Mutation-selective EGFR inhibitors

Abstract

The present disclosure relates to compounds that act as allosteric inhibitors of the epidermal growth factor receptor (EGFR); pharmaceutical compositions containing the compounds; and methods of treating or preventing kinase-mediated disorders (e.g., cancer and other proliferative diseases).

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 479,487, filed January 11, 2023, 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 Nos. R01CA201049 and F32CA247198 awarded by the National Institutes of Health. The government has certain rights in this invention. [Background technology]

[0003] The epidermal growth factor receptor (EGFR, Erb-B1) belongs to a family of receptor tyrosine kinases that mediate the proliferation, differentiation and survival of normal and malignant cells (Arteaga, CL, J. Clin. Oncol. 19, 2001, 32-40). Dysregulation of EGFR has been implicated in many types of human cancer (Seymour, LK, Curr. Drug Targets 2, 2001, 117-133), and receptor overexpression is present in at least 70% of human cancers (e.g., 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, DS, et al., Crit. Rev. Oncol. Hematol. 19, 1995, 183-232; Voldborg BR, et al., Ann. Oncol. 8, 1997, 1197-1206). Therefore, EGFR has emerged as an attractive target for the design and development of diagnostic and therapeutic agents that can specifically bind to and inhibit the receptor's tyrosine kinase activity and signaling pathways in cancer cells. The two most common EGFR activating mutations in non-small cell lung cancer (NSCLC) patients are the deletion of exon 19 (del19) and the L858R point mutation.

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

[0005] To address the resistance caused by the EGFR T790M mutation, covalent EGFR inhibitors have been developed. One such covalent EGFR inhibitor is afatinib, which is potent against both mutant and wild-type (WT) EGFR (Li, D.; et al., Oncogene 27, 2008 (4702-2711)). However, inhibition of WT EGFR can cause toxicities (e.g., skin rash and diarrhea), which can be dose-limiting in the clinic (Yap, TA; et al., J Clin Onc, 28, 2010 (3965-3972)).

[0006] Third-generation covalent EGFR inhibitors, which are selective for mutant EGFR over wild-type EGFR, overcome the limitations of afatinib and show improved clinical efficacy and tolerability (Cross, DEA; et al., Cancer Discov. 4, 2014 (1046-1061)). Osimertinib was initially approved for patients with acquired resistance to reversible inhibitors due to the T790M mutation. It is now approved for first-line therapy. Despite addressing the main resistance mechanisms of first-generation inhibitors, resistance to osimertinib also occurs (Schmid, S., et al., Lung Cancer 147, 2020, 123-129). The mechanism of resistance involves the C797S mutation, which prevents osimertinib from forming a covalent bond with a cysteine ​​residue (Thress, KT, et al., Nature Med. 21, 2015, 560-562). In the case of first-line therapy, this resistance results in either triple variants (del19 / T790M / C797S or L858R / T790M / C797S) or double variants (e.g., L858R / C797S), which cannot be successfully treated with the currently approved set of EGFR inhibitors.

[0007] Therefore, there remains a need for new targeted therapies for NSCLC patients who have developed resistance to existing inhibitors. Summary of the Invention

[0008] In one embodiment, a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof is provided herein.

[0009] In another embodiment, the compound of formula II: [ka] or a pharmaceutically acceptable salt thereof is provided herein.

[0010] In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0011] In yet another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein.

[0012] In yet another aspect, provided herein is a method of inhibiting a kinase in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein.

[0013] In one aspect, provided herein is a method of treating a kinase-mediated disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0014] definition Set forth below are definitions of various terms used to describe the compounds and compositions disclosed herein. These definitions apply to the terms as they are used throughout the specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0015] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well known and commonly employed in the art.

[0016] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, an "element" means one element or more than one element. Furthermore, use of the term "including" as well as other forms (e.g., "include," "includes," and "included") is not limiting.

