Fused bicyclic EGFR inhibitors and methods of using the same

Abstract

The present disclosure relates to fused bicyclic compounds containing a ring core such as 2H-benzo[e][1,3]oxazin-4(3H)-one, 2,3-dihydrothieno[2,3-e][1,3]oxazin-4-one and 2,3-dihydrothieno[3,2-e][1,3]oxazin-4-one, which act as allosteric inhibitors of epidermal growth factor receptor (EGFR); pharmaceutical compositions comprising the compounds, optionally in combination with a second active agent, and methods of treating or preventing kinase-mediated disorders including cancer and other proliferative diseases.

Description

Technical Field

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 366,732, filed Jun. 21, 2022, the entire contents of which are incorporated herein by reference.

[0002] Statement Regarding Federally Sponsored Research or Development This invention was made with government support under Grant No. 5R01CA201049 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention.

Background Art

[0003] The epidermal growth factor receptor (EGFR, Erb-B1) belongs to a family of receptor tyrosine kinases that mediate the growth, differentiation, and survival of normal and malignant cells (Arteaga, C. L., J. Clin. Oncol. 19, 2001, 32-40). Dysregulation of EGFR is involved in many types of human cancer, and overexpression of this receptor is present in at least 70% of human cancers (Seymour, L. K., Curr. Drug Targets 2, 2001, 117-133), including non-small cell lung cancer, breast cancer, glioma, head and neck squamous cell carcinoma, and prostate cancer (Raymond, E., et al., Drugs 60 (Suppl. 1), 2000, 15-23, discussion 41-2; Salomon, D. S., et al., Crit. Rev. Oncol. Hematol. 19, 1995, 183-232; Voldborg B. R., et al., Ann. Oncol. 8, 1997, 1197-1206). Thus, EGFR has emerged as an interesting target for the design and development of diagnostic and therapeutic agents that can specifically bind to and inhibit the receptor tyrosine kinase activity and signaling pathways in cancer cells. The two most common EGFR-activating mutations in patients with non-small cell lung cancer (NSCLC) are deletion of exon 19 (del19) and the L858R point mutation.

[0004] The reversible EGFR inhibitors gefitinib and erlotinib are effective clinical therapies for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations (Mok, T. S., et al., N. Engl. J. Med. 361, 2009, 947-57; Paez, J. G., et al., Science 304, 2004, 1497-500; Lynch, T. J., et al., N. Engl. J. Med. 350, 2004, 2129-39; Rosell, R., et al., Lancet Oncol. 13, 2012, 239-46). However, disease progression occurs in most patients after treatment with these drugs. In 60% of patients, the most common mechanism of acquired resistance is a secondary mutation in EGFR at position T790 (T790M) (Yu, H. A., et al., Clin. Cancer Res. 19, 2013, 2240-7). This mutation results in increased ATP affinity and thus makes it more difficult for the reversible EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib to bind to the EGFR TKI domain (Yun C. H., et al., Proc. Natl. Acad. Sci. USA 105, 2008, 2070-5).

[0005] Covalent EGFR inhibitors have been developed to address resistance conferred by the EGFR T790M mutation. One such covalent EGFR inhibitor is afatinib, which has potent activity against both the mutant and wild-type (WT) EGFR (Li, D.; et al., Oncogene 27, 2008 (4702-2711). However, inhibition of WT EGFR results in toxicities including skin rash and diarrhea and thus may be dose-limiting in the clinic. (Yap, T. A.; et al., J Clin Onc, 28, 2010 (3965-3972)).

[0006] Third-generation covalent EGFR inhibitors that are selective for mutant EGFR over WT EGFR have overcome the limitations of afatinib and demonstrated improved clinical efficacy and tolerability (Cross, D. E. A.; et al., Cancer Discov. 4, 2014 (1046-1061)). Osimertinib was first approved for patients who developed resistance to reversible inhibitors via the T790M mutation and is now also approved as first-line therapy. Despite addressing the major resistance mechanisms of first-generation inhibitors, resistance to osimertinib has also emerged (Schmid, S., et al., Lung Cancer 147, 2020, 123-129). The resistance mechanisms include the C797S mutation, which prevents osimertinib from forming a covalent bond with the cysteine residue (Thress, K. T., et al., Nature Med. 21, 2015, 560-562). This resistance results in triple mutants (del19 / T790M / C797S or L858R / T790M / C797S) or double mutants (e.g., L858R / C797S) in the case of first-line therapy, which cannot be successfully treated with the currently approved series of EGFR inhibitors.

[0007] Therefore, there is still a need for new targeted therapies for NSCLC patients who have developed resistance to existing inhibitors.

SUMMARY OF THE INVENTION

[0008] In one aspect, a compound of formula I:

[0009]

CHEMICAL

[0010] In another aspect, a compound of formula III:

[0011]

CHEMICAL

[0012] In another aspect, a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier is provided herein.

[0013] In yet another aspect, a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein is provided herein.

[0014] In yet a further aspect, a method of inhibiting a kinase in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein is provided herein.

[0015] In one aspect, a method of treating or preventing a kinase-mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein is provided herein.

Mode for Carrying Out the Invention

[0016] Definitions Definitions of the various terms used to describe the compounds and compositions disclosed herein are listed below. These definitions apply to these terms used throughout this specification and the claims, individually or as part of a larger group, unless otherwise defined.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In general, the nomenclature used herein, as well as laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry reactions, are well known and commonly employed in the art.

[0018] As used herein, the articles "a" and "an" refer to the grammatical object of one or more (i.e., at least one) of the articles. By way of example, "an element" means one element or more than one element. Further, the use of the terms "including" and other forms, such as "include", "includes", and "included" is not limiting.

[0019] As used herein, the term "about" is understood by those skilled in the art and varies to some extent depending on the context in which it is used. As used herein, when referring to measurable values, such as amounts, ranges of time, etc., the term "about" encompasses variations that include ±20% or ±10% of the specified value, such as ±5%, ±1%, and ±0.1%, meaning that such variations are appropriate for carrying out the disclosed method.

[0020] Terms such as "administer" as used herein refer to providing a therapeutic agent to a subject. A number of techniques for administering a therapeutic agent exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0021] The terms "treat", "being treated", "treatment", or "treating" include the reduction or alleviation of at least one symptom associated with or caused by the condition, disorder, or disease being treated. In certain embodiments, treatment includes contacting wild-type or mutant EGFR with an effective amount of a compound disclosed herein for a cancer-related condition.

[0022] As used herein, the terms "prevent" or "prevention" mean that no disorder or disease develops when such disorder or disease has not previously occurred, or that no further disorder or disease develops when a disorder or disease has already developed. The ability to prevent some or all of the symptoms associated with a disorder or disease is also considered.

[0023] As used herein, the terms "patient", "individual", or "subject" refer to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets such as sheep, cows, pigs, dogs, cats, and marine mammals. Preferably, the patient, subject, or individual is a human.

[0024] As used herein, the terms "effective amount", "pharmaceutically effective amount", and "therapeutically effective amount" refer to an amount of an agent that is non-toxic and sufficient to produce the desired biological result. The result may be a decrease or alleviation of the signs, symptoms, or causes of a disease, or any other desired modification of the biological system. The appropriate therapeutic amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0025] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that is relatively non-toxic and does not inactivate the biological activity or properties of a compound, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any of the components of the composition in which it is contained.

[0026] As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acidic or basic moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the formed parent compounds, including non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present disclosure can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two (generally, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred). The phrase "pharmaceutically acceptable salt" is not limited to a single salt or a 1:1 salt. For example, "pharmaceutically acceptable salt" also includes bis salts such as bis hydrochloride salts. Lists of suitable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is hereby incorporated by reference in its entirety.

[0027] As used herein, the term "prodrug" refers to a precursor compound that undergoes metabolic activation in vivo to produce an active drug. Thus, for example, a prodrug of a compound provided herein, when administered to a subject, undergoes metabolic activation to produce the compound.

[0028] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the present disclosure and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates the administration of the compound to a patient or subject. A number of techniques for administering a compound exist in the art and include, but are not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0029] As used herein, the term "pharmaceutical combination" means a product resulting from mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g., the compounds of the present disclosure and the co-drug, are both administered to a patient simultaneously in the form of a single entity or a single dosage form. The term "non-fixed combination" means that the active ingredients, e.g., the compounds of the present disclosure and the co-drug, are both administered to a patient as separate entities simultaneously, concurrently, or sequentially, without a specific time limit, such administration resulting in therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapies, e.g., the administration of three or more active ingredients.

[0030] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or carrier involved in enabling the intended function of a compound useful within the present disclosure by retaining or transporting the compound within the body of a patient, e.g., a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material. Usually, such constructs are carried or transported from one organ, or part, of the body to another organ, or part, of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compounds useful within the present disclosure, and not being harmful to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances utilized in pharmaceutical formulations.

[0031] As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, etc. that are compatible with the activity of the compounds useful within the present disclosure and are physiologically acceptable to a patient. Auxiliary active compounds can also be incorporated into the compositions. "Pharmaceutically acceptable carrier" can further include pharmaceutically acceptable salts of the compounds disclosed herein. Other additional ingredients that can be included in the pharmaceutical compositions are known in the art and are described, for example, in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0032] As used herein, the term "EGFR" refers to the epidermal growth factor receptor (also called ErbB-1 or HER1) and can refer to the wild-type receptor or a receptor containing one or more mutations.

[0033] As used herein, the term "HER" or "Her" refers to members of the ErbB receptor tyrosine kinase family, including EGFR, ERBB2, HER3, and HER4.

[0034] As used herein, the term "allosteric site" refers to a site on EGFR other than the ATP binding site, for example, a site characterized by the crystal structure of EGFR. The "allosteric site" can be a site near the ATP binding site, for example, a site characterized by the crystal structure of EGFR. For example, as one allosteric site, one or more of the following amino acid residues of the epidermal growth factor receptor (EGFR): Lys745, Leu788, Ala743, Cys755, Leu777, Phe856, Asp855, Met766, Ile759, Glu762, and / or Ala763 can be mentioned.

[0035] As used herein, the term "agent that inhibits EGFR dimer formation" or iterations thereof refers to an agent that inhibits dimer formation and acts on the C-lobe of the "activator" subunit to the N-lobe of the "receptor" subunit. Examples of agents that inhibit EGFR dimer formation include, but are not limited to, cetuximab, trastuzumab, panitumumab, and Mig6.

[0036] As used herein, the term "alkyl" means, by itself or as part of another substituent, a straight or branched chain hydrocarbon having the indicated number of carbon atoms (i.e., C1-C6 alkyl means an alkyl having 1 to 6 carbon atoms), including straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Other examples of C1-C6 alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0037] As used herein, the term "haloalkyl" refers to an alkyl group as defined above substituted with one or more halo substituents, where alkyl and halo are as defined herein. Haloalkyl includes, for example, chloromethyl, trifluoromethyl, bromoethyl, chlorofluoroethyl, and the like.

[0038] As used herein, the term "alkoxy" refers to an -O-alkyl group where alkyl is as defined herein. Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, and the like.

[0039] As used herein, the term "alkylamine" refers to an -NH-alkyl group, where alkyl is as defined herein. Examples of alkylamines include methylamine, ethylamine, isopropylamine, n-propylamine, n-butylamine, sec-butylamine, t-butylamine, and the like.

[0040] As used herein, the term "haloalkoxy" refers to an -O-haloalkyl group, where haloalkyl is as defined herein. Examples of haloalkoxys include chloromethoxy, trifluoromethoxy, bromoethoxy, chlorofluoroethoxy, and the like.

[0041] As used herein, the term "alkenyl" in certain embodiments refers to a monovalent group derived from a hydrocarbon moiety containing 2 to 6, or 2 to 8 carbon atoms and having at least one carbon-carbon double bond. The alkenyl group may or may not be a point of attachment to another group. The term "alkenyl" includes, but is not limited to, ethenyl, 1-propenyl, 1-butenyl, heptenyl, octenyl, and the like.

[0042] As used herein, the term "alkynyl" in certain embodiments refers to a monovalent group derived from a hydrocarbon moiety containing 2 to 6, or 2 to 8 carbon atoms and having at least one carbon-carbon triple bond. The alkynyl group may or may not be a point of attachment to another group. The term "alkynyl" includes, but is not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0043] As used herein, the term "halo" or "halogen", alone or as part of another substituent, unless otherwise specified, means a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, more preferably fluorine or chlorine.

