Cancer treatment methods using alkyne-substituted quinazoline derivatives

Abstract

This disclosure relates to Compound 1: This disclosure relates to a method for treating or preventing cancer (e.g., advanced solid tumors) using JPEG2026530569000029.jpg42160 or a pharmaceutically acceptable salt thereof. The disclosure also relates to pharmaceutical compositions and pharmaceutical kits suitable for treatment or prevention.

Description

Technical Field

[0001] Cross-Reference to Related Applications This application claims priority and benefit to U.S. Provisional Patent Application No. 63 / 519,781, filed on August 15, 2023, which is hereby incorporated by reference in its entirety for all purposes.

[0002] Sequence Listing The content of the electronic sequence listing (ASET_044_001WO_SeqListing_ST26.xml; size: 14,516 bytes; and date of creation: August 13, 2024) is hereby incorporated by reference in its entirety.

Background Art

[0003] Mutations affecting the intracellular catalytic domain or extracellular ligand binding domain of ErbB receptors can give rise to oncogenic activity (the ErbB protein family consists of four members, including ErbB-1, also referred to as epidermal growth factor receptor (EGFR), and ErbB-2, also referred to as HER2 in humans). ErbB inhibitors are known therapeutics for several cancers. However, not all patients respond satisfactorily to this treatment. Therefore, there has been a long-felt need in the art for novel therapies that can address the varying responsiveness of cancer patients to known treatments. The present disclosure provides compositions and methods for preventing or treating cancer in patients harboring these oncogenic ErbB mutations, wherein varied responses are not observed when patients with these ErbB variants are treated with existing standard therapies.

Summary of the Invention

Means for Solving the Problem

[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 1, or a pharmaceutically acceptable salt thereof.

[0005] In some embodiments, the Disclosure provides Compound 1, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject in need thereof.

[0006] In some embodiments, the Disclosure provides the use of Compound 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for treating or preventing cancer in a subject in need thereof.

[0007] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which this disclosure pertains. In this specification, the singular form includes the plural form unless the context clearly indicates otherwise. Methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this disclosure, but preferred methods and materials are described below. All publications, patent applications, patents, and other references referenced herein are incorporated by reference. References cited herein do not constitute prior art to the claimed invention. In case of any conflict, this specification, including definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative and not intended to limit the scope. In case of any conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0008] Other features and advantages of this disclosure will become apparent from the following detailed description and claims. [Modes for carrying out the invention]

[0009] As used herein, the term "Compound 1" refers to a compound having the following structure: [ka]

[0010] As used herein, the term "Compound 1A" refers to a compound having the following structure. [ka]

[0011] As used herein, the term "compound 1B" refers to a compound having the following structure. [ka]

[0012] Methods and Uses of This Disclosure In some embodiments, the Disclosure provides a method for treating or preventing cancer (e.g., treatment) in a subject in need thereof, comprising administering a pharmaceutically effective amount of compound 1 (e.g., compound 1A or compound 1B), or a pharmaceutically acceptable salt thereof, to the subject three times a week.

[0013] In some embodiments, the Disclosure provides compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof for treating or preventing cancer (e.g., treatment) in a subject in need thereof.

[0014] In some embodiments, the Disclosure provides the use of Compound 1 (e.g., Compound 1A or Compound 1B) or a pharmaceutically acceptable salt thereof in the manufacture of a drug for treating or preventing cancer (e.g., treatment) in a subject in need thereof.

[0015] In some embodiments, compound 1A, compound 1B, or a pharmaceutically acceptable salt thereof is administered.

[0016] In some embodiments, compound 1A or a pharmaceutically acceptable salt thereof is administered.

[0017] In some embodiments, compound 1B or a pharmaceutically acceptable salt thereof is administered.

[0018] Suitable subjects and diseases In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is an adult (e.g., 18 years of age or older).

[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 present disclosure inhibit or modulate the activity of receptor tyrosine kinases, particularly extracellular variants of ErbB receptors, including but not limited to EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-A289V and EGFR-G598V, as well as HER2-S310F. Accordingly, the compounds and compositions of the present disclosure may be useful as medicaments, i.e., as medicaments in therapy, more specifically as medicaments for preventing or treating cancer, as detailed below. Therefore, in a further aspect, the present disclosure provides a method for preventing or treating cancer in a mammal, e.g., a human, suffering from cancer, as detailed below.

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

[0022] In some embodiments, the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, lung cancer, 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 a methylated glioblastoma. In some embodiments, the cancer is a non-methylated glioblastoma.

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

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

[0033] In some embodiments, the cancer is glioblastoma, and the cancer, or tumor or its cells, express at least one oncogenic variant of EGFR.

[0034] In some embodiments, the cancer is relapsing glioblastoma, and the cancer, or tumor or its cells, express at least one oncogenic variant of EGFR.

[0035] In some embodiments, the cancer is recurrent glioblastoma, and the cancer, or tumor or its cells, express 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 recurrent non-small cell lung cancer (NSCLC).

[0040] In some embodiments, the cancer is NSCLC, and the cancer, or tumor or its cells, express at least one oncogenic variant of EGFR.

[0041] In some embodiments, the cancer is recurrent NSCLC, and the cancer, or tumor or its cells, express at least one oncogenic variant of EGFR.

[0042] In some embodiments, the cancer is relapsing NSCLC, and the cancer, or tumor or its cells, express 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 progressive or metastatic NSCLC, and the cancer, or tumor or its cells, express at least one oncogenic variant of EGFR.

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

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

[0047] In some embodiments, the cancer is progressive or metastatic NSCLC, and the cancer, or tumor or its cells, express at least one oncogenic variant of EGFR, and the cancer has not metastasized to the central nervous system (CNS).

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

[0049] In some embodiments, the cancer is NSCLC, and this cancer has metastasized to the cerebrospinal fluid (CSF).

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

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

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

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

[0054] In some embodiments, the subjects suffer from central nervous system (CNS) disorders.

[0055] In some embodiments, the subjects do not have CNS disease.

[0056] In some embodiments, the subjects suffer from piatric disease.

[0057] In some embodiments, the subjects do not suffer from piatric disease.

[0058] In some embodiments, the cancer is NSCLC, and the subject suffers from pallial disease.

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

[0060] In some embodiments, cancer, or tumors or their cells, express oncogenic variants of the ErbB receptor.

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

[0062] As will be understood by those skilled in the art, in the context of a gene (e.g., a gene encoding the ErbB receptor), oncogenic mutations include, but are not limited to, mutations resulting in the substitution of one amino acid for another at a specific site within the ErbB receptor, mutations resulting in the insertion of one or more amino acids between two sites within the ErbB receptor, mutations resulting in the deletion of one or more amino acids between two sites within the ErbB receptor, and mutations resulting in the fusion of the ErbB receptor or a part thereof with another protein or a part thereof. As will be understood by those skilled in the art, in the context of a gene, oncogenic mutations may include, but are not limited to, missense mutations, nonsynonymous mutations, insertions of one or more nucleotides, deletions of one or more nucleotides, inversions, and deletion-insertions.

[0063] As will be understood by those skilled in the art, in the context of proteins (e.g., the ErbB receptor), oncogenic mutations include, but are not limited to, substitution of one amino acid for another at a specific site within the ErbB receptor, insertion of one or more amino acids between two sites within the ErbB receptor, deletion of one or more amino acids between two sites within the ErbB receptor, and fusion of the ErbB receptor or a part thereof with another protein or a part thereof.

[0064] In some embodiments, oncogenic variants of the ErbB receptor include allosteric mutations.

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

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

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

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

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

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

[0071] In some embodiments, cancer, or tumors or their cells, express oncogenic variants of the epidermal growth factor receptor (EGFR).

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

[0073] In some embodiments, oncogenic variants of EGFR include allosteric mutations.

[0074] In some embodiments, cancer, or tumors or their cells, express oncogenic variants of the 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, oncogenic variants of the HER2 receptor include allosteric mutations.

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

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

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

[0080] In some embodiments, the oncogenic variant of EGFR includes the substitution of arginine (R) at position 108 of sequence 1 with lysine (K).

[0081] In some embodiments, oncogenic variants of EGFR include substitution of arginine (R) with cysteine ​​(C) at position 222 of sequence 1.

[0082] In some embodiments, the oncogenic variant of EGFR includes a substitution of alanine (A) with threonine (T) at position 289 of sequence 1.

[0083] In some embodiments, oncogenic variants of EGFR include substitution of alanine (A) with valine (V) at position 289 of sequence 1.

[0084] In some embodiments, oncogenic variants of EGFR include substitution of glycine (G) with valine (V) at position 598 of sequence 1.

[0085] In some embodiments, oncogenic variants of EGFR include substitution of cysteine ​​(C) at position 231 of sequence 1 with phenylalanine (F).

[0086] In some embodiments, the oncogenic variant of EGFR includes serine substitution of cysteine ​​at position 595 of sequence 1.

[0087] In some embodiments, oncogenic variants of EGFR include substitution of glycine (G) with valine (V) at position 598 of sequence 1.

[0088] In some embodiments, oncogenic variants of EGFR include the substitution of serine (S) of cysteine ​​(C) at position 645 of sequence 1.

[0089] In some embodiments, the oncogenic variant of EGFR comprises a substitution of glycine (G) at position 719 of sequence 1, the substitution being selected from cysteine ​​(C), aspartate (D), arginine (R), serine (S), or alanine (A).

[0090] In some embodiments, oncogenic variants of EGFR include the substitution of glycine (G) at position 719 of sequence 1 with serine (S).

[0091] In some embodiments, oncogenic variants of EGFR include the substitution of cysteine ​​(C) at position 797 of sequence 1 with serine (S).

[0092] In some embodiments, cancer, or tumors or their cells, express an oncogenic variant of EGFR, which is an allosteric variant of EGFR, and the oncogenic variant of EGFR includes a structural modification of EGFR, which can form a covalent dimer, which is constitutively active, and which enhances the activity of EGFR upon contact with a type I ErbB inhibitor. In some embodiments, the structural modification of EGFR includes one or more modifications of the nucleic acid sequence, amino acid sequence, secondary structure, tertiary structure, and quaternary structure. In some embodiments, the oncogenic variant includes mutation, splicing events, posttranslational processes, conformational changes, or any combination thereof. In some embodiments, the structural modification of EGFR occurs within the first cysteine-rich (CR1) region and / or the second cysteine-rich (CR2) region of EGFR. In some embodiments, the first cysteine-rich (CR1) region and / or the second cysteine-rich (CR2) region of EGFR comprises amino acid residues T211-R334 and / or C526-S645 of sequence 1, respectively. In some embodiments, the oncogenic variant of EGFR generates a physical barrier to the formation of disulfide bonds within the CR1 and / or CR2 regions. In some embodiments, the oncogenic variant of EGFR removes the physical barrier to the formation of disulfide bonds within the CR1 and / or CR2 regions. In some embodiments, the oncogenic variant of EGFR comprises one or more free or unpaired cysteine ​​(C) residues located at the dimer interface of EGFR.In some embodiments, the oncogenic variants of EGFR are C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333 of sequence 1. The site contains one or more free or unpaired cysteine ​​(C) residues selected from the group consisting of C506-C515, C510-C523, C526-C535, C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628, and C624-C636. In some embodiments, the modification occurs within 10 angstroms 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 of sequence 1.