[0017] As used herein, the term "about" will be understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. As used herein, when referring to a measurable value (e.g., amount, duration, etc.), the term "about" is meant to encompass ±20% or ±10% variations (e.g., ±5%, ±1%, and ±0.1%) from the specified value, although such variations are appropriate for practicing the disclosed methods.

[0018] As used herein, the term "administration" or the like refers to providing a therapeutic agent to a subject. Multiple techniques of administering a therapeutic agent exist in the art, including but not limited to intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0019] The terms "treat," "treated," "treating," or "treatment" include the relief or alleviation of at least one symptom associated with or caused by the condition, disorder, or disease being treated. In certain embodiments, treatment involves contacting a wild-type or mutant EGFR with an effective amount of a compound disclosed herein for symptoms associated with cancer.

[0020] As used herein, the term "prevent" or "prevention" means the absence of the onset of a disorder or disease if one has not already occurred, or the absence of further onset of a disorder or disease if one has already not occurred. Also contemplated is the ability to prevent some or all of the symptoms associated with a disorder or disease.

[0021] As used herein, the terms "patient," "individual," or "subject" refer to a human or non-human mammal. Non-human mammals include farm animals and pets (e.g., sheep, cows, pigs, dogs, cats, and marine mammals). Preferably, the patient, subject, or individual is human.

[0022] As used herein, the terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to produce a desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or other desired alteration of a biological system. The appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0023] As used herein, the term "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that does not interfere with the biological activity or properties of the compound and that is relatively non-toxic (i.e., the substance does not cause undesirable biological effects or interact in a deleterious way with any of the components of the composition in which it is contained), and that may be administered to an individual.

[0024] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines), alkali or organic salts of acidic residues (e.g., carboxylic acids), and the like. The pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form 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; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred. The term "pharmaceutically acceptable salt" is not limited to mono- or 1:1 salts. For example, "pharmaceutically acceptable salts" also includes bis-salts (e.g., bis-hydrochlorides). 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 incorporated herein by reference in its entirety.

[0025] As used herein, the term "prodrug" refers to a precursor compound that undergoes metabolic activation in vivo to yield an active drug. Thus, for example, a prodrug of a compound provided herein, when administered to a subject, undergoes metabolic activation to yield the compound.

[0026] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the scope of the present disclosure and a pharmaceutically acceptable carrier. A pharmaceutical composition facilitates administration of a compound to a patient or subject. Multiple techniques for administering a compound exist in the art, including but not limited to intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0027] As used herein, the term "pharmaceutical combination" refers to a product obtained by mixing or combining two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients (e.g., a compound of the present disclosure and a concomitant medication) are both administered to a patient at the same time in the form or dosage of a single entity. The term "unfixed combination" means that the active ingredients (e.g., a compound of the present disclosure and a concomitant medication) are both administered to a patient as separate entities simultaneously, in parallel, or sequentially, without any specific time constraints, such administration providing therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy (e.g., administering three or more active ingredients).

[0028] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting a compound useful within the present disclosure into or to a patient to perform its intended function. Typically, such structures are transferred or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation (e.g., compounds useful in the present disclosure and not harmful to the patient). Some examples of substances that can function as pharmaceutically acceptable carriers include: sugars (e.g., lactose, glucose, and sucrose); starches (e.g., corn starch and potato starch); cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate); powdered tragacanth; malt; gelatin; talc; excipients (e.g., cocoa butter and suppository waxes); oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil); glycols (e.g., propylene glycol); polyols (e.g., glycerin, sorbitol, mannitol, and polyethylene glycol); esters (e.g., ethyl oleate and ethyl laurate); agar; buffers (e.g., magnesium hydroxide and aluminum hydroxide); surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic, compatible substances used in pharmaceutical formulations.

[0029] As used herein, "pharmaceutically acceptable carrier" includes any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds useful within the present disclosure and are physiologically acceptable to the patient. Supplementary active compounds can also be incorporated into the compositions. "Pharmaceutically acceptable carriers" may also include pharmaceutically acceptable salts of the compounds disclosed herein. Other additional ingredients that can be included in 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.

