WO2024073745A1 - Inhibiteurs d'egfr ou de her2 et méthodes d'utilisation - Google Patents

Inhibiteurs d'egfr ou de her2 et méthodes d'utilisation Download PDF

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Publication number
WO2024073745A1
WO2024073745A1 PCT/US2023/075637 US2023075637W WO2024073745A1 WO 2024073745 A1 WO2024073745 A1 WO 2024073745A1 US 2023075637 W US2023075637 W US 2023075637W WO 2024073745 A1 WO2024073745 A1 WO 2024073745A1
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optionally substituted
alkyl
heterocyclyl
independently
compound
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PCT/US2023/075637
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English (en)
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John Hatcher
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Arbella Therapeutics, Llc
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Publication of WO2024073745A1 publication Critical patent/WO2024073745A1/fr

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    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • TKIs EGFR tyrosine kinase inhibitors
  • NSCLC non-small cell lung cancer
  • responders typically relapse 6-19 months after taking EGFR TKIs as a consequence of becoming resistant to the inhibitors.
  • the most common resistance mutation occurs at the gatekeeper T790M position.
  • EGFR gene mutations e.g., G719X, exon 19 deletions/insertions, L858R, and L861Q
  • T790M the acquired gefitinib resistant mutation
  • osimertinib the acquired gefitinib resistant mutation
  • EGFR exon 20 insertion mutations ⁇ 10% of all EGFR mutations are generally associated with insensitivity to available TKIs (gefitinib, erlotinib, afatinib, and osimertinib).
  • HER2 Human epidermal growth factor receptor 2
  • HER2 mutations which mainly consist of exon 20 insertion mutations, have been reported in approximately 1-4% of NSCLC patients. Phase I and II clinical data demonstrated that patients harboring HER2 mutations partially responded to treatment with afatinib, neratinib, or dacomitinib.
  • HER2 insYVMA Although patients with HER2 insYVMA have reported durable responses to afatinib as a single agent, a recent phase II trial of dacomitinib showed no response in all 13 patients with HER2 insYVMA (A775_G776insYVMA), which represents up to 80% of HER2 mutations in lung cancers.
  • novel therapies for patients with EGFR mutations e.g., exon 20 insertion mutations
  • compounds possessing activity against HER2 mutations are needed, as they may have extended utility in treating tumors harboring such mutations.
  • the present disclosure features a class of novel small molecule compounds that inhibit epidermal growth factor receptor tyrosine kinase (EGFR) and/or human epidermal growth factor receptor 2 (HER2).
  • the compounds are capable of modulating (e.g., inhibiting or decreasing) EGFR and/or HER2 that are resistant to other drugs, e.g., EGFR and/or HER2 with exon 20 mutations, exon 19 mutations, gefitinib resistant T790M mutation, and/or exon 20 insertion mutations.
  • the present disclosure relates to a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 4 , R 6 , X 1 , X 2 , and X 3 are each described herein in detail below.
  • the present disclosure relates to a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 6 , and X 3 are each described herein in detail below.
  • the present disclosure relates to a compound of Formula III: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 4 , R 6 , and X 3 are each described herein in detail below.
  • the present disclosure relates to a compound selected from , , or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a pharmaceutical composition comprising a compound of any one of the formulae described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present disclosure relates to a kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a method of modulating (e.g., inhibiting or decreasing) EGFR or a mutant thereof, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a method of modulating (e.g., inhibiting or decreasing) HER2 or a mutant thereof, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a method of modulating (e.g., inhibiting or decreasing) EGFR or a mutant thereof and HER2 or a mutant thereof, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a method of treating or preventing a disease or disorder, such as a kinase mediated disease or disorder, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • a disease or disorder such as a kinase mediated disease or disorder
  • the present disclosure relates to a method of treating or preventing a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy, such as a therapy with gefitinib or erlotinib, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a method of treating or preventing cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a method of treating or preventing a disease or disorder, such as a kinase mediated disease or disorder, in a subject in need thereof, wherein the subject is identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder, comprising administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • a disease or disorder such as a kinase mediated disease or disorder
  • the present disclosure relates to a compound of the present disclosure for modulating (e.g., inhibiting or decreasing) EGFR or a mutant thereof and/or HER2 or a mutant thereof; for treating or preventing a disease or disorder, such as a kinase mediated disease or disorder; for treating or preventing a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; for treating or preventing cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or for treating or preventing a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder.
  • a disease or disorder such as a kinase mediated disease or disorder
  • HER2 a mutant thereof for the treatment or prevention of the disease or disorder.
  • the present disclosure relates to a compound of the present disclosure for use in the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; in the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; in the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder.
  • a disease or disorder such as a kinase mediated disease or disorder
  • HER2 a mutant thereof for the treatment or prevention of the
  • the present disclosure relates to use of a compound of the present disclosure in the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; in the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; in the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder.
  • a disease or disorder such as a kinase mediated disease or disorder
  • HER2 a mutant thereof for the treatment or prevention of the
  • the present disclosure relates to a compound of the present disclosure for use in the manufacture of a medicament for the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; for the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; for the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder.
  • a disease or disorder such as a kinase mediated disease or disorder
  • HER2 for the treatment or
  • the present disclosure relates to use of a compound of the present disclosure in the manufacture of a medicament for the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; for the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; for the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder.
  • a disease or disorder such as a kinase mediated disease or disorder
  • HER2 for the treatment or
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents an optional double bond; X 1 is N, CR 3 , or CHR 3 ; X 2 is C or N; X 3 is –(CH 2 ) m –; R 1 is C 6 -C 10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R a1 ; R 2 is H or C 1 -C 4 alkyl; R 3 is H or C 1 -C 4 alkyl; R 5 is C 6 -C 10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 hetero
  • the present disclosure relates to a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents an optional double bond; X 1 is N, CR 3 , or CHR 3 ; X 2 is C or N; X 3 is –(CH 2 ) m –; R 1 is C 6 -C 10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R a1 ; R 2 is H or C 1 -C 4 alkyl; R 3 is H or C 1 -C 4 alkyl; R 5 is C 6 -C 10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O
  • the present disclosure relates to a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents an optional double bond; X 1 is CR 3 or CHR 3 ; X 2 is C or N; X 3 is –(CH 2 ) m –; R 1 is C 6 -C 10 aryl or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more R a1 ; R 2 is H; R 3 is H; R 5 is C 6 -C 10 aryl or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heterocyclyl is optionally substituted with one or more R b1 ; R 6 is C6-C10 aryl, C3-C10 cycloalkyl, or heteroaryl comprising one
  • the present disclosure relates to a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents an optional double bond; X 1 is N, CR 3 , or CHR 3 ; X 2 is C or N; X 3 is –(CH 2 ) m –; R 1 is C 6 -C 10 aryl or heteroaryl comprising a 5- or 6-membered ring and 1-2 N heteroatoms, wherein the aryl or heteroaryl is optionally substituted with one or more R a1 ; R 2 is H; R 5 is C6-C10 aryl or heterocyclyl comprising a 5-membered ring and 1-2 N heteroatoms wherein the aryl or heterocyclyl is optionally substituted with one or more R b1 ; R 6 is C 6 -C 10 aryl, C 5 cycloalkyl, or heteroaryl comprising a 5- or 6-membered ring and 1- 2 heteroatoms selected from N, O,
  • the compound is of Formula II: or a pharmaceutically acceptable salt thereof, wherein: X 3 is –(CH 2 ) m –; R 1 is C 6 -C 10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R a1 ; R 2 is H or C 1 -C 4 alkyl; R 3 is H or C 1 -C 4 alkyl; R 5 is C 6 -C 10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the
  • the compound is of Formula IIa: (Iia), or a pharmaceutically acceptable salt thereof, wherein X 3 is –(CH 2 ) m – and m is 0 or 1.