[0093] In some embodiments, cancer, or tumors or their cells express an oncogenic variant of EGFR, the oncogenic variant of EGFR being a mutation of EGFR, and the nucleotide sequence encoding the oncogenic variant of EGFR containing a deletion or substitution containing one or more amino acids encoding an adenosine triphosphate (ATP) binding site. In some embodiments, the ATP binding site contains amino acids E746-A750 of sequence 1. In some embodiments, the ATP binding site or its deletion or substitution contains L858 of sequence 1. In some embodiments, the deletion contains L858 of sequence 1. In some embodiments, leucine (L) at position 858 of sequence 1 is substituted with arginine (R) (L858R).

[0094] In some embodiments, cancer, or tumors or their cells, express an oncogenic variant of EGFR, which is an allosteric variant of EGFR, and the nucleotide sequence encoding the oncogenic variant of EGFR includes an insertion within the sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof includes the sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7). In some embodiments, the sequence encoding exon 20 or a portion thereof includes the sequence encoding a C helix, the end of a C helix, or a loop following a C helix. In some embodiments, the insertion includes the amino acid sequence ASV, SVD, NPH, or FQEA. In some embodiments, the sequence encoding exon 20 or a portion thereof is: (a) insertion of amino acid sequence ASV between positions V769 and D770 of sequence 1; (b) insertion of amino acid sequence SVD between positions D770 and N771 of sequence 1; (c) insertion of amino acid sequence NPH between positions H773 and V774 of sequence 1; (d) insertion of amino acid sequence FQEA between positions A763 and Y764 of sequence 1; (e) insertion of amino acid sequence PH between positions H773 and V774 of sequence 1; (f) insertion of amino acid G between positions D770 and N771 of sequence 1; (g) insertion of amino acid H between positions H773 and V774 of sequence 1; (h) insertion of amino acid sequence HV between positions V774 and C775 of sequence 1; (i) insertion of amino acid H773 and V (j) Insertion of amino acid sequence AH between positions 774; (k) Insertion of amino acid sequence SVA between positions A767 and S768 of sequence 1; (l) Substitution of amino acid sequence GYN between positions 770 and 771 of sequence 1; (m) Insertion of amino acid H between positions N771 and P772 of sequence 1; (n) Insertion of amino acid Y between positions H773 and V774 of sequence 1; (o) Substitution of amino acid sequence YNPY at position 773 of sequence 1; (p) Insertion of amino acid sequence DNP between positions P772 and H773 of sequence 1; (q) Insertion of amino acid sequence VDS between positions S768 and V769 of sequence 1; (r) Insertion of amino acid H between positions D770 and N771 of sequence 1;(s) Insertion of amino acid N between positions N771 and P772 of sequence 1; (t) Insertion of amino acid sequence PNP between positions P772 and H773 of sequence 1; (u) Substitution of DN between positions 770 and 771 of sequence 1 with amino acid sequence GSVDN; (v) Substitution of NP between positions 771 and 772 of sequence 1 with amino acid sequence GYP; (w) Insertion of amino acid G between positions N771 and P772 of sequence 1; (x) Insertion of amino acid sequence GNP between positions P772 and H773 of sequence 1; (y) Insertion of amino acid sequence GSV between positions V769 and D770 of sequence 1; (z) Substitution of VC between positions 774 and 775 of sequence 1 with amino acid sequence GNPHVC; (aa) Insertion of amino acid sequence LQEA between positions A763 and Y764 of sequence 1; (bb) Sequence 1 (cc) Insertion of amino acid sequence GL between D770 and N771 of sequence 1; (dd) Insertion of amino acid sequence NPY between H773 and V774 of sequence 1; (ee) Insertion of amino acid sequence TH between H773 and V774 of sequence 1; (ff) Substitution of NP between 771 and 772 of sequence 1 with amino acid sequence KGP; (gg) Substitution of NP between 771 and 772 of sequence 1 with amino acid sequence SVDNP; (hh) Insertion of amino acid sequence NN between N771 and P772 of sequence 1; (ii) Insertion of amino acid T between N771 and P772 of sequence 1; and (jj) Substitution of SV between 768 and 769 of sequence 1 with amino acid sequence STLASV.

[0095] In some embodiments, oncogenic variants of EGFR may have one or more mutations in exon 18.

[0096] In some embodiments, oncogenic variants of EGFR may have one or more mutations in exon 19.

[0097] In some embodiments, oncogenic variants of EGFR may have one or more mutations in exon 20.

[0098] In some embodiments, cancer, or tumors or their cells, express an oncogenic variant of EGFR, which is an allosteric variant of EGFR.

[0099] In some embodiments, the oncogenic variant of EGFR may 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-C62 0Y, 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 variants of EGFR are 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, and EGFR-P59. 6S, EGFR-P596L, EGFR-P596R, EGFR-G598V, EGFR-G598A, EGFR-G614D, EGFR-C620Y, EGFR-C614W, EGFR-C628F, EGFR-C6 28Y, EGFR-C636Y, EGFR-S645C, EGFR-Δ660, EGFR-Δ768, EGFR-V689M, EGFR-N700D, EGFR-E709K, EGFR-E709Q, EGFR-E70 9A, EGFR-E709G, EGFR-E709V, EGFR-S768I, EGFR-C231F, EGFR-C595S, EGFR-D761Y, EGFR-L718Q, EGFR-G719C, EGFR-G7 19D, EGFR-G719R, EGFR-G719A, EGFR-G719S, EGFR-G724S, EGFR-L858R, EGFR-L858R+C797S, EGFR-L861Q, EGFR-E746-A Select from 750del, 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 includes an insertion within exon 20, the insertion comprising the amino acid sequence of ASV, SVD, NPH, or FQEA.

[0102] In some embodiments, the oncogenic variant of EGFR includes an insertion in exon 20, and the insertion in exon 20 is selected from the group of insertions listed in Table 1.

[0103] [Table 1]

[0104] [Table 2]

[0105] In some embodiments, the oncogenic variant of EGFR includes substitution within exon 20 of EGFR.

[0106] In some embodiments, the oncogenic variant of EGFR includes a substitution in exon 20, and the substitution in exon 20 is selected from the group of substitutions listed in Table 2.

[0107] [Table 3]

[0108] In some embodiments, the oncogenic variant of EGFR may be any of the EGFR variants shown in Table 3.

[0109] [Table 4]

[0110] In some embodiments, Δ19 may include a deletion of residues E746-A750 of EGFR (sequence 1).

[0111] In some embodiments, cancer, or tumors or their cells, (a) express one or more wild-type human epidermal growth factor receptor 2 (HER2) receptors or oncogenic variants of the HER2 receptor.

[0112] In some embodiments, cancer, or tumors or their cells express a wild-type HER2 receptor, the wild-type HER2 receptor comprising the amino acid sequence of SEQ ID NOs: 2, 3, 4, 5, or 6.

[0113] In some embodiments, cancer, or tumors or their cells, express an oncogenic variant of the HER2 receptor, and this oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[0114] In some embodiments, cancer, or tumors or their cells, express an oncogenic variant of the HER2 receptor, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes the substitution of serine (S) at position 310 of SEQ ID NO: 2 or 5 with phenylalanine (F).

[0115] In some embodiments, cancer, or tumors or their cells express an oncogenic variant of the HER2 receptor, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes a tyrosine (Y) substitution of serine (S) at position 310 of SEQ ID NO: 2 or 5.

[0116] In some embodiments, cancer, or tumors or their cells express an oncogenic variant of the HER2 receptor, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes a glutamine (Q) substitution of arginine (R) at position 678 of SEQ ID NO: 2 or 5.

[0117] In some embodiments, cancer, or tumors or their cells express an oncogenic variant of the HER2 receptor, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes a leucine (L) substitution of valine (V) at position 777 of SEQ ID NO: 2 or 5.

[0118] In some embodiments, cancer, or tumors or their cells, express an oncogenic variant of the HER2 receptor, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes a methionine (M) substitution of valine (V) at position 777 of SEQ ID NO: 2 or 5.

[0119] In some embodiments, cancer, or tumors or their cells express an oncogenic variant of the HER2 receptor, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes isoleucine (I) substitution of valine (V) at position 842 of SEQ ID NO: 2 or 5.

[0120] In some embodiments, cancer, or tumors or their cells express an oncogenic variant of the HER2 receptor, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes a substitution of leucine (L) with alanine (A) at position 755 of SEQ ID NO: 2 or 5.