[0030] As used herein, the term "EGFR" refers to the epidermal growth factor receptor (also known as ErbB-1 or HER1) and may refer to the wild-type receptor or a receptor containing one or more mutations.

[0031] As used herein, the term "HER" or "Her" refers to members of the ErbB receptor tyrosine kinase family (e.g., EGFR, ERBB2, HER3, and HER4).

[0032] As used herein, the term "allosteric site" refers to a site on EGFR other than the ATP-binding site, as characterized in the crystal structure of EGFR. An "allosteric site" can be a site close to the ATP-binding site, as characterized in the crystal structure of EGFR. For example, one allosteric site includes one or more of the following amino acid residues of epidermal growth factor receptor (EGFR): Lys745, Leu788, Ala743, Cys755, Leu777, Phe856, Asp855, Met766, Ile759, Glu762, and / or Ala763.

[0033] As used herein, the term "agents that prevent EGFR dimerization" or iterations thereof refers to agents that prevent dimerization in which the C-lobe of the "activating" subunit acts on the N-lobe of the "receptor" subunit. Examples of agents that prevent EGFR dimerization include, but are not limited to, cetuximab, trastuzumab, panitumumab, and Mig6.

[0034] As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C-C alkyl means alkyl having 1 to 6 carbon atoms), including straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, neopentyl, and hexyl. Other examples of C-C alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0035] As used herein, the term "haloalkyl" refers to an alkyl group as defined above that is 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.

[0036] 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.

[0037] As used herein, the term "alkylamine" refers to an -NH-alkyl group, where alkyl is as defined herein. Alkylamines include, for example, methylamine, ethylamine, isopropylamine, n-propylamine, n-butylamine, sec-butylamine, t-butylamine, and the like.

[0038] As used herein, the term "haloalkoxy" refers to an -O-haloalkyl group, where haloalkyl is as defined herein. Haloalkoxy includes, for example, chloromethoxy, trifluoromethoxy, bromoethoxy, chlorofluoroethoxy, and the like.

[0039] As used herein, the term "alkenyl" refers, in certain embodiments, 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. An 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.

[0040] As used herein, the term "alkynyl" refers, in certain embodiments, 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. An 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.

[0041] As used herein, the terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, more preferably fluorine or chlorine.

[0042] As used herein, the term "cycloalkyl" refers to a fully saturated, non-aromatic carbocyclic ring system having one, two, or three rings (such rings may be fused). The term "fused" means that a second ring is present (i.e., linked or formed) by two adjacent atoms being common (i.e., shared) with the first ring. Cycloalkyl also includes bicyclic structures that may be bridged or spirocyclic in nature, with the individual rings in the bicycle being 3 to 8 atoms in width. 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, a cycloalkyl is a 3- to 10-membered cycloalkyl. In another embodiment, a cycloalkyl is a 3- to 6-membered cycloalkyl.

[0043] As used herein, the term "cycloalkenyl" refers to a group having one, two, or three rings, which may be fused, and at least one ring is a sp 2 "Cycloalkenyl" refers to a partially saturated, non-aromatic carbocyclic ring system having a carbon-carbon bond. The term "cycloalkenyl" includes, but is not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, bicyclo[3.1.0]hexenyl, spiro[3.3]heptanenyl, and bicyclo[1.1.1]pentenyl. In one embodiment, a cycloalkenyl is a 3- to 10-membered cycloalkyl. In another embodiment, a cycloalkenyl is a 4- to 7-membered cycloalkyl.

[0044] As used herein, the term "heterocyclyl" or "heterocycloalkyl" means a non-aromatic carbocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, and having 1, 2, or 3 rings (such rings may be fused, where fusion is defined above). Heterocyclyl also includes bicyclic structures which may be bridged or spirocyclic in nature, where each ring in the bicycle is 3 to 8 atoms wide and contains 0, 1, or 2 N, O, or S atoms. The term "heterocyclyl" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), and specifically includes, but is not limited to, epoxydyl, 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-azabicyclo[ 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]non ... Examples of heterocycloalkyl include oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[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, the heterocycloalkyl is a 3- to 10-membered heterocycloalkyl. In another embodiment, the heterocycloalkyl is a 4- to 7-membered heterocyclyl.