[0044] As used herein, the term "cycloalkyl" means a fully saturated non-aromatic carbocyclic system having 1, 2 or 3 rings, which may be fused non-aromatic carbocyclic systems. The term "fused" means that there is a second ring (i.e., bonded or formed thereby) that has two adjacent atoms in common with the first ring (i.e., shared). Cycloalkyl may also be of a bridged or spirocyclic nature and includes bicyclic structures where each individual ring atom within the two rings varies from 3 to 8. The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1.1]pentyl. In one embodiment, cycloalkyl is a 3- to 10-membered cycloalkyl. In another embodiment, cycloalkyl is a 3- to 6-membered cycloalkyl.

[0045] As used herein, the term "cycloalkenyl" means a non-aromatic carbocyclic system having 1, 2 or 3 partially saturated rings, which may be fused and at least one ring contains sp 2 carbon-carbon bonds. The term "cycloalkenyl" includes, but is not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, bicyclo[3.1.0]hexenyl, spiro[3.3]-heptenyl, and bicyclo[1.1.1]pentenyl. In one embodiment, cycloalkenyl is a 3- to 10-membered cycloalkyl. In another embodiment, cycloalkenyl is a 4- to 7-membered cycloalkyl.

[0046] As used herein, the terms "heterocyclyl" or "heterocycloalkyl" independently refer to a non-aromatic carbocyclic system containing 1, 2, 3 or 4 heteroatoms selected from N, O, and S, having 1, 2 or 3 rings, such rings may be fused, and the fused non-aromatic carbocyclic system is as defined above. Heterocyclyl may also be cross-linked or spirocyclic in nature, and each individual ring atom within the bicyclic structure varies from 3 to 8 and includes a bicyclic structure containing 0, 1, or 2 N, O, or S atoms. The term "heterocyclyl" includes, but is not limited to, cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), and includes, but is not limited to, epoxyidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 2-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 6-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 3-aza-bicyclo[3.1.1]heptanyl, 2-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo-[3.1.0]hexanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 3-oxa-7-azabicyclo[3.3.1]-nonanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-aza-bicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxaspiro-[3.3]heptanyl, 2-oxaspiro[3.5]nonanyl, 3-oxaspiro[5.3]nonanyl, and 8-oxabicyclo[3.2.1]octanyl. In one embodiment, heterocycloalkyl is 3- to 10-membered heterocycloalkyl.In another embodiment, the heterocycloalkyl is a 5- to 7-membered heterocyclyl.

[0047] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromatic properties, i.e., having (4n + 2) delocalized π (pi) electrons, where n is an integer.

[0048] As used herein, the term "aryl" refers to an aromatic carbocyclic system containing one, two, or three rings, such rings may be fused, and the fused rings are aromatic carbocyclic systems as defined above. When the rings are fused, one of the rings must be completely unsaturated, and the fused ring(s) may be completely saturated, partially unsaturated, or completely unsaturated. The term "aryl" includes, but is not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. In some embodiments, the aryl group has 6 carbon atoms. In some embodiments, the aryl group has 6 to 10 carbon atoms. In some embodiments, the aryl group has 6 to 16 carbon atoms.

[0049] As used herein, the term "heteroaryl" independently contains 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and is an aromatic carbocyclic system having 1, 2, or 3 rings, and such rings may be fused, and the fused aromatic carbocyclic system is as defined above. The term "heteroaryl" includes, but is not limited to, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-cyclopenta-[c]pyridinyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]-triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl and 4,5,6,7-tetrahydro-2H-indazolyl. In one embodiment, heteroaryl is 5- to 10-membered heteroaryl. In another embodiment, heteroaryl is 5- to 6-membered heteroaryl.

[0050] An aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety may be attached or appended to the moiety shown via a different ring atom (i.e., shown or described without indication of a specific point of attachment), and it should be understood that all possible points of attachment are intended, whether via a carbon atom or, for example, via a trivalent nitrogen atom. For example, the term "pyridinyl" means 2-, 3- or 4-pyridinyl, and the term "thienyl" means 2- or 3-thienyl, etc.

[0051] As used herein, the term "substituted" means that an atom or group of atoms has replaced hydrogen as a substituent attached to another group.

[0052] As used herein, the term "optionally substituted" means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) (singly or in combination) individually and independently selected from the groups described herein.

[0053] Compound Compounds are provided herein that are allosteric inhibitors of epidermal growth factor receptor (EGFR) useful for the treatment of kinase-mediated disorders including cancer and other proliferative diseases.

[0054] In one aspect, a compound of formula I:

[0055]

Chemical Structure

[0056] In one embodiment of Formula I, or a pharmaceutically acceptable salt thereof W and Z are each independently N, C-halo, or CH X and Y are each independently CH or CR 3 wherein provided that at least one of W, X, Y, or Z is CH R 1 is C(O)NHR 9, selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, R 2 is selected from the group consisting of 6- to 10-membered aryl and 5- to 10-membered heteroaryl, both of which are optionally substituted with one, two or three R 6 ; R 3 is independently, for each occurrence, selected from the group consisting of C6-C 10 aryl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted one, two or three times with R 5 ; R 5 is independently, for each occurrence, selected from the group consisting of 3- to 10-membered cycloalkyl, (CH2) 0~3 -(C6-C 10 aryl), (CH2) 0~3 -(5- to 6-membered heteroaryl), and (CH2) 0~3 -(5- to 7-membered heterocyclyl), wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted one, two or three times with R 7 ; R 6 is independently, for each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, and OH, R 7 is independently, for each occurrence, selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and halogen, R 8 is selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy, R 9 is 5- to 10-membered heteroaryl.

[0057] In one embodiment, X is CH or CR 3It is. In another embodiment, X is CH. In yet another embodiment, X is CR 3 It is.

[0058] In yet another further embodiment, Y is CH or CR 3 It is. In one embodiment, Y is CH. In another embodiment, Y is CR 3 It is.

[0059] In one embodiment, two or less of W, X, Y, or Z are N. In another embodiment, one or less of W, X, Y, or Z is N. In yet another further embodiment, only one of X or Y is CR 3 In yet another further embodiment, X is CR 3 In another embodiment, Y is CR 3 It is.

[0060] In another embodiment, the compound of formula I is a compound of formula IIa or IIb:

[0061]

Chemical formula

[0062] In yet another further embodiment, the compound of formula I is a compound of formula IIa. In yet another further embodiment, the compound of formula I is a compound of formula IIb. In one embodiment, n is 1. In another embodiment, n is 1. In yet another further embodiment, n is 2.

[0063] In one embodiment, W is N or CH. In another embodiment, W is N. In yet another further embodiment, W is CH.

[0064] In yet another further embodiment, Z is CH or C-halo. In one embodiment, Z is CH. In another embodiment, Z is C-halo.

[0065] In yet another embodiment, R 1 is C(O)NHR 9 or a 5- to 10-membered heteroaryl.

[0066] In yet another further embodiment, R 1 is

[0067]

Chemical formula

[0068] In one embodiment, R 8 is C1-C3 alkyl.

[0069] In another embodiment, R 1 is

[0070]

Chemical formula

[0071] In yet another further embodiment, R 3 is independently, at each occurrence, an optionally substituted C6-C 5 aryl, substituted one, two or three times with R 10 and R 5 is independently, at each occurrence, selected from the group consisting of (CH2) 7 -(5- to 7-membered heterocyclyl), optionally substituted one, two or three times with R 0~3 and R 7 is independently, at each occurrence, selected from the group consisting of C1-C6 alkyl.

[0072] In yet another further embodiment, R 3 is independently, at each occurrence,

[0073]

Chemical formula

[0074] In one embodiment, R 3 is, independently for each occurrence,

[0075]

Chem.

[0076] In another embodiment, the compound of formula I is where W is N or CH, Z is CH or C-halo, R 1 is C(O)NHR 9 ,

[0077]

Chem.

[0078] In another embodiment, the compound of formula I is a compound of Table 1

[0079]

Table 1

[0080] In another aspect, a compound of formula III:

[0081]

Chem.

[0082]

Chem.

[0083] In one embodiment of Formula III or a pharmaceutically acceptable salt thereof,

[0084]

Chemical formula

[0085] In one embodiment, at least one of X, Y, or Z is S. In another embodiment, two or fewer of X, Y, or Z are S or N. In yet another embodiment, one or fewer of X, Y, or Z are S or N. In yet another embodiment, only one of X or Y is CR 3 In yet another embodiment, X is CR 3 In another embodiment, Y is CR 3 is.

[0086] In another embodiment, the compound of formula III is a compound of formula IIIa:

[0087]

Chemical formula

[0088] In another embodiment, the compound of formula III is a compound of formula IIIb:

[0089]

Chemical formula

[0090] In one embodiment, n is 1. In another embodiment, n is 1. In yet another embodiment, n is 2.

[0091] In yet another embodiment, R1 is C(O)NHR 9 or is a 5- to 10-membered heteroaryl.

[0092] In yet another embodiment, R 1 is

[0093]

Chem.

[0094] In one embodiment, R 8 is C1-C3 alkyl.

[0095] In another embodiment, R 1 is

[0096]

Chem.

[0097] In yet another embodiment,[[]] R 3 is independently, at each occurrence, C6-C 5 aryl optionally substituted one, two or three times with R 10 and R 5 is independently, at each occurrence, selected from the group consisting of (CH2) 7 -(5- to 7-membered heterocyclyl) optionally substituted one, two or three times with R 0~3 and R 7 is independently, at each occurrence, selected from the group consisting of C1-C6 alkyl.

[0098] In yet another embodiment, R 3 is independently, at each occurrence,

[0099]

Chem.

[0100] In one embodiment, R 3 is independently, for each occurrence,

[0101]

Chem.

[0102] In another embodiment, the compound of formula III is a compound of formula IIIa, or a pharmaceutically acceptable salt thereof; [wherein, R 1 is C(O)NHR 9 ,

[0103]

Chem.

[0104]

Chem.

[0105] In another embodiment, the compound of formula III is a compound of Table 2

[0106]

Table 2

[0107] The compounds disclosed herein can exist as tautomers and optical isomers (e.g., enantiomers, diastereomers, mixtures of diastereomers, racemic mixtures, etc.).

[0108] The compounds provided herein can also include all isotopes of atoms that occur in the intermediates or final compounds. Isotopes include atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more of the constituent atoms of the compounds of the present invention may be replaced with isotopes of the atoms at natural or unnatural abundances, or may be substituted. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced with deuterium, or may be substituted. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for including isotopes in organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in various studies, such as NMR spectroscopy, metabolic experiments, and / or assays.

[0109] For a compound provided herein, any atom not specifically indicated as a particular isotope means any stable isotope of that atom. Unless otherwise specified, when a position is specifically indicated as "H" or "hydrogen", that position is considered to have hydrogen with its natural abundance isotope composition. Also, unless otherwise specified, when a position is specifically indicated as "D" or "deuterium", that position is considered to have deuterium at an abundance at least 3000 times greater than the natural abundance of deuterium, and that abundance is 0.015% (i.e., at least 45% incorporation of deuterium).

[0110] It is generally well known in the art that any compound that is converted in vivo to provide a compound disclosed herein is a prodrug within the scope of this disclosure.

[0111] In one aspect, provided herein is a pharmaceutical composition comprising any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0112] In one embodiment, the composition further comprises a second active agent. In another embodiment, the second active agent is selected from the group consisting of a MEK inhibitor, a PI3K inhibitor, and an mTor inhibitor. In yet another embodiment, the second active agent blocks EGFR dimer formation in a subject. In still another embodiment, the second active agent is selected from the group consisting of cetuximab, trastuzumab, and panitumumab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0113] In another aspect, there is provided herein a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition further comprises a second active agent (the second active agent inhibits EGFR dimer formation), and a pharmaceutically acceptable carrier. In some embodiments, the second active agent that inhibits EGFR dimer formation is an antibody. In further embodiments, the second active agent that inhibits EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that inhibits EGFR dimer formation is cetuximab.

