Method of treating cancers with alkyne substituted quinazoline derivatives

Abstract

The present disclosure relates to methods of treating or preventing cancer (e.g., advanced solid cancer) using Compound No. 1: (Compound No. 1) or a pharmaceutically acceptable salt thereof. The present disclosure also relates to pharmaceutical compositions and pharmaceutical kits suitable for the treatment or prevention.

Description

Attorney Docket No. ASET-044 / 001WO 325190-2251 METHOD OF TREATING CANCERS WITH ALKYNE SUBSTITUTED QUINAZOLINE DERIVATIVES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 519,781, filed on August 15, 2023, which is incorporated by reference herein in its entirety for all purposes. SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (ASET_044_001WO_SeqListing_ST26.xml; Size 14,516 bytes; and Date of Creation: August 13, 2024) are herein incorporated by reference in their entireties. BACKGROUND

[0003] Mutations affecting either the intracellular catalytic domain or extracellular ligand binding domain of an ErbB receptor can generate oncogenic activity (the ErbB protein family consists of 4 members including ErbB-1, also named epidermal growth factor receptor (EGFR) and Erb-2, also named HER2 in humans). ErbB inhibitors are a known treatment for a number of cancers. However, not every patient responds satisfactorily to this treatment. Thus, there is a long-felt need in the art for new therapies that are able to address the variable responsiveness of cancer patients to known therapies. The present disclosure provides compositions and methods for preventing or treating cancer in patients with these oncogenic mutations without the variable responsiveness observed when patients having these ErbB mutants are treated using the existing standard of care. SUMMARY

[0004] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of Compound No.1 or a pharmaceutically acceptable salt thereof.

[0005] In some aspects, the present disclosure provides Compound No. 1, or a pharmaceutically acceptable salt thereof for treating or preventing cancer in a subject in need thereof.

[0006] In some aspects, the present disclosure provides use of Compound No. 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating orAttorney Docket No. ASET-044 / 001WO 325190-2251 preventing cancer in a subject in need thereof.

[0007] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0008] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION

[0009] It is understood that the term “Compound No.1,” as used herein, refers to a compound having the following structure:. (Compound No.1)

[0010] It is understood that the term “Compound No.1A,” as used herein, refers to a compound having the following structure:Attorney Docket No. ASET-044 / 001WO 325190-2251. (Compound No.1A)

[0011] It is understood that the term “Compound No.1B,” as used herein, refers to a compound having the following structure:. (Compound No.1B) Methods and Uses of the Present Disclosure

[0012] In some aspects, the present disclosure provides a method of treating or preventing (e.g., treating) cancer in a subject in need thereof, comprising administering to the subject three times per week a pharmaceutically effective amount of Compound No.1 (e.g., Compound No.1A or Compound No.1B), or a pharmaceutically acceptable salt thereof.

[0013] In some aspects, the present disclosure provides Compound No.1 (e.g., Compound No. 1A or Compound No. 1B) or a pharmaceutically acceptable salt thereof for treating or preventing (e.g., treating) cancer in a subject in need thereof.

[0014] In some aspects, the present disclosure provides use of Compound No. 1 (e.g., Compound No.1A or Compound No.1B) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing (e.g., treating) cancer in a subject in need thereof.

[0015] In some embodiments, Compound No.1A, Compound No.1B, or the pharmaceutically acceptable salt thereof is administered.Attorney Docket No. ASET-044 / 001WO 325190-2251

[0016] In some embodiments, Compound No. 1A or the pharmaceutically acceptable salt thereof is administered.

[0017] In some embodiments, Compound No. 1B or the pharmaceutically acceptable salt thereof is administered. Suitable Subjects and Diseases

[0018] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a human adult (e.g., being 18 years of age or order).

[0019] In some embodiments, the subject is a mouse. In some embodiments, the subject is a rat. In some embodiments, the subject is a dog.

[0020] The compounds of the disclosure inhibit or modulate the activity of a receptor tyrosine kinase, in particular extracellular mutants of ErbB-receptors, such as, but not limited to, EGFR- Viii, EGFR-Vii, EGFR-Vvi, EGFR-A289V and EGFR-G598V and HER2-S310F. Thus, the compounds and compositions of the disclosure can be useful as a medicament, i.e. as a medicament in therapy, more specifically for the prevention or treatment of cancer, as detailed below. Therefore, in a further aspect, the present disclosure provides a method of prevention or treatment of a mammal, for example, a human, suffering from cancer, as detailed below.

[0021] In some embodiments, cancer is a solid tumor.

[0022] In some embodiments, the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC), or any subtype thereof.

[0023] In some embodiments, the cancer is glioma.

[0024] In some embodiments, the cancer is glioma that expresses at least one oncogenic variant of EGFR.

[0025] In some embodiments, the cancer is high-grade glioma.

[0026] In some embodiments, the cancer is high-grade glioma that expresses at least one oncogenic variant of EGFR.

[0027] In some embodiments, the cancer is glioblastoma (GBM) or any subtype thereof.

[0028] In some embodiments, the cancer is glioblastoma.

[0029] In some embodiments, the cancer is glioblastoma and the cancer is characterized by overexpression of EGFR.

[0030] In some embodiments, the cancer is methylated glioblastoma. In some embodiments, the cancer is unmethylated glioblastoma.Attorney Docket No. ASET-044 / 001WO 325190-2251

[0031] In some embodiments, the cancer is recurrent glioblastoma.

[0032] In some embodiments, the cancer is relapsed glioblastoma.

[0033] In some embodiments, the cancer is glioblastoma and the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR.

[0034] In some embodiments, the cancer is relapsed glioblastoma and the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR.

[0035] In some embodiments, the cancer is recurrent glioblastoma and the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR.

[0036] In some embodiments, the cancer is non-small cell lung cancer (NSCLC) or any subtype thereof.

[0037] In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0038] In some embodiments, the cancer is recurrent non-small cell lung cancer (NSCLC).

[0039] In some embodiments, the cancer is relapsed non-small cell lung cancer (NSCLC).

[0040] In some embodiments, the cancer is NSCLC and the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR.

[0041] In some embodiments, the cancer is recurrent NSCLC and the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR.

[0042] In some embodiments, the cancer is relapsed NSCLC and the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR.

[0043] In some embodiments, the cancer is advanced or metastatic NSCLC .

[0044] In some embodiments, the cancer is advanced or metastatic NSCLC and the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR.

[0045] In some embodiments, the cancer is NSCLC, wherein the cancer has metastasized to the central nervous system (CNS).

[0046] In some embodiments, the cancer is advanced or metastatic NSCLC, wherein the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR, and wherein the cancer has metastasized to the central nervous system (CNS).

[0047] In some embodiments, the cancer is advanced or metastatic NSCLC, wherein the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR, and wherein the cancer has not metastasized to the central nervous system (CNS).

[0048] In some embodiments, the cancer is NSCLC, wherein the cancer has not metastasized to cerebrospinal fluid (CSF).

[0049] In some embodiments, the cancer is NSCLC, wherein the cancer has metastasized to cerebrospinal fluid (CSF).Attorney Docket No. ASET-044 / 001WO 325190-2251

[0050] In some embodiments, the cancer is glioblastoma, wherein the cancer has not metastasized to cerebrospinal fluid (CSF).

[0051] In some embodiments, the cancer is glioblastoma, wherein the cancer has metastasized to cerebrospinal fluid (CSF).

[0052] In some embodiments, the cancer is NSCLC, wherein the cancer has not metastasized to the brain.

[0053] In some embodiments, the cancer is NSCLC, wherein the cancer has metastasized to the brain.

[0054] In some embodiments, the subject has a central nervous system (CNS) disease.

[0055] In some embodiments, the subject does not have any CNS disease.

[0056] In some embodiments, the subject has a leptomeningeal disease.

[0057] In some embodiments, the subject does not have any leptomeningeal disease.

[0058] In some embodiments, the cancer is NSCLC and the subject has leptomeningeal disease.

[0059] In some embodiments, the cancer is glioblastoma and the subject has leptomeningeal disease.

[0060] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an ErbB receptor.

[0061] It is understood that an oncogenic variant of an ErbB receptor is an ErbB receptor protein that comprises at least one oncogenic mutation and that is produced as the result of the expression of a gene encoding the ErbB receptor that comprises at least one oncogenic mutation.

[0062] As would be appreciated by the skilled artisan, in the context of a gene (e.g. a gene encoding an ErbB receptor), an oncogenic mutation can include, but is not limited to a mutation that results in the substitution of one amino acid for another at a specific position within an ErbB receptor, a mutation that results in an insertion of one or more amino acids between two positions within an ErbB receptor, a mutation that results in the deletion of one more amino acids between two positions within an ErbB receptor, and mutation that results in a fusion of an ErbB receptor or portion thereof, with another protein, or portion thereof. As would be appreciated by the skilled artisan, in the context of a gene, an oncogenic mutation can include, but is not limited to, a missense mutation, a nonsynonymous mutation, an insertion of one or more nucleotides, a deletion of one or more nucleotides, an inversion and a deletion-insertion.

[0063] As would be appreciated by the skilled artisan, in the context of a protein (e.g. an ErbB receptor), an oncogenic mutation can include, but is not limited to, the substitution of one aminoAttorney Docket No. ASET-044 / 001WO 325190-2251 acid for another at a specific position within an ErbB receptor, an insertion of one or more amino acids between two positions within an ErbB receptor, a deletion of one more amino acids between two positions within an ErbB receptor, and a fusion of an ErbB receptor, or portion thereof, with another protein, or portion thereof.

[0064] In some embodiments, the oncogenic variant of the ErbB receptor comprises an allosteric mutation.

[0065] In some embodiments, the oncogenic variant of an ErbB receptor is an allosteric variant of the ErbB receptor.

[0066] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR) or a human epidermal growth factor receptor 2 (HER2) receptor.

[0067] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR).

[0068] In some embodiments, the ErbB receptor is a HER2 receptor.

[0069] In some embodiments, the ErbB receptor is a HER3 receptor.

[0070] In some embodiments, the ErbB receptor is a HER4 receptor.

[0071] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an epidermal growth factor receptor (EGFR).

[0072] In some embodiments, the oncogenic variant of EGFR is an allosteric variant of EGFR.

[0073] In some embodiments, the oncogenic variant of EGFR comprises an allosteric mutation.

[0074] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER2 receptor.

[0075] In some embodiments, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[0076] In some embodiments, the oncogenic variant of the HER2 receptor comprises an allosteric mutation.

[0077] In some embodiments, the oncogenic variant of an EGFR comprises an EGFR variant III (EGFR-Viii) mutation.

[0078] In some embodiments, the oncogenic variant of EGFR comprises an EGFR variant II (EGFR-Vii) mutation.

[0079] In some embodiments, the oncogenic variant of EGFR comprises an EGFR variant VI (EGFR-Vvi) mutation.

[0080] In some embodiments, the oncogenic variant of EGFR comprises a substitution of a lysine (K) for an arginine (R) at position 108 of SEQ ID NO: 1.

[0081] In some embodiments, the oncogenic variant of EGFR comprises a substitution of aAttorney Docket No. ASET-044 / 001WO 325190-2251 cysteine (C) for an arginine (R) at position 222 of SEQ ID NO: 1.

[0082] In some embodiments, the oncogenic variant of EGFR comprises a substitution of a threonine (T) for an alanine (A) at position 289 of SEQ ID NO: 1.

[0083] In some embodiments, the oncogenic variant of EGFR comprises a substitution of a valine (V) for an alanine (A) at position 289 of SEQ ID NO: 1.