  • the compound is of Formula Iib: (Iib), or a pharmaceutically acceptable salt thereof, wherein X 3 is –(CH 2 ) m – and m is 0 or 1
  • the compound is of Formula III: or a pharmaceutically acceptable salt thereof, wherein: X 3 is –(CH 2 ) m –; R 1 is C 6 -C 10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R a1 ; R 2 is H
  • the compound is of Formula IIIa: (IIIa), or a pharmaceutically acceptable salt thereof, wherein X 3 is –(CH 2 ) m – and m is 0 or 1.
  • the compound is of Formula IIIb: or a pharmaceutically acceptable salt thereof, wherein X 3 is –(CH 2 ) m – and m is 0 or 1.
  • the compound is of Formula IV: or a pharmaceutically acceptable salt thereof, wherein: X 3 is –(CH 2 ) m –; R 1 is C 6 -C 10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R a1 ; R 2 is H or C1-C4 alkyl; R 3 is H or C 1 -C 4 alkyl; R 5 is C 6 -C 10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the ary
  • the compound is of Formula IV: or a pharmaceutically acceptable salt thereof, wherein: X 3 is –(CH 2 ) m –; R 1 is C 6 -C 10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R a1 ; R 2 is H or C 1 -C 4 alkyl; R 3 is H or C 1 -C 4 alkyl; R 5 is C 6 -C 10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the
  • the compound is of Formula Iva: N N HN N N O R 1 R 5 (Iva), or a pharmaceutically acceptable salt thereof, wherein X 3 is –(CH 2 ) m – and m is 0 or 1.
  • the compound is of Formula Ivb: or a pharmaceutically acceptable salt thereof, wherein X 3 is –(CH 2 ) m – and m is 0 or 1.
  • m is 0 or 1.
  • m is 0.
  • m is 1.
  • R 2 is H or Me.
  • R 2 is H.
  • R 3 is H or Me.
  • R 3 is H.
  • R 4 is C 1 -C 4 alkyl.
  • R 4 is Me.
  • R 4 is .
  • X 4 is –(CH 2 )–.
  • R 1 is C 6 -C 10 aryl or heteroaryl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more R a1 .
  • R 1 is C 6 -C 10 aryl or heterocyclyl comprising one or two 4- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heterocyclyl is optionally substituted with one or more R a1 .
  • R 1 is C 6 -C 10 aryl, wherein the aryl is optionally substituted with one or more R a1 .
  • R 1 is heteroaryl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more R a1 .
  • R 1 is heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more R a1 .
  • R 1 is C 6 aryl optionally substituted with one or more R a1 .
  • R 1 is heteroaryl comprising one 6-membered ring and 1-4 N atoms, wherein the heteroaryl is optionally substituted with one or more R a1 .
  • R 1 is heteroaryl comprising one 6-membered ring and 1 N atoms, wherein the heteroaryl is optionally substituted with one or more R a1 .
  • R 1 is heteroaryl comprising one 5-membered ring and 1-4 N atoms, wherein the heteroaryl is optionally substituted with one or more R a1 . In some embodiments, R 1 is heteroaryl comprising one 5-membered ring and 1 N atoms, wherein the heteroaryl is optionally substituted with one or more R a1 . In some embodiments, R 1 is heterocyclyl comprising one 5-membered ring and 1-2 N atoms, wherein the heterocyclyl is optionally substituted with one or more R a1 .
  • R 1 is heterocyclyl comprising one 5-membered ring and 1 N atoms, wherein the heterocyclyl is optionally substituted with one or more R a1 .
  • each R a1 is independently W, –CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or heterocyclyl comprising one or two 4- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R a2 .
  • each R a1 is independently W, –CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or heterocyclyl comprising one or two 4- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R a2 .
  • each R a1 is independently W, F, Cl, Me, -OR n6 , – NR n6 -(CH 2 )1-4-NR n7 R n8 , –O-(CH 2 )1-4-NR n7 R n8 , –NR n6 -(CH 2 )1-4-OR n7 , –O-(CH 2 )1-4-OR n7 , , where n6 n7 in each of R , R , and R n8 is independently H or C 1 -C 4 alkyl.
  • each R a1 is independently W, F, Cl, Me, -OMe, CH 3 , In some embodiments, each R a1 is independently W, F, Cl, Me, -OMe, , In some embodiments, at least one R a1 is W.
  • each R a1 is independently –CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or heterocyclyl comprising one or two 4- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R a2 .
  • each R a1 is independently –CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or heterocyclyl comprising one or two 4- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R a2 .
  • each R a1 is independently F, Cl, Me, -OR n6 , –NR n6 -(CH 2 )1-4-NR n7 R n8 , –O-(CH 2 )1-4-NR n7 R n8 , –NR n6 -(CH 2 )1-4-OR n7 , –O-(CH 2 )1-4-OR n7 , independently H or C 1 -C 4 alkyl.
  • each R a1 is independently F, Cl, Me, -OR n6 , – NR n6 -(CH 2 )1-4-NR n7 R n8 , –O-(CH 2 )1-4-NR n7 R n8 , –NR n6 -(CH 2 )1-4-OR n7 , –O-(CH 2 )1-4-OR n7 , , wherein each of R n6 , R n7 , and R n8 is independently H or C 1 -C 4 alkyl.
  • each R a1 is independently F, Cl, Me, -OMe, In some embodiments, each R a1 is independently F, Cl, Me, -OMe, , In some embodiments, each R a2 is independently h halo, hydroxy, –NR n1 R n2 , C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl. In some embodiments, each R a2 is independently hydroxy, –NR n1 R n2 , or methyl.
  • R 5 is C 6 -C 10 aryl or heteroaryl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more R b1 .
  • R 5 is C 6 -C 10 aryl or heterocyclyl comprising one or two 4- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heterocyclyl is optionally substituted with one or more R b1 .
  • R 5 is C 6 -C 10 aryl, wherein the aryl is optionally substituted with one or more R b1 .
  • R 5 is heteroaryl comprising one or two 5- or 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more R b1 .
  • R 5 is heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more R b1 .
  • R 5 is C 6 aryl optionally substituted with one or more R b1 . .
  • R 5 is heteroaryl comprising one 6-membered ring and 1-4 N atoms, wherein the heteroaryl is optionally substituted with one or more R b1 . In some embodiments, R 5 is heteroaryl comprising one 6-membered ring and 1 N atoms, wherein the heteroaryl is optionally substituted with one or more R b1 . In some embodiments, R 5 is heteroaryl comprising one 5- membered ring and 1-4 N atoms, wherein the heteroaryl is optionally substituted with one or more R b1 .
  • R 5 is heteroaryl comprising one 5-membered ring and 1 N atoms, wherein the heteroaryl is optionally substituted with one or more R b1 . In some embodiments, R 5 is heterocyclyl comprising one 5-membered ring and 1-2 N atoms, wherein the heterocyclyl is optionally substituted with one or more R b1 . In some embodiments, R 5 is heterocyclyl comprising one 5-membered ring and 1 N atoms, wherein the heterocyclyl is optionally substituted with one or more R b1 .
  • each R b1 is independently W, –CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or heterocyclyl comprising one or two 4- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R b2 .
  • each R b1 is independently W, F, Cl, Me, -OR n6 , –NR n6 -(CH 2 )1-4-NR n7 R n8 , –O-(CH 2 )1-4-NR n7 R n8 , –NR n6 -(CH 2 )1-4-OR n7 , –O-(CH 2 )1-4-OR n7 , independently H or C 1 -C 4 alkyl.
  • each R b1 is independently W, F, Cl, Me, -OMe, In some embodiments, at least one R b1 is W.
  • each R b1 is independently F Cl Me -OR n6 –NR n6 -(CH 2 )1-4-NR n7 R n8 , –O-(CH 2 )1-4-NR n7 R n8 , –NR n6 -(CH 2 )1-4-OR n7 , –O-(CH 2 )1-4-OR n7 , , where n6 n7 n8 in each of R , R , and R is independently H or C 1 -C 4 alkyl.
  • each R b1 is independently F, Cl, Me, -OMe
  • each R b2 is independently halo, hydroxy, –NR n1 R n2 , C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl.
  • each R b2 is independently hydroxy, –NR n1 R n2 , or methyl.