[0114] A compound that binds to an allosteric site of EGFR, such as a compound of the present disclosure (e.g., a compound of the formula disclosed herein), can optionally be combined with a second active agent (the second active agent inhibits EGFR dimer formation) to modulate EGFR activity. In some embodiments, the compound of the present disclosure can inhibit or reduce EGFR activity without a second active agent (e.g., an antibody, such as cetuximab, trastuzumab, or panitumumab). In other embodiments, the compound of the present disclosure is combined with a second active agent. In one embodiment, the second active agent inhibits EGFR dimer formation and / or can inhibit or reduce EGFR activity. In some embodiments, the second active agent that inhibits EGFR dimer formation is an antibody. In further embodiments, the second active agent that inhibits EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that inhibits EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0115] Method of treatment In one aspect, provided herein is a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein. In one embodiment, the cancer is selected from the group consisting of lung cancer, colon cancer, breast cancer, endometrial cancer, thyroid cancer, glioma, squamous cell carcinoma, and prostate cancer. In another embodiment, the cancer is non-small cell lung cancer (NSCLC).

[0116] In another aspect, provided herein is a method of inhibiting a kinase in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound provided herein. In one embodiment, the kinase is EGFR.

[0117] In yet another aspect, provided herein is a method of treating or preventing a kinase-mediated disorder in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of the present disclosure. In one embodiment, the kinase-mediated disorder is resistant to EGFR targeted therapy. In another embodiment, the EGFR treatment therapy is selected from the group consisting of gefitinib, erlotinib, or osimertinib.

[0118] In some embodiments, the compounds of the present disclosure are capable of modulating (e.g., inhibiting or reducing) the activity of EGFR containing one or more mutations. In some embodiments, the mutant EGFR contains one or more mutations selected from T790M, L718Q, L844V, V948R, L858R, I941R, and C797S. In other embodiments, the mutant EGFR contains a combination of mutations, and the combination is selected from L858R / L718Q, L858R / L844V, L858R / T790M, L858R / T790M / I941R, L858R / C797S, L858R / T790M / C797S, and L858R / T790M / L718Q. In other embodiments, the mutant EGFR contains a combination of mutations, and the combination is selected from L858R / L844V, L858R / T790M, L858R / T790M / I941R, L858R / C797S, L858R / T790M / C797S, and L858R / T790M. In other embodiments, the mutant EGFR contains a combination of mutations, and the combination is selected from L858R / T790M, L858R / T790M / I941R, L858R / C797S, L858R / T790M / C797S, and L858R / T790M.

[0119] In some embodiments, the compounds of the present disclosure can modulate (e.g., inhibit or reduce) the activity of EGFR containing one or more mutations in combination with a second active agent that blocks EGFR dimer formation. In some embodiments, the mutant EGFR contains one or more mutations selected from T790M, L718Q, L844V, V948R, L858R, I941R, and C797S. In other embodiments, the mutant EGFR contains a combination of mutations, and the combination is selected from L858R / L718Q, L858R / L844V, L858R / T790M, L858R / T790M / I941R, L858R / C797S, L858R / T790M / C797S, and L858R / T790M / L718Q. In other embodiments, the mutant EGFR contains a combination of mutations, and the combination is selected from L858R / L844V, L858R / T790M, L858R / T790M / I941R, L858R / C797S, L858R / T790M / C797S, and L858R / T790M. In other embodiments, the mutant EGFR contains a combination of mutations, and the combination is selected from L858R / T790M, L858R / T790M / I941R, L858R / C797S, L858R / T790M / C797S, and L858R / T790M. In some embodiments, the second active agent that blocks EGFR dimer formation is an antibody. In a further embodiment, the second active agent that blocks EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that blocks EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib.

[0120] In some embodiments, the compounds of the present disclosure can modulate (e.g., inhibit or reduce) the activity of EGFR containing one or more mutations, but do not affect the activity of wild-type EGFR.

[0121] In other embodiments, the compounds of the present disclosure can be combined with a second active agent (the second active agent blocks EGFR dimer formation) to modulate (e.g., inhibit or reduce) the activity of EGFR containing one or more mutations, but does not affect the activity of wild-type EGFR. In some embodiments, the second active agent that blocks EGFR dimer formation is an antibody. In further embodiments, the second active agent that blocks EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that blocks EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0122] Modulation of EGFR containing one or more mutations, such as the mutations described herein, but excluding wild-type EGFR, provides methods for the treatment, prevention, or recovery of diseases including, but not limited to, cancer and metastasis, inflammation, arthritis, systemic lupus erythematosus, skin-related disorders, lung disorders, cardiovascular diseases, ischemia, neurodegenerative disorders, liver diseases, gastrointestinal diseases, viral and bacterial infections, central nervous system disorders, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and peripheral nerve disorders.

[0123] In some embodiments, inhibition of EGFR activity is IC 50 measured by.

[0124] In some embodiments, inhibition of EGFR activity is EC 50 measured by.

[0125] In some embodiments, inhibition of EGFR by the compounds of the present disclosure can be measured via a biochemical assay. By way of illustrative and non-limiting example, a homogeneous time-resolved fluorescence (HTRF) assay can be used to determine inhibition of EGFR activity using the conditions and experimental parameters disclosed herein. The HTRF assay can utilize, for example, a substrate (e.g., biotin-Lck-peptide substrate) at a concentration of about 1 μM; EGFR (mutant or WT) at a concentration of about 0.2 nM to about 40 nM; and an inhibitor at a concentration of about 0.000282 μM to about 50 μM. The compounds of the present disclosure screened under these conditions can have an IC 50 value of, for example, about 1 nM to >1 μM; about 1 nM to about 400 nM; about 1 nM to about 150 nM; about 1 nM to about 75 nM; about 1 nM to about 40 nM; about 1 nM to about 25 nM; about 1 nM to about 15 nM; or about 1 nM to about 10 nM. In certain embodiments, for inhibition of EGFR having a mutation or combination of mutations selected from L858R / T790M, L858R, and T790M, the compounds of the present disclosure screened under the above conditions can have an IC 50 value of, for example, about 1 nM to >1 μM; about 1 nM to about 400 nM; about 1 nM to about 150 nM; about 1 nM to about 75 nM; about 1 nM to about 40 nM; about 1 nM to about 25 nM; about 1 nM to about 15 nM; or about 1 nM to about 10 nM.

[0126] In some embodiments, the compounds of the present disclosure bind to allosteric sites of EGFR. In some embodiments, the compounds of the present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Lys745, Leu788, and Ala743. In other embodiments, the compounds of the present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Cys755, Leu777, Phe856, and Asp855. In other embodiments, the compounds of the present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Met766, Ile759, Glu762, and Ala763. In other embodiments, the compounds of the present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Lys745, Leu788, and Ala743; at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Cys755, Leu777, Phe856, and Asp855; and at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Met766, Ile759, Glu762, and Ala763. In other embodiments, the compounds of the present disclosure do not interact with any of the amino acid residues of epidermal growth factor receptor (EGFR) selected from Met793, Gly796, and Cys797.

[0127] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor, which is a more potent inhibitor of a drug-resistant EGFR mutant compared to wild-type EGFR. In some embodiments, the drug-resistant EGFR mutant is resistant to one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, HKI-272, and osimertinib.

[0128] In some embodiments, the drug-resistant EGFR mutant comprises a sensitizing mutation, such as L858R.

[0129] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor in combination with a second activator (the second activator inhibits EGFR dimer formation), and the compound is a more potent inhibitor of drug-resistant EGFR mutants compared to wild-type EGFR. In some embodiments, the drug-resistant EGFR mutant is resistant to one or more known EGFR inhibitors, and the EGFR inhibitors include, but are not limited to, gefitinib, erlotinib, lapatinib, HKI-272, and osimertinib. In some embodiments, the drug-resistant EGFR mutant includes a sensitizing mutation, such as L858R. In some embodiments, the second activator that inhibits EGFR dimer formation is an antibody. In a further embodiment, the second activator that inhibits EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second activator that inhibits EGFR dimer formation is cetuximab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0130] In other embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor in combination with a second activator (the second activator inhibits EGFR dimer formation), and the compound in combination with the second activator is more potent than one or more known EGFR inhibitors including, but not limited to, gefitinib, erlotinib, lapatinib, HKI-272, and osimertinib, in inhibiting the activity of EGFR containing one or more of the mutations described herein, such as T790M, L718Q, L844V, L858R, and C797S. In some embodiments, the second activator that inhibits EGFR dimer formation is an antibody. In further embodiments, the second activator that inhibits EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second activator that inhibits EGFR dimer formation is cetuximab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0131] In other embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor in combination with a second activator (the second activator inhibits EGFR dimer formation), and the compound in combination with the second activator is less potent in inhibiting the activity of wild-type EGFR than one or more known EGFR inhibitors including, but not limited to, gefitinib, erlotinib, lapatinib, HKI-272, and osimertinib. In some embodiments, the second activator that inhibits EGFR dimer formation is an antibody. In further embodiments, the second activator that inhibits EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second activator that inhibits EGFR dimer formation is cetuximab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0132] The potency of the inhibitor can be determined by the EC 50 value. A compound with a low EC 50 value is a more potent inhibitor compared to a compound with a high EC 50 value when determined under substantially similar conditions. In some embodiments, substantially similar conditions include determining EGFR-dependent phosphorylation levels in vitro or in vivo (e.g., in 3T3 cells expressing wild-type EGFR, mutant EGFR, or a fragment of either).

[0133] The potency of the inhibitor can also be determined by the IC 50 value. A compound with a low IC 50 value is a more potent inhibitor when determined under substantially similar conditions compared to a compound with a high IC 50It is a more potent inhibitor compared to compounds with high values. In some embodiments, substantially similar conditions include determining EGFR-dependent phosphorylation levels, either in vitro or in vivo (e.g., in 3T3 cells expressing wild-type EGFR, mutant EGFR, or any fragment thereof).

[0134] EGFR-sensitizing mutations include, but are not limited to, L858R, G719S, G719C, G719A, and / or L861Q. Drug-resistant EGFR mutants can have drug-resistant mutations including, but not limited to, T790M, T854A, L718Q, C797S, or D761Y.

[0135] The selectivity between wild-type EGFR and EGFR containing one or more mutations described herein can also be measured using a cell proliferation assay where cell proliferation is dependent on kinase activity. For example, murine Ba / F3 cells transfected with an appropriate version of wild-type EGFR (e.g., VIII; containing the WT EGFR kinase domain), or Ba / F3 cells transfected with L858R / T790M, L858R / T790M / L718Q, L858R / C797S, L858R / T790M / C797S, or L858R / T790M / I941R can be used. The proliferation assay is performed at a range of inhibitor concentrations (10 μΜ, 3 μΜ, 1.1 μΜ, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM), and the EC 50 is calculated.

[0136] An alternative method for measuring the effect on EGFR activity is to assay for EGFR phosphorylation. Wild-type or mutant (L858R / T790M, L858R / C797S, L858R / T790M / C797S, L858R / T790M / I941R, or L858R / T790M / L718Q) EGFR can be transfected into NIH-3T3 cells (which do not normally express endogenous EGFR), and the ability of an inhibitor to inhibit EGFR phosphorylation (using the concentrations as described above) can be assayed. While increasing the concentration of the inhibitor, the cells were exposed to the inhibitor for 6 hours and stimulated with EGF for 10 minutes. The effect on EGFR phosphorylation was assayed by Western blotting using a phospho-specific (Y1068) EGFR antibody.

[0137] In yet another aspect, the disclosure provides a method of inhibiting an epidermal growth factor receptor (EGFR), comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof disclosed herein. In some embodiments, the method further comprises administering a second active agent, wherein the second active agent blocks EGFR dimerization. In some embodiments, the second active agent that blocks EGFR dimerization is an antibody. In further embodiments, the second active agent that blocks EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that blocks EGFR dimerization is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0138] In another aspect, provided herein is a method of treating or preventing a disease, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is mediated by a kinase. In further embodiments, the kinase comprises a mutated cysteine residue. In further embodiments, the mutated cysteine residue is located at a position equivalent to Cys797 in EGFR, e.g., at or near a position including positions such as Jak3, Blk, Bmx, Btk, HER2 (ErbB2), HER4 (ErbB4), Itk, Tec, and Txk. In some embodiments, the method further comprises administering a second active agent, wherein the second active agent inhibits kinase dimer formation. In some embodiments, the second active agent that inhibits kinase dimer formation is an antibody. In further embodiments, the second active agent inhibits EGFR dimer formation. In further embodiments, the second active agent that inhibits EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that inhibits EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0139] In some embodiments, the disease is mediated by EGFR (e.g., EGFR plays a role in the initiation or development of the disease). In some embodiments, the disease is mediated by a Her-kinase. In further embodiments, the Her-kinase is HER1, HER2, or HER4.