[0084] In some embodiments, the oncogenic variant of EGFR comprises a substitution of a valine (V) for a glycine (G) at position 598 of SEQ ID NO: 1.

[0085] In some embodiments, the oncogenic variant of EGFR comprises a substitution of a phenylalanine (F) for a cysteine (C) at position 231 of SEQ ID NO: 1.

[0086] In some embodiments, the oncogenic variant of EGFR comprises a substitution of a serine for a cysteine at position 595 of SEQ ID NO: 1.

[0087] In some embodiments, the oncogenic variant of EGFR comprises a substitution of a valine (V) for a glycine (G) at position 598 of SEQ ID NO: 1.

[0088] In some embodiments, the oncogenic variant of EGFR comprises a substitution of a cysteine (C) for a serine (S) at position 645 of SEQ ID NO: 1.

[0089] In some embodiments, the oncogenic variant of EGFR comprises a substitution of glycine (G) at position 719 of SEQ ID NO: 1, wherein the substitution is selected from cysteine (C), aspartate (D), arginine (R), serine (S), or alanine (A).

[0090] In some embodiments, the oncogenic variant of EGFR comprises a substitution of serine (S) for a glycine (G) at position 719 of SEQ ID NO: 1.

[0091] In some embodiments, the oncogenic variant of EGFR comprises a substitution of serine (S) for cysteine (C) at position 797 of SEQ ID NO: 1.

[0092] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an EGFR and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, the oncogenic variant of an EGFR comprises a modification of a structure of the EGFR, wherein the oncogenic variant of an EGFR is a capable of forming a covalently linked dimer, wherein the covalently linked dimer is constitutively active and wherein the covalently linked dimer enhances an activity of EGFR when contacted to a Type I ErbB inhibitor. In some embodiments, the modification of the structure of the EGFR comprises a modification of one or more of a nucleic acid sequence, an amino acid sequence, a secondary structure, a tertiary structure, and a quaternary structure. In some embodiments, the oncogenic variant comprises a mutation, a splicing event, a post-translational process, a conformational change or any combination thereof. In some embodiments, the modification of the structure of the EGFR occurs within a first cysteine rich (CR1) and / or second cysteine rich (CR2) region of EGFR. InAttorney Docket No. ASET-044 / 001WO 325190-2251 some embodiments, the first cysteine rich (CR1) and / or second cysteine rich (CR2) region of EGFR comprises amino acid residues T211-R334 and / or C526-S645 of SEQ ID NO: 1, respectively. In some embodiments, the oncogenic variant of an EGFR generates a physical barrier to formation of a disulfide bond within the CR1 and / or the CR2 region. In some embodiments, the oncogenic variant of an EGFR removes a physical barrier to formation of a disulfide bond within the CR1 and / or the CR2 region. In some embodiments, the oncogenic variant of an EGFR comprises one or more free or unpaired Cysteine (C) residues located at a dimer interface of the EGFR. In some embodiments, the oncogenic variant of an EGFR comprises one or more free or unpaired Cysteine (C) residues at a site selected from the group consisting of C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624-C636 according to SEQ ID NO: 1. In some embodiments, the modification occurs within 10 angstroms or less of an intramolecular disulfide bond at a site selected from the group consisting of C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624-C636 according to SEQ ID NO: 1.

[0093] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of EGFR and the oncogenic variant of EGFR is a mutation of EGFR, a nucleotide sequence encoding the oncogenic variant of an EGFR comprises a deletion or the substitution comprises one or more amino acids that encode an adenosine triphosphate (ATP) binding site. In some embodiments, the ATP binding site comprises amino acids E746 to A750 of SEQ ID NO: 1. In some embodiments, the ATP binding site or the deletion or substitution thereof comprises L858 of SEQ ID NO: 1. In some embodiments, the deletion comprises L858 of SEQ ID NO: 1. In some embodiments, an arginine (R) is substituted for the leucine (L) at position 858 (L858R) of SEQ ID NO: 1.

[0094] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an EGFR and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, a nucleotide sequence encoding the oncogenic variant of an EGFR comprises an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal endAttorney Docket No. ASET-044 / 001WO 325190-2251 of the C-helix or a loop following the C-helix. In some embodiments, the insertion comprises the amino acid sequence of ASV, SVD, NPH, or FQEA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence ASV between positions V769 and D770 of SEQ ID NO: 1; (b) an insertion of the amino acid sequence SVD between positions D770 and N771 of SEQ ID NO: 1; (c) an insertion of the amino acid sequence NPH between positions H773 and V774 of SEQ ID NO: 1; (d) an insertion of the amino acid sequence FQEA between positions A763 and Y764 of SEQ ID NO: 1; (e) an insertion of the amino acid sequence PH between positions H773 and V774 of SEQ ID NO: 1; (f) an insertion of the amino acid G between positions D770 and N771 of SEQ ID NO: 1; (g) an insertion of the amino acid H between positions H773 and V774 of SEQ ID NO: 1; (h) an insertion of the amino acid sequence HV between positions V774 and C775 of SEQ ID NO: 1; (i) an insertion of the amino acid sequence AH between positions H773 and V774 of SEQ ID NO: 1; (j) an insertion of the amino acid sequence SVA between positions A767 and S768 of SEQ ID NO: 1; (k) a substitution of the amino acid sequence GYN for the DN between positions 770 and 771 of SEQ ID NO: 1; (l) an insertion of the amino acid H between positions N771 and P772 of SEQ ID NO: 1; (m) an insertion of the amino acid Y between positions H773 and V774 of SEQ ID NO: 1; (n) an insertion of the amino acid sequence PHVC between positions C775 and R776 of SEQ ID NO: 1; (o) a substitution of the amino acid sequence YNPY for the H at position 773 of SEQ ID NO: 1; (p) an insertion of the amino acid sequence DNP between positions P772 and H773 of SEQ ID NO: 1; (q) an insertion of the amino acid sequence VDS between positions S768 and V769 of SEQ ID NO: 1; (r) an insertion of the amino acid H between positions D770 and N771 of SEQ ID NO: 1; (s) an insertion of the amino acid N between positions N771 and P772 of SEQ ID NO: 1; (t) an insertion of the amino acid sequence PNP between positions P772 and H773 of SEQ ID NO: 1; (u) a substitution of the amino acid sequence GSVDN for the DN between positions 770 and 771 of SEQ ID NO: 1; (v) a substitution of the amino acid sequence GYP for the NP between positions 771 and 772 of SEQ ID NO: 1; (w) an insertion of the amino acid G between positions N771 and P772 of SEQ ID NO: 1; (x) an insertion of the amino acid sequence GNP between positions P772 and H773 of SEQ ID NO: 1; (y) an insertion of the amino acid sequence GSV between positions V769 and D770 of SEQ ID NO: 1; (z) a substitution of the amino acid sequence GNPHVC for the VC between positions 774 and 775 of SEQ ID NO: 1; (aa) an insertion of the amino acid sequence LQEA between positions A763 and Y764 of SEQ ID NO: 1; (bb) an insertion of the amino acid sequence GL between positions D770 and N771 of SEQ ID NO: 1; (cc) an insertion of the amino acid Y between positions D770 and N771 of SEQ IDAttorney Docket No. ASET-044 / 001WO 325190-2251 NO: 1; (dd) an insertion of the amino acid sequence NPY between positions H773 and V774 of SEQ ID NO: 1; (ee) an insertion of the amino acid sequence TH between positions H773 and V774 of SEQ ID NO: 1; (ff) a substitution of the amino acid sequence KGP for the NP between positions 771 and 772 of SEQ ID NO: 1; (gg) a substitution of the amino acid sequence SVDNP for the NP between positions 771 and 772 of SEQ ID NO: 1; (hh) an insertion of the amino acid sequence NN between positions N771 and P772 of SEQ ID NO: 1; (ii) an insertion of the amino acid T between positions N771 and P772 of SEQ ID NO: 1; and (jj) a substitution of the amino acid sequence STLASV for the SV between positions 768 and 769 of SEQ ID NO: 1.

[0095] In some embodiments, an oncogenic variant of EGFR can have or more mutations in exon 18.

[0096] In some embodiments, an oncogenic variant of EGFR can have or more mutations in exon 19.

[0097] In some embodiments, an oncogenic variant of EGFR can have or more mutations in exon 20.

[0098] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an EGFR and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR.

[0099] In some embodiments, the oncogenic variant of an EGFR can be any of the following: EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-R222C, EGFR-R252C, EGFR-R252P, EGFR- R256Y, EGFR-T263P, EGFR-Y270C, EGFR-A289T, EGFR-A289V, EGFR-A289D, EGFR- H304Y, EGFR-G331R, EGFR-P596S, EGFR-P596L, EGFR-P596R, EGFR-G598V, EGFR- G598A, EGFR-G614D, EGFR-C620Y, EGFR-C614W, EGFR-C628F, EGFR-C628Y, EGFR- C636Y, EGFR-S645C, EGFR-Δ660, EGFR-Δ768, EGFR-C231F, EGFR-C231F, EGFR- C595S, EGFR-D761Y, EGFR-G719C, EGFR-G719D, EGFR-G719R, EGFR-L858R, EGFR- E746-A750del, EGFR-E746-A750del+C797S, EGFR-E746-A750del+C797S+T790M, EGFR-C797S or any combination thereof.

[0100] In some embodiments, the oncogenic variant of an EGFR is selected from: EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-R108K, EGFR-R222C, EGFR-R252C, EGFR-R252P, EGFR- R256Y, EGFR-T263P, EGFR-Y270C, EGFR-A289T, EGFR-A289V, EGFR-A289D, EGFR- H304Y, EGFR-G331R, EGFR-P596S, EGFR-P596L, EGFR-P596R, EGFR-G598V, EGFR- G598A, EGFR-G614D, EGFR-C620Y, EGFR-C614W, EGFR-C628F, EGFR-C628Y, EGFR- C636Y, EGFR-S645C, EGFR-Δ660, EGFR-Δ768, EGFR-V689M, EGFR-N700D, EGFR-Attorney Docket No. ASET-044 / 001WO 325190-2251 E709K, EGFR-E709Q, EGFR-E709A, EGFR-E709G, EGFR-E709V, EGFR-S768I, EGFR- C231F, EGFR-C595S, EGFR-D761Y, EGFR-L718Q, EGFR-G719C, EGFR-G719D, EGFR- G719R, EGFR-G719A, EGFR-G719S, EGFR-G724S, EGFR-L858R, EGFR-L858R+C797S, EGFR-L861Q, EGFR-E746-A750del, EGFR-E746-A750del+C797S, EGFR-E746- A750del+S768I, EGFR-E746-A750del+C797S+T790M, EGFR-C797S, EGFR-Δ19+C797S, EGFR- Δ19+C797S+ T790M, EGFR- Δ19+S768I, EGFR-G719C+S768I, EGFR-D716Y or any combination thereof.

[0101] In some embodiments, the oncogenic variant of EGFR comprises an insertion within exon 20, wherein the insertion comprises the amino acid sequence of ASV, SVD, NPH or FQEA.

[0102] In some embodiments, the oncogenic variant of EGFR comprises an insertion in exon 20, wherein the insertion in exon 20 is selected from the group of insertions recited in Table 1. Table 1. EGFR Exon 20 insertions (numbering corresponding to SEQ ID NO: 1)Attorney Docket No. ASET-044 / 001WO 325190-2251

[0103] In some embodiments, the oncogenic variant of EGFR comprises a substitution within exon 20 of EGFR.