[0045] As used herein, the term "aromatic" refers to a carbocycle or heterocyclyl having one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer.

[0046] As used herein, the term "aryl" refers to an aromatic carbocyclic ring system containing one, two, or three rings (such rings may be fused, where fusion is defined above). If rings are fused, one of the rings must be fully unsaturated, and the fused ring(s) may be fully saturated, partially unsaturated, or fully unsaturated. The term "aryl" includes, but is not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. In some embodiments, an aryl group has 6 carbon atoms. In some embodiments, an aryl group has 6 to 10 carbon atoms. In some embodiments, an aryl group has 6 to 16 carbon atoms.

[0047] As used herein, the term "heteroaryl" means an aromatic carbocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, and having 1, 2, or 3 rings (such rings may be fused, where fusion is 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]pyridin ... Examples of heteroaryl include clopenta-[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 a 5- to 10-membered heteroaryl. In another embodiment, heteroaryl is a 5- to 6-membered heteroaryl.

[0048] Where an aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety may be attached or otherwise attached to the designated moiety through different ring atoms (i.e., shown or described without indicating a particular point of attachment), it should be understood that all possible points are intended, whether through a carbon atom or, for example, through a trivalent nitrogen atom. For example, the term "pyridinyl" means 2-, 3-, or 4-pyridinyl, and the term "thienyl" means 2- or 3-thienyl. As used herein, the term "substituted" means that an atom or group of atoms replaces a hydrogen as a substituent bonded to another group.

[0049] 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 without substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from the groups described herein.

[0050] compound Provided herein are compounds that are allosteric inhibitors of the epidermal growth factor receptor (EGFR), useful for the treatment of kinase-mediated disorders, including cancer and other proliferative diseases.

[0051] In one embodiment, a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof is provided herein: [ka] represents a single or double bond, A and A' are each independently CH, CR 10 , CH2, O, or N; W and Z are each independently N or CR 9 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 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which may be selected from one, two, or three R 8 optionally replaced by Each R 2 C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 independently selected from the group consisting of NH, CN, and 3- to 10-membered cycloalkyl; Or two R's 2 together with the atom to which they are attached form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycloalkyl; R 3 may, in each occurrence, independently be a halogen, OR 4 , N.R. 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 7-membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl is selected from the group consisting of R 4 and optionally substituted one, two, or three times by aryl, heteroaryl, or heterocyclyl, respectively, 5 is optionally substituted one, two, or three times by R 4 is, in each occurrence, independently selected from H, C1-C6 alkyl, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5- to 6-membered heteroaryl), and (CH2) 0-3-(4- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is selected from the group consisting of R 6 is optionally substituted one, two, or three times by R 5 which, in each occurrence, independently represents C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3- to 10-membered cycloalkyl, halogen, COOH, C(O)O(C1-C6 alkyl), O(CH2) 1-3 -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, CN, (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5- to 6-membered heteroaryl), and (CH2) 0-3 -(4- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is selected from the group consisting of R 7 is optionally substituted one, two, or three times by R 6 which, in each occurrence, independently represents C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH2, or CN; R 7 which, in each occurrence, independently represent C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, SO2NH2, SO2NH(C1-C6 alkyl), SON(C1-C6 alkyl)2, (CH2) 1-2 -OH, C(O)(CH2) 1-2 is selected from the group consisting of substituents selected from —OH, C(O)(C1-C6 alkyl), and C(O)O(C1-C6 alkyl); R 8which, in each occurrence, independently represents C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 selected from the group consisting of NH2, and CN; R 9 is, in each occurrence, independently selected from the group consisting of H, halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; R 10 which, in each occurrence, independently represents C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 selected from the group consisting of NH2, and CN; n is 0, 1, 2, or 3.