[0121] In some embodiments, cancer, or tumors or their cells express an oncogenic variant of the HER2 receptor, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes a proline (P) substitution of leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[0122] In some embodiments, cancer, or tumors or their cells express an oncogenic variant of the HER2 receptor, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes a serine (S) substitution of leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[0123] In some embodiments, cancer, or tumors or their cells, express an oncogenic variant of the HER2 receptor, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the nucleotide sequence encoding the oncogenic variant of the HER2 receptor includes an insertion within the sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof includes the sequence encoding KEILDEAYVMAGVGSPYVSR (SEQ ID NO: 8). In some embodiments, the sequence encoding exon 20 or a portion thereof includes a sequence encoding a C helix, the end of a C helix, or a loop following a C helix. In some embodiments, the insertion includes the amino acid sequence of GSP or YVMA. In some embodiments, the sequence encoding exon 20 or a portion thereof may be: (a) insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (b) insertion of the amino acid sequence GSP between positions P780 and Y781 of SEQ ID NO: 2; (c) insertion of the amino acid sequence YVMA between positions A771 and Y772 of SEQ ID NO: 2; (d) insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (e) insertion of amino acid V between positions V777 and G778 of SEQ ID NO: 2; (f) insertion of amino acid V between positions V777 and G778 of SEQ ID NO: 2; (g) substitution of GV between positions 776 and 777 of SEQ ID NO: 2 with the amino acid sequence AVGCV; (h) substitution of G between positions 776 of SEQ ID NO: 2 with the amino acid sequence LC. (i) Substitution of G between positions 776 and 776 of SEQ ID NO: 2 with amino acid sequence LCV; (j) Insertion of amino acid sequence GSP between positions V777 and G778 of SEQ ID NO: 2; (k) Substitution of LRE between positions 755 and 757 of SEQ ID NO: 2 with amino acid sequence PS; (l) Substitution of SP between positions 779 and 780 of SEQ ID NO: 2 with amino acid sequence CPGSP; (m) Insertion of amino acid C between positions V777 and G778 of SEQ ID NO: 2; (n) Substitution of AG between positions 775 and 776 of SEQ ID NO: 2 with amino acid sequence VVMA; (o) Substitution of G at position 776 of SEQ ID NO: 2 with amino acid sequence VV; (p) Substitution of GV between positions 776 and 777 of SEQ ID NO: 2 with amino acid sequence AVCV; (q) Substitution of GV between positions 776 and 777 of SEQ ID NO: 2 with amino acid sequence VCV;(r) Insertion of amino acid G between position G778 and S779 of SEQ ID NO: 2; (s) Substitution of LRE at positions 755-757 of SEQ ID NO: 2 with amino acid sequence PK; (t) Insertion of amino acid V between position A775 and G776 of SEQ ID NO: 2; (u) Insertion of amino acid sequence YAMA between position A775 and G776 of SEQ ID NO: 2; (v) Substitution of G at position 776 of SEQ ID NO: 2 with amino acid sequence CV; (w) Substitution of GVG at positions 776-778 of SEQ ID NO: 2 with amino acid sequence AVCGG; (x) SEQ ID NO: 2 (y) Substitution of the amino acid sequence of GVG in SEQ ID NO: 2 by CVCG; (z) Substitution of the amino acid sequence of GVG at positions 776-778 in SEQ ID NO: 2 by VVVG; (aa) Substitution of the amino acid sequence of GVGS at positions 776-779 in SEQ ID NO: 2 by VVGES; (bb) Substitution of the amino acid sequence of GV at positions 776 and 777 in SEQ ID NO: 2 by AVGSGV; (cc) Substitution of the amino acid sequence of GV at positions 776 and 777 in SEQ ID NO: 2 by CVC; (dd) SEQ ID NO: 2 (ee) Substitution of amino acid sequence HVC in GV at positions 776 and 777 of SEQ ID NO: 2; (ff) Substitution of amino acid sequence VAGV in GV at positions 776 and 777 of SEQ ID NO: 2; (gg) Substitution of amino acid sequence VVV in GV at positions 776 and 777 of SEQ ID NO: 2; (hh) Insertion of amino acid sequence FPG between G778 and S779 of SEQ ID NO: 2; (ii) Insertion of amino acid sequence GS between S779 and P780 of SEQ ID NO: 2; (jj) Sequence number This includes one or more of the following: (kk) substitution of the VLRE amino acid sequence VPS at positions 754-757 of sequence number 2; (ll) insertion of amino acid E between positions V777 and G778 of sequence number 2; (mm) insertion of amino acid S between positions V777 and G778 of sequence number 2; (nn) insertion of amino acid S between positions V777 and G778 of sequence number 2; and (oo) insertion of amino acid LMAY between positions Y772 and V773 of sequence number 2.

[0124] In some embodiments, cancer, or tumors or their cells express an oncogenic variant of the HER2 receptor, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes HER2-Δ16, HER2-C311R, HER2-S310F, p95-HER2-M611, or any combination thereof.

[0125] In some embodiments, the oncogenic variant of HER2 includes an insertion within exon 20, the insertion containing an amino acid sequence of GSP or YVMA.

[0126] In some embodiments, the oncogenic variant of HER2 includes an insertion in exon 20, and the insertion in exon 20 is selected from the group of insertions listed in Table 4.

[0127] [Table 5]

[0128] In some embodiments, the oncogenic variant of HER2 includes substitution within exon 20 of HER2.

[0129] In some embodiments, the oncogenic variant of EGFR includes a substitution in exon 20, and the substitution in exon 20 is selected from the group of substitutions listed in Table 5.

[0130] [Table 6]

[0131] In some embodiments, the oncogenic variant of HER2 is one of the HER2 variants shown in Table 6.

[0132] [Table 7]

[0133] In some embodiments, cancer, or tumors or their cells, express oncogenic variants of the HER3 receptor. In some embodiments, the oncogenic variant of HER3 is one of the variants shown in Table 7.

[0134] [Table 8]

[0135] In some embodiments, cancer, or tumors or their cells, express an oncogenic variant of the 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 the HER4 receptor includes a deletion of exon 16 (HER4-Δ16).

[0136] In some embodiments, cancer, tumors, or their cells express an oncogenic variant of EGFR, the sequence encoding the oncogenic variant of EGFR includes a deletion of exon 20 or a portion thereof, and the cancer, tumors, or their cells do not contain a second oncogenic mutation in any sequence of EGFR other than exon 20. In some embodiments, the second oncogenic mutation includes a sequence encoding one or more of the EGFR kinase domain (KD), BRAF, NTRK, and KRAS.

[0137] In some embodiments, cancer, tumors, or their cells express an oncogenic variant of EGFR, the sequence encoding the oncogenic variant of EGFR includes a deletion of exon 20 or a portion thereof, and the cancer, tumors, or their cells do not contain markers indicating responsiveness to immunotherapy.

[0138] In some embodiments, oncogenic variants (e.g., allosteric variants) or oncogenic mutations (e.g., allosteric mutations) are detected by diagnostics approved by the U.S. Food and Drug Administration (FDA).

[0139] In some embodiments, cancer, or tumors or their cells express an oncogenic variant of phosphatidylinositol-3-kinase (PI3K). In some embodiments, cancer, or tumors or their cells express a mutant of PI3K, which differs from the wild-type sequence of PI3K. In some embodiments, the cancer is glioblastoma, and the cancer, or tumors or their cells express an oncogenic variant of PI3K. In some embodiments, glioblastoma, and the cancer, or tumors or their cells express a mutant of PI3K, which differs from the wild-type sequence of PI3K.

[0140] It is understood that PI3K oncogenic variants are PI3K proteins that contain at least one oncogenic mutation and are produced as a result of the expression of the gene encoding PI3K containing at least one oncogenic mutation.

[0141] As will be understood by those skilled in the art, in the context of a gene (e.g., a gene encoding PI3K), oncogenic mutations include, but are not limited to, mutations resulting in the substitution of one amino acid for another at a specific site in the PI3K receptor, mutations resulting in the insertion of one or more amino acids between two sites in PI3K, mutations resulting in the deletion of one or more amino acids between two sites in PI3K, and mutations resulting in the fusion of PI3K or a part thereof with another protein or a part thereof. As will be understood by those skilled in the art, in the context of a gene, oncogenic mutations may include, but are not limited to, missense mutations, nonsynonymous mutations, insertions of one or more nucleotides, deletions of one or more nucleotides, inversions, and deletion-insertions.

[0142] As will be understood by those skilled in the art, in the context of proteins (e.g., PI3K receptors), oncogenic mutations include, but are not limited to, substitution of one amino acid with another at a specific position within PI3K, insertion of one or more amino acids between two positions within PI3K, deletion of one or more amino acids between two positions within PI3K, and fusion of PI3K or a portion thereof with another protein or a portion thereof. In some embodiments, cancer, or its tumors or cells, have amplification of the MET gene encoding the receptor tyrosine kinase c-MET (also referred to as MET).

[0143] In some embodiments, the cancer is glioblastoma, and the cancer, or its tumor or cells, express EGFR-vIII. In some embodiments, the cancer is glioblastoma, and the cancer, or its tumor or cells, express EGFR-vII. In some embodiments, the cancer is glioblastoma, and the cancer, or its tumor or cells, express EGFR-vVI. In some embodiments, the cancer is glioblastoma, and the cancer, or its tumor or cells, express EGFR-R108K. In some embodiments, the cancer is glioblastoma, and the cancer, or its tumor or cells, express EGFR-R222C. In some embodiments, the cancer is glioblastoma, and the cancer, or its tumor or cells, express EGFR-C231F. In some embodiments, the cancer is glioblastoma, and the cancer, or its tumor or cells, express EGFR-A289T. In some embodiments, the cancer is glioblastoma, and the cancer, or its tumor or cells, express EGFR-A289V. In some embodiments, the cancer is glioblastoma, and the cancer, or its tumor or cells, express EGFR-C595S. In some embodiments, the cancer is glioblastoma, and the cancer, or its tumor or cells, express EGFR-G598V. In some embodiments, the cancer is glioblastoma, and the cancer, or its tumor or cells, express EGFR-S645C.

[0144] In some embodiments, the cancer is NSCLC, and the cancer, or its tumor or cells, express EGFR-C797S. In some embodiments, the cancer is NSCLC, and the cancer, or its tumor or cells, express EGFR-G719S. In some embodiments, the cancer is progressive and / or metastatic NSCLC, and the cancer, or its tumor or cells, express EGFR-C797S. In some embodiments, the cancer is progressive and / or metastatic NSCLC, and the cancer, or its tumor or cells, express EGFR-G719S. In some embodiments, the cancer is NSCLC, and the cancer, or its tumor or cells, express EGFR-C797S, and the cancer, or its tumor or cells, are insensitive to or resistant to treatment with therapeutic agents other than the compounds of this disclosure (e.g., osimertinib or razertinib). In some embodiments, the cancer is NSCLC, and the cancer, or its tumor or cells, express EGFR-C797S as a resistance mechanism, and the cancer, or its tumor or cells, are insensitive to or resistant to treatment with therapeutic agents other than the compounds of the Disclosure (e.g., osimertinib or razertinib).

[0145] In some embodiments, the deletion of exon 19 may include deletions of E746-A750 (EGFR-E746-A750del).

[0146] In some embodiments, the cancer is NSCLC, and the cancer, or its tumor or cells, express an oncogenic variant of EGFR containing a deletion of exon 19. In some embodiments, the deletion of exon 19 may include a deletion of E746-A750 (EGFR-E746-A750del).

[0147] In some embodiments, the cancer is NSCLC, and the cancer, or its tumor or cells, express an oncogenic variant of EGFR containing an exon 19 deletion + C797S. In some embodiments, the exon 19 deletion is an E746-A750 deletion (EGFR-E746-A750del).

[0148] In some embodiments, the cancer is NSCLC, and the cancer, or its tumor or cells, express an oncogenic variant of EGFR containing an exon 19 deletion + C797S, and the cancer, or its tumor or cells, are insensitive to or resistant to treatment with therapeutic agents other than the compounds of the Disclosure (e.g., osimertinib or razertinib). In some embodiments, the exon 19 deletion is an E746-A750 deletion (EGFR-E746-A750del). In some embodiments, the cancer is NSCLC, and the cancer, or its tumor or cells, express EGFR-L858R.

[0149] In some embodiments, cancer is NSCLC, and cancer, or its tumor or cells, express EGFR-C797S+L858R.

[0150] In some embodiments, the cancer is NSCLC, the cancer, or its tumor or cells express EGFR-C797S+L858R, and the cancer, or its tumor or cells are insensitive to or resistant to treatment with therapeutic agents other than the compounds of the Disclosure (e.g., osimertinib or razertinib).

[0151] In some embodiments, the cancer is NSCLC, and the cancer, or its tumor or cells, express an oncogenic variant of EGFR containing an oncogenic mutation in exon 18.