[0104] In some embodiments, the oncogenic variant of EGFR comprises a substitution in exon 20, wherein the substitution in exon 20 is selected from the group of substitutions recited in Table 2. Table 2. EGFR Exon 20 substitutions (numbering corresponding to SEQ ID NO: 1)Attorney Docket No. ASET-044 / 001WO 325190-2251

[0105] In some embodiments, the oncogenic variant of EGFR can be any of the EGFR variants put forth in Table 3. Table 3. EGFR oncogenic variants

[0106] In some embodiments, Δ19 can comprise the deletion of residues E746-A750 of EGFR (SEQ ID NO: 1).

[0107] In some embodiments, the cancer, or a tumor or a cell thereof, expresses one or more of: (a) a wild type human epidermal growth factor receptor 2 (HER2) receptor or an oncogenic variant of a HER2 receptor.

[0108] In some embodiments, the cancer, or a tumor or a cell thereof, expresses a wild type HER2 receptor, the wild type HER2 receptor comprises the amino acid sequence of SEQ ID NO: 2, 3, 4, 5, or 6.

[0109] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER2 receptor, the oncogenic variant of a HER2 receptor is an allosteric variantAttorney Docket No. ASET-044 / 001WO 325190-2251 of the HER2 receptor.

[0110] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a phenylalanine (F) for a serine (S) at position 310 of SEQ ID NO: 2 or 5.

[0111] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a tyrosine (Y) for a serine (S) at position 310 of SEQ ID NO: 2 or 5.

[0112] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a glutamine (Q) for an arginine (R) at position 678 of SEQ ID NO: 2 or 5.

[0113] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a leucine (L) for a valine (V) at position 777 of SEQ ID NO: 2 or 5.

[0114] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a methionine (M) for a valine (V) at position 777 of SEQ ID NO: 2 or 5.

[0115] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of an isoleucine (I) for a valine (V) at position 842 of SEQ ID NO: 2 or 5.

[0116] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of an alanine (A) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[0117] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a proline (P) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[0118] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenicAttorney Docket No. ASET-044 / 001WO 325190-2251 variant of a HER2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a serine (S) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[0119] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, a nucleotide sequence encoding the oncogenic variant of a HER2 receptor comprises an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMAGVGSPYVSR(SEQ ID NO: 8). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal end of the C-helix or a loop following the C-helix. In some embodiments, the insertion comprises the amino acid sequence of GSP or YVMA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (b) an insertion of the amino acid sequence GSP between positions P780 and Y781 of SEQ ID NO: 2; (c) an insertion of the amino acid sequence YVMA between positions A771 and Y772 of SEQ ID NO: 2; (d) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (e) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (f) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (g) a substitution of the amino acid sequence AVGCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (h) a substitution of the amino acid sequence LC for the G between position 776 of SEQ ID NO: 2; (i) a substitution of the amino acid sequence LCV for the G between position 776 of SEQ ID NO: 2; (j) an insertion of the amino acid sequence GSP between positions V777 and G778 of SEQ ID NO: 2; (k) a substitution of the amino acid sequence PS for the LRE between positions 755 and 757 of SEQ ID NO: 2; (l) a substitution of the amino acid sequence CPGSP for the SP between positions 779 and 780 of SEQ ID NO: 2; (m) an insertion of the amino acid C between positions V777 and G778 of SEQ ID NO: 2; (n) a substitution of the amino acid sequence VVMA for the AG between positions 775 and 776 of SEQ ID NO: 2; (o) a substitution of the amino acid sequence VV for the G at position 776 of SEQ ID NO: 2; (p) a substitution of the amino acid sequence AVCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (q) a substitution of the amino acid sequence VCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (r) an insertion of the amino acid G between positions G778 and S779 of SEQ ID NO: 2; (s) a substitution of the amino acid sequence PK for the LRE between positions 755 and 757 of SEQ ID NO: 2; (t)Attorney Docket No. ASET-044 / 001WO 325190-2251 an insertion of the amino acid V between positions A775 and G776 of SEQ ID NO: 2; (u) an insertion of the amino acid sequence YAMA between positions A775 and G776 of SEQ ID NO: 2; (v) a substitution of the amino acid sequence CV for the G at position 776 of SEQ ID NO: 2; (w) a substitution of the amino acid sequence AVCGG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (x) a substitution of the amino acid sequence CVCG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (y) a substitution of the amino acid sequence VVVG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (z) a substitution of the amino acid sequence SVGG for the GVGS between positions 776 and 779 of SEQ ID NO: 2; (aa) a substitution of the amino acid sequence VVGES for the GVGS between positions 776 and 779 of SEQ ID NO: 2; (bb) a substitution of the amino acid sequence AVGSGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (cc) a substitution of the amino acid sequence CVC for the GV between positions 776 and 777 of SEQ ID NO: 2; (dd) a substitution of the amino acid sequence HVC for the GV between positions 776 and 777 of SEQ ID NO: 2; (ee) a substitution of the amino acid sequence VAAGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (ff) a substitution of the amino acid sequence VAGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (gg) a substitution of the amino acid sequence VVV for the GV between positions 776 and 777 of SEQ ID NO: 2; (hh) an insertion of the amino acid sequence FPG between positions G778 and S779 of SEQ ID NO: 2; (ii) an insertion of the amino acid sequence GS between positions S779 and P780 of SEQ ID NO: 2; (jj) a substitution of the amino acid sequence VPS for the VLRE between positions 754 and 757 of SEQ ID NO: 2; (kk) an insertion of the amino acid E between positions V777 and G778 of SEQ ID NO: 2; (ll) an insertion of the amino acid sequence MAGV between positions V777 and G778 of SEQ ID NO: 2; (mm) an insertion of the amino acid S between positions V777 and G778 of SEQ ID NO: 2; (nn) an insertion of the amino acid sequence SCV between positions V777 and G778 of SEQ ID NO: 2; and (oo) an insertion of the amino acid sequence LMAY between positions Y772 and V773 of SEQ ID NO: 2.

[0120] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises HER2-Δ16, HER2-C311R, HER2-S310F, p95-HER2-M611 or any combination thereof.

[0121] In some embodiments, the oncogenic variant of HER2 comprises an insertion within exon 20, wherein the insertion comprises the amino acid sequence of GSP or YVMA.

[0122] In some embodiments, the oncogenic variant of HER2 comprises an insertion in exonAttorney Docket No. ASET-044 / 001WO 325190-2251 20, wherein the insertion in exon 20 is selected from the group of insertions recited in Table 4. Table 4. HER2 Exon 20 insertions (numbering corresponding to SEQ ID NO: 2)

[0123] In some embodiments, the oncogenic variant of HER2 comprises a substitution within exon 20 of HER2.

[0124] In some embodiments, the oncogenic variant of EGFR comprises a substitution in exon 20, wherein the substitution in exon 20 is selected from the group of substitutions recited in Table 5.Attorney Docket No. ASET-044 / 001WO 325190-2251 Table 5. HER2 Exon 20 substitutions (numbering corresponding to SEQ ID NO: 2)

[0125] In some embodiments, the oncogenic variant of HER2 is any of the HER2 variants put forth in Table 6.Attorney Docket No. ASET-044 / 001WO 325190-2251 Table 6. HER2 Oncogenic Variants

[0126] In some embodiments, the cancer, or a tumor or cell thereof, expresses an oncogenic variant of a HER3 receptor. In some embodiments, the oncogenic variant of HER3 is any of the variants put forth in Table 7. Table 7. HER3 Oncogenic Variants

[0127] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER4 receptor. In some embodiments, the oncogenic variant of the HER4 receptor is an allosteric variant of the HER4 receptor. In some embodiments, the oncogenic variant of a HER4 receptor comprises deletion of exon 16 (HER4-Δ16).

[0128] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an EGFR, wherein the sequence encoding the oncogenic variant of the EGFR comprises a deletion of exon 20 or a portion thereof and wherein the cancer, the tumor or the cell thereof does not comprise a second oncogenic variation in a sequence other than exon 20 of EGFR. In some embodiments, the second oncogenic variation comprises a sequence encoding one or more of an EGFR kinase domain (KD), BRAF, NTRK, and KRAS.

[0129] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an EGFR, wherein the sequence encoding the oncogenic variant of the EGFR comprises a deletion of exon 20 or a portion thereof and wherein the cancer, the tumor or theAttorney Docket No. ASET-044 / 001WO 325190-2251 cell thereof does not comprise a marker indicating responsiveness to immunotherapy.

[0130] In some embodiments, the oncogenic variant (e.g., allosteric variant) or the oncogenic mutation (e.g., allosteric mutation) is detected by a Food and Drug Administration (FDA)- approved diagnosis.

[0131] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a phosphatidylinositol-3-kinase (PI3K). In some embodiments, the cancer, or a tumor or cell thereof, expresses a mutant form of a PI3K, wherein the mutant form of the PI3K differs from the wildtype sequence of the PI3K. In some embodiments, the cancer is glioblastoma, and the cancer, or a tumor or cell thereof, expresses an oncogenic variant of a PI3K. In some embodiments, the cancer is glioblastoma, and the cancer, or a tumor or cell thereof, expresses a mutant form of a PI3K, wherein the mutant form of the PI3K differs from the wildtype sequence of the PI3K.

[0132] It is understood that an oncogenic variant of a PI3K is a PI3K protein that comprises at least one oncogenic mutation and that is produced as the result of the expression of a gene encoding the PI3K that comprises at least one oncogenic mutation.

[0133] As would be appreciated by the skilled artisan, in the context of a gene (e.g. a gene encoding a PI3K), an oncogenic mutation can include, but is not limited to a mutation that results in the substitution of one amino acid for another at a specific position within a PI3K, a mutation that results in an insertion of one or more amino acids between two positions within PI3K, a mutation that results in the deletion of one more amino acids between two positions within a PI3K, and a mutation that results in a fusion of a PI3K or portion thereof, with another protein, or portion thereof. As would be appreciated by the skilled artisan, in the context of a gene, an oncogenic mutation can include, but is not limited to, a missense mutation, a nonsynonymous mutation, an insertion of one or more nucleotides, a deletion of one or more nucleotides, an inversion and a deletion-insertion.

[0134] As would be appreciated by the skilled artisan, in the context of a protein (e.g. a PI3K), an oncogenic mutation can include, but is not limited to, the substitution of one amino acid for another at a specific position within a PI3K, an insertion of one or more amino acids between two positions within a PI3K, a deletion of one more amino acids between two positions within a PI3K, and a fusion of a PI3K, or portion thereof, with another protein, or portion thereof.

[0135] In some embodiments, the cancer, or a tumor or cell thereof, has an amplification of the MET gene, which encodes the receptor tyrosine kinase c-MET (also referred to as MET).

[0136] In some aspects, the cancer is glioblastoma, and the cancer, or a tumor or cell thereof, expresses EGFRvIII. In some aspects, the cancer is glioblastoma, and the cancer, or a tumorAttorney Docket No. ASET-044 / 001WO 325190-2251 or cell thereof, expresses EGFRvII. In some aspects, the cancer is glioblastoma, and the cancer, or a tumor or cell thereof, expresses EGFRvVI. In some aspects, the cancer is glioblastoma, and the cancer, or a tumor or cell thereof, expresses EGFR-R108K. In some aspects, the cancer is glioblastoma, and the cancer, or a tumor or cell thereof, expresses EGFR-R222C. In some aspects, the cancer is glioblastoma, and the cancer, or a tumor or cell thereof, expresses EGFR- C231F. In some aspects, the cancer is glioblastoma, and the cancer, or a tumor or cell thereof, expresses EGFR-A289T. In some aspects, the cancer is glioblastoma, and the cancer, or a tumor or cell thereof, expresses EGFR-A289V. In some aspects, the cancer is glioblastoma, and the cancer, or a tumor or cell thereof, expresses EGFR-C595S. In some aspects, the cancer is glioblastoma, and the cancer, or a tumor or cell thereof, expresses EGFR-G598V. In some aspects, the cancer is glioblastoma, and the cancer, or a tumor or cell thereof, expresses EGFR- S645C.

