventis described in US 4,169,846 );
  • Capecitabine e.g. Xeloda® by Roche
  • gemcitabine hydrochloride e.g. Gemzar® by Eli Lilly and Company
  • nelarabine or Arranon® and Atriance® by GlaxoSmithKline
  • Antineoplastic agents oxaliplatin (e.g. Eloxatin® ay Sanofi-Aventis described
  • EGFR inhibitors Gefitinib (or Iressa®), Afatinib (or Tovok® by Boehringer Ingelheim), cetuximab (e.g. Erbitux® by Bristol-Myers Squibb), pani- tumumab (e.g. Vectibix® by Amgen);
  • HER dimerization inhibitors Pertuzumab (e.g. Omnitarg®, by Genentech); Human Granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (e.g. Neupogen® by Amgen);
  • Immunomodulators Afutuzumab (by Roche), pegfilgrastim (e.g. Neulasta® by Amgen), lenalidomide (e.g. CC-5013, e.g. Revlimid®), thalidomide (e.g. Thalomid®);
  • CD40 inhibitors Dacetuzumab (e.g. SGN-40 or huS2C6, by Seattle Genetics, Inc); Pro- apoptotic receptor agonists (PARAs): Dulanermin (e.g. AMG-951, by Amgen/Genentech);
  • Hedgehog antagonists Vismodegib (or GDC-0449, described in WO 06/028958);
  • PI3K inhibitors Pictilisib (or GDC-0941 described in WO 09/036082 and WO 09/055730 ), Dactolisib (or BEZ 235 or NVP-BEZ 235, described in WO 06/122806);
  • Phospholipase A2 inhibitors Anagrelide (e.g. Agrylin®);
  • BCL-2 inhibitors Navitoclax (or ABT-263, described in WO 09/155386);
  • Mitogen-activated protein kinase (MEK) inhibitors XL-518 (Cas No. 1029872-29-4, by ACC Corp.); Aromatase inhibitors: Exemestane (e.g. Aromasin® by Pfizer), letrozole (e.g. Femara® by Novartis), anastrozole (e.g. Arimidex®);
  • Topoisomerase I inhibitors Irinotecan (e.g. Camptosar® by Pfizer), topotecan hydrochloride (e.g. Hycamtin® by GlaxoSmithKline);
  • Topoisomerase II inhibitors etoposide (e.g. VP-16 and Etoposide phosphate, e.g. Toposar®, VePesid® and Etopophos®), teniposide (e.g. VM-26, e.g. Vumon®); mTOR inhibitors: Temsirolimus (e.g. Torisel® by Pfizer), ridaforolimus (formally known as deferolimus, (or AP23573 and MK8669, described in WO 03/064383), everolimus (e.g. Afini- tor® by Novartis);
  • etoposide e.g. VP-16 and Etoposide phosphate, e.g. Toposar®, VePesid® and Etopophos®
  • teniposide e.g. VM-26, e.g. Vumon®
  • mTOR inhibitors Temsirolimus (e.g. To
  • Osteoclastic bone resorption inhibitors zoledronic acid (or Zometa® by Novartis);
  • CD33 Antibody Drug Conjugates Gemtuzumab ozogamicin (e.g. Mylotarg® by Pfizer/Wyeth);
  • CD22 Antibody Drug Conjugates Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, by Hangzhou Sage Chemical Co., Ltd.);
  • CD20 Antibody Drug Conjugates Ibritumomab tiuxetan (e.g. Zevalin®); Somatostain analogs: octreotide (e.g. octreotide acetate, e.g. Sandostatin® and Sandostatin LAR®);
  • Ibritumomab tiuxetan e.g. Zevalin®
  • Somatostain analogs octreotide (e.g. octreotide acetate, e.g. Sandostatin® and Sandostatin LAR®);
  • Synthetic Interleukin- 11 (IL-11): oprelvekin (e.g. Neumega® by Pfizer/Wyeth); Synthetic erythropoietin: Darbepoetin alfa (e.g. Aranesp® by Amgen);
  • Denosumab e.g. Pro- lia® by Amgen
  • Thrombopoietin mimetic peptibodies Romiplostim (e.g. Nplate® by Amgen;
  • Palifermin e.g. Kepivance® by Amgen
  • IGF-1R Anti-Insulin-like Growth Factor-1 receptor antibodies: Figitumumab (e.g. CP- 751,871, by ACC Corp), robatumumab (CAS No. 934235-44-6);
  • Anti-CSl antibodies Elotuzumab (HuLuc63, CAS No. 915296-00-3);
  • CD52 antibodies Alemtuzumab (e.g. Campath®);
  • CTLA-4 inhibitors Tremelimumab (IgG2 monoclonal antibody by Pfizer, formerly known as ticilimumab, CP-675,206), ipilimumab (CTLA-4 antibody, e.g. MDX-010, CAS No. 477202- 00-9);
  • Histone deacetylase inhibitors Voninostat (e.g. Zolinza® by Merck); Alkylating agents: Temozolomide (e.g. Temodar® and Temodal® by Schering- Plough/Merck), dactinomycin (e.g. actinomycin-D and e.g. Cosmegen®), melphalan (e.g. L-PAM, L-sarcolysin, and phenylalanine mustard, e.g. Alkeran®), altretamine (e.g. hexamethylmelamine (HMM), e.g. Hexalen®), carmustine (e.g. BiCNU®), bendamustine (e.g.