[0052] In yet another embodiment, [ka] represents a single bond. In yet another embodiment, [ka] indicates a double bond.

[0053] In one embodiment, A is CH. In another embodiment, A is CH. In yet another embodiment, at least one of A and A' is CH or CR. 10 In yet another embodiment, at least one of A and A' is CH, CR 10or CH2. In one embodiment, A' is N. In another embodiment, A' is CH. In yet another embodiment, A' is CH2.

[0054] In one embodiment, W is N. In another embodiment, W is CR 9 In one embodiment, W is CH or C-halo. In yet another embodiment, Z is N. In yet another embodiment, Z is CR 9 In one embodiment, Z is CH or C-halo.

[0055] In another embodiment, X is CR 3 In yet another embodiment, Y is CR 3 In yet another embodiment, X is CR 3 In one embodiment, Y is CR 3 is.

[0056] In one embodiment, R 1 is one, two, or three R 8 In another embodiment, R 1 is one, two, or three R 8 In another embodiment, R 1 is thiazolyl or pyridinyl, both of which may contain one, two, or three R 8 In yet another embodiment, R 1 teeth, [ka] selected from the group consisting of Both of these can be used with 1, 2, or 3 R 8 is optionally replaced by

[0057] In yet another embodiment, the compound of formula I is a compound of formula Ia: [ka] or a pharmaceutically acceptable salt thereof.

[0058] In one embodiment, the compound of formula I is a compound of formula Ib: [ka] or a pharmaceutically acceptable salt thereof.

[0059] In another embodiment, the compound of formula I is a compound of formula Id: [ka] or a pharmaceutically acceptable salt thereof.

[0060] In another embodiment, R 2 is halogen or C1-C3 alkyl. In yet another embodiment, R 2 is halogen. In yet another embodiment, R 2 is C1-C3 alkyl. In another embodiment, two R 2 together with the atom to which they are attached form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycloalkyl. 2 together with the atom to which they are attached form a 3- to 10-membered cycloalkyl.

[0061] In one embodiment, R 3 is one or two R 5 In another embodiment, R 3 is one or two R 5 In yet another embodiment, R 5 is R 7 In one embodiment, R is a 4- to 7-membered heterocyclyl optionally substituted 1, 2, or 3 times by 5 is R 7 In yet another embodiment, R is a 5-membered heterocyclyl optionally substituted 1, 2, or 3 times with 5is piperidinyl or piperazinyl, both of which are R 7 In one embodiment, R 3 teeth, [ka] is.

[0062] In another embodiment, R 7 is C1-C6 alkyl. In yet another embodiment, R 7 is methyl.

[0063] In yet another embodiment, R 4 is, at each occurrence, independently selected from the group consisting of H and C1-C6 alkyl.

[0064] In yet another embodiment, R 9 is H, halo, or C1-C3 haloalkyl. In one embodiment, R 9 is H. In another embodiment, R 9 is halo. In yet another embodiment, R 9 is C1-C3 haloalkyl. In yet another embodiment, R 9 is C1-C3 alkoxy.

[0065] In yet another embodiment, n is 0 or 1. In one embodiment, n is 0. In another embodiment, n is 1.

[0066] In yet another embodiment, [ka] represents a single or double bond, A and A' are each independently CH, CH, O, or N; W and Z are each independently CH or CR 9 and X and Y are each independently CH or CR 3 and R 1 But one, two, or three R 8 is a 5- to 10-membered heteroaryl optionally substituted with R 2 is halogen or C1-C3 alkyl; Or two R's 2 together with the atom to which they are attached form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycloalkyl; R 3 But one or two R 5 is a 6- to 10-membered aryl substituted with R 5 But R 7 and a 4- to 7-membered heterocyclyl optionally substituted 1, 2, or 3 times by R 7 is C1-C6 alkyl, R 8 which, in each occurrence, independently represents C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 selected from the group consisting of NH2, and CN; R 9 is, at each occurrence, independently selected from the group consisting of halo, C-C alkyl, C-C haloalkyl, and C-C alkoxy; n is 0 or 1.