[0137] In some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof expresses EGFR-C797S. some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof expresses EGFR-G719S. In some aspects, the cancer is advanced and / or metastatic NSCLC, and the cancer, or a tumor or cell thereof expresses EGFR-C797S. In some aspects, the cancer is advanced and / or metastatic NSCLC, and the cancer, or a tumor or cell thereof expresses EGFR-G719S. In some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof, expresses EGFR-C797S, wherein the cancer, or a tumor or cell thereof, is insensitive or resistant to treatment with a therapeutic agent different from the compound of the present disclosure (e.g., osimertinib or lazertinib). In some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof, expresses EGFR-C797S as a resistance mechanism, wherein the cancer, or a tumor or cell thereof, is insensitive or resistant to treatment with a therapeutic agent different from the compound of the present disclosure (e.g., osimertinib or lazertinib).

[0138] In some aspects, a deletion of exon 19 can comprise a deletion of E746-A750 (EGFR- E746-A750del).

[0139] In some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof, expresses an oncogenic variant of EGFR comprising a deletion of exon 19. In some aspects, the deletion of exon 19 is a deletion of E746-A750 (EGFR-E746-A750del).

[0140] In some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof, expresses an oncogenic variant of EGFR comprising a deletion of exon 19 + C797S. In some aspects, the deletion of exon 19 is a deletion of E746-A750 (EGFR-E746-A750del).

[0141] In some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof,Attorney Docket No. ASET-044 / 001WO 325190-2251 expresses an oncogenic variant of EGFR comprising a deletion of exon 19 + C797S, wherein the cancer, or a tumor or cell thereof, is insensitive or resistant to treatment with a therapeutic agent different from the compound of the present disclosure (e.g., osimertinib or lazertinib). In some aspects, the deletion of exon 19 is a deletion of E746-A750 (EGFR-E746-A750del).In some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof, expresses EGFR- L858R.

[0142] In some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof, expresses EGFR-C797S+L858R.

[0143] In some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof, expresses EGFR-C797S+L858R, wherein the cancer, or a tumor or cell thereof, is insensitive or resistant to treatment with a therapeutic agent different from the compound of the present disclosure (e.g., osimertinib or lazertinib).

[0144] In some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof, expresses an oncogenic variant of EGFR comprising an oncogenic mutation in Exon 18.

[0145] In some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof, expresses EGFR-G719C, EGFR-G719D, EGFR-G719R, EGFR-G719A, or EGFR-G719S.

[0146] In some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof, expresses EGFR-G719C, EGFR-G719D, EGFR-G719R, EGFR-G719A, EGFR-G719S, EGFR-S768I, EGFR-V769L, EGFR-E709G, EGFR-E709A, EGFR-D716Y or any combination thereof.

[0147] In some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof, expresses EGFR-S768I.

[0148] In some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof, expresses EGFR-L861Q.

[0149] In some aspects, the cancer is NSCLC, and the cancer, or a tumor or cell thereof, has an amplification of the MET gene.

[0150] In some embodiments, prior to the treatment with the compound of the present disclosure, the subject has not undergone any surgery for treating the cancer.

[0151] In some embodiments, prior to the treatment with the compound of the present disclosure, the subject has undergone one or more surgeries for treating the cancer.

[0152] In some embodiments, prior to the treatment with the compound of the present disclosure, the subject has received no previous treatment, or has received a single cycle of chemoradiotherapy.

[0153] In some embodiments, prior to the treatment with the compound of the presentAttorney Docket No. ASET-044 / 001WO 325190-2251 disclosure, the subject has received no previous treatment, or has received a single cycle of immune checkpoint inhibitor.

[0154] In some embodiments, prior to the treatment with the compound of the present disclosure, the subject has received at least one chemoradiotherapy.

[0155] In some embodiments, the subject has recurrent GBM and has previously undergone one or more surgeries and have received at least one chemoradiotherapy.

[0156] In some embodiments, prior to the treatment with the compound of the present disclosure, the subject is treated with a therapeutic agent different from the compound of the present disclosure.

[0157] In some embodiments, the cancer, or a tumor or a cell thereof, is insensitive or resistant to treatment with a third-generation EGFR inhibitor.

[0158] In some embodiments, the cancer, or a tumor or a cell thereof, is insensitive or resistant to treatment with an EGFR inhibitor different from a compound of the present disclosure.

[0159] A non-exhaustive and non-limiting list of third-generation EGFR inhibitors consists of afatinib, avitinib, dacomitinib, erlotinib, gefitinib, lazertinib, mavelertinib, naquotinib, nazartinib, olmutinib, osimertinib, and rociletinib.

[0160] In some embodiments, the cancer, or a tumor or a cell thereof, is insensitive or resistant to treatment with one or more of afatinib, avitinib, dacomitinib, erlotinib, gefitinib, lazertinib, mavelertinib, naquotinib, nazartinib, olmutinib, osimertinib, and rociletinib.

[0161] In some embodiments, the cancer, or a tumor or a cell thereof, is insensitive or resistant to treatment with osimertinib or lazertinib.

[0162] In some embodiments, the cancer is NSCLC and is insensitive or resistant to treatment with a third-generation EGFR inhibitor. In some embodiments, the cancer is NSCLC and is insensitive or resistant to treatment with a third-generation EGFR inhibitor in combination with a platinum containing chemotherapy.

[0163] In some embodiments, the cancer is NSCLC and is insensitive or resistant to treatment with a third-generation EGFR inhibitor, and wherein the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR. In some embodiments, the cancer is NSCLC and is insensitive or resistant to treatment with a third-generation EGFR inhibitor in combination with a platinum containing chemotherapy, and wherein the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR. In some embodiments, the oncogenic variant of EGFR can be EGFR-C797S, EGFR-L861Q, EGFR-G719C, EGFR- G719D, EGFR-G719R, EGFR-G719A, EGFR-G719S, EGFR-S768I or EGFR-V769L.

[0164] In some embodiments, the cancer is advanced and / or metastatic NSCLC and isAttorney Docket No. ASET-044 / 001WO 325190-2251 insensitive or resistant to treatment with a third-generation EGFR inhibitor. In some embodiments, the cancer is advanced and / or metastatic NSCLC and is insensitive or resistant to treatment with a third-generation EGFR inhibitor in combination with a platinum containing chemotherapy.

[0165] In some embodiments, the cancer is advanced and / or metastatic NSCLC and is insensitive or resistant to treatment with a third-generation EGFR inhibitor, and wherein the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR. In some embodiments, the cancer is advanced and / or metastatic NSCLC and is insensitive or resistant to treatment with a third-generation EGFR inhibitor in combination with a platinum containing chemotherapy, and wherein the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR. In some embodiments, the oncogenic variant of EGFR can be EGFR-C797S, EGFR-L861Q, EGFR-G719C, EGFR-G719D, EGFR-G719R, EGFR-G719A, EGFR-G719S, EGFR-S768I or EGFR-V769L.

[0166] In some embodiments, the cancer is NSCLC and is insensitive or resistant to treatment with one or more of afatinib, avitinib, dacomitinib, erlotinib, gefitinib, lazertinib, mavelertinib, naquotinib, nazartinib, olmutinib, osimertinib, and rociletinib.

[0167] In some embodiments, the cancer is NSCLC and is insensitive or resistant to treatment with osimertinib or lazertinib.

[0168] In some embodiments, the cancer, or a tumor or a cell thereof, is insensitive or resistant to treatment with a therapeutic agent different from the compound of the present disclosure. In some embodiments, the cancer, or a tumor or a cell thereof, is insensitive or resistant to treatment with a Type I inhibitor. In some embodiments, the cancer, or a tumor or a cell thereof, is insensitive or resistant to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 and AZD9291.

[0169] In some embodiments, the subject has an adverse reaction to treatment with a therapeutic agent different from the compound of the present disclosure. In some embodiments, the subject has an adverse reaction to treatment with a Type I inhibitor. In some embodiments, the subject has an adverse reaction to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 and AZD9291. In some embodiments, the adverse reaction is an activation of the oncogenic variant of an EGFR and wherein the oncogenic variant comprises a mutation in an extracellularAttorney Docket No. ASET-044 / 001WO 325190-2251 domain of the receptor. In some embodiments, the adverse reaction is an activation of the oncogenic variant of a HER2 Receptor and wherein the oncogenic variant comprises a mutation in an extracellular domain of the receptor.

[0170] In some embodiments, the subject has been previously administered at least one initial therapy that is different from a compound of the present disclosure, and the subject has experienced disease progression despite the administration of said at least one initial therapy, wherein the initial therapy comprises the administration of at least one EGFR inhibitor different from a compound of the present disclosure, at least one platinum containing chemotherapy, at least one anti-PD-L1 therapy or any combination thereof.

[0171] In some embodiments, the subject can have NSCLC and the subject has been previously administered at least one initial therapy that is different from a compound of the present disclosure for the treatment of said NSCLC, and the subject has experienced disease progression despite the administration of said at least one initial therapy, wherein the initial therapy comprises the administration of at least one EGFR inhibitor different from a compound of the present disclosure, at least one platinum containing chemotherapy, at least one anti-PD- L1 therapy or any combination thereof.

[0172] In some embodiments, the subject has advanced and / or metastatic NSCLC, wherein the NSCLC, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR, and wherein the subject has been previously administered at least one EGFR inhibitor different from a compound of the present disclosure in combination with at least one platinum containing chemotherapy. In some embodiments, the subject has advanced and / or metastatic NSCLC, wherein the NSCLC, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR, and wherein the subject has been previously administered at least one EGFR inhibitor different from a compound of the present disclosure in combination with at least one platinum containing chemotherapy and at least one anti-PD-L1 therapy. In some embodiments, the at least one EGFR inhibitor can be Osimertinib. In some aspects, the at least one oncogenic variant of EGFR can be EGFR-Δ19, EGFR-L858R, EGFR-L861Q, EGFR-G719C, EGFR- G719D, EGFR-G719R, EGFR-G719A, EGFR-G719S, EGFR-S768I, EGFR-V769L or EGFR- C797S.

[0173] In some embodiments, the subject has advanced and / or metastatic NSCLC, wherein the NSCLC, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR, and wherein the subject has been previously administered at least one EGFR inhibitor different from a compound of the present disclosure in combination with at least one platinum containing chemotherapy. In some embodiments, the subject has advanced and / or metastatic NSCLC,Attorney Docket No. ASET-044 / 001WO 325190-2251 wherein the NSCLC, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR, and wherein the subject has been previously administered at least one EGFR inhibitor different from a compound of the present disclosure in combination with at least one platinum containing chemotherapy and at least one anti-PD-L1 therapy. In some embodiments, the at least one EGFR inhibitor can be Osimertinib. In some aspects, the at least one oncogenic variant of EGFR can be EGFR-G719C, EGFR-G719D, EGFR-G719R, EGFR-G719A, EGFR- G719S, EGFR-S768I, EGFR-V769L, EGFR-E709G, EGFR-E709A or EGFR-D716Y. In some embodiments, the NSCLC can have metastasized to the CNS. In some embodiments, the NSCLC can have not metastasized to the CNS.