[0140] In certain embodiments, the disease is resistant to known EGFR inhibitors, which include, but are not limited to, gefitinib, erlotinib, or osimertinib. In certain embodiments, a diagnostic test is performed to determine whether the disease is associated with an activating mutation in EGFR. In certain embodiments, a diagnostic test is performed to determine whether the disease is associated with an EGFR having an activating mutation and / or a drug-resistant mutation. Activating mutations include, but are not limited to, L858R, G719S, G719C, G719A, L718Q, and / or L861Q. Drug-resistant EGFR variants can have drug-resistant mutations including, but not limited to, T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests can include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those of skill in the art that can detect nucleotide sequences.

[0141] In certain embodiments, the disease is cancer or a proliferative disorder.

[0142] In further embodiments, the disease is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, or a solid tumor. In further embodiments, the disease is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer. In still further embodiments, the disease is non-small cell lung cancer.

[0143] In certain embodiments, the disease is resistant to known EGFR inhibitors, which include, but are not limited to, gefitinib, erlotinib, or osimertinib. In certain embodiments, the diagnostic test is performed to determine whether the disease is associated with an activating mutation in EGFR. In certain embodiments, the diagnostic test is performed to determine whether the disease is associated with EGFR having an activating mutation and / or a drug-resistant mutation. Activating mutations include, but are not limited to, L858R, G719S, G719C, G719A, L718Q, and / or L861Q. The drug-resistant EGFR variant can have a drug-resistant mutation including, but not limited to, T790M, T854A, L718Q, C797S, or D761Y. The diagnostic test can include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those skilled in the art capable of detecting nucleotide sequences.

[0144] In yet another aspect, provided herein is a method of treating a kinase-mediated disorder, the method comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof disclosed herein. In some embodiments, the compound is an inhibitor of HER1, HER2, or HER4. In other embodiments, an additional therapeutic agent is administered to the subject. In other embodiments, the compound and the additional therapeutic agent are administered simultaneously or sequentially.

[0145] In another aspect, the present disclosure provides a method of treating a kinase-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a second active agent, wherein the second active agent is a method of preventing EGFR dimer formation. In some embodiments, the compound is an inhibitor of HER1, HER2, or HER4. In other embodiments, an additional therapeutic agent is administered to the subject. In other embodiments, the compound, the second active agent that prevents EGFR dimer formation, and the additional therapeutic agent are administered simultaneously or sequentially. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0146] In other embodiments, the disease is cancer. In further embodiments, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, stomach cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, or solid tumor. In further embodiments, the disease is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer. In still further embodiments, the disease is non-small cell lung cancer.

[0147] In another aspect, a method of treating cancer is provided herein, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, wherein the cancer cells comprise activated EGFR.

[0148] In another aspect, a method of treating cancer, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, which contains activated EGFR in cancer cells, and a second active agent, wherein the second active agent inhibits EGFR dimer formation, is provided herein. In some embodiments, the second active agent that inhibits EGFR dimer formation is an antibody. In further embodiments, the second active agent that inhibits EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that inhibits EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0149] In certain embodiments, EGFR activation is selected from EGFR mutation, EGFR amplification, EGFR expression, and EGFR ligand-mediated activation.

[0150] In further embodiments, the EGFR mutation is selected from G719S, G719C, G719A, L858R, and L861Q.

[0151] In yet another aspect, a method of treating cancer in a subject, wherein the subject is identified as in need of EGFR inhibition for the treatment of cancer, the method comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, is provided herein.

[0152] In certain embodiments, a subject identified as in need of EGFR inhibition is resistant to known EGFR inhibitors, including but not limited to gefitinib, erlotinib, or osimertinib. In certain embodiments, a diagnostic test is performed to determine whether the subject has an activating mutation in EGFR. In certain embodiments, a diagnostic test is performed to determine whether the subject has an EGFR with activating and / or drug-resistant mutations. Activating mutations include but are not limited to L858R, G719S, G719C, G719A, L718Q, and / or L861Q. Drug-resistant EGFR variants can have drug-resistant mutations including but not limited to T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests can include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those of skill in the art capable of detecting nucleotide sequences.

[0153] In one aspect, provided herein is a method of preventing resistance (including but not limited to gefitinib, erlotinib, or osimertinib) to known EGFR inhibitors in a subject, the method comprising administering to the subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof disclosed herein.

[0154] In another aspect, provided herein is a method of preventing resistance (including, but not limited to, gefitinib, erlotinib, or osimertinib) to known EGFR inhibitors in a disease, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a second active agent, wherein the second active agent prevents EGFR dimer formation. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab.

[0155] In one embodiment of the methods disclosed herein, the subject is human.

[0156] In another aspect, the present disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating or preventing a disease in which EGFR plays a role.

[0157] In one aspect, provided herein is a method of treating or preventing a condition selected from the group consisting of autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immunologically mediated diseases, bone diseases, metabolic diseases, nervous system diseases and neurodegenerative diseases, cardiovascular diseases, hormone-related diseases, allergies, asthma, and Alzheimer's disease. In other embodiments, the condition is selected from proliferative disorders and neurodegenerative disorders.

[0158] One aspect of the present disclosure provides compounds useful for the treatment of diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, proliferative or hyperproliferative diseases, and neurodegenerative diseases. Examples of proliferative and hyperproliferative diseases include, but are not limited to, cancer. The term "cancer" includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, urogenital, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, colorectal, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract, kidney cancer, myeloid disorders, lymphatic disorders, Hodgkin's, hairy cell, oral and pharynx (oral cavity), lip, tongue, mouth, pharynx, small intestine, colon, rectum, large intestine, rectum, brain and central nervous system, chronic myelogenous leukemia (CML), and leukemia. The term "cancer" includes, but is not limited to, the following cancers: myeloma, lymphoma, or cancer selected from the group consisting of stomach, kidney, head and neck, oral pharynx, non-small cell lung cancer (NSCLC), endometrium, hepatocellular carcinoma, non-Hodgkin lymphoma, and lung.

[0159] The term "cancer" also refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, etc. For example, cancers include, but are not limited to, mesothelioma, leukemia and lymphoma, such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotropic virus (HTLV), such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphoma, and multiple myeloma, non-Hodgkin lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndromes, childhood solid tumors, such as brain tumors, neuroblastomas, retinoblastomas, Wilms tumors, bone tumors, and soft tissue sarcomas, common adult solid tumors, such as head and neck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal), genitourinary cancers (e.g., prostate, bladder, kidney, uterus, ovary, testis), lung cancers (e.g., small cell and non-small cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer. Additional exemplary forms of cancer that can be treated by the subject compound include, but are not limited to, cancers of the skeleton or smooth muscle, stomach cancer, small intestine cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0160] Additional cancers for which the compounds described herein may be useful for prevention, treatment and research include, for example, colon cancer, familial adenomatous polyposis cancer and hereditary non-polyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, cancer of the lip, larynx, hypopharynx, tongue, salivary gland, stomach, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), kidney cancer, renal cell carcinoma, cervical cancer, corpus cancer of the uterus, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumor, for example, glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tissue tumor, gallbladder cancer, bronchial cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, sarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma. In one aspect of the present disclosure, the present disclosure provides the use of one or more compounds of the present disclosure in the manufacture of a medicament for the treatment of cancers including, but not limited to, various types of cancers disclosed herein.

[0161] In some embodiments, the compounds of the present disclosure are useful for treating cancers such as colorectal, thyroid, breast, and lung cancer; and myeloproliferative disorders such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis. In some embodiments, the compounds of the present disclosure are useful for treating hematopoietic disorders, particularly acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute promyelocytic leukemia, and acute lymphoblastic leukemia (ALL).

[0162] The term "cancerous cell" as provided herein includes cells affected with any one of the conditions specified above.

[0163] The present disclosure further provides methods for the treatment or prevention of cell proliferative disorders such as hyperplasia, dysplasia, and pre-cancerous lesions. Dysplasia is the earliest form of pre-cancerous lesion recognizable by a pathologist in a biopsy. The subject compound can be administered for the purpose of preventing the hyperplasia, dysplasia, or pre-cancerous lesion from continuously expanding or becoming cancerous. Examples of pre-cancerous lesions can occur in the skin, esophageal tissue, and intraepithelial tissues of the breast and neck.

[0164] Examples of neurodegenerative diseases include, but are not limited to, adrenoleukodystrophy (ALD), Alexander disease, Alpers syndrome, Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, fatal familial insomnia, frontotemporal lobar degeneration, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, Lewy body dementia, neuroborreliosis, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple system atrophy, multiple sclerosis, narcolepsy, Niemann-Pick disease, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration secondary to pernicious anemia, Spielmeyer-Vogt-Sjögren-Batten disease (also known as Batten disease), spinocerebellar ataxia (numerous types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, tabes dorsalis, and toxic encephalopathy.

[0165] Another aspect of the disclosure provides a method for treating a disease selected from a proliferative or hyperproliferative disease or a neurodegenerative disease, or for reducing the severity of a disease, the method comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable composition comprising the compound. In other embodiments, the method further comprises administering a second active agent, wherein the second active agent inhibits EGFR dimer formation. In some embodiments, the second active agent that inhibits EGFR dimer formation is an antibody. In further embodiments, the second active agent that inhibits EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that inhibits EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0166] The activity of the compounds and compositions of the disclosure as EGFR kinase inhibitors can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine inhibition of either kinase activity or the ATPase activity of the activated kinase. Competitive in vitro assays can be measured by quantifying the ability of an inhibitor to bind to a protein kinase, radiolabeling the inhibitor prior to binding, isolating the inhibitor / kinase complex, and determining the amount of radiolabel bound, or by performing a competition experiment in which a novel inhibitor is incubated with a kinase bound to a known radioligand. Detailed conditions for assaying the compounds utilized as inhibitors of various kinases in the present disclosure are described in the following examples.

[0167] In accordance with the foregoing, the present disclosure provides a method for preventing or treating any of the diseases or disorders described above in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and optionally a second active agent, wherein the second active agent blocks EGFR dimer formation. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition being treated, and the desired effect.

[0168] In other embodiments, the compound and the second active agent that blocks EGFR dimer formation are administered simultaneously or sequentially.

[0169] Administration / Dosage / Formulation Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butylene glycol, dimethylformamide, oils (especially cottonseed, groundnut, corn (maize), germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, the oral compositions can also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0170] Injectable preparations (for example, sterile aqueous or oily suspensions for injection) can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in a non-toxic parenterally acceptable diluent or solvent, for example, a solution of 1,3-butanediol. Among others, water, Ringer's solution, U.S.P., and isotonic sodium chloride solution can be utilized as acceptable vehicles and solvents. In addition, sterile, non-volatile oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating non-volatile oil can be utilized, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, are used in injectable preparations.

[0171] In order to prolong the action of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material having poor water solubility. Thus, the absorption rate of a drug depends on its dissolution rate and, thus, can depend on crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0172] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which are solid at ambient temperature but liquid at body temperature and thus melt within the rectum or vaginal cavity to release the active compound.

[0173] Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0174] The active compound can also be in microencapsulated form using one or more excipients as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings, release control coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound can also be admixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms can also, as is normal practice, contain additional substances other than inert diluents, such as tabletting lubricants and other tabletting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form can also contain buffering agents.

[0175] Dosage forms for topical or transdermal administration of the compounds of the present disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and, optionally, any required preservative or buffer. Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of the present disclosure.

[0176] Ointments, pastes, creams and gels can contain, in addition to the active compound of the present disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0177] Powders and sprays can contain, in addition to the compound of the present disclosure, excipients such as lactose, talc, silicic acid, aluminium hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays can further contain conventional propellants, such as chlorofluorohydrocarbons.

[0178] Transdermal patches have the additional advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable vehicle. Penetration enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0179] In accordance with the methods of treatment of the present disclosure, a disorder is treated or prevented in a subject, such as a human or other animal, by administering to the subject a therapeutically effective amount of a compound of the present disclosure in an amount and for a period of time necessary to achieve the desired result. The term "therapeutically effective amount" of a compound of the present disclosure, as used herein, means an amount of the compound sufficient to reduce the symptoms of a disorder in a subject. As is well understood in the medical arts, the therapeutically effective amount of a compound of the present disclosure is based on a reasonable benefit-risk ratio applicable to any medical treatment.