  • VHI Voninostat
  • Alkylating agents Temozolomide (e.g. Temodar® and Temodal® by Schering- Plough/Merck)
  • dactinomycin e.g. actinomycin-D and e.g. Cos
  • Treanda® busulfan (e.g. Busulfex® and Myleran®), carboplatin (e.g. Paraplatin®), lomustine (e.g. CCNU, e.g. CeeNU®), cisplatin (e.g. CDDP, e.g. Platinol® and Platinol®-AQ), chlorambucil (e.g. Leukeran®), cyclophosphamide (e.g. Cytoxan® and Neosar®), dacarbazine (e.g. DTIC, DIC and imidazole carboxamide, e.g. DTIC-Dome®), altretamine (e.g.
  • busulfan e.g. Busulfex® and Myleran®
  • carboplatin e.g. Paraplatin®
  • lomustine e.g. CCNU, e.g. CeeNU®
  • cisplatin e.g. CDDP, e.g
  • HMM hexamethylmelamine
  • ifosfamide e.g. Ifex®
  • procarbazine e.g. Matulane®
  • mechlorethamine e.g. nitrogen mustard, mustine and mechloroethamine hydrochloride, e.g. Mustargen®
  • streptozocin e.g. Zanosar®
  • thiotepa e.g. thiophosphoamide, TESPA and TSP A, e.g. Thioplex®;
  • Biologic response modifiers bacillus calmette-guerin (e.g. theraCys® and TICE® BCG), denileukin diftitox (e.g. Ontak®);
  • Anti-tumor antibiotics doxorubicin (e.g. Adriamycin® and Rubex®), bleomycin (e.g. le- noxane®), daunorubicin (e.g. dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, e.g. Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, e.g. DaunoX- ome®), mitoxantrone (e.g. DHAD, e.g. Novantrone®), epirubicin (e.g. EllenceTM), idarubicin (e.g. Idamycin®, Idamycin PFS®), mitomycin C (e.g. Mutamycin®);
  • doxorubicin e.g. Adriamycin® and Rubex®
  • bleomycin e.g. le- noxane®
  • daunorubicin
  • Anti-microtubule agents Estramustine (e.g. Emcyl®);
  • Cathepsin K inhibitors Odanacatib (or MK-0822, by Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, described in WO 03/075836);
  • Epothilone B analogs Ixabepilone (e.g. Lxempra® by Bristol-Myers Squibb);
  • HSP Heat Shock Protein
  • TpoR agonists Eltrombopag (e.g. Promacta® and Revolade® by GlaxoSmithKline);
  • Anti-mitotic agents Docetaxel (e.g. Taxotere® by Sanofi -Aventis);
  • Adrenal steroid inhibitors aminoglutethimide (e.g. Cytadren®);
  • Nilutamide e.g. Nilandron® and Anandron®
  • bicalutamide sold under tradename Casodex®
  • flutamide e.g. FulexinTM
  • Androgens Fluoxymesterone (e.g. halotestin®); Proteasome inhibitors: Bortezomib (e.g. Velcade®); CDK1 inhibitors: Alvocidib (e.g. flovopirdol or HMR-1275, described in US 5,621,002);
  • GnRH Gonadotropin-releasing hormone receptor agonists: Leuprolide or leuprolide acetate (e.g. Viadure® by Bayer AG, Eligard® by Sanofi -Aventis and Lupron® by Abbott Lab);
  • Taxane anti-neoplastic agents Cabazitaxel, larotaxel;
  • 5HTla receptor agonists Xaliproden (or SR57746, described in US 5,266,573);
  • HPC vaccines Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck;
  • Iron Chelating agents Deferasinox (e.g. Exjade® by Novartis);
  • Anti-metabolites Claribine (2-chlorodeoxyadenosine, e.g. leustatin®), 5 -fluorouracil (e.g. Adrucil®), 6-thioguanine (e.g. Purinethol®), pemetrexed (e.g. Alimta®), cytarabine (e.g. arabino- sylcytosine (Ara-C), e.g. Cytosar-U®), cytarabine liposomal (e.g. Liposomal Ara-C, e.g. Depo- CytTM), decitabine (e.g. Dacogen®), hydroxyurea (e.g.