[0152] In some embodiments, the cancer is NSCLC, and the cancer, or its tumor or cells, express EGFR-G719C, EGFR-G719D, EGFR-G719R, EGFR-G719A, or EGFR-G719S.

[0153] In some embodiments, the cancer is NSCLC, and the cancer, or its tumor or cells, express EGFR-G719C, EGFR-G719D, EGFR-G719R, EGFR-G719A, EGFR-G719S, EGFR-S768I, EGFR-V769L, EGFR-E709G, EGFR-E709A, EGFR-D716Y, or any combination thereof.

[0154] In some embodiments, cancer is NSCLC, and cancer, or its tumor or cells, express EGFR-S768I.

[0155] In some embodiments, cancer is NSCLC, and cancer, or its tumor or cells, express EGFR-L861Q.

[0156] In some embodiments, the cancer is NSCLC, and the cancer, or its tumor or cells, have amplification of the MET gene.

[0157] In some embodiments, the subject has not undergone any surgery to treat cancer prior to treatment with the compounds of this disclosure.

[0158] In some embodiments, the subject has undergone one or more surgeries to treat cancer prior to treatment with the compounds of the present disclosure.

[0159] In some embodiments, prior to treatment with the compounds of this disclosure, the subject is either untreated or has undergone one cycle of chemoradiotherapy.

[0160] In some embodiments, prior to treatment with the compounds of this disclosure, the subject is either untreated or has undergone one cycle of chemoradiotherapy.

[0161] In some embodiments, the subject has received at least one chemoradiotherapy treatment prior to treatment with the compounds of the present disclosure.

[0162] In some embodiments, the subjects have recurrent GBM, have undergone one or more surgeries previously, and have received at least one chemoradiotherapy.

[0163] In some embodiments, the subject has been treated with a therapeutic agent different from the compound of the disclosure prior to treatment with the compound of the disclosure.

[0164] In some embodiments, cancer, or tumors or their cells, are insensitive to or resistant to treatment with third-generation EGFR inhibitors.

[0165] In some embodiments, cancer, or tumors or their cells, are insensitive to or resistant to treatment with EGFR inhibitors other than those of the compounds of this disclosure.

[0166] A non-exclusive and non-restrictive list of third-generation EGFR inhibitors includes afatinib, abitinib, dacomitinib, erlotinib, gefitinib, razertinib, mavelertinib, nacotinib, nazartinib, olmutinib, osimertinib, and rosiletinib.

[0167] In some embodiments, cancer, or tumors or their cells, are insensitive to or resistant to treatment with one or more of the following: afatinib, abitinib, dacomitinib, erlotinib, gefitinib, razertinib, mavelertinib, nacotinib, nazartinib, olmutinib, osimertinib, and rosiletinib.

[0168] In some embodiments, cancer, or tumors or their cells, are insensitive to or resistant to treatment with osimertinib or razertinib.

[0169] In some embodiments, the cancer is NSCLC and is insensitive to or resistant to treatment with third-generation EGFR inhibitors. In some embodiments, the cancer is NSCLC and is insensitive to or resistant to treatment with third-generation EGFR inhibitors in combination with platinum-containing chemotherapy.

[0170] In some embodiments, the cancer is NSCLC and is insensitive to or resistant to treatment with a third-generation EGFR inhibitor, and the cancer, or its tumor or cells, express at least one oncogenic variant of EGFR. In some embodiments, the cancer is NSCLC and is insensitive to or resistant to treatment with a third-generation EGFR inhibitor in combination with platinum-containing chemotherapy, and the cancer, or its tumor or cells, express at least one oncogenic variant of EGFR. In some embodiments, the oncogenic variant of EGFR may be EGFR-C797S, EGFR-L861Q, EGFR-G719C, EGFR-G719D, EGFR-G719R, EGFR-G719A, EGFR-G719S, EGFR-S768I, or EGFR-V769L.

[0171] In some embodiments, the cancer is advanced and / or metastatic NSCLC and is insensitive to or resistant to treatment with third-generation EGFR inhibitors. In some embodiments, the cancer is advanced and / or metastatic NSCLC and is insensitive to or resistant to treatment with third-generation EGFR inhibitors in combination with platinum-containing chemotherapy.

[0172] In some embodiments, the cancer is advanced and / or metastatic NSCLC and is insensitive to or resistant to treatment with third-generation EGFR inhibitors, and the cancer, or its tumor or cells, express at least one oncogenic variant of EGFR. In some embodiments, the cancer is advanced and / or metastatic NSCLC and is insensitive to or resistant to treatment with third-generation EGFR inhibitors in combination with platinum-containing chemotherapy, and the cancer, or its tumor or cells, express at least one oncogenic variant of EGFR. In some embodiments, the oncogenic variant of EGFR may be EGFR-C797S, EGFR-L861Q, EGFR-G719C, EGFR-G719D, EGFR-G719R, EGFR-G719A, EGFR-G719S, EGFR-S768I, or EGFR-V769L.

[0173] In some embodiments, cancer is insensitive to or resistant to treatment with one or more of the following: afatinib, abitinib, dacomitinib, erlotinib, gefitinib, razertinib, mabelerutinib, nacotinib, nazartinib, olmutinib, osimertinib, and rosiletinib.

[0174] In some embodiments, the cancer is NSCLC, which is insensitive to or resistant to treatment with osimertinib or razertinib.

[0175] In some embodiments, cancer, or tumors or their cells are insensitive to or resistant to treatment with therapeutic agents other than the compounds of the Disclosure. In some embodiments, cancer, or tumors or their cells are insensitive to or resistant to treatment with type I inhibitors. In some embodiments, cancer, or tumors or their cells are insensitive to or resistant to treatment with one or more of gefitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, peritinib, WZ4002, WZ8040, WZ3146, CO-1686, and AZD9291.

[0176] In some embodiments, subjects exhibit adverse reactions to treatment with therapeutic agents other than the compounds of this disclosure. In some embodiments, subjects exhibit adverse reactions to treatment with type I inhibitors. In some embodiments, subjects exhibit adverse reactions to treatment with one or more selected from gefitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, peritinib, WZ4002, WZ8040, WZ3146, CO-1686, and AZD9291. In some embodiments, the adverse reaction is activation of an oncogenic variant of EGFR, the oncogenic variant includes a mutation in the extracellular domain of the receptor. In some embodiments, the adverse reaction is the activation of an oncogenic variant of the HER2 receptor, the oncogenic variant includes a mutation in the extracellular domain of the receptor.

[0177] In some embodiments, the subject has previously received at least one initial therapy different from the compounds of the Disclosure, and the subject has experienced disease progression despite the administration of the at least one initial therapy, the initial therapy comprising the administration of at least one EGFR inhibitor different from the compounds of the Disclosure, at least one platinum-containing chemotherapy, at least one anti-PD-L1 therapy, or any combination thereof.

[0178] In some embodiments, the subject may have NSCLC, the subject has previously received at least one initial therapy different from the compounds of the Disclosure for the treatment of said NSCLC, the subject has experienced disease progression despite the administration of said at least one initial therapy, the initial therapy comprising the administration of at least one EGFR inhibitor different from the compounds of the Disclosure, at least one platinum-containing chemotherapy, at least one anti-PD-L1 therapy, or any combination thereof.

[0179] In some embodiments, the subject has progressive and / or metastatic NSCLC, the NSCLC, or its tumor or cells express at least one oncogenic variant of EGFR, and the subject has been previously administered at least one EGFR inhibitor different from the compounds of the Disclosure in combination with at least one platinum-containing chemotherapy. In some embodiments, the subject has progressive and / or metastatic NSCLC, the NSCLC, or its tumor or cells express at least one oncogenic variant of EGFR, and the subject has been previously administered at least one EGFR inhibitor different from the compounds of the 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 may be osimertinib. In some embodiments, at least one oncogenic variant of EGFR may be EGFR-Δ19, EGFR-L858R, EGFR-L861Q, EGFR-G719C, EGFR-G719D, EGFR-G719R, EGFR-G719A, EGFR-G719S, EGFR-S768I, EGFR-V769L, or EGFR-C797S.

[0180] In some embodiments, the subject has progressive and / or metastatic NSCLC, the NSCLC, or its tumor or cells express at least one oncogenic variant of EGFR, and the subject has been previously administered at least one EGFR inhibitor different from the compounds of the Disclosure in combination with at least one platinum-containing chemotherapy. In some embodiments, the subject has progressive and / or metastatic NSCLC, the NSCLC, or its tumor or cells express at least one oncogenic variant of EGFR, and the subject has been previously administered at least one EGFR inhibitor different from the compounds of the 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 may be osimertinib. In some embodiments, at least one oncogenic variant of EGFR may 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, NSCLC may have metastasized to the CNS. In some embodiments, NSCLC may not have metastasized to the CNS.

[0181] In some embodiments, the subject has progressive and / or metastatic NSCLC, the NSCLC, or its tumor or cells express at least one oncogenic variant of EGFR, the at least one oncogenic variant of EGFR being EGFR-C797S, and the subject has been previously administered at least one EGFR inhibitor different from the compounds of the Disclosure in combination with at least one platinum-containing chemotherapy. In some embodiments, the subject has progressive and / or metastatic NSCLC, the NSCLC, or its tumor or cells express at least one oncogenic variant of EGFR, the at least one oncogenic variant of EGFR being EGFR-C797S, and the subject has been previously administered at least one EGFR inhibitor different from the compounds of the 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 may be osimertinib. In some embodiments, the NSCLC may have metastasized to the CNS. In some embodiments, NSCLC may not be transferred to the CNS.

[0182] In some embodiments, the subject has progressive and / or metastatic NSCLC, the NSCLC, or the tumor or its cells express at least one oncogenic variant of EGFR, and the subject has been previously treated with at least one platinum-containing chemotherapy. In some embodiments, the subject has progressive and / or metastatic NSCLC, the NSCLC, or its tumor or its cells express at least one oncogenic variant of EGFR, and the subject has been previously treated with 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 may be EGFR-G719C, EGFR-G719D, EGFR-G719R, EGFR-G719A, or EGFR-G719S. In some embodiments, the NSCLC may have metastasized to the CNS. In some embodiments, the NSCLC may not have metastasized to the CNS.

[0183] In some embodiments, the therapeutically effective dose reduces the severity of cancer signs or symptoms.

[0184] In some embodiments, signs of cancer include tumor grade, and a reduction in the severity of signs includes a reduction in tumor grade.

[0185] In some embodiments, signs of cancer include tumor metastasis, and reduction of the severity of signs includes removal of metastasis or reduction of the rate or extent of metastasis.

[0186] In some embodiments, signs of cancer include tumor volume, and reduction of the severity of signs includes removal or reduction of the tumor volume.

[0187] In some embodiments, the symptoms of cancer include pain, and the reduction of the severity of the symptoms includes the elimination or reduction of pain.