  • W is NR 8 C(O)R 9 or C(O)R 9 .
  • W is selected from formulae (i-1)-(i-5), (i-9)-(i-16), (i-18), (i-19), (i-28), (i-29), and (i-36)-(i-39). In some embodiments, W is selected from formulae (i-1), (i-3), (i-9), (i-13), (i-14), (i-16), (i-18), (i-19), (i-29), and (i-36)-(i-39). In some embodiments, W is selected from formulae (i-2), (i-10), (i-15), (i-28), and (i-34). In some embodiments, W is selected from formulae (i-4), (i-5), and (i-10).
  • W is selected from formulae (i-11) and (i-12). In some embodiments, W is selected from formulae (i-6)-(i-8), (i-17), (i-20)-(i-27), (i-30)-(i-35), (i-40), and (i-41). In some embodiments, W is selected from formulae (i-6)-(i-8), (i-17), (i-20)-(i-27), (i-30), (i-34), (i-40), and (i-41). In some embodiments, at least one In some embodiments, L 3 is –NR L3a –. In some embodiments, R L3a is H. In some embodiments, R E1 is H. In some embodiments, R E2 is H.
  • R E3 is H. In some embodiments, R E1 , R E2 , and R E3 are each H. In some embodiments, Y is O. In some embodiments, R 6 is phenyl, bicyclo [1,1,1] pentyl, or heteroaryl comprising one 5- or 6-membered rings and 1-3 N atoms, wherein the phenyl or heteroaryl is optionally substituted with one or more R c1 . In some embodiments, R 6 is phenyl or heteroaryl comprising one 5- or 6-membered rings and 1-3 N atoms, wherein the phenyl or heteroaryl is optionally substituted with one or more R c1 .
  • R 6 is phenyl, pyridyl, thiazolyl, or pyrazolyl, optionally substituted with one or more R c1 .
  • each R c1 is independently –CN, F, Me, or -OMe.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R a1 , R a2 , R b1 , R b2 , R c1 , X 1 , X 2 , X 3 , X 4 , and W can each be selected from any of the substituents as described herein, for example, in Formula I’ or Formula I.
  • any of the substituents described herein for any of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R a1 , R a2 , R b1 , R b2 , R c1 , X 1 , X 2 , X 3 , X 4 , and W for example, in any of Formulae I, II, III, IV, Iia, Iib, IIIa, IIIb, Iva, or Ivb, can be combined with any of the substituents described herein for one or more of the remainder of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R a1 , R a2 , R b1 , R b2 , R c1 , X 1 , X 2 , X 3 , X 4 , and W, for example, in any of
  • Non-limiting illustrative compounds of the disclosure are listed in Table 1.
  • the compound is selected from the compounds discosed in Table 1 (e.g., Compound Nos.1-40).
  • the compound has the structure of any one of the compounds discosed in Table 1 (e.g., Compound Nos.1-40).
  • a compound selected from , , or a pharmaceutically acceptable salt thereof is a compound selected from the group consisting of: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8-methyl-7-oxo-6-phenyl-7,8- dihydropteridin-2-yl)amino)phenyl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8-methyl-6-(1-methyl-1H- pyrazol-3-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)acrylamide; N-(2-((dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8-methyl-7-
  • the compounds of the disclosure may inhibit one or more receptors of the ErbB receptor tyrosine kinase family.
  • a compound of the present disclosure may inhibit EGFR, HER2, HER3, and/or HER4, and/or any mutant thereof.
  • a compound of the present disclosure inhibits EGFR.
  • a compound of the present disclosure inhibits a mutant EGFR.
  • a compound of the present disclosure inhibits HER2.
  • a compound of the present disclosure inhibits a mutant HER2.
  • a compound of the present disclosure inhibits EGFR and HER2 and/or a mutant thereof.
  • the compounds of the disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of EGFR or a mutant thereof and/or HER2 or a mutant thereof.
  • the compounds of the present disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of EGFR containing one or more mutations.
  • the mutant EGFR contains one or more mutations described herein.
  • the compounds of the present disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of EGFR containing one or more mutations, but do not affect the activity of a wild-type EGFR.
  • the compounds of the disclosure exhibit greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR.
  • the compounds of the disclosure exhibit at least 2-fold, 3-fold, 5-fold, 10- fold, 25-fold, 50-fold or 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In some embodiments, the compounds of the disclosure exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In some embodiments, the compounds of the disclosure exhibit from about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR.
  • the compounds of the disclosure exhibit from about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In some embodiments, the compounds of the disclosure exhibit from about 100-fold to about 1000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In some embodiments, the compounds of the disclosure exhibit from about 1000-fold to about 10000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In some embodiments, the compounds of the present disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of HER2 containing one or more mutations.
  • the mutant HER2 contains one or more mutations described herein.
  • the compounds of the present disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of HER2 containing one or more mutations, but do not affect the activity of a wild-type HER2.
  • the compounds of the disclosure exhibit greater inhibition of HER2 containing one or more mutations as described herein relative to a wild-type HER2.
  • the compounds of the disclosure exhibit at least 2-fold, 3-fold, 5-fold, 10- fold, 25-fold, 50-fold or 100-fold greater inhibition of HER2 containing one or more mutations as described herein relative to a wild-type HER2.
  • the compounds of the disclosure exhibit up to 1000-fold greater inhibition of HER2 containing one or more mutations as described herein relative to a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit from about 2-fold to about 10-fold greater inhibition of HER2 containing one or more mutations as described herein relative to a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit from about 10-fold to about 100-fold greater inhibition of HER2 containing one or more mutations as described herein relative to a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit from about 100-fold to about 1000-fold greater inhibition of HER2 containing one or more mutations as described herein relative to a wild-type HER2.
  • the compounds of the disclosure exhibit from about 1000-fold to about 10000-fold greater inhibition of HER2 containing one or more mutations as described herein relative to a wild-type HER2.
  • the compounds of the present disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of EGFR containing one or more mutations and HER2 containing one or more mutations.
  • the mutant EGFR or mutant HER2 contains one or more mutations described herein.
  • the compounds of the present disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of EGFR containing one or more mutations and HER2 containing one or more mutations, but do not affect the activity of a wild-type EGFR or a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit greater inhibition of EGFR containing one or more mutations and HER2 containing one or more mutations as described herein relative to a wild-type EGFR or a wild-type HER2.
  • the compounds of the disclosure exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of EGFR containing one or more mutations and HER2 containing one or more mutations as described herein relative to a wild-type EGFR or a wild-type HER2. In some embodiments, the compounds of the disclosure exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations and HER2 containing one or more mutations as described herein relative to a wild-type EGFR or a wild-type HER2.
  • the compounds of the disclosure exhibit from about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations and HER2 containing one or more mutations as described herein relative to a wild-type EGFR or a wild- type HER2. In some embodiments, the compounds of the disclosure exhibit from about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations and HER2 containing one or more mutations as described herein relative to a wild-type EGFR or a wild- type HER2.
  • the compounds of the disclosure exhibit from about 100-fold to about 1000-fold greater inhibition of EGFR containing one or more mutations and HER2 containing one or more mutations as described herein relative to a wild-type EGFR or a wild- type HER2. In some embodiments, the compounds of the disclosure exhibit from about 1000- fold to about 10000-fold greater inhibition of EGFR containing one or more mutations and HER2 containing one or more mutations as described herein relative to a wild-type EGFR or a wild-type HER2.
  • More potent modulation e.g., inhibition
  • EGFR containing one or more mutations and/or HER2 containing one or more mutations such as those described herein, relative to a wild-type EGFR or a wild-type HER2
  • diseases including, but not limited to, cancer and metastasis, inflammation, arthritis, systemic lupus erthematosus, skin-related disorders, pulmonary disorders, cardiovascular disease, ischemia, neurodegenerative disorders, liver disease, gastrointestinal disorders, viral and bacterial infections, central nervous system disorders, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and peripheral neuropathy.