  • fludarabine e.g. Fludara®
  • floxuridine e.g. FUDR®
  • cladribine e.g. 2-chlorodeoxyadenosine (2-CdA) e.g. LeustatinTM
  • methotrexate e.g. amethopterin, methotrexate sodium (MTX), e.g. Rheumatrex® and TrexallTM
  • pentostatin e.g. Nipent®
  • Bisphosphonates Pamidronate (e.g. Aredia®), zoledronic acid (e.g. Zometa®);
  • Demethylating agents 5-azacitidine (e.g. Vidaza®), decitabine (e.g. Dacogen®);
  • Paclitaxel protein-bound e.g. Abraxane®
  • vinblastine e.g. vinblastine sulfate, vincaleukoblastine and VLB, e.g. Alkaban-AQ® and Velban®
  • vincristine e.g. vincristine sulfate, LCR, and VCR, e.g. Oncovin® and Vincasar Pfs®
  • vinorelbine e.g. Navelbine®
  • paclitaxel e.g. Taxol and OnxalTM
  • Retinoids Alitretinoin (e.g. Panretin®), tretinoin (all-trans retinoic acid, e.g. ATRA, e.g. Vesanoid®), Isotretinoin (13-cis-retinoic acid, e.g. Accutane®, Amnesteem®, Claravis®, Claims®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (e.g. Targre- tin®);
  • Glucocorticosteroids Hydrocortisone (e.g. cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and e.g. Ala-Cort®, Hydrocortisone Phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dexamethasone, prednisolone (e.g. Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (e.g. Deltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone (e.g.
  • prednisolone e.g. Delta-Cortel®, Orapred®, Pediapred® and Prelone®
  • prednisone e.g. Deltasone®, Liquid Red®, Meticorten® and Orasone®
  • methylprednisolone
  • 6-Methylprednisolone Methylprednisolone Acetate, Methylprednisolone Sodium Succinate, e.g. Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®); Cytokines: interleukin-2 (e.g. aldesleukin and IL-2, e.g. Proleukin®), interleukin- 11 (e.g. oprevelkin, e.g. Neumega®), alpha interferon alfa (e.g. IFN-alpha, e.g. Intron® A, and Roferon- A®);
  • interleukin-2 e.g. aldesleukin and IL-2, e.g. Proleukin®
  • interleukin- 11 e.g. oprevelkin, e.g. Neumega®
  • alpha interferon alfa e.g. IFN-alpha,
  • Lutinizing hormone releasing hormone (LHRH) agonists Goserelin (e.g. Zoladex®); Progesterones: megestrol (e.g. megestrol acetate, e.g. Megace®);
  • Miscellaneous cytotoxic agents Arsenic trioxide (e.g. Trisenox®), asparaginase (e.g. L- asparaginase, Erwinia L-asparaginase, e.g. Elspar® and Kidrolase®);
  • Arsenic trioxide e.g. Trisenox®
  • asparaginase e.g. L- asparaginase, Erwinia L-asparaginase, e.g. Elspar® and Kidrolase®
  • asparaginase e.g. L- asparaginase, Erwinia L-asparaginase, e.g. Elspar® and Kidrolase®
  • NK-1 receptor antagonists Casopitant (e.g. Rezonic® and Zunrisa® by GlaxoSmithKline); or
  • Cytoprotective agents Amifostine (e.g. Ethyol®), leucovorin (e.g. calcium leucovorin, cit- rovorum factor and folinic acid).
  • Amifostine e.g. Ethyol®
  • leucovorin e.g. calcium leucovorin, cit- rovorum factor and folinic acid.
  • combinations may include combinations with a therapeutically active agent such as osimertinib, afatinib, neratinib, poziotinib, TAK-788, or dacomitinib.
  • a therapeutically active agent such as osimertinib, afatinib, neratinib, poziotinib, TAK-788, or dacomitinib.
  • combinations may include combinations with osimertinib, afatinib, neratinib, poziotinib, TAK-788, or dacomitinib.
  • acquiring resistance refers to a condition wherein a cancer that was sensitive to the inhibitory effects of at least one anti-cancer treatment becomes non-responsive or less-responsive over time to the effects of that at least one anti-cancer treatment.