[0188] In some embodiments, the therapeutically effective dose induces a period of remission.

[0189] In some embodiments, the therapeutically effective dose improves the prognosis of the subject.

[0190] Such use (or method of prevention or treatment) of a subject involves administering a therapeutically effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a subject in need of such prevention or treatment, targeting allosteric variants and / or oncogenic variants of the EGFR and HER2 receptors.

[0191] Administration of compound 1 In some embodiments, the subject is human.

[0192] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered orally.

[0193] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered with one or more drug-free periods.

[0194] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered without a drug-free period.

[0195] In some embodiments, prior to 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.

[0196] In some embodiments, the subject is fed approximately 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to administration.

[0197] Dosage, duration of administration, and frequency of administration In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered daily.

[0198] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered once daily.

[0199] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered daily in the following doses: Approximately 100±20mg, approximately 100±10mg, approximately 100±5mg, approximately 100±4mg, approximately 100±3mg, approximately 100±2mg, or approximately 100±1mg (for example, approximately 100mg); Approximately 150±20mg, approximately 150±10mg, approximately 150±5mg, approximately 150±4mg, approximately 150±3mg, approximately 150±2mg, or approximately 150±1mg (for example, approximately 150mg); Approximately 200±20mg, approximately 200±10mg, approximately 200±5mg, approximately 200±4mg, approximately 200±3mg, approximately 200±2mg, or approximately 200±1mg (for example, approximately 200mg); or Approximately 300±20mg, approximately 300±10mg, approximately 300±5mg, approximately 300±4mg, approximately 300±3mg, approximately 300±2mg, or approximately 300±1mg (for example, approximately 300mg).

[0200] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered daily in amounts of approximately 100 ± 20 mg, approximately 100 ± 10 mg, approximately 100 ± 5 mg, approximately 100 ± 4 mg, approximately 100 ± 3 mg, approximately 100 ± 2 mg, or approximately 100 ± 1 mg (e.g., approximately 100 mg).

[0201] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered daily at approximately 150 ± 20 mg, approximately 150 ± 10 mg, approximately 150 ± 5 mg, approximately 150 ± 4 mg, approximately 150 ± 3 mg, approximately 150 ± 2 mg, or approximately 150 ± 1 mg (e.g., approximately 150 mg).

[0202] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered daily in doses of approximately 200 ± 20 mg, approximately 200 ± 10 mg, approximately 200 ± 5 mg, approximately 200 ± 4 mg, approximately 200 ± 3 mg, approximately 200 ± 2 mg, or approximately 200 ± 1 mg (e.g., approximately 200 mg).

[0203] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered daily in doses of approximately 300 ± 20 mg, approximately 300 ± 10 mg, approximately 300 ± 5 mg, approximately 300 ± 4 mg, approximately 300 ± 3 mg, approximately 300 ± 2 mg, or approximately 300 ± 1 mg (e.g., approximately 300 mg).

[0204] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered weekly.

[0205] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered three times a week.

[0206] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered three times a week (e.g., on the 1st, 3rd, and 5th days of each week).

[0207] It is understood that day 1 can be any day of the calendar week. In some embodiments, day 1 is Sunday. In some embodiments, day 1 is Monday. In some embodiments, day 1 is Tuesday, Wednesday, Thursday, Friday, or Saturday.

[0208] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered orally three times a week.

[0209] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered three times a week (e.g., on days 1, 3, and 5) in the following doses: Approximately 300±20mg, approximately 300±10mg, approximately 300±5mg, approximately 300±4mg, approximately 300±3mg, approximately 300±2mg, or approximately 300±1mg (for example, approximately 300mg); Approximately 400±50 mg, approximately 400±40 mg, approximately 400±30 mg, approximately 400±20 mg, approximately 400±10 mg, approximately 400±5 mg, approximately 400±4 mg, approximately 400±3 mg, approximately 400±2 mg, or approximately 400±1 mg (for example, approximately 400 mg); or Approximately 500±50mg, approximately 500±40mg, approximately 500±30mg, approximately 500±20mg, approximately 500±10mg, approximately 500±5mg, approximately 500±4mg, approximately 500±3mg, approximately 500±2mg, or approximately 500±1mg (for example, approximately 500mg).

[0210] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered three times a week (e.g., on days 1, 3, and 5) in doses of approximately 300 ± 20 mg, approximately 300 ± 10 mg, approximately 300 ± 5 mg, approximately 300 ± 4 mg, approximately 300 ± 3 mg, approximately 300 ± 2 mg, or approximately 300 ± 1 mg (e.g., approximately 300 mg).

[0211] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered three times a week (e.g., on days 1, 3, and 5) in doses of approximately 400±50 mg, approximately 400±40 mg, approximately 400±30 mg, approximately 400±20 mg, approximately 400±10 mg, approximately 400±5 mg, approximately 400±4 mg, approximately 400±3 mg, approximately 400±2 mg, or approximately 400±1 mg (e.g., approximately 400 mg).

[0212] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered three times a week (e.g., on days 1, 3, and 5) in doses of approximately 500±50 mg, approximately 500±40 mg, approximately 500±30 mg, approximately 500±20 mg, approximately 500±10 mg, approximately 500±5 mg, approximately 500±4 mg, approximately 500±3 mg, approximately 500±2 mg, or approximately 500±1 mg (e.g., approximately 500 mg).

[0213] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered for approximately 21 days, approximately 28 days, approximately 35 days, approximately 42 days, approximately 63 days, approximately 84 days, approximately 105 days, approximately 126 days, approximately 147 days, approximately 168 days, approximately 189 days, or approximately 210 days.

[0214] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered for a period exceeding 210 days.

[0215] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered until cancer progression or adverse effects (e.g., unacceptable toxicity) are observed.

[0216] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered for about 21 days.

[0217] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered for about 21 days, followed by a 30-day drug-free period.

[0218] In some embodiments, the treatment or prevention lasts for 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.

[0219] In some embodiments, treatment or prevention comprises one or more treatment cycles, each treatment cycle comprising approximately 21 days of administration of compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof, followed by a 30-day rest period.

[0220] Combination with temozolomide (TMZ) In some embodiments, the method further includes administering a therapeutically effective dose of temozolomide.

[0221] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutically effective dose of temozolomide.

[0222] In some embodiments, compound 1 (e.g., compound 1A or compound 1B), or a pharmaceutically acceptable salt thereof, and temozolomide are administered simultaneously, sequentially, or alternately.

[0223] In some embodiments, compound 1 (e.g., compound 1A or compound 1B), or a pharmaceutically acceptable salt thereof, and temozolomide are administered simultaneously.

[0224] In some embodiments, compound 1 (e.g., compound 1A or compound 1B), or a pharmaceutically acceptable salt thereof, and temozolomide are administered simultaneously, sequentially, or alternately.

[0225] In some embodiments, compound 1 (e.g., compound 1A or compound 1B), or a pharmaceutically acceptable salt thereof, and temozolomide are administered in close proximity in time.

[0226] In some embodiments, compound 1 (e.g., compound 1A or compound 1B), or a pharmaceutically acceptable salt thereof, and temozolomide are administered alternately.

[0227] In some embodiments, compound 1 (e.g., compound 1A or compound 1B), or a pharmaceutically acceptable salt thereof, and temozolomide are administered in separate formulations.

[0228] In some embodiments, compound 1 (e.g., compound 1A or compound 1B), or a pharmaceutically acceptable salt thereof, and temozolomide are administered as a co-formulation.

[0229] In some embodiments, compound 1 (e.g., compound 1A or compound 1B), or a pharmaceutically acceptable salt thereof, and temozolomide are administered for approximately 28 days.

[0230] In some embodiments, compound 1 (e.g., compound 1A or compound 1B), or a pharmaceutically acceptable salt thereof, and temozolomide are administered for approximately 28 days, approximately 56 days, approximately 84 days, approximately 112 days, approximately 140 days, approximately 168 days, approximately 196 days, approximately 224 days, approximately 252 days, or approximately 280 days.

[0231] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered for a period exceeding 280 days.

[0232] In some embodiments, compound 1 (e.g., compound 1A or compound 1B) or a pharmaceutically acceptable salt thereof is administered until cancer progression or adverse effects (e.g., unacceptable toxicity) are observed.

[0233] Exemplary Embodiments Exemplary Embodiment 1. A method for treating or preventing cancer in a person in need thereof, comprising a pharmaceutically effective amount of compound 1: [ka] A method comprising administering a pharmaceutically acceptable salt thereof to a subject.

[0234] Exemplary Embodiment 2. Compound 1, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject in need thereof.

[0235] Exemplary Embodiment 3. Use of Compound 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for treating or preventing cancer in a subject in need thereof.

[0236] Exemplary Embodiment 4. Cancer is a glioma, and the method, compound, or use of any one of Embodiments 1 to 3.

[0237] Exemplary Embodiment 5. The cancer is a high-grade glioma, and the method, compound, or use of any one of Embodiments 1 to 4.

[0238] Exemplary Embodiment 6. The cancer is a high-grade glioma expressing at least one oncogenic variant of EGFR, using any one of the methods, compounds, or uses of Embodiments 1 to 5.

[0239] Exemplary Embodiment 7. The cancer is glioblastoma, and the method, compound, or use of any one of Embodiments 1 to 6.

[0240] Exemplary Embodiment 8. A method, compound, or use of any one of Embodiments 1 to 7, in which compound 1A, compound 1B, or a pharmaceutically acceptable salt thereof is administered.

[0241] Exemplary Embodiment 9. A method, compound, or use of any one of Embodiments 1 to 8, wherein compound 1A or a pharmaceutically acceptable salt thereof is administered.

[0242] Exemplary Embodiment 10. A method, compound, or use of any one of Embodiments 1 to 9, wherein compound 1B or a pharmaceutically acceptable salt thereof is administered.

[0243] Exemplary Embodiment 11. The subject is a human, and the method, compound, or use of any one of Embodiments 1 to 10.

[0244] Exemplary Embodiment 12. Compound 1 or a pharmaceutically acceptable salt thereof is administered once daily in any one of the methods, compounds, or uses described in Embodiments 1 to 11.

[0245] Exemplary Embodiment 13. Compound 1 or a pharmaceutically acceptable salt thereof is administered daily. Approximately 100±20 mg, approximately 100±10 mg, approximately 100±5 mg, approximately 100±4 mg, approximately 100±3 mg, approximately 100±2 mg, or approximately 100±1 mg; Approximately 150±20 mg, approximately 150±10 mg, approximately 150±5 mg, approximately 150±4 mg, approximately 150±3 mg, approximately 150±2 mg, or approximately 150±1 mg; Approximately 200±20mg, approximately 200±10mg, approximately 200±5mg, approximately 200±4mg, approximately 200±3mg, approximately 200±2mg, or approximately 200±1mg; Approximately 300±20mg, approximately 300±10mg, approximately 300±5mg, approximately 300±4mg, approximately 300±3mg, approximately 300±2mg, or approximately 300±1mg One of the methods, compounds, or uses described in Embodiments 1 to 12, administered in the specified dose.