  • diseases including, but not limited to, cancer and metastasis, inflammation, arthritis, systemic lupus erthematosus, skin-related disorders, pulmonary disorders, cardiovascular disease, ischemia, neurodegenerative disorders, liver disease, gastrointestinal disorders, viral and bacterial infections, central nervous system disorders, Alzheimer's disease, Parkinson'
  • the inhibition of activity of EGFR or HER2 or a mutant thereof is measured by IC 50 . In some embodiments, the inhibition of activity of EGFR or HER2 or a mutant thereof is measured by EC 50 . In some embodiments, the compounds of the disclosure are potent inhibitor of a drug- resistant EGFR mutant relative to a wild-type EGFR.
  • the compounds of the disclosure are more potent than one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib, sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785, CP-724714, CUDC-101, AEE788, AC480, and TAK-285.
  • EGFR inhibitors including but not limited to gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib, sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785, CP-724714, CUDC-101,
  • the compounds of the disclosure are at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent (e.g., as measured by IC 50 ) than one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib, sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785, CP-724714, CUDC-101, AEE788, AC480, and TAK-285.
  • one or more known EGFR inhibitors including but not limited to gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib
  • the compounds of the disclosure are potent inhibitor of a drug- resistant HER2 mutant relative to a wild-type HER2.
  • the compounds of the disclosure are more potent than one or more known HER2 inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib, sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785, CP-724714, CUDC-101, AEE788, AC480, TAK-285, poziotinib, and pyrotinib.
  • the compounds of the disclosure are at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about 100-fold more potent (e.g., as measured by IC 50 ) than one or more known HER2 inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib, sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785, CP-724714, CUDC-101, AEE788, AC480, TAK-285, poziotinib, and pyrotinib.
  • HER2 inhibitors including but not limited to gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib,
  • the compounds of the disclosure are potent inhibitor of a drug- resistant EGFR mutant and drug-resistant HER2 mutant relative to a wild-type EGFR and a wild- type HER2.
  • the compounds of the disclosure are more potent than one or more known EGRF and/or HER2 inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib, sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785, CP-724714, CUDC-101, AEE788, AC480, TAK-285, poziotinib, and pyrotinib.
  • the compounds of the disclosure are at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about 100-fold more potent (e.g., as measured by IC 50 ) than one or more known EGRF and/or HER2 inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib, sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785, CP-724714, CUDC-101, AEE788, AC480, TAK-285, poziotinib, and pyrotinib.
  • potent e.g., as measured by IC 50
  • HER2 inhibitors including but not limited to gefitinib, erlotinib, lapatinib, afat
  • Potency of a compound can be determined by IC 50 value.
  • a compound with a lower IC 50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC 50 value.
  • the substantially similar conditions comprise determining an EGFR-dependent or a HER2-dependent phosphorylation level in cells expressing a wild-type EGFR, a wild-type HER2, or a mutant thereof, such as those described herein, or a fragment of any thereof.
  • the selectivity between wild-type EGFR and EGFR containing one or more mutations as described herein or between wild-type HER2 and HER2 containing one or more mutations as described herein can be measured using cellular proliferation assays where cell proliferation is dependent on kinase activity.
  • cellular proliferation assays where cell proliferation is dependent on kinase activity.
  • Ba/F3 cells transfected with wild-type EGFR, or Ba/F3 cells transfected with a mutant EGFR can be used.
  • Proliferation assays are performed at a range of inhibitor concentrations (10 ⁇ M, 3 ⁇ M, 1.1 ⁇ M, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and an EC 50 is calculated.
  • An alternative method to measure effects on EGFR and/or HER2 activity is to assay phosphorylation of wild-type EGFR, wild-type HER2, and/or a mutant thereof, such as those described herein.
  • Wild-type EGFR, wild-type HER2, or a mutant thereof, such as those described herein can be transfected into cells which do not normally express endogenous EGFR or HER2.
  • the ability of the inhibitor (using concentrations as above) to inhibit phosphorylation can be assayed.
  • Another aspect of the disclosure is an isotopically labeled compound of any of the compounds disclosed herein.
  • Such compounds have one or more isotope atoms which may or may not be radioactive (e.g., 3 H, 2 H, 14 C, 13 C, 18 F, 35 S, 32 P, 125 I, and 131 I) introduced into the compound.
  • isotope atoms which may or may not be radioactive (e.g., 3 H, 2 H, 14 C, 13 C, 18 F, 35 S, 32 P, 125 I, and 131 I) introduced into the compound.
  • Such compounds are useful for drug metabolism studies and diagnostics, as well as therapeutic applications.
  • the disclosure also provides for a pharmaceutical composition comprising a therapeutically effective amount of a compound of the disclosure, or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the disclosure provides a kit comprising a compound capable of inhibiting protein kinase activity of at least one protein kinase selected from one or more compounds disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, optionally in combination with a second agent and instructions for use in treating cancer.
  • the compound in the kit inhibits more than one protein kinase
  • the disclosure provides a method of synthesizing a compound disclosed herein. The synthesis of the compounds of the disclosure can be found herein and in the Examples below. Other embodiments are a method of making a compound of any of the formulae herein using any one, or combination of, reactions delineated herein.
  • the method can include the use of one or more intermediates or chemical reagents delineated herein.
  • a compound of the disclosure can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a compound of the disclosure can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • the salt forms of the compounds of the disclosure can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of the disclosure can be prepared from the corresponding base addition salt or acid addition salt from, respectively.
  • a compound of the disclosure in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a compound of the disclosure in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).
  • a suitable acid e.g., hydrochloric acid, etc.
  • Prodrugs of the compounds of the disclosure can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p.1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound of the disclosure with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).
  • a suitable carbamylating agent e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like.
  • suitable carbamylating agent e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like.
  • Protected derivatives of the compounds of the disclosure can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, “Protecting Groups in Organic Chemistry”, 3 rd edition, John Wiley and Sons, Inc., 1999.
  • Compounds of the present disclosure can be conveniently prepared or formed
  • Acids and bases useful in the methods herein are known in the art.
  • Acid catalysts are any acidic chemical, which can be inorganic (e.g., hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium triflate) in nature. Acids are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions.
  • Bases are any basic chemical, which can be inorganic (e.g., sodium bicarbonate, potassium hydroxide) or organic (e.g., triethylamine, pyridine) in nature. Bases are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions. Combinations of substituents and variables envisioned by the disclosure are only those that result in the formation of stable compounds.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
  • any variable e.g., R 7
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R 7 at each occurrence is selected independently from the definition of R 7 .
  • substituents and/or variables are permissible, but only if such combinations result in stable compounds within a designated atom’s normal valency.
  • some of the compounds of the disclosure have one or more double bonds, or one or more asymmetric centers.
  • Such compounds can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z- double isomeric forms, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion. All such isomeric forms of such compounds are expressly included in the present disclosure.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described herein, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art.
  • 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.
  • 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.
  • tautomeric pairs are: ketone-enol, amide-nitrile, lactam- lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), amine-enamine and enamine-enamine.
  • the compounds of the disclosure may also be represented in multiple tautomeric forms, in such instances, the disclosure expressly includes all tautomeric forms of the compounds described herein (e.g., alkylation of a ring system may result in alkylation at multiple sites, the disclosure expressly includes all such reaction products).
  • the structural formula of the compound represents a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like.
  • the structural formula of the compound represents a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like.
  • the compounds of the present disclosure for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • Non-limiting examples of hydrates include monohydrates, dihydrates, etc.
  • Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. In addition, the solvents, temperatures, reaction durations, etc.
  • the compounds of the disclosure may be modified by appending various functionalities via any synthetic means delineated herein to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the compounds of the disclosure are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • cancer includes, but is not limited to, the following cancers: epidermoid Oral: buccal cavity, lip, tongue, mouth, pharynx; Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphom
  • the term “cancerous cell” as provided herein includes a cell afflicted by any one of the above- identified conditions.
  • the terms “disease(s)”, “disorder(s)”, and “condition(s)” are used interchangeably, unless the context clearly dictates otherwise.