[0174] In some embodiments, the subject has advanced and / or metastatic NSCLC, wherein the NSCLC, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR, wherein the at least one oncogenic variant of EGFR is EGFR-C797S, and wherein the subject has been previously administered at least one EGFR inhibitor different from a compound of the present disclosure in combination with at least one platinum containing chemotherapy. In some embodiments, the subject has advanced and / or metastatic NSCLC, wherein the NSCLC, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR, wherein the at least one oncogenic variant of EGFR is EGFR-C797S, and wherein the subject has been previously administered at least one EGFR inhibitor different from a compound of the present disclosure in combination with at least one platinum containing chemotherapy and at least one anti-PD- L1 therapy. In some embodiments, the at least one EGFR inhibitor can be Osimertinib. In some embodiments, the NSCLC can have metastasized to the CNS. In some embodiments, the NSCLC can have not metastasized to the CNS.

[0175] In some embodiments, the subject has advanced and / or metastatic NSCLC, wherein the NSCLC, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR, and wherein the subject has been previously administered at least one platinum containing chemotherapy. In some embodiments, the subject has advanced and / or metastatic NSCLC, wherein the NSCLC, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR, and wherein the subject has been previously administered at least one platinum containing chemotherapy in combination with at least one anti-PD-L1 therapy. In some embodiments, the at least one oncogenic variant of EGFR can be EGFR-G719C, EGFR- G719D, EGFR-G719R, EGFR-G719A, or EGFR-G719S. In some embodiments, the NSCLC can have metastasized to the CNS. In some embodiments, the NSCLC can have not metastasized to the CNS.

[0176] In some embodiments, the therapeutically effective amount reduces a severity of a signAttorney Docket No. ASET-044 / 001WO 325190-2251 or symptom of the cancer.

[0177] In some embodiments, the sign of the cancer comprises a tumor grade and wherein a reduction of the severity of the sign comprises a decrease of the tumor grade.

[0178] In some embodiments, the sign of the cancer comprises a tumor metastasis and wherein a reduction of the severity of the sign comprises an elimination of the metastasis or a reduction in the rate or extent the metastasis.

[0179] In some embodiments, the sign of the cancer comprises a tumor volume and wherein a reduction of the severity of the sign comprises an elimination of the tumor or a reduction in the volume.

[0180] In some embodiments, the symptom of the cancer comprises pain and wherein a reduction of the severity of the sign comprises an elimination or a reduction in the pain.

[0181] In some embodiments, the therapeutically effective amount induces a period of remission.

[0182] In some embodiments, the therapeutically effective amount improves a prognosis of the subject.

[0183] Such a use (or method of prevention or treatment) of a subject comprises administering to a subject in need of such prevention or treatment a therapeutically effective amount of a compound of the disclosure or pharmaceutically acceptable salts thereof or a pharmaceutical composition thereof by targeting allosteric and / or oncogenic variants of EGFR and HER2 receptor. Administrations of Compound No.1

[0184] In some embodiments, the subject is a human.

[0185] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is orally administered.

[0186] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered with one or more drug holidays.

[0187] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered without any drug holiday.

[0188] In some embodiments, prior to the administration, the subject is fasted for at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours.Attorney Docket No. ASET-044 / 001WO 325190-2251

[0189] In some embodiments, prior to the administration, the subject is fed with about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours. Administration Doses, Lengths, and Frequencies

[0190] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered daily.

[0191] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered once per day.

[0192] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered daily at a dosage of: about 100±20 mg, about 100±10 mg, about 100±5 mg, about 100±4 mg, about 100±3 mg, about 100±2 mg, or about 100±1 mg (e.g., about 100 mg); about 150±20 mg, about 150±10 mg, about 150±5 mg, about 150±4 mg, about 150±3 mg, about 150±2 mg, or about 150±1 mg (e.g., about 150 mg); about 200±20 mg, about 200±10 mg, about 200±5 mg, about 200±4 mg, about 200±3 mg, about 200±2 mg, or about 200±1 mg (e.g., about 200 mg); or about 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±1 mg (e.g., about 300 mg).

[0193] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered daily at a dosage of about 100±20 mg, about 100±10 mg, about 100±5 mg, about 100±4 mg, about 100±3 mg, about 100±2 mg, or about 100±1 mg (e.g., about 100 mg).

[0194] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered daily at a dosage of about 150±20 mg, about 150±10 mg, about 150±5 mg, about 150±4 mg, about 150±3 mg, about 150±2 mg, or about 150±1 mg (e.g., about 150 mg).

[0195] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered daily at a dosage of about 200±20 mg, about 200±10 mg, about 200±5 mg, about 200±4 mg, about 200±3 mg, about 200±2 mg, or about 200±1 mg (e.g., about 200 mg).

[0196] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered daily at a dosage of aboutAttorney Docket No. ASET-044 / 001WO 325190-2251 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±1 mg (e.g., about 300 mg).

[0197] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered weekly.

[0198] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered three times per week.

[0199] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered three times per week (e.g., at day 1, day 3, and day 5 of each week)

[0200] It is understood that day 1 can be any day of a calendar week. In some embodiments, day 1 is a Sunday. In some embodiments, day 1 is a Monday. In some embodiments, day 1 is a Tuesday, Wednesday, Thursday, Friday, or Saturday.

[0201] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is orally administered three times per week.

[0202] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered three times per week (e.g., at day 1, day 3, and day 5) at a dosage of: about 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±1 mg (e.g., about 300 mg); about 400±50 mg, about 400±40 mg, about 400±30 mg, about 400±20 mg, about 400±10 mg, about 400±5 mg, about 400±4 mg, about 400±3 mg, about 400±2 mg, or about 400±1 mg (e.g., about 400 mg); or about 500±50 mg, about 500±40 mg, about 500±30 mg, about 500±20 mg, about 500±10 mg, about 500±5 mg, about 500±4 mg, about 500±3 mg, about 500±2 mg, or about 500±1 mg (e.g., about 500 mg).

[0203] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered three times per week (e.g., at day 1, day 3, and day 5) at a dosage of about 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±1 mg (e.g., about 300 mg).

[0204] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered three times per week (e.g., at day 1, day 3, and day 5) at a dosage of about 400±50 mg, about 400±40 mg, about 400±30 mg, about 400±20 mg, about 400±10 mg, about 400±5 mg, about 400±4 mg, about 400±3 mg,Attorney Docket No. ASET-044 / 001WO 325190-2251 about 400±2 mg, or about 400±1 mg (e.g., about 400 mg).

[0205] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered three times per week (e.g., at day 1, day 3, and day 5) at a dosage of about 500±50 mg, about 500±40 mg, about 500±30 mg, about 500±20 mg, about 500±10 mg, about 500±5 mg, about 500±4 mg, about 500±3 mg, about 500±2 mg, or about 500±1 mg (e.g., about 500 mg).

[0206] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered for about 21 days, about 28 days, about 35 days, about 42 days, about 63 days, about 84 days, about 105 days, about 126 days, about 147 days, about 168 days, about 189 days, or about 210 days.

[0207] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered for longer than 210 days.

[0208] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered until a progression of cancer or an adverse effect (e.g., an intolerable toxicity) is observed.

[0209] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered for about 21 days.

[0210] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered for about 21 days, followed by a 30-day drug holiday.

[0211] In some embodiments, the treating or preventing lasts about 1 month, about 2 months, about 3 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months, or about 24 months.

[0212] In some embodiments, the treating or preventing comprises one or more treatment cycles, wherein each treatment cycle comprises administering Compound No. 1 (e.g., Compound No.1A or Compound No.1B) or the pharmaceutically acceptable salt thereof for about 21 days, followed by a 30-day drug holiday. Combination with Temozolomide (TMZ)

[0213] In some embodiments, the method further comprises administering a therapeutically effective amount of temozolomide.

[0214] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered in combination with a therapeutically effective amount of temozolomide.Attorney Docket No. ASET-044 / 001WO 325190-2251

[0215] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B), or the pharmaceutically acceptable salt thereof, and temozolomide are administered simultaneously, sequentially, or in alternation.

[0216] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B), or the pharmaceutically acceptable salt thereof, and temozolomide are administered simultaneously.

[0217] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B), or the pharmaceutically acceptable salt thereof, and temozolomide are administered sequentially.

[0218] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B), or the pharmaceutically acceptable salt thereof, and temozolomide are administered temporal proximity.

[0219] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B), or the pharmaceutically acceptable salt thereof, and temozolomide are administered in alternation.

[0220] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B), or the pharmaceutically acceptable salt thereof, and temozolomide are administered in separate formulations.

[0221] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B), or the pharmaceutically acceptable salt thereof, and temozolomide are administered in a co-formulation.

[0222] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B), or the pharmaceutically acceptable salt thereof, and temozolomide are administered about 28 days.

[0223] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B), or the pharmaceutically acceptable salt thereof, and temozolomide are administered about 28 days, about 56 days, about 84 days, about 112 days, about 140 days, about 168 days, about 196 days, about 224 days, about 252 days, or about 280 days.

[0224] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered for longer than 280 days.

[0225] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B) or the pharmaceutically acceptable salt thereof is administered until a progression of cancer or an adverse effect (e.g., an intolerable toxicity) is observed.Attorney Docket No. ASET-044 / 001WO 325190-2251 Exemplary Embodiments

[0226] Exemplary Embodiment No.1. A method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of Compound No.1:or a pharmaceutically acceptable salt thereof.

[0227] Exemplary Embodiment No. 2. Compound No. 1, or a pharmaceutically acceptable salt thereof for treating or preventing cancer in a subject in need thereof.

[0228] Exemplary Embodiment No. 3. Use of Compound No. 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof.

[0229] Exemplary Embodiment No. 4. The method, compound, or use of any one of the preceding embodiments, wherein the cancer is glioma.

[0230] Exemplary Embodiment No. 5. The method, compound, or use of any one of the preceding embodiments, wherein the cancer is high-grade glioma.

[0231] Exemplary Embodiment No. 6. The method, compound, or use of any one of the preceding embodiments, wherein the cancer is high-grade glioma that expresses at least one oncogenic variant of EGFR.

[0232] Exemplary Embodiment No. 7. The method, compound, or use of any one of the preceding embodiments, wherein the cancer is glioblastoma.

[0233] Exemplary Embodiment No. 8. The method, compound, or use of any one of the preceding embodiments, wherein Compound No. 1A, Compound No. 1B, or the pharmaceutically acceptable salt thereof is administered.

[0234] Exemplary Embodiment No. 9. The method, compound, or use of any one of the preceding embodiments, wherein Compound No. 1A or the pharmaceutically acceptable salt thereof is administered.

[0235] Exemplary Embodiment No. 10. The method, compound, or use of any one of the preceding embodiments, wherein Compound No. 1B or the pharmaceutically acceptable saltAttorney Docket No. ASET-044 / 001WO 325190-2251 thereof is administered.

[0236] Exemplary Embodiment No. 11. The method, compound, or use of any one of the preceding embodiments, wherein the subject is a human.

[0237] Exemplary Embodiment No. 12. The method, compound, or use of any one of the preceding embodiments, wherein Compound No. 1 or the pharmaceutically acceptable salt thereof is administered once per day.

[0238] Exemplary Embodiment No. 13. The method, compound, or use of any one of the preceding embodiments, wherein Compound No. 1 or the pharmaceutically acceptable salt thereof is administered daily at a dosage of: about 100±20 mg, about 100±10 mg, about 100±5 mg, about 100±4 mg, about 100±3 mg, about 100±2 mg, or about 100±1 mg; about 150±20 mg, about 150±10 mg, about 150±5 mg, about 150±4 mg, about 150±3 mg, about 150±2 mg, or about 150±1 mg; about 200±20 mg, about 200±10 mg, about 200±5 mg, about 200±4 mg, about 200±3 mg, about 200±2 mg, or about 200±1 mg; about 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±1 mg.