[0246] Exemplary Embodiment 14. Compound 1 or a pharmaceutically acceptable salt thereof is administered daily in doses 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, according to any one of the methods, compounds, or uses described in Embodiments 1 to 13.

[0247] Exemplary Embodiment 15. Compound 1 or a pharmaceutically acceptable salt thereof is administered daily in doses 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, according to any one method, compound, or use of Embodiments 1 to 14.

[0248] Exemplary Embodiment 16. Compound 1 or a pharmaceutically acceptable salt thereof is administered daily in doses of approximately 200 ± 20 mg, approximately 200 ± 10 mg, approximately 200 ± 5 mg, approximately 200 ± 4 mg, approximately 200 ± 3 mg, approximately 200 ± 2 mg, or approximately 200 ± 1 mg, according to any one method, compound, or use of Embodiments 1 to 15.

[0249] Exemplary Embodiment 17. Compound 1 or a pharmaceutically acceptable salt thereof is administered daily in doses of approximately 300 ± 20 mg, approximately 300 ± 10 mg, approximately 300 ± 5 mg, approximately 300 ± 4 mg, approximately 300 ± 3 mg, approximately 300 ± 2 mg, or approximately 300 ± 1 mg, according to any one of the methods, compounds, or uses described in Embodiments 1 to 16.

[0250] Exemplary Embodiment 18. Compound 1 or a pharmaceutically acceptable salt thereof is administered three times per week in any one of the methods, compounds, or uses described in Embodiments 1 to 17.

[0251] Exemplary Embodiment 19. Compound 1 or a pharmaceutically acceptable salt thereof is administered three times a week. Approximately 300±20mg, approximately 300±10mg, approximately 300±5mg, approximately 300±4mg, approximately 300±3mg, approximately 300±2mg, or approximately 300±1mg; Approximately 400±50 mg, approximately 400±40 mg, approximately 400±30 mg, approximately 400±20 mg, approximately 400±10 mg, approximately 400±5 mg, approximately 400±4 mg, approximately 400±3 mg, approximately 400±2 mg, or approximately 400±1 mg; or Approximately 500±50mg, approximately 500±40mg, approximately 500±30mg, approximately 500±20mg, approximately 500±10mg, approximately 500±5mg, approximately 500±4mg, approximately 500±3mg, approximately 500±2mg, or approximately 500±1mg One of the methods, compounds, or uses described in Embodiments 1 to 18, administered in the specified dose.

[0252] Exemplary Embodiment 20. Compound 1 or a pharmaceutically acceptable salt thereof is administered three times a week in doses of approximately 300 ± 20 mg, approximately 300 ± 10 mg, approximately 300 ± 5 mg, approximately 300 ± 4 mg, approximately 300 ± 3 mg, approximately 300 ± 2 mg, or approximately 300 ± 1 mg, according to any one of the methods, compounds, or uses described in Embodiments 1 to 19.

[0253] Exemplary Embodiment 21. Compound 1 or a pharmaceutically acceptable salt thereof is administered three times a week in doses of approximately 400±50 mg, approximately 400±40 mg, approximately 400±30 mg, approximately 400±20 mg, approximately 400±10 mg, approximately 400±5 mg, approximately 400±4 mg, approximately 400±3 mg, approximately 400±2 mg, or approximately 400±1 mg, according to any one of the methods, compounds, or uses described in Embodiments 1 to 20.

[0254] Exemplary Embodiment 22. Compound 1 or a pharmaceutically acceptable salt thereof is administered three times a week in doses of approximately 500±50 mg, approximately 500±40 mg, approximately 500±30 mg, approximately 500±20 mg, approximately 500±10 mg, approximately 500±5 mg, approximately 500±4 mg, approximately 500±3 mg, approximately 500±2 mg, or approximately 500±1 mg, according to any one of Embodiments 1 to 21, by any one of these methods, compounds, or uses.

[0255] definition It will be understood that the compounds disclosed herein may be presented in a specific configuration. Such a specific configuration should not be construed as limiting this disclosure to isomers, tautomers, regioisomers, or stereoisomers, nor does it exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers. In some embodiments, the presentation of a compound herein in a specific configuration encompasses and refers to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof; the presentation further refers to the specific configuration of the compound.

[0256] Furthermore, it will be understood that the compounds disclosed herein may be presented without a specific configuration (e.g., without a specific stereochemistry). Such presentations shall encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, the presentation of a compound herein without a specific configuration is intended to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.

[0257] As used herein, the term “isomer” means a compound having the same molecular formula but differing in the arrangement of its atomic bonds or the spatial configuration of its atoms. Isomers that differ in spatial configuration of their atoms are called “stereoisomers.” Stereoiomers that are not mirror images of each other are called “diastereoisomers,” and stereoisomers that are mirror images of each other but cannot be superimposed are called “enantiomers,” or in some cases, optical isomers. A mixture containing equal amounts of individual enantiomer forms with opposite chiralities is called a “racemic mixture.”

[0258] As used herein, the term “chiral center” refers to a carbon atom bonded to four non-identical substituents.

[0259] As used herein, the term “chiral isomer” means a compound having at least one chiral center. Compounds having two or more chiral centers may exist either as individual diastereomers or as a mixture of diastereomers, called a “diastereomer mixture.” Where a single chiral center is present, the stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center under consideration are ranked according to the Kahn-Ingold-Prelogue priority rule. (Cahn et al.,Angew.Chem.Inter.Edit.1966,5,385;errata511;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).

[0260] As used herein, the term “geometric isomer” means the existence of diastereomers due to rotational hindrance around a double bond or cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in name by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same side or opposite side of the double bond in the molecule, according to the Kahn-Ingold-Prelogue order rule.

[0261] The terms “nucleic acid” and “polynucleotide” are used interchangeably herein and refer to single-stranded or double-stranded RNA, DNA, or mixed polymers. Polynucleotides may include genomic sequences, extragenomic and plasmid sequences, and smaller, engineered gene segments that express or can be adapted to express polypeptides.

[0262] "Isolated nucleic acids" are nucleic acids substantially separated from other genomic DNA sequences, as well as naturally occurring sequences, from naturally associated proteins or complexes such as ribosomes and polymerases. This term encompasses nucleic acid sequences removed from their naturally occurring environment, including recombinant or cloned DNA isolates, and chemically synthesized or biologically synthesized analogs. Substantially pure nucleic acids include isolated forms of nucleic acids. Naturally, this refers to originally isolated nucleic acids and does not exclude genes or sequences later added to nucleic acids isolated by humans.

[0263] The term "polypeptide" is used in its conventional sense, i.e., as a sequence of amino acids. Polypeptides are not limited to products of a specific length. Peptides, oligopeptides, and proteins are included in the definition of polypeptide, and such terms may be used interchangeably herein unless otherwise specified. This term also does not exclude post-expression modifications of polypeptides, such as glycosylation, acetylation, phosphorylation, and other modifications known in the art, both natural and unnatural. A polypeptide may be an entire protein or a partial sequence thereof.

[0264] "Isolated polypeptide" is a polypeptide identified, isolated, and / or recovered from its natural environment. In preferred embodiments, the isolated polypeptide is purified by (1) a Lowry method to more than 95% by weight, most preferably more than 99% by weight, of the polypeptide; (2) a spinning cup sequencer to a degree sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence; or (3) SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or preferably silver staining until homogeneous. Since the isolated polypeptide lacks at least one component of the polypeptide's natural environment, it contains polypeptides that are present in situ within recombinant cells. However, typically, isolated polypeptides are prepared by at least one purification step.

[0265] "Natural sequence" polynucleotides have the same nucleotide sequence as naturally occurring polynucleotides. "Natural sequence" polypeptides have the same amino acid sequence as naturally occurring polypeptides (e.g., EGFR) from any species. Such natural sequence polynucleotides and polypeptides can be isolated from nature or produced by recombinant or synthetic means.

[0266] When this term is used herein, a polynucleotide "variant" is typically a polynucleotide that differs from a polynucleotide specifically disclosed herein in one or more substitutions, deletions, additions, and / or insertions.

[0267] When the term is used herein, a polypeptide "variant" is typically a polynucleotide that differs from a polypeptide specifically disclosed herein by one or more substitutions, deletions, additions and / or insertions, or inversions. Such variants may be naturally occurring, non-natural, or synthetically produced.

[0268] The EGFR mutations (or variants) described herein may include one or more substitutions, deletions, additions, and / or inversions of amino acid sequences that result in altered protein function. Mutations may be detected, for example, by comparison or alignment of a nucleic acid sequence or amino acid sequence with a wild-type sequence.

[0269] When comparing polynucleotide sequences and polypeptide sequences, two sequences are said to be "identical" if the sequences of nucleotides or amino acids in the two sequences are identical when aligned for maximum matching, as described below. Comparison between two sequences is generally carried out by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. As used herein, a "comparison window" refers to a segment of at least about 20 consecutive positions, usually from 30 to about 75, or from 40 to about 50 consecutive positions. After optimally aligning the two sequences, the sequence can be compared with a reference sequence having the same number of consecutive positions.

[0270] Optimal alignment of sequences for comparison can be achieved using the Megaalign program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, WI) with default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, MO (1978) A model of evolutionary change in proteins-Matrices for detecting distant relationships. In Dayhoff, MO (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. Gand Sharp, PM (1989) CABIOS 5: 151-153; Myers, E. Wand Muller W. (1988) CABIOS 4: 11-17; Robinson, ED (1971) Comb. Theor 11:105;Santou,N.Nes,M.(1987)Mol.Biol.Evol.4:406-425;Sneath,PHAand Sokal,RR(1973)Numerical Taxonomy-the Principles and Practice of Numerical Taxonomy,Freeman Press,San Francisco,CA;Wilbur,WJand Lipman, DJ (1983) Proc. Natl. Acad., Sci. USA 80:726-730.

[0271] Alternatively, optimal alignment of sequences for comparison can be determined by the local identity algorithm of Smith and Waterman (1981) Add. APL. Math 2:482, by the identity alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the similarity search method of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85:2444, by computer-implemented 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.

[0272] One preferred example of algorithms 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 present invention. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information.

[0273] In one exemplary example, for a nucleotide sequence, the cumulative score can be calculated using parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatched residues; always < 0). Word elongation in each direction stops when the cumulative alignment score decreases by X from its maximum attainable value; when the cumulative score becomes 0 or less due to the accumulation of one or more negative-scoring residue alignments; or when the end of either sequence is reached. The parameters W, T, and X of the BLAST algorithm determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses, by default, word length (W) 11, expected value (E) 10, and BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. ACAD. Sci. USA 89:10915) alignment (B) 50, expected value (E) 10, M=5, N=-4, and comparison of both strands.