  • the term “EGFR” herein refers to epidermal growth factor receptor kinase.
  • the term “HER2”, “Her2”, “ERBB2”, or “Erbb2” herein refers to human epidermal growth factor receptor 2.
  • HER2 is also known as CD340 or Neu.
  • the term “mutant EGFR” or “EGFR mutant” refers to EGFR with one or more mutations.
  • the EGFR mutant has one or more mutations of exon 18, exon 19 (e.g., exon 19 deletion or exon 19 insertion), exon 20 (e.g., exon 20 insertion), and/or exon 21.
  • the mutant EGFR contains one or more mutations selected from an exon 19 deletion (Del 19), an exon 20 insertion (Ins 20), L718Q, G719S, G719C, G719A, D761Y, T790M, C797S, L844V, T854A, L858R, L861Q, I941R, V948R, D770delinsGY, D770_N771insSVD, V769_D770insASV, Y764_V765insHH, H773dupH, D770_N771insNPG, H773_V774insNPH, P772_H773insPNP, N771_P
  • the mutant EGFR contains one or more mutations selected from D770delinsGY, D770_N771insSVD, V769_D770insASV, Y764_V765insHH, H773dupH, D770_N771insNPG, H773_V774insNPH, P772_H773insPNP, and N771_P772insH.
  • the mutant EGFR contains a combination of two or more mutations (such as mutations described herein).
  • the mutant EGFR contains a combination of two or more mutations selected from Del 19/L718Q, Del 19/T790M, Del 19/L844V, Del 19/T790M/L718Q, Del/T790M/C797S, Del 19/T790M/L844V, L858R/L718Q, L858R/L844V, L858R/T790M, L858R/T790M/L718Q, L858R/T790M/C797S, and L858R/T790M/I941R.
  • An EGFR sensitizing mutation comprises without limitation G719S, G719C, G719A, L861Q, L858R, Del 19, and/or Ins 20.
  • a drug-resistant EGFR mutant can have without limitation a drug resistance mutation comprising L718Q, D761Y, T790M, T854A, D770delinsGY, D770_N771insSVD, V769_D770insASV, Y764_V765insHH, A775_G776insYVMA, and/or H773dupH.
  • the term “mutant HER2” or “HER2 mutant” refers to HER2 with one or more mutations.
  • the HER2 mutant has one or more mutations of exon 18, exon 19 (e.g., exon 19 deletion or exon 19 insertion), exon 20 (e.g., exon 20 insertion), and/or exon 21.
  • the mutant HER2 contains one or more mutations selected from an exon 19 deletion (Del 19), an exon 20 insertion (Ins 20), T798M, T798I, L869R, A775_G776insYVMA, A775_G776insSVMA, A775_G776insI, G776delinsVC, G776delinsLC, P780_Y781insGSP, M774delinsWLV, and G778_S779insCPG.
  • the mutant EGFR contains a combination of two or more mutations (such as mutations described herein).
  • pharmaceutically acceptable salt refers to those salts of the compounds formed by the process of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the disclosure, or separately by reacting the free base or acid function with a suitable acid or base.
  • suitable acid or base examples include, but are not limited to, nontoxic acid addition salts: salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamo
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • pharmaceutically acceptable ester refers to esters of the compounds formed by the process of the present disclosure which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds formed by the process of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present disclosure.
  • Prodrug means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to afford any compound delineated by the formulae of the present disclosure.
  • prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol.4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.
  • ⁇ refers to a mammal.
  • a subject therefore refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, and the like.
  • the subject is a human.
  • a patient When the subject is a human, the subject may be referred to herein as a patient.
  • a therapeutically effective amount of a compound or pharmaceutical composition of the disclosure will be at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.
  • the specific inhibitory dose for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • “Treat”, “treating”, and “treatment” refer to a method of alleviating or abating a disease and/or its attendant symptoms.
  • the disclosure also encompasses pharmaceutical compositions containing, and methods of treating disorders through administering, pharmaceutically acceptable prodrugs of compounds of the disclosure.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the disclosure.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3- methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J. Med. Chem.1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals containing, In some embodiments, between one and six, or one and eight carbon atoms, respectively.
  • Examples of C 1 -C 6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl radicals; and examples of C 1 -C 8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert- butyl, neopentyl, n-hexyl, heptyl, octyl radicals.
  • alkenyl denotes a monovalent group derived from a hydrocarbon moiety containing, In some embodiments, from two to six, or two to eight carbon atoms having at least one carbon-carbon double bond. The double bond may or may not be the point of attachment to another group.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl and the like.
  • alkynyl denotes a monovalent group derived from a hydrocarbon moiety containing, In some embodiments, from two to six, or two to eight carbon atoms having at least one carbon-carbon triple bond. The triple bond may or may not be the point of attachment to another group.
  • Alkynyl groups include, but are not limited to, for example, ethynyl, propynyl, butynyl, 1-methyl-2-butyn-1-yl, heptynyl, octynyl and the like.
  • alkoxy refers to an -O-alkyl radical.
  • aryl refers to a mono- or poly-cyclic carbocyclic ring system having one or more aromatic rings, fused or non-fused, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • heteroaryl refers to a mono- or poly-cyclic (e.g., bi-, or tri- cyclic or more) fused or non-fused, radical or ring system having at least one aromatic ring, having from five to ten ring atoms of which at least one ring atom is selected from S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon.
  • mono- or poly-cyclic e.g., bi-, or tri- cyclic or more fused or non-fused, radical or ring system having at least one aromatic ring, having from five to ten ring atoms of which at least one ring atom is selected from S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.
  • any of the heteroaryls and substituted heteroaryls described herein can be any aromatic group. Aromatic groups can be substituted or unsubstituted.
  • cycloalkyl or "carbocyclyl” as used herein, denotes a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound.
  • Examples of C 3 -C 8 -cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C 3 -C 12 -cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.
  • a monovalent group derived from a monocyclic or polycyclic carbocyclic ring compound having at least one carbon- carbon double bond by the removal of a single hydrogen atom examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.
  • haloalkyl can include alkyl structures that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl includes haloalkyl groups in which the halo is fluorine (e.g., -C1-C6 alkyl-CF3, -C1-C6 alkyl-C2F).
  • haloalkyl include trifluoroethyl, trifluoropropyl, trifluoromethyl, fluoromethyl, diflurormethyl, and fluoroisopropyl.
  • heteroalkyl refers to a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, P, S, and Si may be placed at any position of the heteroalkyl group.
  • heteroalkyl Up to two or three heteroatoms may be consecutive, such as, for example, -CH 2 -NH- OCH 3 and -CH 2 -O-Si(CH 3 ) 3 .
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as –CH 2 O-CH 3 , –NR C R D , or the like, it will be understood that the terms heteroalkyl and –CH 2 O-CH 3 or –NR C R D are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity.
  • heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as –CH 2 O-CH 3 , –NR C R D , or the like. If a count of carbons is included, that refers to the total number of carbons not including heteroatoms. For example, C 1-10 heteroalkyl includes at least 1 and up to 10 total carbons. In some cases the total number of heteroatoms in a heteroalkyl is 1, 1-2, 1-3, or 1-4. If not otherwise defined, heteroalkyl includes 1-10 carbons and 1-4 heteroatoms.
  • heterocyclyl refers to a non-aromatic 3-, 4-, 5-, 6- or 7- membered ring or a bi- or tri-cyclic group fused of non-fused system, where (i) each ring contains between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, and (iv) the nitrogen heteroatom may optionally be quaternized.
  • heterocyclyl groups include, but are not limited to, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • alkylamino refers to a group having the structure NH(C 1 -C 12 alkyl), e.g., NH(C 1 -C 6 alkyl), where C 1 -C 6 alkyl is as previously defined.
  • dialkylamino refers to a group having the structure N(C 1 -C 12 alkyl) 2 , e.g., N(C1-C6 alkyl)2, where C1-C6 alkyl is as previously defined.