[0239] Exemplary Embodiment No. 14. The method, compound, or use of any one of the preceding embodiments, wherein Compound No. 1 or the pharmaceutically acceptable salt thereof is administered daily at a dosage of about 100±20 mg, about 100±10 mg, about 100±5 mg, about 100±4 mg, about 100±3 mg, about 100±2 mg, or about 100±1 mg.

[0240] Exemplary Embodiment No. 15. The method, compound, or use of any one of the preceding embodiments, wherein Compound No. 1 or the pharmaceutically acceptable salt thereof is administered daily at a dosage of about 150±20 mg, about 150±10 mg, about 150±5 mg, about 150±4 mg, about 150±3 mg, about 150±2 mg, or about 150±1 mg.

[0241] Exemplary Embodiment No. 16. The method, compound, or use of any one of the preceding embodiments, wherein Compound No. 1 or the pharmaceutically acceptable salt thereof is administered daily at a dosage of about 200±20 mg, about 200±10 mg, about 200±5 mg, about 200±4 mg, about 200±3 mg, about 200±2 mg, or about 200±1 mg.

[0242] Exemplary Embodiment No. 17. The method, compound, or use of any one of the preceding embodiments, wherein Compound No. 1 or the pharmaceutically acceptable salt thereof is administered daily at a dosage of about 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±1 mg.

[0243] Exemplary Embodiment No. 18. The method, compound, or use of any one of theAttorney Docket No. ASET-044 / 001WO 325190-2251 preceding embodiments, wherein Compound No. 1 or the pharmaceutically acceptable salt thereof is administered three times per week.

[0244] Exemplary Embodiment No. 19. The method, compound, or use of any one of the preceding embodiments, wherein Compound No. 1 or the pharmaceutically acceptable salt thereof is administered three times per week at a dosage of: about 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±1 mg; about 400±50 mg, about 400±40 mg, about 400±30 mg, about 400±20 mg, about 400±10 mg, about 400±5 mg, about 400±4 mg, about 400±3 mg, about 400±2 mg, or about 400±1 mg; or about 500±50 mg, about 500±40 mg, about 500±30 mg, about 500±20 mg, about 500±10 mg, about 500±5 mg, about 500±4 mg, about 500±3 mg, about 500±2 mg, or about 500±1 mg.

[0245] Exemplary Embodiment No. 20. The method, compound, or use of any one of the preceding embodiments, wherein Compound No. 1 or the pharmaceutically acceptable salt thereof is administered three times per week at a dosage of about 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±1 mg.

[0246] Exemplary Embodiment No. 21. The method, compound, or use of any one of the preceding embodiments, wherein Compound No. 1 or the pharmaceutically acceptable salt thereof is administered three times per week at a dosage of about 400±50 mg, about 400±40 mg, about 400±30 mg, about 400±20 mg, about 400±10 mg, about 400±5 mg, about 400±4 mg, about 400±3 mg, about 400±2 mg, or about 400±1 mg.

[0247] Exemplary Embodiment No. 22. The method, compound, or use of any one of the preceding embodiments, wherein Compound No. 1 or the pharmaceutically acceptable salt thereof is administered three times per week at a dosage of about 500±50 mg, about 500±40 mg, about 500±30 mg, about 500±20 mg, about 500±10 mg, about 500±5 mg, about 500±4 mg, about 500±3 mg, about 500±2 mg, or about 500±1 mg. Definitions

[0248] It will be understood that while compounds disclosed herein may be presented in one particular configuration. Such particular configuration is not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers. In some embodiments, the presentation of a compound herein in a particular configuration intends to encompass, and toAttorney Docket No. ASET-044 / 001WO 325190-2251 refer to, each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof; while the presentation further intends to refer to the specific configuration of the compound.

[0249] Further, it will be understood that while compounds disclosed herein may be presented without specified configuration (e.g., without specified stereochemistry). Such presentation intends to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, the presentation of a compound herein without specified configuration intends to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.

[0250] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0251] As used herein, the term “chiral centre” refers to a carbon atom bonded to four nonidentical substituents.

[0252] As used herein, the term “chiral isomer” means a compound with at least one chiral centre. Compounds with more than one chiral centre may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral centre is present, a stereoisomer may be characterised by the absolute configuration (R or S) of that chiral centre. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral centre. The substituents attached to the chiral centre 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. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc.1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ.1964, 41, 116).

[0253] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0254] The terms “nucleic acid” and “polynucleotide” are used interchangeably herein to referAttorney Docket No. ASET-044 / 001WO 325190-2251 to single- or double-stranded RNA, DNA, or mixed polymers. Polynucleotides may include genomic sequences, extra-genomic and plasmid sequences, and smaller engineered gene segments that express, or may be adapted to express polypeptides.

[0255] An “isolated nucleic acid” is a nucleic acid that is substantially separated from other genome DNA sequences as well as proteins or complexes such as ribosomes and polymerases, which naturally accompany a native sequence. The term embraces a nucleic acid sequence that has been removed from its naturally occurring environment, and includes recombinant or cloned DNA isolates and chemically synthesized analogues or analogues biologically synthesized by heterologous systems. A substantially pure nucleic acid includes isolated forms of the nucleic acid. Of course, this refers to the nucleic acid as originally isolated and does not exclude genes or sequences later added to the isolated nucleic acid by the hand of man.

[0256] The term “polypeptide” is used in its conventional meaning, i.e., as a sequence of amino acids. The polypeptides are not limited to a specific length of the product. Peptides, oligopeptides, and proteins are included within the definition of polypeptide, and such terms may be used interchangeably herein unless specifically indicated otherwise. This term also does not refer to or exclude post-expression modifications of the polypeptide, for example, glycosylations, acetylations, phosphorylations and the like, as well as other modifications known in the art, both naturally occurring and non-naturally occurring. A polypeptide may be an entire protein, or a subsequence thereof.

[0257] An “isolated polypeptide” is one that has been identified and separated and / or recovered from a component of its natural environment. In preferred embodiments, the isolated polypeptide will be purified (1) to greater than 95% by weight of polypeptide as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or, preferably, silver stain. Isolated polypeptide includes the polypeptide in situ within recombinant cells since at least one component of the polypeptide's natural environment will not be present. Ordinarily, however, isolated polypeptide will be prepared by at least one purification step.

[0258] A “native sequence” polynucleotide is one that has the same nucleotide sequence as a polynucleotide derived from nature. A “native sequence” polypeptide is one that has the same amino acid sequence as a polypeptide (e.g. EGFR) derived from nature (e.g., from any species). Such native sequence polynucleotides and polypeptides can be isolated from nature or can be produced by recombinant or synthetic means.Attorney Docket No. ASET-044 / 001WO 325190-2251

[0259] A polynucleotide “variant,” as the term is used herein, is a polynucleotide that typically differs from a polynucleotide specifically disclosed herein in one or more substitutions, deletions, additions and / or insertions.

[0260] A polypeptide “variant,” as the term is used herein, is a polypeptide that typically differs from a polypeptide specifically disclosed herein in one or more substitutions, deletions, additions and / or insertions, or inversions. Such variants may be naturally occurring, non- naturally occurring, or may be synthetically generated.

[0261] EGFR mutations (or variants) of the disclosure may comprise one or more substitutions, deletions, additions and / or insertions, or inversions of the amino acid sequence that are alter the function of the resultant protein. Mutations may be detected, for example, by comparison or alignment of a nucleic or amino acid sequence with a wild type sequence.

[0262] When comparing polynucleotide and polypeptide sequences, two sequences are said to be “identical” if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence, as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A “comparison window” as used herein, refers to a segment of at least about 20 contiguous positions, usually 30 to about 75, 40 to about 50, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.

[0263] Optimal alignment of sequences for comparison may be conducted using the Megalign program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, WI), using default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, M.O. (1978) A model of evolutionary change in proteins – Matrices for detecting distant relationships. In Dayhoff, M.O. (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington DC Vol. 5, Suppl. 3, pp. 345-358; Hein J. (1990) Unified Approach to Alignment and Phylogenes pp. 626-645 Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, CA; Higgins, D.G. and Sharp, P.M. (1989) CABIOS 5:151-153; Myers, E.W. and Muller W. (1988) CABIOS 4:11-17; Robinson, E.D. (1971) Comb. Theor 11:105; Santou, N. Nes, M. (1987) Mol. Biol. Evol.4:406- 425; Sneath, P.H.A. and Sokal, R.R. (1973) Numerical Taxonomy – the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, CA; Wilbur, W.J. and Lipman, D.J. (1983) Proc. Natl. Acad., Sci. USA 80:726-730.

[0264] Alternatively, optimal alignment of sequences for comparison may be conducted by the local identity algorithm of Smith and Waterman (1981) Add. APL. Math 2:482, by the identityAttorney Docket No. ASET-044 / 001WO 325190-2251 alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol.48:443, by the search for similarity methods of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85: 2444, by computerized implementations of these algorithms (GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 575 Science Dr., Madison, WI), or by inspection.

[0265] One preferred example of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nucl. Acids Res.25:3389-3402 and Altschul et al. (1990) J. Mol. Biol.215:403-410, respectively. BLAST and BLAST 2.0 can be used, for example with the parameters described herein, to determine percent sequence identity for the polynucleotides and polypeptides of the invention. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information.

[0266] In one illustrative example, cumulative scores can be calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915) alignments, (B) of 50, expectation (E) of 10, M=5, N=-4 and a comparison of both strands.

[0267] For amino acid sequences, a scoring matrix can be used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment.

[0268] In one approach, the “percentage of sequence identity” is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions orAttorney Docket No. ASET-044 / 001WO 325190-2251 deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residues occur in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e., the window size) and multiplying the results by 100 to yield the percentage of sequence identity.

[0269] A wild type EGFR sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 mrpsgtagaa llallaalcp asraleekkv cqgtsnkltq lgtfedhfls lqrmfnncev 61 vlgnleityv qrnydlsflk tiqevagyvl ialntverip lenlqiirgn myyensyala 121 vlsnydankt glkelpmrnl qeilhgavrf snnpalcnve siqwrdivss dflsnmsmdf 181 qnhlgscqkc dpscpngscw gageencqkl tkiicaqqcs grcrgkspsd cchnqcaagc 241 tgpresdclv crkfrdeatc kdtcpplmly npttyqmdvn pegkysfgat cvkkcprnyv 301 vtdhgscvra cgadsyemee dgvrkckkce gpcrkvcngi gigefkdsls inatnikhfk 361 nctsisgdlh ilpvafrgds fthtppldpq eldilktvke itgflliqaw penrtdlhaf 421 enleiirgrt kqhgqfslav vslnitslgl rslkeisdgd viisgnknlc yantinwkkl 481 fgtsgqktki isnrgensck atgqvchalc spegcwgpep rdcvscrnvs rgrecvdkck 541 llegeprefv enseciqchp eclpqamnit ctgrgpdnci qcahyidgph cvktcpagvm 601 genntlvwky adaghvchlc hpnctygctg pglegcptng pkipsiatgm vgalllllvv 661 algiglfmrr rhivrkrtlr rllqerelve pltpsgeapn qallrilket efkkikvlgs 721 gafgtvykgl wipegekvki pvaikelrea tspkankeil deayvmasvd nphvcrllgi 781 cltstvqlit qlmpfgclld yvrehkdnig sqyllnwcvq iakgmnyled rrlvhrdlaa 841 rnvlvktpqh vkitdfglak llgaeekeyh aeggkvpikw malesilhri ythqsdvwsyAttorney Docket No. ASET-044 / 001WO 325190-2251 901 gvtvwelmtf gskpydgipa seissilekg erlpqppict idvymimvkc wmidadsrpk 961 freliiefsk mardpqrylv iqgdermhlp sptdsnfyra lmdeedmddv vdadeylipq 1021 qgffsspsts rtpllsslsa tsnnstvaci drnglqscpi kedsflqrys sdptgalted 1081 siddtflpvp eyinqsvpkr pagsvqnpvy hnqplnpaps rdphyqdphs tavgnpeyln 1141 tvqptcvnst fdspahwaqk gshqisldnp dyqqdffpke akpngifkgs taenaeylrv 1201 apqssefiga (SEQ ID NO: 1, corresponding to epidermal growth factor receptor [Homo sapiens] and Genbank Accession No. CAA25240).