[0180] Generally, the compounds of the present disclosure are administered in a therapeutically effective amount, alone or in combination with one or more therapeutic agents, via any conventional and acceptable mode known in the art. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound being used, and other factors. Generally, satisfactory results have been shown to be obtained systemically with a daily dosage of about 0.03 - 2.5 mg / kg (body weight). The daily dosage shown in larger mammals, such as humans, is in the range of about 0.5 mg to about 100 mg and is conveniently administered, for example, in divided doses up to four times a day or in a sustained release form. Suitable unit dosage forms for oral administration contain approximately 1 - 50 mg of the active ingredient.

[0181] In certain embodiments, a therapeutic amount or dosage of a compound of the present disclosure may range from about 0.1 mg / Kg to about 500 mg / Kg, or from about 1 to about 50 mg / Kg. Generally, a treatment regimen according to the present disclosure involves administering to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of the present disclosure per day, in a single dose or multiple doses. The therapeutic amount or dosage will also vary depending on the route of administration, as well as the likelihood of co-use with other agents.

[0182] When the condition of the subject improves, a maintenance amount of the compound, composition or combination of the present disclosure may be administered, if necessary. Subsequently, the dosage or frequency or both of administration may be reduced as a function of the symptoms to a level at which the improved condition is maintained. When the symptoms have been alleviated to the desired level, treatment should be discontinued. However, the subject may, on a long-term basis, require intermittent treatment due to recurrence of any of the disease symptoms.

[0183] However, it should be understood that the total daily usage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific inhibitory dosage for any particular patient will depend on the disorder being treated and the severity of the disorder; the activity of the specific compound being utilized; the specific composition being utilized; the age, weight, general health, gender and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound being utilized; the duration of the treatment; drugs used in combination with or concurrently with the specific compound being utilized; and various factors including those well known in the medical arts.

[0184] The present disclosure also provides a kit comprising a pharmaceutical combination, for example, a) a first agent which is a compound of the present disclosure disclosed herein in free form or in a pharmaceutically acceptable salt form, and b) at least one co-administered agent. The kit can include instructions for its administration.

[0185] In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. For example, agents that block EGFR dimer formation, chemotherapeutic agents or other anti-proliferative agents can be used in combination with the compounds of the present disclosure to treat proliferative diseases and cancer.

[0186] Some examples of materials that can function as pharmaceutically acceptable carriers, but are not limited to these, include ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates, glycine, sorbic acid, or potassium sorbate; partial glyceride mixtures of plant saturated fatty acids; water; salts or electrolytes, such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate; wax; polyethylene polyoxypropylene-block polymer; lanolin; sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer. Further, non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, and coloring agents, release agents, coating agents, sweetening agents, flavoring agents and fragrances, preservatives and antioxidants can also be present in the composition at the discretion of the formulator. The protein kinase inhibitor or its pharmaceutically acceptable salt can be formulated into a pharmaceutical composition for administration to animals or humans. These pharmaceutical compositions contain an amount of the protein inhibitor effective to treat or prevent a protein kinase-mediated condition and a pharmaceutically acceptable carrier, which are other embodiments of the present disclosure.

[0187] Kit In one aspect, provided herein is a kit comprising a compound capable of inhibiting kinase activity, selected from one or more of the compounds disclosed herein or a pharmaceutically acceptable salt thereof, and instructions for use in the treatment of cancer. In certain embodiments, the kit further comprises components for performing a test to determine whether a subject has an activating mutation and / or a drug resistance mutation in EGFR.

[0188] In another aspect, the present disclosure provides a kit comprising a compound capable of inhibiting EGFR activity, selected from the compounds disclosed herein or a pharmaceutically acceptable salt thereof.

[0189] In another aspect, the present disclosure provides a kit comprising a compound capable of inhibiting kinase activity, selected from one or more of the compounds disclosed herein or a pharmaceutically acceptable salt thereof; a second active agent (the second active agent inhibits EGFR dimer formation); and instructions for use in the treatment of cancer. In certain embodiments, the kit further comprises components for performing a test to determine whether a subject has an activating mutation and / or a drug resistance mutation in EGFR. In some embodiments, the second active agent that inhibits EGFR dimer formation is an antibody. In further embodiments, the second active agent that inhibits EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that inhibits EGFR dimer formation is cetuximab.

[0190] In another aspect, the present disclosure provides a kit comprising a compound capable of inhibiting EGFR activity and a second active agent, selected from the compounds disclosed herein or pharmaceutically acceptable salts thereof, wherein the second active agent is capable of preventing EGFR dimer formation. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0191] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the present disclosure to the specific procedures described herein in terms of scope or spirit. The examples are provided to illustrate certain specific embodiments and are not intended to impose any limitation on the scope of the present disclosure. It should be further understood that various other embodiments, modifications, and equivalents thereof that may be suggested to those skilled in the art can be used without departing from the spirit and / or scope of the present disclosure and the appended claims.

Examples

[0192] This application is further illustrated by the following examples and should not be construed as being further limited. The practice of the present disclosure, unless otherwise indicated, utilizes conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the skill of those in the art.

[0193] Abbreviations AcOH Acetic acid ACN Acetonitrile DCM Dichloromethane DIEA Diisopropylethylamine DMF Dimethylformamide EtOAc Ethyl acetate HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate MeOH Methanol RT Room temperature TFA Trifluoroacetic acid THF Tetrahydrofuran tol Toluene TsOH p-Toluenesulfonic acid

[0194] [Example 1] Synthesis procedure Scheme 1. Synthesis of compound 001

[0195] [Chemical formula]

[0196] Ethyl 2-(5-bromo-2-hydroxybenzamide)-2-(3-fluorophenyl)acetate Diisopropylethylamine (870 μL, 5 mmol) was added to a mixture of ethyl 2-amino-2-(3-fluorophenyl)acetate (350 mg, 1.5 mmol), 5-bromo-2-hydroxybenzoic acid (217 mg, 1 mmol) and HATU (760 mg, 2 mmol) in DMF (3 mL). The reaction mixture was stirred at 60 °C for 1.5 hours, cooled, poured into brine (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0 - 80% EtOAc in hexane) to give the title compound (261 mg, 66%). 11H NMR (500 MHz, CDCl3) δ: 11.85 (s, 1H) 7.63 (d, 1H) 7.52 (dd, 1H) 7.39 (m, 2H) 7.25 (m, 1H), 7.17 (m, 1H) 7.08 (m, 1H) 6.90 (d, 1H) 5.70 (d, 1H) 4.33 (q, 1H) 4.26 (q, 1H) 1.28 (t, 3H); MS m / z: [M+1] + , 396.0.

[0197] Ethyl 2-(6-bromo-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-2-(3-fluorophenyl)acetate A mixture of ethyl 2-(5-bromo-2-hydroxybenzamide)-2-(3-fluorophenyl)acetate (261 mg, 0.66 mmol), paraformaldehyde (42 mg, 1.45 mmol), and 4-methylbenzenesulfonic acid (250 mg, 1.39 mmol) in toluene (5 mL) was heated at 100 °C for 2 h. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (0 - 30% EtOAc in hexane) to give the title compound (250 mg, 93%). 1 1H NMR (500 MHz, CDCl3) δ: 8.14 (d, 1H) 7.56 (dd, 1H) 7.42 (m, 1H) 7.13 (m, 2H) 7.08 (m, 1H) 6.87 (d, 1H) 6.51 (s, 1H) 5.47 (d, 1H) 5.01 (d, 1H) 4.35 (m, 2H) 1.35 (t, 3H); MS m / z: [M+1] + , 408.0.

[0198] 2-(6-Bromo-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-2-(3-fluorophenyl)acetic acid A mixture of ethyl 2-(6-bromo-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-2-(3-fluorophenyl)acetate (250 mg, 0.61 mmol) in water (2 mL), THF (2 mL), and MeOH (2 mL) was treated with LiOH-H2O (64 mg, 1.53 mmol). The reaction mixture was stirred at room temperature for 15 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in water (15 mL). The solution was acidified to pH 3 with 6N HCl and extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (225 mg, 97%). 1 H NMR (500 MHz, CDCl3) δ: 8.12 (d, 1H) 7.57 (dd, 1H) 7.44 (m, 1H) 7.20 (d, 1H) 7.14 (m, 2H) 6.86 (d, 1H) 6.52 (s, 1H) 5.41 (d, 1H) 4.99 (d, 1H); MS m / z: [M+1] + , 379.9.

[0199] 2-(6-Bromo-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-2-(3-fluorophenyl)-N-(thiazol-2-yl)acetamide Diisopropylethylamine (177 μL, 1.02 mmol) was added to a mixture of 2-(6-bromo-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-2-(3-fluorophenyl)acetic acid (130 mg, 0.34 mmol), 2-aminothiazole (51 mg, 0.51 mmol) and HATU (258 mg, 0.68 mmol) in DMF (1.5 mL). The reaction mixture was stirred at 50 °C for 1.5 hours. After cooling to room temperature, the mixture was poured into water (20 mL), and the resulting precipitate was filtered, washed with water, and dried to afford the title compound (95 mg, 60%). 11H NMR (500 MHz, DMSO-d6) δ: 7.94 (d, 1H) 7.74 (dd, 1H) 7.52 (m, 2H) 7.33 (m, 2H) 7.17 (m, 2H) 7.08 (d, 1H) 6.53 (s, 1H) 5.48 (d, 1H) 5.12 (d, 1H); MS m / z: [M+1] + , 461.9.

[0200] Compound 1 2-(3-Fluorophenyl)-2-(6-(4-(1-Methylpiperidin-4-yl)phenyl)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-N-(thiazol-2-yl)acetamide

[0201]

Chem.

[0202] A mixture of 2-(6-Bromo-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-2-(3-fluorophenyl)-N-(thiazol-2-yl)acetamide (45 mg, 0.097 mmol), Na2CO3 (31 mg, 0.29 mmol) and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (36 mg, 0.12 mmol) in dioxane (2 mL) and water (0.5 mL) was degassed in a sealed tube and filled with N2 three times. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.009 mmol) was added, the vessel was resealed and filled with N2. The mixture was heated at 105 °C for 1 h. After cooling, the whole reaction mixture was purified by reverse-phase-HPLC eluting with 0 - 80%, ACN / H2O (modified with 0.038% TFA) to give the title compound (10 mg, 19%). 11H NMR (500 MHz, DMSO-d6) δ: 9.29 (br s, 1H) 8.08 (d, 1H) 7.88 (dd, 1H) 7.65 (d, 2H) 7.54 (m, 1H) 7.53 (d, 1H) 7.35 (d, 2H) 7.33 (m, 2H) 7.18 (m, 3H) 6.56 (s, 1H) 5.51 (d, 1H) 5.14 (d, 1H) 3.54 (d, 2H) 3.10 (m, 2H) 2.85 (m, 1H) 2.83 (d, 3H) 2.06 (d, 2H) 1.85 (m, 2H); MS m / z: [M+1] + , 557.2.

[0203] Compound 2 2-(3-Fluorophenyl)-2-(6-(4-(4-methylpiperazin-1-yl)phenyl)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-N-(thiazol-2-yl)acetamide

[0204]

Chem.

[0205] Compound 2 was prepared from 2-(3-fluorophenyl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-N-(thiazol-2-yl)acetamide and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine in a manner similar to that of Compound 1. 11H NMR (500 MHz, DMSO-d6) δ: 9.64 (br s, 1H) 8.03 (d, 1H) 7.84 (dd, 1H) 7.59 (d, 2H) 7.55 (m, 1H) 7.53 (d, 1H) 7.34 (d, 1H) 7.31 (m, 1H) 7.18 (d, 2H) 7.14 (d, 1H) 7.11 (d, 2H) 6.56 (s, 1H) 5.49 (d, 1H) 5.12 (d, 1H) 3.93 (d, 2H) 3.54 (d, 2H) 3.18 (m, 2H) 3.00 (m, 2H) 2.87 (d, 3H); MS m / z: [M+1] + , 558.2.

[0206] Compounds 3 - 5 were prepared from methyl 2 - amino - 2-(3 - fluorophenyl)acetate and the corresponding benzoic acids in a manner similar to that of Compound 1.