  • hal halo
  • halogen refer to an atom selected from fluorine, chlorine, bromine, and iodine.
  • a compound of the disclosure may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the disclosure. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of hydrogen in a given structure with the radical of a specified substituent.
  • an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, and the substituent may be either the same or different at every position.
  • alkyl, alkenyl, alkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl, or the like can be substituted, by independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to: -F, -CI, -Br, - I, -OH, protected hydroxy, -NO 2 , -CN, -NH 2 , protected amino, -NH-C 1 -C 12 -alkyl, -NH-C 2 -C 12 - alkenyl, -NH-C 2 -C 12 -alkenyl, -NH -C 3 -C 12 -cycloalkyl, -NH-aryl, -NH -heteroaryl, -NH - heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C
  • the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group).
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl–(10)–acyl derivative, N′–p–toluenesulfonylaminoacyl derivative, N′–phenylaminothioacyl derivative, N– benzoylphenylalanyl derivative, N–acetylmethionine derivative, 4,5–diphenyl–3–oxazolin–2– one, N–phthalimide, N–dithiasuccinimide (Dts), N–2,3–diphenylmaleimide, N–2,5– dimethylpyrrole, N–1,1,4,4–tetramethyldisilylazacyclopentane adduct (STABASE), 5– substituted 1,3–dimethyl–1,3,5–triazacyclohexan–2–one, 5–substituted 1,3–dibenzyl–1,3,5– triazacyclohexan–2–one, 1–substituted 3,5–d
  • LG is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule.
  • a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March’s Advanced Org an ic Chemistry 6th ed. (501-502).
  • halo e.g., chloro, bromo, iodo
  • activated substituted hydroxyl groups
  • Suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates.
  • halogen such as F, Cl, Br, or I (iodine
  • the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, –OTs), methanesulfonate (mesylate, –OMs), p-bromobenzenesulfonyloxy (brosylate, –OBs), or trifluoromethanesulfonate (triflate, –OTf).
  • the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy.
  • the leaving group is a nosylate, such as 2- nitrobenzenesulfonyloxy.
  • the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group.
  • the leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate.
  • Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.
  • “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.
  • stereoisomers 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”.
  • a carbon atom bonded to four non-identical substituents is termed a “chiral center”.
  • Chiral isomer means a compound with at least one chiral center.
  • 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.1966, 5, 385; errata 511; Cahn et al., Angew.
  • “Geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds. 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.
  • 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 solid form, usually one tautomer predominates. In solutions where tautomerization 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 interconvertable by tautomerizations is called tautomerism.
  • 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 H 2 O. Methods of Synthesizing the Compounds A compound of the present disclosure may be made by a variety of methods, including standard chemistry.
  • the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used.
  • the processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • Suitable synthetic routes are depicted in the schemes below.
  • a compound of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein.
  • Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition, John Wiley & Sons: New York, 2001; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999, incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art.
  • a compound disclosed herein may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes.
  • protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
  • a compound of the present disclosure can be synthesized by following the steps outlined in General Scheme A. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated. General Scheme A In some embodiments, a compound of the present disclosure may also be prepared according to General Scheme B. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated. General Scheme B In some embodiments, a compound of the present disclosure may also be prepared according to General Scheme C. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.
  • Biological Assays A compound of the present disclosure can be tested for its activity with various biological assays. Suitable assays include, but are not limited to, western blot analysis, MTS assay, and Cell Titer Glo (CTG) luminescent cell viability assay.
  • CTG assays can be performed on various cells lines, such as A431, wild-type EGFRs, or insertion mutants EGFRs transformed Ba/F3 cells (e.g., L858R, L858R/T790M, L858R/C797S L858R/T790M/C797S, Del19, Del19/T790M, Del19/C797S, Del19/T790M/C797S).
  • Non-limiting, representative assays are described briefly below.
  • Proliferation Inhibition Assay Cell growth inhibition can be assessed by MTS assay or by Cell Titer Glo Luminescent Cell viability assay (Promega®).
  • Cells are seeded and grow in culture plates before they are exposed to representative compounds of the disclosure for various duration. The viability of the cells are then assessed. Data are normalized to untreated cells and displayed graphically using GraphPad Prism (GraphPad Software, Inc.). The growth curves can be fitted using a nonlinear regression model with sigmoidal dose response. Western blot analysis Cells are seeded and grow in culture plates, and then treated with representative compounds of the disclosure the following day for various duration. Cells are washed with PBS and lysed.
  • the lysates are separated by SDS-PAGE gel, transferred to nitrocellulose membranes, and probed with the appropriate antibodies, such as phospho-EGFR(Tyr1068) (3777), total EGFR (2232), p-Akt(Ser473) (4060), total Akt (9272), p-ERK(Thr202/Tyr204) (4370), total ERK (9102), and HSP90 (SC-7947).
  • antibodies such as phospho-EGFR(Tyr1068) (3777), total EGFR (2232), p-Akt(Ser473) (4060), total Akt (9272), p-ERK(Thr202/Tyr204) (4370), total ERK (9102), and HSP90 (SC-7947).
  • various types of cell lines may be used in testing the compound of the present disclosure. Non-limiting illustrative cell lines are listed in the table below.
  • Table 2 Methods of Use Another aspect of the present disclosure relates to a method of modulating (e.g., inhibiting or decreasing) EGFR and/or HER2, and/or a mutant thereof, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure (e.g., a compound of Formula I), or a pharmaceutically acceptable salt or ester thereof.
  • a compound of the present disclosure e.g., a compound of Formula I
  • Another aspect of the present disclosure relates to a method of treating or preventing a disease or disorder (e.g., cancer) in which EGFR and/or HER2, and/or a mutant thereof, plays a role, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure (e.g., a compound of Formula I), or a pharmaceutically acceptable salt or ester thereof.
  • a disease or disorder e.g., cancer
  • the disease or disorder is resistant to an EGFR targeted therapy and/or a HER2 targeted therapy.
  • the EGFR targeted therapy and/or the HER2 targeted therapy is a therapy with an inhibitor of EGFR, HER2, and/or a mutant thereof, such as the inhibitors described herein.
  • the disease is cancer or a proliferative disease.
  • the cancer cell comprises a mutant EGFR and/or a mutant HER2.
  • the cancer is a cancer of B cell origin.
  • the cancer is a lineage dependent cancer.
  • the cancer is a lineage dependent cancer where EGFR and/or HER2, and/or a mutant thereof, plays a role in the initiation and/or development of the cancer.
  • the subject is identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder.
  • the disclosure provides a method of treating any of the disorders described herein, wherein the subject is a human. In some embodiments, the disclosure provides a method of preventing any of the disorders described herein, wherein the subject is a human.
  • Another aspect of the present disclosure relates to a compound of the present disclosure (e.g., a compound of Formula I), or a pharmaceutically acceptable salt or ester thereof, for modulating (e.g., inhibiting or decreasing) EGFR or a mutant thereof and/or HER2 or a mutant thereof; for treating or preventing a disease or disorder, such as a kinase mediated disease or disorder; for treating or preventing a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; for treating or preventing cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or for treating or preventing a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need
  • a compound of the present disclosure e.g., a compound of Formula I
  • a pharmaceutically acceptable salt or ester thereof for use in the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; in the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; in the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder.
  • a disease or disorder such as a kinase mediated disease
  • Another aspect of the present disclosure relates to use of a compound of the present disclosure (e.g., a compound of Formula I), or a pharmaceutically acceptable salt or ester thereof, in the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; in the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; in the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or in the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder.
  • a disease or disorder such as
  • a compound of the present disclosure e.g., a compound of Formula I
  • a pharmaceutically acceptable salt or ester thereof for use in the manufacture of a medicament for the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; for the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; for the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder.
  • a disease or disorder such as a
  • Another aspect of the present disclosure relates to use of a compound of the present disclosure (e.g., a compound of Formula I), or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for the modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof; for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder; for the treatment or prevention of a disease or disorder resistant to an EGFR targeted therapy and/or a HER2 targeted therapy; for the treatment or prevention of cancer, wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; or for the treatment or prevention of a disease or disorder, such as a kinase mediated disease or disorder in a subject identified as being in need of modulation (e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof for the treatment or prevention of the disease or disorder.