  • the cancer may be a cancer characterized by an oncogenic variant of EGFR, wherein the cancer was previous sensitive to the inhibitory effects of at least one EGFR TKI, but has become non-responsive or less-responsive over time to the effects of the at least one EGFR-TKI.
  • acquired resistance to EGFR-TKIs in EGFR-mutant cancers occurs due to one or more additional mutations to EGFR or non-EGFR genetic alterations in bypass signaling that develops after the onset of an EGFR-TKI treatment regimen.
  • non-limiting exemplary acquired resistance EGFR- mutants in NSCLCs include, but are not limited to, EGFR T790M substitutions, in particular C797 substitutions, i.e. C797S and C797G substitutions.
  • an intrinsic (or primary) resistance refers to a condition wherein a cancer with a EGFR mutation is not responsive to the inhibitory effects of initial EGFR-TKI treatment.
  • a diagnosis of TKI resistance may be accomplished by way of monitoring tumor progression during treatment with the respective TKI(s) by e.g. comparing tumor status with time, such as by means of radiography, for example, X-ray, CT scan, and other known monitoring methods, by palpitation of the cancer or by monitoring tumor biomarker levels, indicating tumor growth, new tumors or metastasis or tumor growth, or else by testing for the occurrence of an EGFR mutation C797.
  • the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs.
  • the subject is a mammal.
  • the mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig.
  • the subject can also be a bird or fowl.
  • the subject is a human.
  • the term “subject in need thereof’ refers to a subject having a disease or having an increased risk of developing the disease.
  • a subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein.
  • a subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein.
  • a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large).
  • a subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment).
  • the subject may be resistant at start of treatment or may become resistant during treatment.
  • the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein.
  • the subject in need thereof received at least one prior therapy.
  • treating describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term “treat” can also include treatment of a cell in vitro or an animal model.
  • a compound of the present disclosure can or may also be used to prevent a relevant disease, condition, or disorder, or used to identify suitable candidates for such purposes.
  • the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
  • compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.
  • Embodiment 1 A compound of formula I: or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:
  • X 1 is -O-, -S-, or -NR 2 -; each R a independently is -H or -Ci-4 alkyl; each R b independently is -H or -Ci-4 alkyl; each R c independently is -H or -Ci-4 alkyl; each R d independently is -H or -Ci-4 alkyl;
  • R 1 is -H or -Ci-4 alkyl
  • R 2 is -H or -Ci-4 alkyl
  • R 3 is -H or -O-Ci-4 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and
  • Ar 1 is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH 2 , -NH(CI-6 alkyl), -N(CI-C 6 alkyl) 2 , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH 2 , - NH(CI-C 6 alkyl), or -N(CI-C 6 alkyl) 2 .
  • Embodiment 2 The compound of embodiment 1, wherein the compound is not 2-[4-[4- (3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-l-yl]-7V-methylacetamide or 2-(3-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)-N- methylacetamide.
  • Embodiment 3 The compound of any one of the preceding embodiments, wherein when X 1 is O, R 3 is -OMe, R 1 , R a , R b , R c , and R d are each -H, n and m are each 2, then Ar 1 is not 3- chloro-2-fluorophenyl, and when X 1 is O, R 3 is -OMe, R 1 , R a , R b , R c , and R d are each -H, n and m are each 1, then Ar 1 is not 3-chloro-2-fluorophenyl.
  • Embodiment 4 The compound of any one of the preceding embodiments, wherein:
  • X 1 is -O-, -S-, or -NR 2 -; each R a independently is -H or -Ci-4 alkyl; each R b independently is -H or -Ci-4 alkyl; each R c independently is -H or -Ci-4 alkyl; each R d independently is -H or -Ci-4 alkyl; R 1 is -H or -Ci-4 alkyl;
  • R 2 is -H or -Ci-4 alkyl
  • R 3 is -H or -O-Ci-4 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and
  • Ar 1 is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH 2 , -NH(CI-6 alkyl), -N(CI-C 6 alkyl) 2 , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH 2 , - NH(CI-C 6 alkyl), or -N(CI-C 6 alkyl) 2 ; provided that the compound is not 2-[4-[4-(3-chloro-2-fluoroan
  • Embodiment 5 The compound of any one of the preceding embodiments, wherein:
  • X 1 is -O-, -S-, or -NR 2 -; each R a independently is -H or -Ci-4 alkyl; each R b independently is -H or -Ci-4 alkyl; each R c independently is -H or -Ci-4 alkyl; each R d independently is -H or -Ci-4 alkyl;
  • R 1 is -H or -C1-4 alkyl
  • R 2 is -H or -C1-4 alkyl
  • R 3 is -H or -O-C1-4 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and
  • Ar 1 is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH 2 , -NH(CI-6 alkyl), -N(CI-C 6 alkyl) 2 , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH 2 , - NH(CI-C 6 alkyl), or -N(CI-C 6 alkyl) 2 ; provided that when X 1 is O, R 3 is -OMe, R 1 , R a
  • Embodiment 6 The compound of any one of the preceding embodiments, wherein X 1 is -O-.