[0274] For amino acid sequences, a scoring matrix can be used to calculate the cumulative score. Word extension in each direction stops when the cumulative alignment score decreases by an amount X from its maximum value; when the cumulative score becomes 0 or less due to the accumulation of one or more negative-scoring residue alignments; or when the end of any sequence is reached. The parameters W, T, and X of the BLAST algorithm determine the sensitivity and speed of the alignment.

[0275] One method determines the "percentage of sequence identity" by comparing two optimally aligned sequences over a comparison window of at least 20 positions, where, when the two sequences are optimally aligned, the portion of the polynucleotide or polypeptide sequence within the comparison window may contain no more than 20 percent, typically 5–15 percent, or 10–12 percent of additions or deletions (i.e., gaps) compared to the reference sequence (which contains neither additions nor deletions). The percentage is calculated by determining the number of positions where identical nucleic acid bases or amino acid residues exist in both sequences to obtain the number of matching positions, dividing this number of matching positions by the total number of positions in the reference sequence (i.e., the window size), and multiplying the result by 100 to obtain the percentage of sequence identity.

[0276] The wild-type EGFR sequence of this disclosure may include or be composed of the following amino acid sequence. [ka] [ka]

[0277] The wild-type HER2 receptor sequence of this disclosure may include or be composed of the following amino acid sequence. [ka] [ka]

[0278] The wild-type HER2 receptor sequence of this disclosure may include or be composed of the following amino acid sequence. [ka] [ka]

[0279] The wild-type HER2 receptor sequence of the present disclosure may comprise or consist of the following amino acid sequence.

Chemical Formula

Chemical Formula

Chemical Formula

[0280] The wild-type HER2 receptor sequence of the present disclosure may comprise or consist of the following amino acid sequence.

Chemical Formula

Chemical Formula

[0281] The wild-type HER2 receptor sequence of the present disclosure may comprise or consist of the following amino acid sequence.

Chemical Formula

[0282] A person skilled in the art will recognize which combinations are synthetically feasible and practical based on the definitions provided throughout the present application; for example, combinations of groups that result in heteroatoms directly linked to each other are generally not contemplated.

[0283] As used herein, the term “about” means a range that encompasses any normal variation as understood by those skilled in the art in the relevant field. In some embodiments, unless otherwise specified or particularly evident from the context (except where such a number exceeds 100% of a possible value), the term “about” means 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 given reference value.

[0284] As used herein, the term “pharmaceutically acceptable salt” refers to a derivative of a compound of the present disclosure, which is modified by forming a salt of the parent compound with respect to its acid or base. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, EDTA, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycosylated asanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, and milk. Examples include acids, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphusylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinous acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and derivatives from inorganic or organic acids selected from commonly existing amine acids, such as glycine, alanine, phenylalanine, and arginine. Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvate, 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]-octa-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, and muconic acid.This disclosure also includes salts formed by the substitution of acidic protons present in the parent compound with metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions; or by coordination bonding with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, or N-methylglucamine. In salt form, it is understood that the ratio of the compound to the salt cation or anion may be 1:1, or any other ratio, such as 3:1, 2:1, 1:2, or 1:3. All references to pharmaceutically acceptable salts should be understood to include the solubilated form (solvate) or crystalline form (polymorph) of the same salt as defined herein.

[0285] It is understood that the compounds described herein include the compounds themselves, and, where applicable, their pharmaceutically acceptable salts and their solvates. Pharmaceutically acceptable salts may be formed, for example, between a pharmaceutically acceptable anion and a positively charged group (e.g., amino) on the compound. Suitable anions include chlorides, bromides, iodides, sulfates, bisulfates, sulfamates, nitrates, phosphates, citrates, methanesulfons, trifluoroacetates, glutamates, glucurons, glutarates, malates, maleates, succinates, fumarates, tartrates, tosylates, salicylates, lactates, naphthalenesulfons, and acetates (e.g., trifluoroacetates).

[0286] It is understood that the compounds of this disclosure, for example, salts of the compounds, may exist in hydrated or unhydrated (anhydrous) forms, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates and dihydrates. Non-limiting examples of solvates include ethanol solvate and acetone solvate.

[0287] As used herein, expressions such as "one or more A, B, or C," "one or more A, B, or C," "one or more A, B, and C," "one or more A, B, and C," "selected from the group consisting of A, B, and C," and "selected from A, B, and C" are used interchangeably and, unless otherwise indicated, all refer to a selection from the group consisting of A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof.

[0288] Throughout this specification, when a composition is described as having, including, or comprising certain components, it is understood that the composition may also be substantially composed of or consist of the listed components. Similarly, when a method or process is described as having, including, or comprising certain process steps, the process may also be substantially composed of or consist of the listed process steps. Furthermore, it should be understood that, insofar as the invention is implementable, the order of steps or the order in which certain operations are performed is not important. Moreover, two or more steps or operations may be performed simultaneously.

[0289] It is understood that the compounds disclosed herein can be prepared in various ways from readily prepared intermediates using commercially available starting materials, compounds known in the literature, or standard synthetic methods and procedures known to those skilled in the art or that would be apparent to those skilled in the art 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 relevant scientific literature or standard textbooks in the art. Not limited to one or more sources, but including, Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 thedition,John Wiley & Sons:New York,2001;Greene,TW,Wuts,PGM,Protective Groups in Organic Synthesis,3 rd Classic texts such as 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 herein by reference) are useful and well-regarded reference texts on organic synthesis, known to those skilled in the art.

[0290] As used herein, the term “subject” includes human and non-human mammals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. Mammals may be, for example, humans, or suitable non-human mammals, such as primates, mice, rats, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. The subject may also be birds or poultry. In some embodiments, the subject is human.

[0291] As used herein, the term “subject in need” refers to a subject who has a disease (to be treated) or is at high risk of developing a disease (to be prevented). A subject in need may be a subject that has been previously diagnosed or confirmed to have one of the diseases or disorders disclosed herein. A subject in need may also have (for example, be a subject currently suffering from) one of the diseases or disorders disclosed herein. Alternatively, a subject in need may be a subject at high risk of developing such a disease or disorder compared to the general population (i.e., a subject more likely to develop such a disorder compared to the general population). A subject in need may be refractory or resistant to one of the diseases or disorders disclosed herein (i.e., a disease or disorder disclosed herein that is not responding to or has not yet responded to treatment). A subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, a subject in need has received all known effective therapies for one of the diseases or disorders disclosed herein, but has failed. In some embodiments, a subject in need has received at least one prior treatment.

[0292] As used herein, the terms “to treat” or “to heal” describe managing and caring for a patient for the purpose of combating a disease, condition, or disorder, and include administering the compounds of the Disclosure, or their pharmaceutically acceptable salts, polymorphs, or solvates, to alleviate the symptoms or complications of a disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term “to treat” may also include treatment in vitro in cell or animal models.

[0293] It is understood that the compounds of this disclosure, or any pharmaceutically acceptable salts, polymorphs, or solvates thereof, may or may be used to prevent related diseases, conditions, or disorders, or to identify suitable candidates for such purposes.

[0294] As used herein, the terms “prevent,” “prevent,” or “protect from” describe reducing or eliminating the onset of symptoms or complications of such disease, condition, or disorder.

[0295] As used herein, the term “temporal proximity” means that the administration of one therapeutic agent (compound 1 (e.g., compound 1A or compound 1B)) occurs within a period before or after the administration of another therapeutic agent (e.g., temozolomide), resulting in an overlap in the therapeutic effect of the one therapeutic agent with that of the other. In some embodiments, the therapeutic effect of one therapeutic agent completely overlaps with that of the other. In some embodiments, “temporal proximity” means that the administration of one therapeutic agent occurs within a period before or after the administration of another therapeutic agent, resulting in a synergistic effect between the two therapeutic agents. “Temporal proximity” can vary depending on a variety of factors, including, but is not limited to, the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the person receiving the therapeutic agent; the disease or condition being treated or improved; the therapeutic outcome to be achieved; the dosage, frequency, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route through which the therapeutic agent is administered. In some embodiments, “temporal proximity” means within 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, or 24 hours. In some embodiments, multiple doses of one therapeutic agent can be administered in temporal proximity to a single dose of another therapeutic agent. In some embodiments, temporal proximity may vary during a treatment cycle or within a dosing regimen.

[0296] As used herein, the term “pharmaceutically acceptable” means, within the bounds of sound medical judgment, those compounds, anions, cations, materials, compositions, carriers and / or dosage forms suitable for use in contact with human and animal tissues, with a reasonable benefit-to-risk ratio, without excessive toxicity, irritation, allergic reactions, or other problems or complications.

[0297] As used herein, the term “pharmaceutical effective dose” refers to the amount of a drug used to treat, induce remission of, or prevent a specific disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective dose for a subject depends on the subject's weight, size, and health; the nature and severity of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The pharmacochemical effective dose for a given situation can be determined by routine experimentation, within the scope of the clinician's skill and judgment.

[0298] With respect to the compounds of this disclosure that can further form salts, it is understood that all of these forms are also intended within the scope of the claimed disclosure.

[0299] As used herein, the term “pharmaceutically acceptable salt” refers to a derivative of a compound of the present disclosure, which is modified by forming a salt of the parent compound with an acid or base. In some embodiments, a 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 salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, EDTA, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycosylated asanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, and milk. Examples include acids, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphusylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinous acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and derivatives from inorganic or organic acids selected from commonly existing amine acids, such as glycine, alanine, phenylalanine, and arginine.

[0300] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvate, 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]-octa-2-en-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, and muconic acid. The disclosure also includes salts formed by the substitution of an acidic proton present in the parent compound with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or by coordination bonding with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, or N-methylglucamine. In salt form, it is understood that the ratio of the compound to the salt cation or anion can be 1:1, or any other allocation, such as 3:1, 2:1, 1:2, or 1:3.

[0301] It should be understood that all references to pharmaceutically acceptable salts include the solubilated form (solvate) or crystalline form (polymorph) of the same salt as defined herein.

[0302] As used herein, the term “prodrug” refers to a drug that, when administered to a mammal, is converted whole or partially to a target compound. In some embodiments, the prodrug of a compound is also a pharmaceutically acceptable salt of the compound.

[0303] It is understood that the compounds of this disclosure may also be prepared as esters, for example, pharmaceutically acceptable esters. For example, carboxylic acid functional groups in the compounds may be converted to their corresponding esters, such as methyl esters, ethyl esters, or other esters. Alcohol groups in the compounds may also be converted to their corresponding esters, such as acetate esters, propionic acid esters, or other esters.

[0304] The compound, or a pharmaceutically acceptable salt thereof, may be administered orally, nasally, percutaneously, pulmonaryly, by inhalation, orally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of specific routes of administration.