[0207]

Table 3

[0208] 3 - Bromo - 2 - fluoro - 6 - hydroxybenzoic acid Boron tribromide (1.74 mL, 18.1 mmol) was added dropwise to a solution of 3 - bromo - 2 - fluoro - 6 - methoxybenzoic acid (1.5 g, 6.02 mmol) in dichloromethane (17 mL) at -78 °C under nitrogen, stirred for 1 h, then stirred at room temperature for 1 h. The reaction was quenched with water, stirred for 10 min, then poured into brine (10 mL) and extracted with DCM (3 × 30 mL). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give the title compound (742 mg, 53%). 1 1H NMR (500 MHz, DMSO-d6) δ: 7.61 (m, 1H) 6.75 (d, 1H); MS m / z: [M+1] + , 236.9.

[0209] Scheme 2. Synthesis of Compound 6

[0210] [Chem.]

[0211] 2-Hydroxy-4-iodobenzamide A mixture of methyl 2-hydroxy-4-iodobenzamide (3.0 g, 10.79 mmol) and ammonium hydroxide (8.5 mL, 269.7 mmol) in isopropanol (10 mL) was stirred at 60 °C for 5 h. After cooling, the reaction mixture was concentrated under reduced pressure, added to saturated brine (10 mL), and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with saturated brine, dried over MgSO4, filtered, concentrated under reduced pressure, and the residue was purified by silica chromatography (0 - 50% EtOAc / hexane) to give the title compound (1.97 g, 70%). MS m / z: [M+1] + , 263.7.

[0212] 7-Iodo-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one A mixture of 2-hydroxy-4-iodobenzamide (1.8 g, 6.84 mmol), formic acid (6 mL), and 37% formaldehyde (6 mL) was stirred at 95 °C for 2 h. After cooling, the reaction mixture was neutralized with saturated aqueous Na2CO3 and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with saturated brine, dried over MgSO4, filtered, concentrated under reduced pressure, and the residue was purified by silica chromatography (0 - 85% EtOAc / hexane). The intermediate product was dissolved in toluene (25 mL), stirred at 105 °C for 3.5 h, and then concentrated under reduced pressure to give the title compound (750 mg, 40%). 1 H NMR (500 MHz, DMSO-d6) δ: 10.19 (br s, 1H) 7.57 (d, 1H) 7.23 (s, 1H) 7.09 (d, 1H) 4.83 (d, 2H); MS m / z: [M+1] + , 276.0.

[0213] Methyl 2-(5-fluoro-2-methoxyphenyl)-2-(7-iodo-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)acetate A mixture of 7-iodo-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one (610 mg, 2.22 mmol), methyl 2-bromo-2-(5-fluoro-2-methoxyphenyl)acetate (645 mg, 2.33 mmol), and Cs2CO3 (1.45 g, 4.44 mmol) in DMF (15 mL) was stirred at 65 °C for 1 h. Another aliquot of methyl 2-bromo-2-(5-fluoro-2-methoxyphenyl)acetate (100 mg, 0.36 mmol) was added and the reaction mixture was heated for an additional 15 min. After cooling, the reaction mixture was poured into saturated brine (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with saturated brine, dried over MgSO4, filtered, concentrated under reduced pressure, and purified by silica chromatography (0–40% EtOAc / hexane) to afford the title compound (248 mg, 24%). 1 H NMR (500 MHz, DMSO-d6) δ: 7.57 (m, 2H) 7.50 (d, 1H) 7.26 (m, 1H) 7.15 (m, 2H) 6.26 (s, 1H) 5.41 (d, 1H) 5.14 (d, 1H) 3.77 (s, 3H) 3.72 (s, 3H); MS m / z: [M+1] + , 472.1.

[0214] 2-(5-Fluoro-2-methoxyphenyl)-2-(7-iodo-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)acetic acid A mixture of methyl 2-(5-fluoro-2-methoxyphenyl)-2-(7-iodo-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)acetate (245 mg, 0.52 mmol) and lithium hydroxide monohydrate (33 mg, 0.78 mmol) in water (1 mL), methanol (1 mL), and THF (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and then poured into water and adjusted to pH 2 with hydrochloric acid (1.5 N). The mixture was filtered to give the title compound (205 mg, 86%). 1 H NMR (500 MHz, DMSO-d6) δ: 7.57 (s, 1H) 7.56 (d, 1H) 7.49 (d, 1H) 7.25 (m, 1H) 7.13 (m, 1H) 7.12 (m, 1H) 6.19 (s, 1H) 5.41 (d, 1H) 5.15 (d, 1H) 3.76 (s, 3H); MS m / z: [M+1] + , 457.7.

[0215] N-(2-Aminophenyl)-2-(5-fluoro-2-methoxyphenyl)-2-(7-iodo-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)acetamide Diisopropylethylamine (0.234 mL, 1.35 mmol) was added to a mixture of 2-(5-fluoro-2-methoxyphenyl)-2-(7-iodo-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)acetic acid (205 mg, 0.448 mmol), 1,2-phenylenediamine (97 mg, 0.897 mmol), and HATU (341 mg, 0.897 mmol) in DMF (3 mL), and the mixture was stirred at 50 °C for 3 hours. After cooling, the reaction mixture was poured into saturated brine (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with saturated brine, dried over MgSO4, filtered, concentrated under reduced pressure, and purified by reverse-phase HPLC eluting with 0 - 80% ACN / H2O (0.038% TFA modifier) to give the title compound. This was used in the next step. 11H NMR (500 MHz, DMSO-d6) δ: 9.73 (s, 1H), 7.61 (d, 1H), 7.57 (dd, 1H), 7.48 (d, 1H), 7.28 (m, 1H), 7.19 (dd, 1H), 7.16 (dd, 1H), 7.13 (dd, 1H), 6.95 (m, 1H), 6.75 (dd, 1H), 6.59 (m, 1H), 6.51 (s, 1H), 5.42 (d, 1H), 5.09 (d, 1H), 3.74 (s, 3H); MS m / z: [M+1] + , 547.7.

[0216] 3-((1H-Benzimidazol-2-yl)(5-fluoro-2-methoxyphenyl)methyl)-7-iodo-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one A solution of N-(2-aminophenyl)-2-(5-fluoro-2-methoxyphenyl)-2-(7-iodo-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)acetamide (10 mL) in acetic acid was heated at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (98 mg, 40% over 2 steps). 1 1H NMR (500 MHz, DMSO-d6) δ: 7.60 (m, 4H), 7.53 (s, 1H), 7.28 (m, 3H), 7.19 (s, 1H), 7.17 (dd, 1H), 6.94 (d, 1H), 5.52 (d, 1H), 5.34 (d, 1H), 3.72 (s, 3H); MS m / z: [M+1] + , 529.7.

[0217] 3-((1H-Benzimidazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-7-iodo-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one Boron tribromide (0.034 mL, 0.357 mmol) was added dropwise to a solution of 3-((1H-benzo[d]imidazol-2-yl)(5-fluoro-2-methoxyphenyl)methyl)-7-iodo-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one (98 mg, 0.178 mmol) in dichloromethane (2 mL) at -78 °C, and the mixture was stirred for 2 h. The reaction was then stirred at room temperature overnight. Another aliquot of boron tribromide (0.069 mL, 0.714 mmol) was added and the mixture was stirred at room temperature for 7 h. The reaction was quenched with water, poured into saturated brine (10 mL), and extracted with DCM (3 × 30 mL). The combined organic extracts were washed with saturated brine, dried over MgSO4, and concentrated under reduced pressure to afford the title compound (45 mg, 49%). MS (m / z): [M+1] + , 516.2.

[0218] 3-((1H-benzo[d]imidazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-7-(4-(1-methylpiperidin-4-yl)phenyl)-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one

[0219] [Chemical Structure] 3 - ((1H - Benzo[d]imidazol - 2 - yl)(5 - fluoropheny - 2 - hydroxyphenyl)methyl) - 7 - iodo - 2,3 - dihydro - 4H - benzo[e][1,3]oxazin - 4 - one (45 mg, 0.0873 mmol), 1 - methyl - 4 - (4 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)phenyl)piperidine (289 mg, 0.96 mmol), Pd(dppf)Cl2 - DCM (14 mg, 0.0175 mmol), and Na2CO3 (28 mg, 0.262 mmol) in a mixture of dioxane (3.75 mL) and water (1.2 mL) were heated in a sealed vial under N2 at 90 °C for 17.5 h. After cooling, the reaction mixture was filtered through a syringe filter and purified by reverse - phase HPLC eluting with 0 - 80% ACN / H2O (modified with 0.038% TFA) to afford Compound 006 (6.5 mg, 13%). 1 H NMR (500 MHz, DMSO - d6) δ: 9.98 (s, 1H) 9.28 (br s, 1H) 7.91 (d, 1H) 7.73 (d, 2H) 7.58 (m, 2H) 7.49 (dd, 1H) 7.37 (d, 2H) 7.34 (d, 1H) 7.24 (m, 2H) 7.20 (s, 1H) 7.10 (m, 1H) 6.91 (dd, 1H), 6.79 (d, 1H) 5.58 (d, 1H) 5.38 (d, 1H) 3.54 (d, 2H) 3.10 (m, 2H) 2.86 (m, 1H) 2.84 (d, 3H) 2.06 (d, 2H) 1.84 (m, 2H); MS m / z: [M + 1] + , 563.0.

[0220] Methyl 2 - bromo - 2 - (5 - fluoropheny - 2 - methoxyphenyl)acetate was prepared according to the procedure described in WO2021 / 096948.

[0221] Scheme 3. Synthesis of Compound 7

[0222]

Chem.

[0223] 6-Iodo-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one A mixture of 2-hydroxy-5-iodobenzamide (2.82 g, 10.7 mmol), formic acid (15 mL), and 37% formaldehyde (15 mL) was stirred at 95 °C for 1 h. After cooling, the reaction mixture was quenched with water and extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with saturated brine, dried over MgSO4, filtered, concentrated under reduced pressure, and the residue was purified by normal-phase flash chromatography (0 - 60% EtOAc / hexane) to give the title compound (368 mg) and 3-(hydroxymethyl)-7-iodo-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one as a byproduct. This byproduct was dissolved in toluene (25 mL) and stirred at 105 °C overnight and then concentrated under reduced pressure to give an additional batch of the title compound as a white solid. This was combined with the first batch (818 mg, 28%). 1 H NMR (500 MHz, DMSO-d6) δ: 8.74 (br s, 1H) 8.00 (d, 1H) 7.82 (dd, 1H) 6.91 (d, 1H) 5.17 (d, 2H); MS (m / z): [M+1] + , 275.88.

[0224] Methyl 2-(5-fluoro-2-(methoxymethoxy)phenyl)-2-(6-iodo-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)acetate A mixture of 6-iodo-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one (0.818 g, 2.76 mmol), methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate (1.06 g, 3.32 mmol), and cesium carbonate (1.80 g, 5.52 mmol) in DMF (20 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into saturated brine (30 mL) and extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with saturated brine, dried over MgSO4, filtered, concentrated under reduced pressure, and purified by normal-phase flash chromatography (0 - 70% EtOAc / hexane) to afford the title compound as a colorless oil (362 mg, 26%). 1 H NMR (500 MHz, DMSO-d6) δ: 8.09 (d, 1H) 7.86 (dd, 1H) 7.25 (m, 1H) 7.19 (m, 2H) 6.91 (d, 1H) 6.32 (s, 1H) 5.43 (d, 1H) 5.21 (d, 1H) 5.20 (d, 1H) 5.16 (d, 1H) 3.74 (s, 3H) 3.31 (s, 3H); MS (m / z): [M+1] + , 501.89.