  • Embodiment 7 The compound of any one of the preceding embodiments, wherein X 1 is -S-.
  • Embodiment 8 The compound of any one of the preceding embodiments, wherein X 1 is -NR 2 -.
  • Embodiment 9 The compound of any one of the preceding embodiments, wherein X 1 is -NH-.
  • Embodiment 10 The compound of any one of the preceding embodiments, wherein X 1 is -N(CH 3 )-.
  • Embodiment 11 The compound of any one of the preceding embodiments, wherein R 1 is -H.
  • Embodiment 12 The compound of any one of the preceding embodiments, wherein R 3 is -H.
  • Embodiment 13 The compound of any one of the preceding embodiments, wherein R 3 is -OMe.
  • Embodiment 14 The compound of any one of the preceding embodiments, wherein at least one R a is -H.
  • Embodiment 15 The compound of any one of the preceding embodiments, wherein at least one R a is -Ci-4 alkyl.
  • Embodiment 16 The compound of any one of the preceding embodiments, wherein at least one R b is -H.
  • Embodiment 17 The compound of any one of the preceding embodiments, wherein at least one R b is -Ci-4 alkyl.
  • Embodiment 18 The compound of any one of the preceding embodiments, wherein at least one R c is -H.
  • Embodiment 19 The compound of any one of the preceding embodiments, wherein at least one R c is -Ci-4 alkyl.
  • Embodiment 20 The compound of any one of the preceding embodiments, wherein at least one R d is -H.
  • Embodiment 21 The compound of any one of the preceding embodiments, wherein at least one R d is -Ci-4 alkyl.
  • Embodiment 22 The compound of any one of the preceding embodiments, wherein m is
  • Embodiment 23 The compound of any one of the preceding embodiments, wherein m is
  • Embodiment 24 The compound of any one of the preceding embodiments, wherein n is
  • Embodiment 25 The compound of any one of the preceding embodiments, wherein n is 2.
  • Embodiment 26 The compound of any one of the preceding embodiments, wherein m is
  • n 1
  • Embodiment 27 The compound of any one of the preceding embodiments, wherein m is
  • n 2 and n is 2.
  • Embodiment 28 The compound of any one of the preceding embodiments, wherein Ar 1 is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI- 6 alkyl), -N(CI-C 6 alkyl) 2 , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the Ci- 6 alkyl, Ci-6 alkoxy, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl) 2 , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substituted with one or more hydroxy, C1-6 alkoxy, -NH 2 , -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl) 2 .
  • Embodiment 29 The compound of any one of the preceding embodiments, wherein Ar 1 is phenyl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH 2 , - NH(CI-6 alkyl), -N(Ci-Ce alkyl) 2 , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl) 2 , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substituted with one or more hydroxy, C1-6 alkoxy, -NH 2 , -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl) 2 .
  • Embodiment 29 The compound
  • Embodiment 31 The compound of any one of the preceding embodiments, wherein Ar 1 is phenyl optionally substituted with one or more halogen, -CF3, or C1-6 alkyl.
  • Embodiment 32 The compound of any one of the preceding embodiments, wherein Ar 1 is Ce-io aryl optionally substituted with one or more halogen.
  • Embodiment 33 The compound of any one of the preceding embodiments, wherein Ar 1 is phenyl optionally substituted with one or more halogen.
  • Embodiment 34 The compound of any one of the preceding embodiments, wherein Ar 1
  • Embodiment 35 The compound of any one of the preceding embodiments, being of any one of Formulae (la), (lb), (Ic), (Id), (le), (If), (Ig), or (Ih): or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • Embodiment 36 The compound of any one of the preceding embodiments, being of Formula (II): or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • Embodiment 37 The compound of any one of the preceding embodiments, being of any one of Formulae (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), or (Ilh):
  • Embodiment 38 The compound of any one of the preceding embodiments, being of Formula (III) or Formula (IV): or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • Embodiment 39 The compound of any one of the preceding embodiments, being of any one of Formulae (Illa), (Illb), (IIIc), (Hid), (IVa), (IVb), (IVc), or (IVd):
  • Embodiment 40 The compound of any one of the preceding embodiments, wherein the compound is selected from a compound described in Table I, or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • Embodiment 41 The compound of any one of the preceding embodiments, wherein the compound is selected from Compound Nos. 2-15, or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • Embodiment 42 An isotopic derivative of the compound of any one of the preceding embodiments.