  • the EGFR is a wild-type EGFR. In other embodiments, the EGFR has one or more mutations, such as those described herein. In some embodiments, the HER2 is a wild-type HER2. In other embodiments, the HER2 has one or more mutations, such as those described herein.
  • diseases include, but are not limited to, a proliferative or hyperproliferative disease. Examples of proliferative and hyperproliferative diseases include, without limitation, cancer.
  • cancer includes, but is not limited to, the following cancers: breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus; larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone; colon; colorectal; adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; liver carcinoma and biliary passages; kidney carcinoma; myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine; colonrectum, large intestine, rectum, brain and
  • cancer includes, but is not limited to, the following cancers: myeloma, lymphoma, or a cancer selected from gastric, renal, or and the following cancers: head and neck, oropharangeal, non-small cell lung cancer (NSCLC), endometrial, hepatocarcinoma, Non-Hodgkins lymphoma, and pulmonary.
  • NSCLC non-small cell lung cancer
  • cancer refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like.
  • cancers include, but are not limited to, mesothelioma, leukemias and lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T-cell lymphotrophic virus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-cell lymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, and multiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma.
  • CCL cutaneous T-cell lymphomas
  • myelodisplastic syndrome childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal), genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular), lung cancer (e.g., small-cell and non-small cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin's syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer.
  • childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft-t
  • Additional exemplary forms of cancer which may be treated by the subject compounds include, but are not limited to, cancer of skeletal or smooth muscle, stomach cancer, cancer of the small intestine, rectum carcinoma, cancer of the salivary gland, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer. Additional cancers that the compounds described herein may be useful in preventing, treating and studying are, for example, colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, or melanoma.
  • cancers include, but are not limited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), renal carcinoma, kidney parenchyma carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gall bladder carcinoma, bronchial carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma,
  • the present disclosure provides for the use of one or more a compound of the disclosure in the manufacture of a medicament for the treatment of cancer, including without limitation the various types of cancer disclosed herein.
  • the disclosure further embraces the treatment or prevention of cell proliferative disorders such as hyperplasias, dysplasias and pre-cancerous lesions.
  • Dysplasia is the earliest form of pre- cancerous lesion recognizable in a biopsy by a pathologist.
  • the subject compounds may be administered for the purpose of preventing said hyperplasias, dysplasias or pre-cancerous lesions from continuing to expand or from becoming cancerous. Examples of pre-cancerous lesions may occur in skin, esophageal tissue, breast and cervical intra-epithelial tissue.
  • compositions in another aspect, provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable ester, salt, or prodrug thereof, together with a pharmaceutically acceptable carrier.
  • a compound of the disclosure can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • Pharmaceutical compositions comprising a compound of the present disclosure in free form or in a pharmaceutically acceptable salt form in association.
  • oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose, sucrose,
  • compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.
  • the compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Suitable formulations for transdermal applications include an effective amount of a compound of the present disclosure with a carrier.
  • a carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • Matrix transdermal formulations may also be used.
  • Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • compositions of the present disclosure comprise a therapeutically effective amount of a compound of the present disclosure formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the pharmaceutical compositions of the disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray.
  • Liquid dosage forms for oral administration 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, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents.
  • Dosage forms for topical or transdermal administration of a compound of the disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of the disclosure.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of the 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.
  • Powders and sprays can contain, in addition to a compound of the disclosure, 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.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • disorders are treated or prevented in a subject, such as a human or other animal, by administering to the subject a therapeutically effective amount of a compound of the disclosure, in such amounts and for such time as is necessary to achieve the desired result.
  • a therapeutically effective amount of a compound of the disclosure means a sufficient amount of the compound so as to decrease the symptoms of a disorder in a subject.
  • a therapeutically effective amount of a compound of the disclosure will be at a reasonable benefit/risk ratio applicable to any medical treatment.
  • a compound of the disclosure will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents.
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. Therapeutic amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.
  • a maintenance dose of a compound, composition or combination of the disclosure may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease.
  • the subject may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.
  • the specific inhibitory dose for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non- fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g., a compound of the disclosure and a co- agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g., a compound of the disclosure and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g., the administration of three or more active ingredients.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylenepolyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc;
  • the protein kinase inhibitors or pharmaceutical salts thereof may be formulated into pharmaceutical compositions for administration to animals or humans.
  • These pharmaceutical compositions which comprise an amount of the protein inhibitor effective to treat or prevent a protein kinase- mediated condition and a pharmaceutically acceptable carrier, are other embodiments of the present disclosure.
  • the disclosure provides a kit comprising a compound capable of inhibiting kinase activity selected from one or more compounds of disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and instructions for use in treating cancer.
  • the disclosure provides a kit comprising a compound capable of inhibiting EGFR and/or HER2 activity selected from a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Example 7 Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6-(3- methoxyphenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)phenyl)acrylamide (compound 7) Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (b) To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 25.8mmol) in DMF (80 mL) was added NBS (13.8 g, 77.6 mmol).
  • reaction mixture was stirred at room temperature for 1 hour, diluted with brine (10 mL) and extracted with DCM (30 mL ⁇ 3), the combined organic phase was concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford compound 15 as an orange solid (40 mg, 29 % isolated yield of 2 steps).
  • Example 33 Synthesis of 8-(((trans)-1-acryloyl-4-methoxypyrrolidin-3-yl)methyl)-2-((3- chloro-1-methyl-1H-pyrazol-4-yl)amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (compound 33) Synthesis of 3-chloro-1-methyl-1H-pyrazole (b) To a solution of 1-methyl-1H-pyrazol-3-amine (7.5 g, 77.3 mmol) in concentrated HCl (30 mL) was added a solution of sodium nitrite (5.87 g, 85.1 mmol) in H 2 O (10.0 mL) over a 10 min period at 0 °C.
  • Example 36 Synthesis of N-(3-(2-((3-chloro-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4- yl)amino)-7-oxo-6-phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound 36) 36 Synthesis of 4-(3-chloro-1H-pyrazol-1-yl)-1-methylpiperidine (b) To a solution of 1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-amine (1.8 g, 10 mmol) in concentrated hydrochloric acid (20 mL) at 0 °C was added a solution of sodium nitrite (759 mg, 11 mmol) in water (6 mL) dropwise while maintaining the temperature below 10 °C.
  • reaction mixture was stirred for 30 min, a solution of copper (I) chloride (825 mg , 8.33 mmol) in concentrated hydrochloric acid (8 mL) was added dropwise and the resulting reaction mixture was then heated to 60 °C. A catalytic amount of copper chloride (100 mg) was added at 60 °C.
  • the reaction mixture was stirred for 5 min and then poured onto 100 mL of crushed ice containing 50 % sodium hydroxide (5 mL) and stirred well.
  • the aqueous solution was extracted with dichloromethane (2 ⁇ 150 mL), and the combined organic phase was washed with water (50 mL), dried over magnesium sulfate and concentrated under reduced pressure.
  • tert-butyl (3-(2-(methylsulfonyl)-7-oxo-6-phenylpyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)carbamate (296 mg, 0.60 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was stirred at room temperature for 16 hours, and then diluted with water (20 mL). The aqueous phase was extracted with EtOAc (20 mL ⁇ 3). The combined organic phase was washed with water (20 mL ⁇ 2), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Example 37 Synthesis of N-(3-(2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-6-(2,4- difluorophenyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound 37) Prepared according to the procedure for compound 31.
  • Example 40 Synthesis of 8-(((3R,4R)-1-acryloyl-4-methoxypyrrolidin-3-yl)methyl)-2-((6- morpholinopyridin-3-yl)amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (compound 40) Synthesis of N-(6-fluoropyridin-3-yl)acetamide (b) To a solution of 6-fluoropyridin-3-amine (1.0 g, 8.93 mmol) and Et 3 N (1.81 g, 17.9 mmol) in DCM (20 mL) was added a solution of AcCl (0.84 g, 10.7 mmol) in DCM (5 mL) drop-wisely at 0 o C.