[0067] In another embodiment, the compound of formula II: [ka] or a pharmaceutically acceptable salt thereof is provided herein: A and A' are each independently CH, CR 10 , or N, R 1is 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 may be selected from one, two, or three R 8 optionally replaced by Each R 2 C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 independently selected from the group consisting of NH, CN, and 3- to 10-membered cycloalkyl; Or two R's 2 together with the atom to which they are attached form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycloalkyl; R 3 may, in each occurrence, independently be a halogen, OR 4 , N.R. 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 7-membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl is selected from the group consisting of R 4 and optionally substituted one, two, or three times by aryl, heteroaryl, or heterocyclyl, respectively, 5 is optionally substituted one, two, or three times by R 4 is, in each occurrence, independently selected from H, C1-C6 alkyl, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3-(C4-C7 cycloalkenyl), (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5- to 6-membered heteroaryl), and (CH2) 0-3 -(4- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is selected from the group consisting of R 6 is optionally substituted one, two, or three times by R 5 which, in each occurrence, independently represents C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3- to 10-membered cycloalkyl, halogen, COOH, C(O)O(C1-C6 alkyl), O(CH2) 1-3 -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, CN, (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5- to 6-membered heteroaryl), and (CH2) 0-3 -(4- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is selected from the group consisting of R 7 is optionally substituted one, two, or three times by R 6 which, in each occurrence, independently represents C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH2, or CN; R 7 which, in each occurrence, independently represent C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, SO2NH2, SO2NH(C1-C6 alkyl), SON(C1-C6 alkyl)2, (CH2) 1-2-OH, C(O)(CH2) 1-2 is selected from the group consisting of substituents selected from —OH, C(O)(C1-C6 alkyl), and C(O)O(C1-C6 alkyl); R 8 which, in each occurrence, independently represents C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 selected from the group consisting of NH2, and CN; R 10 which, in each occurrence, independently represents C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 selected from the group consisting of NH2, and CN; n is 0, 1, 2, or 3.

[0068] In one embodiment, A is CH. In another embodiment, A is N. In yet another embodiment, A is CR 8 In one embodiment, A' is N. In yet another embodiment, A' is CH. In yet another embodiment, at least one of A and A' is CH or CR. 8 is.

[0069] In one embodiment, R 1 is one, two, or three R 8 In another embodiment, R 1 is one, two, or three R 8 In yet another embodiment, R 1is thiazolyl or pyridinyl, both of which may contain one, two, or three R 8 In yet another embodiment, R 1 teeth, [ka] selected from the group consisting of Both of these can be used with 1, 2, or 3 R 8 is optionally replaced by

[0070] In one embodiment, the compound of formula II is a compound of formula IIa: [ka] or a pharmaceutically acceptable salt thereof.

[0071] In one embodiment, R 2 is halogen. In another embodiment, two R 2 together with the atom to which they are attached form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycloalkyl. 2 together with the atom to which they are attached form a 3- to 10-membered cycloalkyl.

[0072] In another embodiment, R 3 is one or two R 5 In yet another embodiment, R 3 is one or two R 5 In yet another embodiment, R 5 is R 7 In one embodiment, R is a 4- to 7-membered heterocyclyl optionally substituted 1, 2, or 3 times by 5 is R 7 In another embodiment, R is a 5-membered heterocyclyl optionally substituted 1, 2, or 3 times with 3 teeth, [ka] is.

[0073] In yet another embodiment, R 7 is C1-C6 alkyl. In yet another embodiment, R 7 is methyl.