  • Embodiment 43 The isotopic derivative, being an isotopic derivative of a compound described in Table I, or a pharmaceutically acceptable salt thereof.
  • Embodiment 44 A pharmaceutical composition comprising the compound of any one of the preceding embodiments and one or more pharmaceutically acceptable carriers or excipients.
  • Embodiment 45 A method of treating or preventing cancer in a subject, comprising administering to the subject the compound of any one of the preceding embodiments.
  • Embodiment 46 A compound of any one of the preceding embodiments for treating or preventing cancer in a subject.
  • Embodiment 47 Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for treating or preventing cancer in a subject.
  • Embodiment 48 Use of the compound of any one of the preceding embodiments for treating or preventing cancer in a subject.
  • Embodiment 49 The method, compound, or use of any one of embodiments 45-48, wherein the cancer is characterized by an EGFR mutation C797.
  • Embodiment 50 The method, compound, or use of embodiment 49, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.
  • Embodiment 51 The method, compound, or use of any one of embodiments 45-50, wherein the subject is a human.
  • Embodiment 52 The method, compound, or use of any one of embodiments 45-51, wherein the subject has previously undergone at least one round of anti-cancer therapy.
  • Embodiment 53 The method, compound, or use of any one of embodiments 45-52, wherein the subject has previously undergone at least one round of anti-cancer therapy and has acquired resistance to treatment with the anti-cancer therapy.
  • Embodiment 54 The method, compound, or use of any one of embodiments 45-53, wherein the cancer is a carcinoma, a lymphoma, a blastoma, a sarcoma, a leukemia, a brain cancer, a breast cancer, a blood cancer, a bone cancer, a lung cancer, a skin cancer, a liver cancer, an ovarian cancer, a bladder cancer, a renal cancer, a kidney cancer, a gastric cancer, a thyroid cancer, a pancreatic cancer, an esophageal cancer, a prostate cancer, a cervical cancer, a uterine cancer, a stomach cancer, a soft tissue cancer, a laryngeal cancer, a small intestine cancer, a testicular cancer, an anal cancer, a vulvar cancer, a joint cancer, an oral cancer, a pharynx cancer, a renal pelvis cancer, intrahepatic bile duct cancer, bronchus cancer or a
  • Embodiment 55 The method, compound, or use of any one of embodiments 45-54, wherein the cancer is metastatic, recurrent, or multi-drug resistant.
  • Embodiment 56 The method, compound, or use of any one of embodiments 45-55, wherein the cancer is non-small cell lung cancer (NSCLC), glioblastoma, breast, head or neck, colon, gastric, pancreatic, bladder cancer.
  • NSCLC non-small cell lung cancer
  • glioblastoma breast, head or neck, colon, gastric, pancreatic, bladder cancer.
  • Embodiment 57 The method, compound, or use of embodiment 56, wherein the cancer is NSCLC.
  • Embodiment 58 The method, compound, or use of embodiment 57, wherein the NSCLC is in the brain.
  • Embodiment 59 The method, compound, or use of any one of embodiments 45-58, wherein the cancer is a cancer that is resistant to treatment with EGFR TKIs.
  • salts of the compounds of Formula (I) are synthesized and tested in the examples. It is understood that neutral compounds of Formula (I) may be similarly synthesized and tested using the exemplary procedures described in the examples. Further, it is understood that the salts (e.g., sodium salt) of the compounds of Formula (I) may be converted to the corresponding neutral compounds using routine techniques in the art (e.g., pH adjustment and, optionally, extraction (e.g., into an aqueous phase)).
  • Compounds of Formula (I) can be prepared using the methods detailed herein. Those skilled in the art may be able to envisage alternative synthetic routes, using a variety of starting materials and reagents to prepare the disclosed compounds of Formula (I) and to make further modifications. For exemplary purpose, salts of some of the compounds of Formula (I) are synthesized and tested in the examples. It is understood that neutral compounds of Formula (I) may be similarly synthesized and tested using the exemplary procedures described in the examples.
  • salts e.g., hydrochloride salt
  • the salts of the compounds of Formula (I) may be converted to the corresponding neutral compounds using routine techniques in the art (e.g., pH adjustment and, optionally, extraction (e.g., into an aqueous phase)).