  • Example 41 Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-6-methoxy-5-((8- methyl-7-oxo-6-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)pyridin-3- yl)acrylamide (compound 41) Prepared according to the procedure for 42. LCMS (m/z): 532.3 [M+H] + .
  • Example 42 Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-methyl-7- oxo-6-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)acrylamide (compound 42) Synthesis of ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate To a solution ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate(5.0 g, 21.6 mmol) and Et3N (6.53 g, 64.7 mmol) in 1,4-dioxane (80 mL) was added methanamine hydrogen chloride(2.17 g, 32.3 mmol).
  • Example 43 Synthesis of N-(3-(6-benzyl-2-((6-morpholinopyridin-3-yl)amino)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound 43) tert-butyl (3-(6-benzyl-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)- yl)phenyl)carbamate (b) To a mixture of ethyl 3-phenylpropanoate (2.22 g, 12.5 mmol) in NMP (40 mL) was added 60% NaH (0.5 g, 12.5 mmol) at 0 o C.
  • tert-butyl (3-((5-formyl-2- (methylthio)pyrimidin-4-yl)amino)phenyl)carbamate in NMP (10 mL) was added.
  • the resulting mixture was stirred at 60 o C for 3h.
  • the mixture was diluted with brine (250 mL), and the aqueous phase was extracted with EtOAc (70 mL ⁇ 3).
  • the combined organic phase was washed with water (50 mL ⁇ 3), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • a solution of tert-butyl (3-(6-benzyl-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl)carbamate 600 mg, 1.27 mmol
  • DCM 20 mL
  • m-CPBA 1.1 g, 6.32 mmol
  • N-(2-methoxy-6-morpholinopyridin-3-yl)acetamide (intermediate C) To a solution of 2-methoxy-6-morpholinopyridin-3-amine (1.5 g, 8.368 mmol) and Et 3 N (1.81 g, 17.9 mmol) in DCM (20 mL) was added a solution of AcCl (0.84 g, 10.7 mmol) in DCM (5 mL) drop-wisely at 0 o C. The resulting mixture was stirred at room temperature for 2 hours, and then diluted with water (50 mL) and DCM (30 mL). The organic phase was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Example 47 Synthesis of N-(5-((8-methyl-7-oxo-6-phenyl-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-2-morpholinopyridin-3-yl)acrylamide
  • compound 47 2-morpholino-5-nitronicotinic acid
  • b A solution of 2-chloro-5-nitronicotinic acid (5.0 g, 24.8 mmol), morpholine (3.23 g, 37.2 mmol), DIPEA (6.38 g, 49.6 mmol) in CH 3 CN (60.0 mL) was stirred for 12 hour at 80 °C. LCMS showed the reaction was completed.
  • tert-butyl (5-amino-2-morpholinopyridin-3-yl)carbamate (d) A mixture of tert-butyl (2-morpholino-5-nitropyridin-3-yl)carbamate (0.38 g, 2.34 mmol), 10% Pd/C (0.19 g, cat.) in ethyl acetate (30 mL) was stirred at room temperature for 12 hours under H 2 atmosphere. LCMS showed the reaction was completed. The mixture was filtered and concentrated to give the crude compound (d) as an light yellow oil (0.34 g, 99% yield). LCMS (m/z): 295[M+H] + .
  • tert-butyl (5-((8-methyl-7-oxo-6-phenyl-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2- morpholinopyridin-3-yl)carbamate (i) To a solution of tert-butyl (5-acetamido-2-morpholinopyridin-3-yl)carbamate (336 mg, 1.0 mmol) in DMF (5 mL) was added NaH (48 mg, 1.2 mmol) at 0 o C.
  • Example 48 Synthesis of N-(3-(2-((6-morpholinopyridin-3-yl)amino)-7-oxo-6- phenoxypyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (compound 48) N-(6-fluoropyridin-3-yl)acetamide (b) To a solution of 6-fluoropyridin-3-amine (1.0 g, 8.93 mmol) and Et 3 N (1.81 g, 17.9 mmol) in DCM (20 mL) was added a solution of AcCl (0.84 g, 10.7 mmol) in DCM (5 mL) drop-wisely at 0 o C.
  • N-(6-morpholinopyridin-3-yl)acetamide (d) To a solution of N-(6-fluoropyridin-3-yl)acetamide (1.1 g, 7.14 mmol) in DMSO (20 mL) was added morpholine (1.24 g, 14.3 mmol) and K 2 CO 3 (1.97 g, 14.3 mmol). The reaction mixture was stirred at 100 o C for 16 hours. After cooled down to room temperature, the mixture was diluted with water (50 mL), and the aqueous phase was extracted with EtOAc (50 mL ⁇ 3).
  • m-CPBA 995 mg, 4.92 mmol
  • Biological Assays Proliferation inhibition assays Cell growth inhibition was assessed by MTS assay for Ba/F3, DFCI58-229, and DFCI127c cells, or by Cell Titer Glo (CTG) Luminescent Cell viability assay (Promega®) for DFCI362JC cells. 3000 Ba/F3 cells were seeded for per well in 96-well plates, and were exposed to representative compounds of the disclosure (3.3 nM to 10 ⁇ M) for 72 hours. For DFCI58-229, DFCI127c, and DFCI362JC cells, 5000 cells were seeded per well. All experimental points included 6 to 12 wells. Data were normalized to untreated cells and displayed graphically using GraphPad Prism (GraphPad Software, Inc.).
  • Lysates were separated by SDS-PAGE gel, transferred to nitrocellulose membranes, and probed with the following antibodies: phospho-EGFR(Tyr1068) (3777), total EGFR (2232), p-Akt(Ser473) (4060), total Akt (9272), p-ERK(Thr202/Tyr204) (4370), total ERK (9102) (Cell Signaling), and HSP90 (SC- 7947) (Santa Cruz Biotechnology®).
  • phospho-EGFR(Tyr1068) (3777), total EGFR (2232), p-Akt(Ser473) (4060), total Akt (9272), p-ERK(Thr202/Tyr204) (4370), total ERK (9102) (Cell Signaling), and HSP90 (SC- 7947) (Santa Cruz Biotechnology®).
  • DFCI58-229 cell DFCI127c cell
  • DFCI362JC cell 5000 cells were seeded per well in 96-well plates and were exposed to indicated compounds with a concentration of 3.3 to 10 ⁇ M for 72 hours. Western blot analysis was then performed on the cells. The cells were plated at 5x10 5 cells per well in 6-well plates and treated with the indicated concentrations of the compound. After 6 hours of treatment, cells were washed with PBS and lysed with NP40 buffer (Calbiochem) supplemented with Complete Mini protease inhibitor and PhosSTOP phosphatase inhibitors (Roche).
  • Lysates were then separated by SDS-PAGE gel, transferred to nitrocellulose membranes, and probed with the following antibodies: phospho-EGFR(Tyr1068) (3777), total EGFR (2232), p-Akt(Ser473) (4060), total Akt (9272), p-ERK(Thr202/Tyr204) (4370), total ERK (9102) (Cell Signaling), and HSP90 (SC-7947) (Santa Cruz Biotechnology). Activities of representative compounds of the present disclosure in inhibiting EGFR were tested by CellTiter-Glo® luminescent cell viability assay.
  • TAK-788 The chemical structure of the compound referred to herein as TAK-788 may also be referred to herein as mobocertinib. Activities of representative compounds of the present disclosure are shown in Tables 3- 10.

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Abstract

L'invention concerne des composés (I) qui modulent l'activité de HER2 ou EGFR, ou un mutant de ceux-ci ; des compositions pharmaceutiques comprenant les composés ; et des méthodes d'utilisation des composés ou des compositions pharmaceutiques pour traiter ou prévenir des maladies associées à HER2 ou EGFR, ou un mutant de ceux-ci.
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