[0074] In one embodiment, A and A' are each independently CH or N; R 1 But one, two, or three R 8 is a 5- to 10-membered heteroaryl optionally substituted with R 2 is a halogen, Or two R's 2 together with the atom to which they are attached form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycloalkyl; R 3 But one or two R 5 is a 6- to 10-membered aryl substituted with R 5 But R 7 and a 4- to 7-membered heterocyclyl optionally substituted 1, 2, or 3 times by R 7 is C1-C6 alkyl, R 8 is, in each occurrence, independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 selected from the group consisting of NH2, and CN; n is 0 or 1.

[0075] In another embodiment, the compound of formula I or II is selected from the group consisting of the compounds in Table 1. [Table 1-1] [Table 1-2] or a pharmaceutically acceptable salt thereof.

[0076] Compounds disclosed herein can exist as tautomers and optical isomers (eg, enantiomers, diastereomers, diastereomeric mixtures, racemic mixtures, etc.).

[0077] The compounds provided herein may also include all isotopes of atoms present in intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the present invention can be replaced or substituted with a naturally or non-naturally occurring isotope of the atom. In some embodiments, the compounds contain at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced or substituted with deuterium. In some embodiments, the compounds contain two or more deuterium atoms. In some embodiments, the compounds contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, 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 a variety of studies, such as NMR spectroscopy, metabolic studies, and / or assays.

[0078] In the compounds presented herein, atoms not specifically designated as a particular isotope are meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," it is understood that the position contains hydrogen at its natural abundance isotopic composition. Also, unless otherwise specified, when a position is specifically designated as "D" or "deuterium," it is understood that the position contains at least 3000 times more deuterium than the natural abundance of deuterium, 0.015% (i.e., at least 45% deuterium is incorporated).

[0079] In general, it is known in the art that any compound that is transformed in vivo to provide a compound disclosed herein is a prodrug within the scope of this disclosure.

[0080] 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.

[0081] 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 prevents EGFR dimer formation in the subject. In yet 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.

[0082] In another aspect, provided herein is 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, wherein the second active agent prevents EGFR dimer formation, and a pharmaceutically acceptable carrier. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab.

[0083] Compounds that bind to the allosteric site of EGFR, such as compounds of the present disclosure (e.g., compounds of the formulae disclosed herein), can be optionally combined with a second active agent (wherein the second active agent prevents EGFR dimerization) to modulate EGFR activity. In some embodiments, the compounds of the present disclosure can inhibit or reduce EGFR activity without a second active agent (e.g., an antibody, e.g., cetuximab, trastuzumab, or panitumumab). In other embodiments, the compounds of the present disclosure can be combined with a second active agent. In one embodiment, the second active agent prevents EGFR dimerization and / or can inhibit or reduce EGFR activity. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents 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.

[0084] Treatment method 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).

[0085] 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.

[0086] In yet another aspect, a method for treating or preventing a kinase-mediated disorder in an individual in need thereof is provided, 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-targeted therapy is selected from the group consisting of gefitinib, erlotinib, or osimertinib.

[0087] In some embodiments, compounds of the present disclosure are capable of modulating (e.g., inhibiting or decreasing) 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 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 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 selected from L858R / T790M, L858R / T790M / I941R, L858R / C797S, L858R / T790M / C797S, and L858R / T790M.

[0088] In some embodiments, a compound of the present disclosure in combination with a second active agent (wherein the second active agent prevents EGFR dimerization) is capable of modulating (e.g., inhibiting or reducing) the activity of an EGFR that contains 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 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 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 selected from L858R / T790M, L858R / T790M / I941R, L858R / C797S, L858R / T790M / C797S, and L858R / T790M. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents 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.

[0089] In some embodiments, compounds of the present disclosure are capable of modulating (e.g., inhibiting or reducing) the activity of EGFR containing one or more mutations, but do not affect the activity of wild-type EGFR.

[0090] In other embodiments, a compound of the present disclosure in combination with a second active agent (wherein the second active agent prevents EGFR dimerization) can 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 prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents 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.