  • the filtrate was purified by /?re/?-HPLC(column: Xtimate C18 150*25 mm*5 pm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 29%-59%,10min) and prep- HPLC(column: Phenomenex Synergi C18 150*30 mm*4 pm; mobile phase: [water(0.225%FA)- ACN];B%: l%-30%,12min) to afford 2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methox- yquinazolin-6-yl)amino)piperidin-l-yl)-A-methylacetamide (173 mg, 366 pmol, 42% yield) as a yellow solid.
  • the filtrate was purified by prep-HPLC (column: Waters Xbridge 150*50 10 pm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 26%-56%,11.5 min) to give 2-(4-((4- ((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)thio)piperidin-l-yl)-A-methyla- cetamide (121 mg, 247 pmol, 31% yield) as a white solid.
  • the filtrate was purified by /c -HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water(10 mM NH4HCO3)-ACN];B%: 20%-50%,10min) and lyophilized to give 2-(3-((4-((3-chloro-2-fluoro- phenyl)amino)quinazolin-6-yl)thio)azetidin-l-yl)-7V-methylacetamide (22.89 mg, 55.7 pmol, 11% yield, 97% purity) as a yellow solid.
  • reaction mixture was poured into water (80.0 mL) and stirred for 10 min.
  • the aqueous phase was extracted with ethyl acetate (3 x 50.0 mL).
  • the combined organic phase was washed with saturated sodium bicarbonate (80.0 mL) and brine (60.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue.
  • the filtrate was purified by /c -HPLC (column: Waters Xbridge 150*25 5 um; mobile phase: [water(10mMNH4HCO3)-ACN];B%: 20%-50%,10 min) to afford 2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)(methyl)amino)pi- peri din- l-yl)-7V-m ethylacetamide (81.0 mg, 166 pmol, 34% yield) as a yellow solid.
  • the filtrate was purified by /i/c -HPLC (column: Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 20%-50%,10 min) and (column: Phenomenex Gemini 150*25 mm*10 pm;mobile phase: [water(0.225%FA)-ACN];B%: l%-30%, 10 min) to give 2-(3- ((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)(methyl)amino)azetidin-l-yl)- /'/-methylacetamide (15.5 mg, 33.8 pmol, 15% yield) as a white solid.
  • the filtrate was purified by /i/c -HPLC (column: Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 26%-56%,10min) and (column: Phenomenex Synergi Cl 8 150*30 mm*4 pm;mobile phase: [water(0.225%FA)-ACN];B%: 5%-35%, 10 min) to give 2-(3- ((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)thio)azetidin-l-yl)-A-methyla- cetamide (41.1 mg, 89.1 pmol, 27% yield) as a white solid.
  • the filtrate was purified by prep- HPLC (column: Waters Xbridge 150*25 5 um; mobile phase: [water(10mM NH4HCO3)- ACN];B%: 28%-45%,10 min) to give 2-(3-((4-((3-chloro-2-fluorophenyl)amino)-7-methox- yquinazolin-6-yl)amino)azetidin-l-yl)-A-m ethyl acetamide (7.14 mg, 16.1 pmol, 6% yield) as a white solid.
  • reaction mixture was concentrated under vacuum to give / ’-(azeti din-3 -yl)- 7 ⁇ -(3-chloro-2-fluorophenyl)quinazoline-4, 6-diamine (300 mg, crude, hydrochloric acid) as a yellow solid.
  • the reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (3 x 50.0 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give a residue which was purified by prep- HPLC (column: Xtimate C18 150*25 mm*5 pm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 18%-48%, 10 min). The desired fraction was collected and concentrated to remove acetonitrile.
  • reaction mixture was poured into water (40.0 mL) and the aqueous phase was extracted with ethyl acetate (3 x 60.0 mL). The combined organic phase was washed with brine (40.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue.
  • the reaction mixture was filtered to give a filtrate, the filtrate was purified by /i/c -HPLC (column: Phenomenex Synergi Max-RP 150*50 mm* 10 pm; mobile phase: [water(0.225%FA)-ACN];B%: 1 %-31%, 11 min) to afford 2-(3-((4-((3- chloro-2-fluorophenyl)amino)quinazolin-6-yl)oxy)azetidin- 1 -yl )-ct/-m ethyl acetami de (15.5 mg, 37.2 pmol, 4.2% yield) as a white solid.
  • the reaction mixture was filtered and the filtrate was purified by /c -HPLC [column: Waters Xbridge 150*25 5 pm; mobile phase: [water(10mM NH4HCO3)-ACN];B%: 20%-50%,10 min] and lyophilized to give 2-(4-((4-((3 -chloro- 2-fluoro- phenyl)amino)quinazolin-6-yl)oxy)piperidin-l-yl)-N-methylacetamide (100.03 mg, 225 pmol , 31 % yield, 99% purity) as a gray solid.