[0270] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 melaalcrwg lllallppga astqvctgtd mklrlpaspe thldmlrhly qgcqvvqgnl 61 eltylptnas lsflqdiqev qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng 121 dplnnttpvt gaspgglrel qlrslteilk ggvliqrnpq lcyqdtilwk difhknnqla 181 ltlidtnrsr achpcspmck gsrcwgesse dcqsltrtvc aggcarckgp lptdccheqc 241 aagctgpkhs dclaclhfnh sgicelhcpa lvtyntdtfe smpnpegryt fgascvtacp 301 ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar vcyglgmehl revravtsan 361 iqefagckki fgslaflpes fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp 421 dlsvfqnlqv irgrilhnga ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481 pwdqlfrnph qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec 541 veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc 601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk gcpaeqrasp ltsiisavvgAttorney Docket No. ASET-044 / 001WO 325190-2251 661 illvvvlgvv fgilikrrqq kirkytmrrl lqetelvepl tpsgampnqa qmrilketel 721 rkvkvlgsga fgtvykgiwi pdgenvkipv aikvlrents pkankeilde ayvmagvgsp 781 yvsrllgicl tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841 lvhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft 901 hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictid vymimvkcwm 961 idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl dstfyrslle dddmgdlvda 1021 eeylvpqqgf fcpdpapgag gmvhhrhrss strsgggdlt lglepseeea prsplapseg 1081 agsdvfdgdl gmgaakglqs lpthdpsplq rysedptvpl psetdgyvap ltcspqpeyv 1141 nqpdvrpqpp spregplpaa rpagatlerp ktlspgkngv vkdvfafgga venpeyltpq 1201 ggaapqphpp pafspafdnl yywdqdpper gappstfkgt ptaenpeylg ldvpv (SEQ ID NO: 2, corresponding to receptor tyrosine-protein kinase erbB-2 isoform a precursor [Homo sapiens] and GenBank Accession No. NP_004439).

[0271] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas lsflqdiqev qgyvliahnq 61 vrqvplqrlr ivrgtqlfed nyalavldng dplnnttpvt gaspgglrel qlrslteilk 121 ggvliqrnpq lcyqdtilwk difhknnqla ltlidtnrsr achpcspmck gsrcwgesse 181 dcqsltrtvc aggcarckgp lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241 lvtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr 301 cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes fdgdpasnta 361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv irgrilhnga ysltlqglgiAttorney Docket No. ASET-044 / 001WO 325190-2251 421 swlglrslre lgsglalihh nthlcfvhtv pwdqlfrnph qallhtanrp edecvgegla 481 chqlcarghc wgpgptqcvn csqflrgqec veecrvlqgl preyvnarhc lpchpecqpq 541 ngsvtcfgpe adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601 thscvdlddk gcpaeqrasp ltsiisavvg illvvvlgvv fgilikrrqq kirkytmrrl 661 lqetelvepl tpsgampnqa qmrilketel rkvkvlgsga fgtvykgiwi pdgenvkipv 721 aikvlrents pkankeilde ayvmagvgsp yvsrllgicl tstvqlvtql mpygclldhv 781 renrgrlgsq dllnwcmqia kgmsyledvr lvhrdlaarn vlvkspnhvk itdfglarll 841 dideteyhad ggkvpikwma lesilrrrft hqsdvwsygv tvwelmtfga kpydgipare 901 ipdllekger lpqppictid vymimvkcwm idsecrprfr elvsefsrma rdpqrfvviq 961 nedlgpaspl dstfyrslle dddmgdlvda eeylvpqqgf fcpdpapgag gmvhhrhrss 1021 strsgggdlt lglepseeea prsplapseg agsdvfdgdl gmgaakglqs lpthdpsplq 1081 rysedptvpl psetdgyvap ltcspqpeyv nqpdvrpqpp spregplpaa rpagatlerp 1141 ktlspgkngv vkdvfafgga venpeyltpq ggaapqphpp pafspafdnl yywdqdpper 1201 gappstfkgt ptaenpeylg ldvpv (SEQ ID NO: 3, corresponding to receptor tyrosine-protein kinase erbB-2 isoform b [Homo sapiens] and GenBank Accession No. NP_001005862).

[0272] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 mprgswkpqv ctgtdmklrl paspethldm lrhlyqgcqv vqgnleltyl ptnaslsflq 61 diqevqgyvl iahnqvrqvp lqrlrivrgt qlfednyala vldngdplnn ttpvtgaspgAttorney Docket No. ASET-044 / 001WO 325190-2251 121 glrelqlrsl teilkggvli qrnpqlcyqd tilwkdifhk nnqlaltlid tnrsrachpc 181 spmckgsrcw gessedcqsl trtvcaggca rckgplptdc cheqcaagct gpkhsdclac 241 lhfnhsgice lhcpalvtyn tdtfesmpnp egrytfgasc vtacpynyls tdvgsctlvc 301 plhnqevtae dgtqrcekcs kpcarvcygl gmehlrevra vtsaniqefa gckkifgsla 361 flpesfdgdp asntaplqpe qlqvfetlee itgylyisaw pdslpdlsvf qnlqvirgri 421 lhngaysltl qglgiswlgl rslrelgsgl alihhnthlc fvhtvpwdql frnphqallh 481 tanrpedecv geglachqlc arghcwgpgp tqcvncsqfl rgqecveecr vlqglpreyv 541 narhclpchp ecqpqngsvt cfgpeadqcv acahykdppf cvarcpsgvk pdlsympiwk 601 fpdeegacqp cpincthscv dlddkgcpae qraspltsii savvgillvv vlgvvfgili 661 krrqqkirky tmrrllqete lvepltpsga mpnqaqmril ketelrkvkv lgsgafgtvy 721 kgiwipdgen vkipvaikvl rentspkank eildeayvma gvgspyvsrl lgicltstvq 781 lvtqlmpygc lldhvrenrg rlgsqdllnw cmqiakgmsy ledvrlvhrd laarnvlvks 841 pnhvkitdfg larlldidet eyhadggkvp ikwmalesil rrrfthqsdv wsygvtvwel 901 mtfgakpydg ipareipdll ekgerlpqpp ictidvymim vkcwmidsec rprfrelvse 961 fsrmardpqr fvviqnedlg paspldstfy rslledddmg dlvdaeeylv pqqgffcpdp 1021 apgaggmvhh rhrssstrsg ggdltlglep seeeaprspl apsegagsdv fdgdlgmgaa 1081 kglqslpthd psplqrysed ptvplpsetd gyvapltcsp qpeyvnqpdv rpqppspreg 1141 plpaarpaga tlerpktlsp gkngvvkdvf afggavenpe yltpqggaap qphpppafspAttorney Docket No. ASET-044 / 001WO 325190-2251 1201 afdnlyywdq dppergapps tfkgtptaen peylgldvpv (SEQ ID NO: 4, corresponding to receptor tyrosine-protein kinase erbB-2 isoform c [Homo sapiens] and GenBank Accession No. NP_001276865).

[0273] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 melaalcrwg lllallppga astqvctgtd mklrlpaspe thldmlrhly qgcqvvqgnl 61 eltylptnas lsflqdiqev qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng 121 dplnnttpvt gaspgglrel qlrslteilk ggvliqrnpq lcyqdtilwk difhknnqla 181 ltlidtnrsr achpcspmck gsrcwgesse dcqsltrtvc aggcarckgp lptdccheqc 241 aagctgpkhs dclaclhfnh sgicelhcpa lvtyntdtfe smpnpegryt fgascvtacp 301 ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar vcyglgmehl revravtsan 361 iqefagckki fgslaflpes fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp 421 dlsvfqnlqv irgrilhnga ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481 pwdqlfrnph qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec 541 veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc 601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk gcpaeqrasp ltsiisavvg 661 illvvvlgvv fgilikrrqq kirkytmrrl lqetelvepl tpsgampnqa qmrilketel 721 rkvkvlgsga fgtvykgiwi pdgenvkipv aikvlrents pkankeilde ayvmagvgsp 781 yvsrllgicl tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841 lvhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrftAttorney Docket No. ASET-044 / 001WO 325190-2251 901 hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictid vymimvkcwm 961 idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl dstfyrslle dddmgdlvda 1021 eeylvpqqgf fcpdpapgag gmvhhrhrss strnm (SEQ ID NO: 5, corresponding to receptor tyrosine-protein kinase erbB-2 isoform d precursor [Homo sapiens] and GenBank Accession No. NP_001276866).

[0274] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas lsflqdiqev qgyvliahnq 61 vrqvplqrlr ivrgtqlfed nyalavldng dplnnttpvt gaspgglrel qlrslteilk 121 ggvliqrnpq lcyqdtilwk difhknnqla ltlidtnrsr achpcspmck gsrcwgesse 181 dcqsltrtvc aggcarckgp lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241 lvtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr 301 cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes fdgdpasnta 361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv irgrilhnga ysltlqglgi 421 swlglrslre lgsglalihh nthlcfvhtv pwdqlfrnph qallhtanrp edecvgegla 481 chqlcarghc wgpgptqcvn csqflrgqec veecrvlqgl preyvnarhc lpchpecqpq 541 ngsvtcfgpe adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601 ths (SEQ ID NO: 6, corresponding to receptor tyrosine-protein kinase erbB-2 isoform e [Homo sapiens] and GenBank Accession No. NP_001276867).

[0275] Based on the definitions given throughout the application the skilled person knows which combinations are synthetically feasible and realistic, e.g. typically combinations of groups leading to heteroatoms directly linked to each other are not contemplated.

[0276] As used herein, the term “about” refers to a range covering any normal fluctuationsAttorney Docket No. ASET-044 / 001WO 325190-2251 appreciated by one of ordinary skill in the relevant art. In some embodiments, the term “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0277] As used herein, the term “pharmaceutically acceptable salt” refers to a derivative of the compound of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc. Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo- [2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3. It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the sameAttorney Docket No. ASET-044 / 001WO 325190-2251 salt.

[0278] It is understood that the compounds described herein include the compounds themselves, as well as their pharmaceutically acceptable salts, and their solvates, if applicable. A pharmaceutically acceptable salt, for example, can be formed between a pharmaceutically acceptable anion and a positively charged group (e.g., amino) on a compound. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0279] It is understood that 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. Nonlimiting examples of hydrates include monohydrates and dihydrates. Nonlimiting examples of solvates include ethanol solvates and acetone solvates.

[0280] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and / or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

[0281] It is understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0282] It is understood that compounds 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,Attorney Docket No. ASET-044 / 001WO 325190-2251 J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art.

[0283] As used herein, the term “subject” includes human and non-human mammal, as well as cell lines, cell culture, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human.

[0284] As used herein, the term “subject in need thereof”, refers to a subject having a disease (to be treated) or having an increased risk of developing the disease (to be prevented). A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who has (e.g., is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that doesn't respond or hasn’t yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.