[0305] A drug regimen utilizing a compound is selected according to various factors, including the patient's type, breed, age, weight, sex, and medical condition; the severity of the condition being treated; the route of administration; the patient's renal and hepatic function; and the specific compound or salt thereof to be used. A physician or veterinarian of average competence can easily determine and prescribe the effective dose of medication necessary to prevent, manage, or halt the progression of the condition.

[0306] The technology for formulating and administering the disclosed compounds in this disclosure is described in Remington: The Science and Practice of Pharmacy, 19 th This can be found in edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical formulation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds are present in such pharmaceutical compositions in an amount sufficient to provide a desired dose within the range described herein.

[0307] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds disclosed herein. These in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0308] All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of this disclosure are evident from the various examples. The examples provided illustrate various components and methods useful for carrying out this disclosure. The examples do not limit the claimed disclosure. Those skilled in the art can identify and use other components and methods useful for carrying out this disclosure based on this disclosure.

[0309] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document were specifically and individually indicated to be incorporated herein by reference. The citation of any publication or patent document does not constitute recognition of any relevant prior art, nor does it constitute any endorsement of its content or date. Having described the present invention in this specification, those skilled in the art will recognize that the present invention can be carried out in various embodiments, and that the foregoing description and the following examples are illustrative and not intended to limit the scope of the claims. [Examples]

[0310] Example 1. Exemplary study of compound 1B An open-label, multicenter Phase 0 / 1 trial of compound 1B will be conducted in patients with recurrent rHGG (Arm B) with EGFR modification (Arm A) or fusion, who are scheduled for resection. The trial will consist of Phase 0 and expanded Phase 1b, as described below.

[0311] Phase 0 Arms A and B: The Phase 0 trial includes treatment of recurrent HGG participants with compound 1B at dose-escalating levels in Arm A.

[0312] To evaluate the enumerated PK and PD endpoints, blood, CSF, and brain tumor tissue (gadolinium-enhanced and unenhanced tumor tissue will be collected and analyzed separately) intraoperatively after the final dose of compound 1B on day 5. Additionally, blood samples will be obtained pre-administration (trough level), and 0.5, 1, 2, 4, 6, 8, and 24 hours after administration on day 5. (Note: A 24-hour blood sample will be taken on day 6).

[0313] Arm A: Participants with recurrent high-grade gliomas with EGFR changes in preserved tissue scheduled for resection will be enrolled in two time cohorts (cohorts 1a and 1b). The final preoperative dose will be administered 2–4 hours or 7–9 hours before tumor resection.

[0314] [Table 9]

[0315] The optimal time interval (OTI) is the surgical time interval (STI) from the final preoperative dose to tumor resection, used to detect the maximum unbound drug concentration in non-enhancing tumors. Once the OTI is determined, additional participants for dose escalation are enrolled in Arm A at the OTI (either 2–4 hours or 7–9 hours after the last dose) (Cohort 2).

[0316] [Table 10]

[0317] The dose level for Arm B is selected based on the PK-unbound drug concentration in the non-enhancing tumor outcome from Arm A.

[0318] Arm B: Enrollment in Arm B will begin after participants have been enrolled in Arm A and the optimal time interval (OTI) and optimal dose level have been determined. Patients with recurrent HGG with EGFR fusion (n=10) will be treated with compound 1B for 5 days prior to surgical resection.

[0319] Arms A and B: Pharmacokinetic (PK) analysis The total and unbound concentrations of compound 1B in plasma, tumor-enhancing and non-enhancing regions, and cerebrospinal fluid (CSF) are determined from the tests. The tumor-to-plasma ratio is calculated.

[0320] A positive PK response is defined as an unbound concentration of compound 1B within the gadolinium-non-enhancing region of the tumor being ≥ 5 × IC50 (18.5 nM).

[0321] Pharmacodynamic (PD) analysis To evaluate the PD endpoint, tumor tissue sections are slowly frozen and formalin-embedded. Formalin-fixed, paraffin-embedded (FFPE) tissue sections are stained for pEGFR and pERK expression using immunohistochemistry (IHC). Additional biomarkers, including pS6, pAKT, ClCas3, and MIB-1, are performed in preserved and surgical tumor tissue. Retrospective single-cell RNA-seq analysis is performed on tissue from phase 0 and subsequent resections at the time of recurrence.

[0322] Phase 1 Expanded Cohort: Participants with tumors showing a PK response will continue in the expanded cohort.

[0323] Arm A: Participants with tumors exhibiting a PK response will continue treatment with the same dose in 28-day cycles following surgery. Participants will accept compound 1B until disease progression, unacceptable toxicity or death, withdrawal of consent, loss of follow-up, or termination of the study by the sponsor.

[0324] Arm B: Tumor patients who demonstrated a PK response to the Phase 0 component will enter the expanded treatment phase of this study and will receive compound 1B until disease progression, unacceptable toxicity or death, withdrawal of consent, loss of follow-up, or termination of the study by the sponsor.

[0325] Equal portions Details of one or more embodiments of this disclosure are described in the accompanying description above. Methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this disclosure, but preferred methods and materials are described below. Other features, purposes, and advantages of this disclosure will become apparent from this specification and the claims. In this specification and the accompanying claims, singular nouns include plural subjects unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference. The foregoing description is provided for illustrative purposes only and is not intended to limit this disclosure to the exact form disclosed, but rather to be limited by the claims accompanying this specification.

Claims

1. A method for treating or preventing cancer in a person in need thereof, comprising a pharmaceutically effective amount of compound 1: 【Chemistry 1】 A method comprising administering a pharmaceutically acceptable salt thereof to the subject.

2. Compound 1, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a person in need thereof.

3. The use of compound 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for the treatment or prevention of cancer in a person in need thereof.

4. The method, compound, or use according to any one of claims 1 to 3, wherein the cancer is a glioma.

5. The method, compound, or use according to any one of claims 1 to 4, wherein the cancer is a high-grade glioma.

6. The method, compound, or use according to any one of claims 1 to 5, wherein the cancer is a high-grade glioma expressing at least one oncogenic variant of EGFR.

7. The method, compound, or use according to any one of claims 1 to 6, wherein the cancer is glioblastoma.

8. The method, compound, or use according to any one of claims 1 to 7, wherein compound 1A, compound 1B, or a pharmaceutically acceptable salt thereof is administered.

9. The method, compound, or use according to any one of claims 1 to 8, wherein compound 1A or a pharmaceutically acceptable salt thereof is administered.

10. The method, compound, or use according to any one of claims 1 to 9, wherein compound 1B or a pharmaceutically acceptable salt thereof is administered.

11. The subject is a human, the method, compound, or use according to any one of claims 1 to 10.

12. Compound 1 or a pharmaceutically acceptable salt thereof is administered once daily, according to the method, compound, or use according to any one of claims 1 to 11.

13. Compound 1 or its pharmaceutically acceptable salt is taken daily. Approximately 100 ± 20 mg, approximately 100 ± 10 mg, approximately 100 ± 5 mg, approximately 100 ± 4 mg, approximately 100 ± 3 mg, approximately 100 ± 2 mg, or approximately 100 ± 1 mg; Approximately 150 ± 20 mg, approximately 150 ± 10 mg, approximately 150 ± 5 mg, approximately 150 ± 4 mg, approximately 150 ± 3 mg, approximately 150 ± 2 mg, or approximately 150 ± 1 mg; Approximately 200 ± 20 mg, approximately 200 ± 10 mg, approximately 200 ± 5 mg, approximately 200 ± 4 mg, approximately 200 ± 3 mg, approximately 200 ± 2 mg, or approximately 200 ± 1 mg; Approximately 300 ± 20 mg, approximately 300 ± 10 mg, approximately 300 ± 5 mg, approximately 300 ± 4 mg, approximately 300 ± 3 mg, approximately 300 ± 2 mg, or approximately 300 ± 1 mg The method, compound, or use according to any one of claims 1 to 12, administered in the specified dose.

14. Compound 1 or a pharmaceutically acceptable salt thereof is administered daily in doses 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, according to any one of claims 1 to 13, the method, compound, or use described in any one of claims 1 to 13.

15. Compound 1 or a pharmaceutically acceptable salt thereof is administered daily in doses 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, according to any one of claims 1 to 14, the method, compound, or use.

16. The method, compound, or use according to any one of claims 1 to 15, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered daily in doses 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. Compound 1 or a pharmaceutically acceptable salt thereof is administered daily in doses 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, according to any one of claims 1 to 16, the method, compound, or use described in any one of claims 1 to 16.

18. Compound 1 or a pharmaceutically acceptable salt thereof is administered three times a week, according to the method, compound, or use according to any one of claims 1 to 17.

19. Compound 1 or a pharmaceutically acceptable salt thereof is administered three times a week. Approximately 300 ± 20 mg, approximately 300 ± 10 mg, approximately 300 ± 5 mg, approximately 300 ± 4 mg, approximately 300 ± 3 mg, approximately 300 ± 2 mg, or approximately 300 ± 1 mg; Approximately 400 ± 50 mg, approximately 400 ± 40 mg, approximately 400 ± 30 mg, approximately 400 ± 20 mg, approximately 400 ± 10 mg, approximately 400 ± 5 mg, approximately 400 ± 4 mg, approximately 400 ± 3 mg, approximately 400 ± 2 mg, or approximately 400 ± 1 mg; or Approximately 500 ± 50 mg, approximately 500 ± 40 mg, approximately 500 ± 30 mg, approximately 500 ± 20 mg, approximately 500 ± 10 mg, approximately 500 ± 5 mg, approximately 500 ± 4 mg, approximately 500 ± 3 mg, approximately 500 ± 2 mg, or approximately 500 ± 1 mg The method, compound, or use according to any one of claims 1 to 18, administered in the dose of [specified dose].

20. Compound 1 or a pharmaceutically acceptable salt thereof is administered three times a week in doses 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, as described in any one of claims 1 to 19, the method, compound, or use according to any one of claims 1 to 19.

21. Compound 1 or a pharmaceutically acceptable salt thereof is administered three times a week in doses of approximately 400 ± 50 mg, approximately 400 ± 40 mg, approximately 400 ± 30 mg, approximately 400 ± 20 mg, approximately 400 ± 10 mg, approximately 400 ± 5 mg, approximately 400 ± 4 mg, approximately 400 ± 3 mg, approximately 400 ± 2 mg, or approximately 400 ± 1 mg, according to any one of claims 1 to 20, the method, compound, or use described in any one of claims 1 to 20.

22. Compound 1 or a pharmaceutically acceptable salt thereof is administered three times a week in doses of approximately 500 ± 50 mg, approximately 500 ± 40 mg, approximately 500 ± 30 mg, approximately 500 ± 20 mg, approximately 500 ± 10 mg, approximately 500 ± 5 mg, approximately 500 ± 4 mg, approximately 500 ± 3 mg, approximately 500 ± 2 mg, or approximately 500 ± 1 mg, according to any one of claims 1 to 21, the method, compound, or use described in any one of claims 1 to 21.

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