  • EGFR mutants were subcloned into pMXs-IRES-Blasticidin (RTV-016, Cell Biolabs, San Diego, C A).
  • Retroviral expression vector retrovirus was produced by transient transfection of HEK 293T cells with the retroviral EGFR mutant expression vector pMXs-IRES-Blasticidin (RTV-016, Cell Biolabs), pCMV-Gag-Pol vector and pCMV-VSV-G-Envelope vector.
  • HEK 293T/17 cells were plated in 100 mm collagen coated plate (354450, Coming Life Sciences, Tewksbury, MA) (4x105 per plate) and incubated overnight.
  • retroviral plasmids (3 mg of EGFR mutant, 1.0 mg of pCMV-Gag-Pol and 0.5 mg pCMV-VSV-G) were mixed in 500 mL of Optimem (31985, Life Technologies). The mixture was incubated at room temperature for 5 minutes and then added to Optimem containing transfection reagent Lipofectamine (11668, Invitrogen) and incubated for 20 minutes. The mixture was then added dropwise to HEK 293T cells. The next day the medium was replaced with fresh culture medium and the retrovirus was harvested at 24 hours and 48 hours.
  • BaF3 cells (1.5E5 cells) were infected with 1 mL of viral supernatant supplemented with 8 mg/mL polybrene by centrifuging for 30 minutes at 1000 rpm. Cells were placed in a 37 °C incubator overnight. Cells were then spun for 5 minutes to pellet the cells. Supernatant was removed and cells re-infected a fresh 1 mL of viral supernatant supplemented with 8 mg/mL polybrene by centrifuging for 30 minutes at 1000 rpm. Cells were placed in 37 °C incubator overnight. Cells were then maintained in RPMI containing 10% Heat Inactivated FBS, 2% L-glutamine containing 10 ng/mL IL-3.
  • Blasticidin resistant populations were washed twice in phosphate buffered saline before plating in media lacking IL-3 to select for IL-3 independent growth.
  • the number of viable cells was determined and normalized to vehicle-treated controls. Inhibition of proliferation, relative to vehicle-treated controls was expressed as a fraction of 1 and graphed using PRISM® software (Graphpad Software, San Diego, CA). ECso values were determined with the same application
  • the A431 lung cancer cell line which natively expresses WT-EGFR, was used to assess WT-EGFR inhibition.
  • BT474 which natively expresses WT-HER2, was used to assess WT-HER2 inhibition.
  • To perform the proliferation assays cells were plated in 96-well plates and subjected to various doses of compound to generate a dose-response curve for each cell line. Proliferation was assessed using the Cell Titer Gio cell proliferation kit (Promegea # G7573). Cell Titer Gio reagent was thawed and allowed to equilibrate at room temperature for 30 minutes. Plated and dosed cells were also allowed to equilibrate at room temperature for 30 minutes.
  • Cell Titer Gio was added to plated cells at 15 pL per well, the plate was shaken for 20 minutes at room temperature, and luminescence was measured using Victor X3 Multimode plate reader (Perkin Elmer). Cell Titer Gio readings were taken following 72 hours (T72) after addition of compound. Doseresponse curves were generated for each cell line and ICso values were generated.
  • Table A assigns each compound an ICso code: A, B, C, D, or E.
  • A represents an ICso value ⁇ 5 nM
  • B represents an ICso value >5 nM and ⁇ 25 nM
  • C represents an ICso value >25 nM and ⁇ 100 nM
  • D represents an IC50 value >100 nM and ⁇ 200 nM
  • E represents an IC50 value >200 nm.
  • Table A also assigns each compound a code for selectivity for EGFR exon-19 del +C797S/EGFR wt: + indicates selectivity >lx and ⁇ 25x; ++ indicates selectivity >25x and ⁇ 50x; +++ indicates selectivity >50x and ⁇ 75x; ++++ indicates selectivity >75x and

Abstract

La présente invention concerne des composés de Formule (I) ou un stéréoisomère, un polymorphe, un hydrate, un solvate ou un sel pharmaceutiquement acceptable de ceux-ci. La présente invention concerne également des utilisations des composés, par exemple, dans le traitement ou la prévention du cancer.
PCT/US2022/015249 2021-02-05 2022-02-04 Dérivés de quinazoline, dérivés de pyridopyrimidine, dérivés de pyrimidopyrimidine et leurs utilisations WO2022170052A1 (fr)

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