[0285] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model.

[0286] It is understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevantAttorney Docket No. ASET-044 / 001WO 325190-2251 disease, condition or disorder, or used to identify suitable candidates for such purposes.

[0287] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0288] As used herein, the term “temporal proximity” refers to that administration of one therapeutic agent (Compound No. 1 (e.g., Compound No. 1A or Compound No. 1B)) occurs within a time period before or after the administration of another therapeutic agent (e.g., temozolomide), such that the therapeutic effect of the one therapeutic agent overlaps with the therapeutic effect of the other therapeutic agent. In some embodiments, the therapeutic effect of the one therapeutic agent completely overlaps with the therapeutic effect of the other therapeutic agent. In some embodiments, “temporal proximity” means that administration of one therapeutic agent occurs within a time period before or after the administration of another therapeutic agent, such that there is a synergistic effect between the one therapeutic agent and the other therapeutic agent. “Temporal proximity” may vary according to various factors, including but not limited to, the age, gender, weight, genetic background, medical condition, disease history, and treatment history of the subject to which the therapeutic agents are to be administered; the disease or condition to be treated or ameliorated; the therapeutic outcome to be achieved; the dosage, dosing frequency, and dosing duration of the therapeutic agents; the pharmacokinetics and pharmacodynamics of the therapeutic agents; and the route(s) through which the therapeutic agents are administered. In some embodiments, “temporal proximity” means within 15 minutes, within 30 minutes, within an hour, within two hours, within four hours, within six hours, within eight hours, within 12 hours, within 18 hours, or within 24 hours. In some embodiments, multiple administration of one therapeutic agent can occur in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity may change during a treatment cycle or within a dosing regimen.

[0289] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0290] As used herein, the term “pharmaceutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assayAttorney Docket No. ASET-044 / 001WO 325190-2251 method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Pharmaceutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0291] It is understood that, for the compounds of the present disclosure beingcapable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure.

[0292] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. In some embodiments, the pharmaceutically acceptable salt of a compound is also a prodrug of the compound. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2- hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0293] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine,Attorney Docket No. ASET-044 / 001WO 325190-2251 diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ration other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0294] It is understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0295] As used herein, the term “prodrug” refers to any agent which, when administered to a mammal, is converted in whole or in part to a targeted compound. In some embodiments, the prodrug of a compound is also a pharmaceutically acceptable salt of the compound.

[0296] It is understood that the compounds of the present disclosure can also be prepared as esters, for example, pharmaceutically acceptable esters. For example, a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g., a methyl, ethyl or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, e.g., acetate, propionate or other ester.

[0297] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognize the advantages of certain routes of administration.

[0298] The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0299] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19thedition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

[0300] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays canAttorney Docket No. ASET-044 / 001WO 325190-2251 include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0301] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0302] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow. EXAMPLES Example 1. Exemplary Study of Compound No.1B

[0303] An open-label, multicenter, Phase 0 / 1 trial of Compound No.1B in patients with EGFR alterations (Arm A) or recurrent rHGG with fusions (Arm B) who are scheduled for resection is performed. As described below, the trial is composed of a Phase 0 and an expansion Phase 1b component. Phase 0 Arms A and B:

[0304] The Phase 0 study includes treatment of recurrent HGG participants with Compound No.1B at ascending dose levels in Arm A.

[0305] To assess the PK and PD endpoints listed, blood, CSF and brain tumor tissue (gadolinium enhancing and non-enhancing tumor tissue will be collected and analyzed separately) are collected intraoperatively on Day 5 post-last Compound No. 1B dose. Additionally, blood samples are obtained on Day 5 at pre-dosing (trough level), 0.5, 1, 2, 4, 6, 8 and 24 hours post dose. (Note: 24 h blood sample on Day 6).

[0306] Arm A: Recurrent high-grade glioma participants with EGFR alterations in their archival tissue who are scheduled for resection are enrolled into two-time cohorts (Cohorts 1aAttorney Docket No. ASET-044 / 001WO 325190-2251 and 1b). The final presurgical dose is administered 2-4 hours or 7-9 hours before tumor resection.

[0307] The Optimal Time-Interval (OTI) is the surgical time interval (STI) from final presurgical dose to tumor resection to detect maximal unbound drug concentration in nonenhancing tumor. Once the OTI is determined, additional participants in ascending doses are enrolled at OTI in Arm A, either 2-4 hours or 7-9 hours after the last dose (Cohort 2).

[0308] The dose level for Arm B is selected based on the PK unbound drug concentration in nonenhancing tumor results from Arm A.

[0309] Arm B: Enrollment in Arm B begins after participants have been enrolled in Arm A and Optimal Time Interval (OTI) and optimal dose level has been determined. Recurrent HGG patients (n=10) with EGFR fusion are treated with Compound No. 1B for 5 days prior to surgical resection. Arms A and B: Pharmacokinetic (PK) Analysis

[0310] Total and unbound concentration of Compound No.1B in plasma, tumor enhancing and non-enhancing region as well as cerebrospinal fluid (CSF) are determined from the study. Tumor-to-plasma ratio is calculated.

[0311] A positive PK response is defined as unbound concentrations of Compound No.1B ≥ 5 x IC50 (18.5 nM) within the gadolinium-non-enhancing region of the tumor. Pharmacodynamics (PD) Analysis

[0312] To assess the PD endpoints, tumor tissue sections are slow freezing and formalin embedded. Formalin Fixed Paraffin Embedded (FFPE) tissue sections are stained for pEGFR and pERK expression using immunohistochemistry (IHC). Additional biomarkers includingAttorney Docket No. ASET-044 / 001WO 325190-2251 pS6, pAKT, ClCas3 and MIB-1 are performed in archival and surgical tumor tissue.

[0313] Retrospective single-cell RNA-seq analysis of tissue from Phase 0 and subsequent resections at recurrence are performed. Phase 1 Expansion Cohort:

[0314] Participants with tumors demonstrating PK-response continue the Expansion Cohort.

[0315] Arm A: Participants with tumors demonstrating PK response continue treatment with the same dose continuously in 28-day cycles after surgery. Participants receive Compound No. 1B until the progression of disease, unacceptable toxicity or death, withdrawal of consent, loss to follow-up, or study termination by sponsor.

[0316] Arm B: Patients with tumors that have a PK response in the Phase 0 component enter the therapeutic expansion phase of this study and receive Compound No.1B until progression of disease, unacceptable toxicity or death, withdrawal of consent, loss to follow-up, or study termination by sponsor. EQUIVALENTS

[0317] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference. The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.

Claims

Attorney Docket No. ASET-044 / 001WO 325190-2251 CLAIMS 1. A method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of Compound No.1:or a pharmaceutically acceptable salt thereof.

2. Compound No. 1, or a pharmaceutically acceptable salt thereof for treating or preventing cancer in a subject in need thereof.

3. Use of Compound No. 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof.

4. The method, compound, or use of any one of the preceding claims, wherein the cancer is glioma.

5. The method, compound, or use of any one of the preceding claims, wherein the cancer is high-grade glioma.

6. The method, compound, or use of any one of the preceding claims, wherein the cancer is high-grade glioma that expresses at least one oncogenic variant of EGFR.

7. The method, compound, or use of any one of the preceding claims, wherein the cancer is glioblastoma.

8. The method, compound, or use of any one of the preceding claims, wherein Compound No.1A, Compound No.1B, or the pharmaceutically acceptable salt thereof is administered.Attorney Docket No. ASET-044 / 001WO 325190-2251 9. The method, compound, or use of any one of the preceding claims, wherein Compound No.1A or the pharmaceutically acceptable salt thereof is administered.

10. The method, compound, or use of any one of the preceding claims, wherein Compound No.1B or the pharmaceutically acceptable salt thereof is administered.

11. The method, compound, or use of any one of the preceding claims, wherein the subject is a human.

12. The method, compound, or use of any one of the preceding claims, wherein Compound No.1 or the pharmaceutically acceptable salt thereof is administered once per day.

13. The method, compound, or use of any one of the preceding claims, wherein Compound No.1 or the pharmaceutically acceptable salt thereof is administered daily at a dosage of: about 100±20 mg, about 100±10 mg, about 100±5 mg, about 100±4 mg, about 100±3 mg, about 100±2 mg, or about 100±1 mg; about 150±20 mg, about 150±10 mg, about 150±5 mg, about 150±4 mg, about 150±3 mg, about 150±2 mg, or about 150±1 mg; about 200±20 mg, about 200±10 mg, about 200±5 mg, about 200±4 mg, about 200±3 mg, about 200±2 mg, or about 200±1 mg; about 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±1 mg.

14. The method, compound, or use of any one of the preceding claims, wherein Compound No.1 or the pharmaceutically acceptable salt thereof is administered daily at a dosage of about 100±20 mg, about 100±10 mg, about 100±5 mg, about 100±4 mg, about 100±3 mg, about 100±2 mg, or about 100±1 mg.

15. The method, compound, or use of any one of the preceding claims, wherein Compound No.1 or the pharmaceutically acceptable salt thereof is administered daily at a dosage of about 150±20 mg, about 150±10 mg, about 150±5 mg, about 150±4 mg, about 150±3 mg, about 150±2 mg, or about 150±1 mg.

16. The method, compound, or use of any one of the preceding claims, wherein CompoundAttorney Docket No. ASET-044 / 001WO 325190-2251 No.1 or the pharmaceutically acceptable salt thereof is administered daily at a dosage of about 200±20 mg, about 200±10 mg, about 200±5 mg, about 200±4 mg, about 200±3 mg, about 200±2 mg, or about 200±1 mg.

17. The method, compound, or use of any one of the preceding claims, wherein Compound No.1 or the pharmaceutically acceptable salt thereof is administered daily at a dosage of about 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±1 mg.

18. The method, compound, or use of any one of the preceding claims, wherein Compound No.1 or the pharmaceutically acceptable salt thereof is administered three times per week.

19. The method, compound, or use of any one of the preceding claims, wherein Compound No.1 or the pharmaceutically acceptable salt thereof is administered three times per week at a dosage of: about 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±1 mg; about 400±50 mg, about 400±40 mg, about 400±30 mg, about 400±20 mg, about 400±10 mg, about 400±5 mg, about 400±4 mg, about 400±3 mg, about 400±2 mg, or about 400±1 mg; or about 500±50 mg, about 500±40 mg, about 500±30 mg, about 500±20 mg, about 500±10 mg, about 500±5 mg, about 500±4 mg, about 500±3 mg, about 500±2 mg, or about 500±1 mg.

20. The method, compound, or use of any one of the preceding claims, wherein Compound No.1 or the pharmaceutically acceptable salt thereof is administered three times per week at a dosage of about 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±1 mg.

21. The method, compound, or use of any one of the preceding claims, wherein Compound No.1 or the pharmaceutically acceptable salt thereof is administered three times per week at a dosage of about 400±50 mg, about 400±40 mg, about 400±30 mg, about 400±20 mg, about 400±10 mg, about 400±5 mg, about 400±4 mg, about 400±3 mg, about 400±2 mg, or about 400±1 mg.Attorney Docket No. ASET-044 / 001WO 325190-2251 22. The method, compound, or use of any one of the preceding claims, wherein Compound No.1 or the pharmaceutically acceptable salt thereof is administered three times per week at a dosage of about 500±50 mg, about 500±40 mg, about 500±30 mg, about 500±20 mg, about 500±10 mg, about 500±5 mg, about 500±4 mg, about 500±3 mg, about 500±2 mg, or about 500±1 mg.

Images