[0225] Methyl 2-(5-fluoro-2-(methoxymethoxy)phenyl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)acetate Methyl 2-(5-fluoro-2-(methoxymethoxy)phenyl)-2-(6-iodo-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)acetate (0.362 g, 0.722 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (0.433 g, 1.44 mmol), Pd(dppf)Cl2-DCM (0.118 g, 0.144 mmol), and Na2CO3 (0.229 g, 2.16 mmol) in dioxane (5 mL) and water (1.6 mL) were heated in a sealed vial under N2 at 90 °C for 30 min. After cooling, the reaction mixture was poured into saturated brine (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure, and purified by reverse-phase HPLC eluting with 0 - 80% ACN / H2O (0.038% TFA modifier) to give the title compound as a white solid (240 mg, 61%). 1 H NMR (500 MHz, DMSO-d6) δ: 9.27 (br s, 1H) 8.06 (d, 1H) 7.86 (dd, 1H) 7.66 (d, 2H) 7.35 (d, 2H) 7.26 (m, 1H) 7.20 (m, 2H) 7.16 (d, 1H) 6.36 (s, 1H) 5.47 (d, 1H) 5.23 (d, 1H) 5.22 (d, 1H) 5.18 (d, 1H) 3.75 (s, 3H) 3.54 (d, 2H) 3.10 (m, 2H) 2.85 (m, 1H) 2.84 (d, 3H) 2.06 (d, 2H) 1.85 (m, 2H); MS (m / z): [M+1] + , 549.19.

[0226] 2-(5-Fluoro-2-(methoxymethoxy)phenyl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)acetic acid Methyl 2-(5-fluoro-2-(methoxymethoxy)phenyl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)acetate (0.240 g, 0.437 mmol) and lithium hydroxide monohydrate (0.028 g, 0.656 mmol) in water (2 mL), methanol (2 mL), and THF (2 mL) were stirred at room temperature for 30 minutes. Another aliquot of lithium hydroxide (0.028 g, 0.656 mmol) was added and the reaction was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, then poured into water and adjusted to pH 7 with hydrochloric acid (1 N). The mixture was filtered and the title compound was recovered as a purple solid (100 mg, 43%). MS (m / z): [M+1] + , 535.16.

[0227] 3-((1H-Benzimidazol-2-yl)(5-fluoro-2-(methoxymethoxy)phenyl)methyl)-6-(4-(1-methylpiperidin-4-yl)phenyl)-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one DIEA (0.163 mL, 0.935 mmol) was added to a mixture of 2-(5-fluoro-2-(methoxymethoxy)phenyl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)acetic acid (0.100 g, 0.187 mmol), 1,2-phenylenediamine (0.040 g, 0.374 mmol), and HATU (0.142 g, 0.374 mmol) in DMF (3 mL) and stirred at room temperature for 30 minutes. The reaction mixture was poured into saturated brine (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was used without further purification in the next step. MS (m / z): [M+1] + , 625.53.

[0228] The solution of the above material in acetic acid (6 mL) was heated at 65 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and used as such without further purification in the next step. MS (m / z): [M+1] + , 607.26.

[0229] 3-((1H-Benzimidazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-6-(4-(1-methylpiperidin-4-yl)phenyl)-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one 2,2,2-trifluoroacetate

[0230] [Chemical formula] A solution of 3-((1H-benzimidazol-2-yl)(5-fluoro-2-(methoxymethoxy)phenyl)methyl)-6-(4-(1-methylpiperidin-4-yl)phenyl)-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one in DCM (2 mL) and TFA (2 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase HPLC eluting with 0 - 80% ACN / H2O (0.038% TFA modifier) to give Compound 007 as the TFA salt as a white solid (31 mg from the acid, 24% yield). 1 H NMR (500 MHz, DMSO-d6) δ: 10.02 (br s, 1H) 9.30 (br s, 1H) 8.06 (d, 1H) 7.86 (dd, 1H) 7.67 (d, 2H) 7.59 (m, 2H) 7.35 (d, 2H) 7.26 (m, 2H) 7.20 (s, 1H) 7.17 (d, 1H) 7.13 (m, 1H) 6.92 (dd, 1H) 6.81 (m, 1H) 5.59 (d, 1H) 5.37 (d, 1H) 3.54 (d, 2H) 3.12 (m, 2H) 2.84 (m, 4H) 2.06 (d, 2H) 1.84 (m, 2H); MS (m / z): [M+1] + , 563.19.

[0231] Methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate was prepared according to the procedure described in WO2021096948.

[0232] [Example 2] HTRF-based EGFR biochemical assay The biochemical activity of EGFR was measured using a homogeneous time-resolved fluorescence (HTRF) assay (Cisbio). Inhibitors and a standardized DMSO solution were first dispensed into an empty black low-volume 384-well plate (Corning) equipped with a D300 digital liquid dispenser (HP). All reactions were performed at room temperature, and solutions were added to the plate using a Multidrop Combi Reagent Dispenser (ThermoFisher). The reaction mixture (10 μL final volume) contained 1 μM tyrosine kinase peptide-biotin substrate and mutant EGFR in reaction buffer (50 mM HEPES pH 7.0, 5 mM MgCl2, 1 mM MnCl2, 0.01% BSA, 2 mM TCEP, 0.1 mM NaVO4). The enzyme concentration was adjusted to accept different kinase activities (L858R 0.1 nM, L858R / T790M 0.02 nM). The enzyme reaction solution (2× concentration, 5 μL) was added to the 384-well plate containing the compound and incubated for 30 minutes. With the addition of 5 μL of ATP up to a final concentration of 100 μM, the enzyme reaction was initiated and reacted for 20 minutes. The reaction was quenched by the addition of 10 μL of phospho-tyrosine antibody-europium(III) cryptate (1:180 volume ratio) and streptavidin XL665 (46.7 nM) in detection buffer containing EDTA, then incubated at room temperature for 1 hour and read on a PHERAstar plate reader (excitation = 337 nm, emission = 620 nm and 665 nm). The IC 50 values were determined by non-linear least squares fitting method in GraphPad Prism 7.0d, in triplicate, by an inhibition curve (an 11-point curve from 1.0 μM to 0.130 nM or a 23-point curve from 1.0 μM to 0.130 pM). The data obtained are shown in Table 3 below.

[0233] [Table 4]

[0234] [Example 3] Ba / F3 cell proliferation model EGFR mutants L858R and L858R / T790M Ba / F3 cells have been described previously (Zhou, W., et al. Nature 462, 2009, 1070-1074). All cell lines were maintained in RPMI 1640 (Cellgro; Mediatech Inc., Herndon, VA) supplemented with 10% FBS, 100 units / mL penicillin, and 100 units / mL streptomycin. The EGFR I941R mutation was introduced via site-directed mutagenesis using the Quick Change Site-Directed Mutagenesis kit (Stratagene; La Jolla, CA) according to the manufacturer's instructions. All constructs were confirmed by DNA sequencing. The constructs were transferred into the retroviral vector JP1540 using the Cre recombination system (Agilent Technologies, Santa Clara, CA). Ba / F3 cells were then infected with the retrovirus according to a standard protocol as previously described (Zhou, et al, Nature 2009). Stable clones were obtained by selection with puromycin (2 μg / ml).

[0235] Growth and growth inhibition were evaluated by the Cell Titer Glo assay (Promega, Madison, WI) and performed according to the manufacturer's instructions. The Cell Titer Glo assay is a luminescence-based method used to determine the number of viable cells based on the quantification of ATP present, and the number of viable cells is directly proportional to the amount of metabolically active cells present. Ba / F3 cells of different EGFR genotypes were exposed to the compounds disclosed herein for 72 hours, and the number of cells used in each experiment was determined empirically as previously established (Zhou, et al., Nature 2009). All experimental points were plated in triplicate within 384-well plates, and all experiments were repeated at least three times. A luminometer was used to detect the luminescent signal, and the data were graphed using GraphPad Prism version 5.0 in the window (GraphPad Software; www.graphpad.com). Curves were fitted using a non-linear regression model with a sigmoid dose response. The results of this assay for the compounds disclosed herein are shown in Table 4 below.

[0236] [Table 5]

[0237] The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the present disclosure in addition to those described will become apparent to those of ordinary skill in the art from the foregoing description and the accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

[0238] All references cited herein (e.g., publications or patents or patent applications) are incorporated herein by reference in their entirety and for all purposes as if each individual reference (e.g., publication or patent or patent application) were specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the scope of the following claims.

Claims

1. A compound of formula I 【Chemical 1】 or a pharmaceutically acceptable salt thereof: wherein, W and Z are each independently N, CH, C-halo, C-(C １ ~C ３ -alkyl), or C-(C １ ~C ３ -alkoxy), and X and Y are each independently N, CH, or CR ３ and provided that at least one of W, X, Y, or Z is CH, R １ is selected from the group consisting of C(O)NHR ９ , 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which are optionally substituted with one, two or three R ８ s, and R ２ is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which are optionally substituted with one, two or three R ６ groups, R ３ is, independently for each occurrence, halogen, OR ４ , NR ４ R ４ , SO ２ R ４ , SO ２ NHR ４ , NHSO ２ R ４ , C(O)OR ４ , C(O)NHR ４ , C(O)R ４ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, 3- to 7-membered cycloalkyl, C ４ -C ７ cycloalkenyl, C ６ -C １０ aryl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted one, two, or three times with R ４ and the aryl, heteroaryl, or heterocyclyl is optionally substituted one, two, or three times with R ５ . R ４ independently, for each occurrence, is H, (CH ２ ), ０～３ -(C ３ to C ７ cycloalkyl), (CH ２ ), ０～３ -(C ４ to C ７ cycloalkenyl), (CH ２ ), ０～３ -(C ６ to C １０ aryl), (CH ２ ), ０～３ -(5- to 6-membered heteroaryl), and (CH ２ ), ０～３ -(5- to 7-membered heterocyclyl), selected from the group consisting of, said aryl, heteroaryl, or heterocyclyl being optionally substituted one, two, or three times each with R ５ ; R ５ is, independently for each occurrence, C １ to C ６ alkyl, C １ to C ６ haloalkyl, C １ to C ６ alkoxy, C １ to C ６ haloalkoxy, C １ to C ３ alkylamine, 3- to 10-membered cycloalkyl, halogen, COOH, C(O)O(C １ to C ６ alkyl), O(CH ２ ), １～３ -OH, NH ２ , NH(C １ to C ６ alkyl), N(C １ to C ６ alkyl), ２ , OH, CN, (CH ２ ), ０～３ -(C ６ to C １０ aryl), (CH ２ ), ０～３ -(5- to 6-membered heteroaryl), and (CH ２ ), ０～３ -(5- to 7-membered heterocyclyl), and is selected from the group consisting of, wherein said aryl, heteroaryl, or heterocyclyl is optionally substituted one, two or three times each with R ７ ; R ６ independently, for each occurrence, is selected from the group consisting of C １ to C ３ alkyl, C １ to C ３ haloalkyl, C １ to C ３ alkoxy, C １ to C ３ haloalkoxy, C １ to C ３ alkylamine, halogen, OH, NO ２ , NH ２ , NH(C １ to C ６ alkyl), N(C １ to C ６ alkyl), ２ , (CH ２ ), １～４ OH, S(O) ０～２ H, S(O) ０～２ NH ２ , or CN; Alternatively, two Rs ６ together with the atoms to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl, R ７ is, independently for each occurrence, C １ to C ６ alkyl, C １ to C ６ haloalkyl, C １ to C ６ alkoxy, C １ to C ６ haloalkoxy, halogen, NH ２ , NH(C １ to C ６ alkyl), N(C １ to C ６ alkyl) ２ , SO ２ NH ２ , SO ２ NH(C １ to C ６ alkyl), SO ２ N(C １ to C ６ alkyl) ２ , (CH ２ ) １～２ -OH, C(O)(CH ２ ) １～２ -OH, C(O)(C １ to C ６ alkyl), and C(O)O(C １ to C ６ alkyl) selected from the group consisting of, Alternatively, two Rs ７ together with the atoms to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl, R ８ independently, for each occurrence, is hydrogen, C １ to C ３ alkyl, C １ to C ３ haloalkyl, C １ to C ３ alkoxy, C １ to C ３ haloalkoxy, C １ to C ３ alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO ２ , NH ２ , NH(C １ to C ６ alkyl), N(C １ to C ６ alkyl) ２ , (CH ２ ) １～４ OH, S(O) ０～２ H, S(O) ０～２ NH ２ , or CN, and is selected from the group consisting of R ９ is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl].

2. W and Z are each independently N, C-halo, or CH, X and Y are each independently CH or CR ３ wherein provided that at least one of W, X, Y, or Z is CH, R １ is C(O)NHR ９ and is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl R ２ is selected from the group consisting of 6- to 10-membered aryl and 5- to 10-membered heteroaryl, both being optionally substituted with one, two or three R ６ groups, R ３ is, independently, for each occurrence, C ６ to C １０ selected from the group consisting of aryl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted one, two, or three times with R ５ respectively, R ５ is, independently, for each occurrence, selected from the group consisting of 3- to 10-membered cycloalkyl, (CH ２ ), ０～３ -(C ６ to C １０ aryl), (CH ２ ), ０～３ -(5- to 6-membered heteroaryl), and (CH ２ ), ０～３ -(5- to 7-membered heterocyclyl), wherein said aryl, heteroaryl, or heterocyclyl is each optionally substituted one, two, or three times with R ７ ; R ６ is, independently, for each occurrence, C １ to C ３ alkyl, C １ to C ３ haloalkyl, C １ to C ３ alkoxy, C １ to C ３ haloalkoxy, C １ to C ３ selected from the group consisting of alkylamine, halogen, and OH, R ７ is, independently, for each occurrence, selected from the group consisting of C １ to C ６ alkyl, C １ to C ６ haloalkyl, C １ to C ６ alkoxy, and halogen R ８ is selected from the group consisting of hydrogen, C １ to C ３ alkyl, C １ to C ３ haloalkyl, and C １ to C ３ alkoxy, R ９ The compound according to claim 1, wherein R is a 5- to 10-membered heteroaryl.

3. The compound of formula I is a compound of formula IIa or IIb: [Chemical Formula 2] or a pharmaceutically acceptable salt thereof wherein n is 0, 1, or 2, the compound according to claim 1 or 2.

4. The compound according to any one of claims 1 to 3, wherein W is CH.

5. The compound according to any one of claims 1 to 4, wherein Z is CH or C-halo.

6. The compound according to any one of claims 1 to 5, wherein Z is C-halo.

7. R １ is C(O)NHR ９ or a 5- to 10-membered heteroaryl, the compound according to any one of claims 1 to 6.

8. R １ is 【Chemical Formula 3】 selected from the group consisting of, R ８ is C １ to C ３ is alkyl, the compound according to any one of claims 1 to 7.

9. R １ is [Chemical Formula 4] the compound according to any one of claims 1 to 8

10. R ３ is, independently, for each occurrence, R ５ which is optionally substituted one, two or three times with C ６ to C １０ which is aryl, R ５ is, independently, in each of the existences, R ７ is optionally substituted one, two or three times with (CH ２ ) ０～３ - (5- to 7-membered heterocyclyl) and is selected from the group consisting of R ７ is, independently, for each occurrence, C １ -C ６ A compound according to any one of claims 1 to 9, selected from the group consisting of alkyls.

11. R ３ independently occurs each time [Chemical Formula 5] The compound according to any one of claims 1 to 10, selected from the group consisting of

12. R ３ independently occurs each time ​ The compound according to any one of claims 1 to 11, selected from the group consisting of

13. The compound according to any one of claims 1 to 12, wherein the compound of formula I is selected from the group consisting of the compounds in Table 1 or a pharmaceutically acceptable salt thereof.

14. A compound of formula III: [Chemical Formula 7] or a pharmaceutically acceptable salt thereof wherein, [Chemical Formula 8] represents any double bond, W is N, C, or CH, Z is selected from the group consisting of S, O, N, NH, CH ２ , C-halo, and CH X and Y are each independently S, O, N, CH, NR ３ , or CR ３ and provided that at least one of X, Y, or Z is CH, R １ is selected from the group consisting of C(O)NHR ９ , 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which are optionally substituted with one, two or three R ８ and is optionally substituted with R ２ is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which are optionally substituted with one, two or three R ６ groups, R ３ is, independently, for each occurrence, halogen, OR ４ , NR ４ R ４ , SO ２ R ４ , SO ２ NHR ４ , NHSO ２ R ４ , C(O)OR ４ , C(O)NHR ４ , C(O)R ４ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, 3- to 7-membered cycloalkyl, C ４ -C ７ cycloalkenyl, C ６ -C １０ aryl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, and is selected from the group consisting of, alkyl, alkenyl, or alkynyl is optionally substituted one, two or three times with R ４ and aryl, heteroaryl, or heterocyclyl is optionally substituted one, two or three times with R ５ respectively, R ４ independently, for each occurrence, is H, (CH ２ ), ０～３ -(C ３ ~C ７ cycloalkyl), (CH ２ ), ０～３ -(C ４ ~C ７ cycloalkenyl), (CH ２ ), ０～３ -(C ６ ~C １０ aryl), (CH ２ ), ０～３ -(5- to 6-membered heteroaryl), and (CH ２ ), ０～３ -(5- to 7-membered heterocyclyl), each independently selected from the group consisting of, wherein said aryl, heteroaryl, or heterocyclyl is optionally substituted one, two, or three times with R ５ ; R ５ is, independently, for each occurrence, C １ to C ６ alkyl, C １ to C ６ haloalkyl, C １ to C ６ alkoxy, C １ to C ６ haloalkoxy, C １ to C ３ alkylamine, 3- to 10-membered cycloalkyl, halogen, COOH, C(O)O(C １ to C ６ alkyl), O(CH ２ １～３ -OH, NH ２ , NH(C １ to C ６ alkyl), N(C １ to C ６ alkyl) ２ , OH, CN, (CH ２ ) ０～３ -(C ６ to C １０ aryl), (CH ２ ) ０～３ -(5- to 6-membered heteroaryl), O(CH ２ ) ０～３ -(4- to 7-membered heterocyclyl), and (CH ２ ) ０～３ -(4- to 7-membered heterocyclyl), and is selected from the group consisting of, wherein the alkyl, alkoxy, aryl, heteroaryl, or heterocyclyl is optionally substituted one, two or three times with R ７ respectively,​ R ６ is, independently for each occurrence, selected from the group consisting of C １ to C ３ alkyl, C １ to C ３ haloalkyl, C １ to C ３ alkoxy, C １ to C ３ haloalkoxy, C １ to C ３ alkylamine, halogen, OH, NO ２ , NH ２ , NH(C １ to C ６ alkyl), N(C １ to C ６ alkyl) ２ , (CH ２ ) １～４ OH, S(O) ０～２ H, S(O) ０～２ NH ２ , or CN Alternatively, two Rs ６ together with the atoms to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl, R ７ is, independently for each occurrence, selected from the group consisting of substituents selected from C １ to C ６ alkyl, C １ to C ６ haloalkyl, C １ to C ６ alkoxy, C １ to C ６ haloalkoxy, halogen, NH ２ , NH(C １ to C ６ alkyl), N(C １ to C ６ alkyl) ２ , SO ２ NH ２ , SO ２ NH(C １ to C ６ alkyl), SO ２ N(C １ to C ６ alkyl) ２ , (CH ２ ), １～２ -OH, C(O)(CH ２ ), １～２ -OH, C(O)(C １ to C ６ alkyl), and C(O)O(C １ to C ６ alkyl), and is selected from the group consisting of substituents independently selected therefrom, Alternatively, two Rs ７ together with the atoms to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl, R ８ independently, for each occurrence, is selected from the group consisting of C １ to C ３ alkyl, C １ to C ３ haloalkyl, C １ to C ３ alkoxy, C １ to C ３ haloalkoxy, C １ to C ３ alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO ２ , NH ２ , NH(C １ to C ６ alkyl), N(C １ to C ６ alkyl), ２ , (CH ２ ) １～４ OH, S(O) ０～２ H, S(O) ０～２ NH ２ , or CN, R ９ is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl].

15. 【Chemical Formula 9】 represents any double bond, W is C, Z is selected from the group consisting of S, O, N, NH, CH ２ , C-halo, and CH X and Y are each independently S, O, N, CH, NR ３ , or CR ３ and provided that at least one of X, Y, or Z is CH, R １ is C(O)NHR ９ and is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl R ２ is selected from the group consisting of 6- to 10-membered aryl and 5- to 10-membered heteroaryl, both being optionally substituted with one, two or three R ６ groups, R ３ is, independently, for each occurrence, C ６ to C １０ selected from the group consisting of aryl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted one, two, or three times with R ５ respectively, R ５ is, independently, for each occurrence, a 3- to 10-membered cycloalkyl, (CH ２ ), ０～３ -(C ６ -C １０ aryl), (CH ２ ), ０～３ -(5- to 6-membered heteroaryl), O(CH ２ ), ０～３ -(4- to 7-membered heterocyclyl), and (CH ２ ), ０～３ -(4- to 7-membered heterocyclyl) independently selected from the group consisting of, said aryl, heteroaryl, or heterocyclyl being optionally substituted one, two or three times each with R ７ ; R ６ is, independently, for each occurrence, C １ to C ３ alkyl, C １ to C ３ haloalkyl, C １ to C ３ alkoxy, C １ to C ３ haloalkoxy, C １ to C ３ selected from the group consisting of alkylamine, halogen, and OH R ７ is, independently, for each occurrence, selected from the group consisting of C １ to C ６ alkyl, C １ to C ６ haloalkyl, C １ to C ６ alkoxy, and halogen R ８ is selected from the group consisting of hydrogen, C １ to C ３ alkyl, C １ to C ３ haloalkyl, and C １ to C ３ alkoxy R ９ The compound according to claim 14, wherein R is a 5- to 10-membered heteroaryl.

16. The compound of formula III is a compound of formula IIIa: 【Chemical Formula 10】 or a pharmaceutically acceptable salt thereof wherein n is 0, 1, or 2, the compound according to claim 14 or 15.

17. The compound of formula III is a compound of formula IIIb: 【Chemical 11】 or a pharmaceutically acceptable salt thereof wherein n is 0, 1, or 2, the compound according to claim 14 or 15.

18. R １ is C(O)NHR ９ or a 5- to 10-membered heteroaryl, the compound according to any one of claims 14 to 17.

19. R １ is 【Chemical Formula 12】 selected from the group consisting of, R ８ is C １ ~C ３ is alkyl, and the compound according to any one of claims 14 to 18.

20. R １ is 【Chemical 13】 the compound according to any one of claims 14 to 19

21. R ３ is, independently, for each occurrence, R ５ which is arbitrarily substituted one, two or three times with C ６ ~C １０ is aryl, R ５ is independently, for each occurrence, optionally replaced one, two or three times by R ７ in (CH ２ ) ０～３ - (5- to 7-membered heterocyclyl) and is selected from the group consisting of R ７ is, independently, for each occurrence, C １ -C ６ selected from the group consisting of alkyl, a compound according to any one of claims 14 to 20.

22. R ３ is, independently, for each occurrence, 【Chemical 14】 The compound according to any one of claims 14 to 21, selected from the group consisting of

23. R ３ is, independently, for each occurrence, 【Chemical Formula 15】 The compound according to any one of claims 14 to 22, selected from the group consisting of

24. The compound according to any one of claims 14 to 23, wherein the compound of formula III is selected from the group consisting of the compounds of Table 2 or pharmaceutically acceptable salts thereof.

25. A pharmaceutical composition comprising the compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

26. The pharmaceutical composition according to claim 25, further comprising a second active agent.

27. The pharmaceutical composition according to claim 26, wherein the second active agent is selected from the group consisting of MEK inhibitors, PI3K inhibitors, and mTor inhibitors.

28. The pharmaceutical composition according to claim 26, wherein the second active agent inhibits EGFR dimer formation in a subject.

29. The pharmaceutical composition according to claim 26, wherein the second active agent is selected from the group consisting of cetuximab, trastuzumab, and panitumumab.

30. The pharmaceutical composition according to claim 26, wherein the second active agent is an ATP-competitive EGFR inhibitor.

31. The pharmaceutical composition according to claim 30, wherein the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib.

32. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 24 or the composition according to any one of claims 25 to 31.

33. The method according to claim 32, wherein the cancer is selected from the group consisting of lung cancer, colon cancer, breast cancer, endometrial cancer, thyroid cancer, glioma, squamous cell carcinoma, and prostate cancer.

34. The method according to claim 32, wherein the cancer is non-small cell lung cancer (NSCLC).

35. A method of inhibiting a kinase in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 24 or the composition according to any one of claims 25 to 31.

36. The method according to claim 35, wherein the kinase is EGFR.

37. A method of treating or preventing a kinase-mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 24 or a composition according to any one of claims 25 to 31.

38. The method according to claim 37, wherein the kinase-mediated disorder is resistant to EGFR targeted therapy.

39. The method according to claim 38, wherein the EGFR treatment therapy is selected from the group consisting of gefitinib, erlotinib, and osimertinib.

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