[0091] Modulation of EGFR (as described herein, but not wild-type EGFR) containing one or more mutations provides an approach to the treatment, prevention, or amelioration of diseases, including, but not limited to, cancer and metastasis, inflammation, arthritis, systemic lupus erythematosus, skin-related disorders, pulmonary disorders, cardiovascular disease, ischemia, neurodegenerative disorders, liver disease, gastrointestinal disorders, viral and bacterial infections, central nervous system disorders, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and peripheral neuropathy.

[0092] In some embodiments, the inhibition of EGFR activity is 50 It is measured in

[0093] In some embodiments, the inhibition of EGFR activity is 50 It is measured in

[0094] In some embodiments, inhibition of EGFR by compounds of the present disclosure can be measured by biochemical assays. As an illustrative, 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. HTRF assays may use, for example, a substrate (e.g., biotin-Lck-peptide substrate) concentration of about 1 μM, an EGFR (mutant or WT) concentration of about 0.2 nM to about 40 nM, and an inhibitor concentration of about 0.000282 μM to about 50 μM. Compounds of the present disclosure screened under these conditions may exhibit, for example, an IC of about 1 nM to greater than 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. 50 In certain embodiments, compounds of the present disclosure screened under the above conditions for inhibition of EGFR having a mutation or combination of mutations selected from L858R / T790M, L858R, and T790M may exhibit an IC value of, for example, about 1 nM to greater than 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. 50 The value may be indicated.

[0095] In some embodiments, compounds of the present disclosure bind to an allosteric site of EGFR. In some embodiments, 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, 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, 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, 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, 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.

[0096] In some embodiments, the present disclosure provides compounds comprising allosteric kinase inhibitors, which are more potent inhibitors of drug-resistant EGFR mutants compared to wild-type EGFR. In some embodiments, the drug-resistant EGFR mutants are resistant to one or more known EGFR inhibitors (including, but not limited to, gefitinib, erlotinib, lapatinib, HKI-272, and osimertinib).

[0097] In some embodiments, the drug-resistant EGFR mutant comprises a sensitizing mutation, such as L858R.

[0098] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor in combination with a second active agent, wherein the second active agent prevents EGFR dimerization, 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 mutants are resistant to one or more known EGFR inhibitors (including, but not limited to, gefitinib, erlotinib, lapatinib, HKI-272, and osimertinib). In some embodiments, the drug-resistant EGFR mutants contain a sensitizing mutation, such as L858R. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents 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.

[0099] In other embodiments, the present disclosure provides compounds comprising an allosteric kinase inhibitor in combination with a second active agent, wherein the second active agent prevents EGFR dimerization, and the compound in combination with the second active agent is more potent at inhibiting the activity of EGFRs containing one or more mutations described herein (e.g., T790M, L718Q, L844V, L858R, and C797S) than one or more known EGFR inhibitors (including, but not limited to, gefitinib, erlotinib, lapatinib, HKI-272, and osimertinib). In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents 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.

[0100] In other embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor together with a second active agent, wherein the second active agent prevents EGFR dimerization, and the compound in combination with the second active agent is less potent at 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 active agent that prevents EGFR dimerization is an antibody. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents 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.

[0101] The efficacy of the inhibitor is 50 The EC value can be determined by measuring the EC under substantially similar conditions. 50 Compounds with low EC 50 A compound with a higher phosphorylation level is a more potent inhibitor than a compound with a higher phosphorylation level. In some embodiments, the substantially similar conditions include determining the level of EGFR-dependent phosphorylation in vitro or in vivo (e.g., in 3T3 cells expressing wild-type EGFR, mutant EGFR, or a fragment of either thereof).

[0102] The potency of the inhibitor is determined by IC 50 It can also be determined by IC values ​​measured under substantially similar conditions. 50 Compounds with low IC 50 A compound with a higher phosphorylation level is a more potent inhibitor than a compound with a higher phosphorylation level. In some embodiments, the substantially similar conditions include determining the level of EGFR-dependent phosphorylation in vitro or in vivo (e.g., in 3T3 cells expressing wild-type EGFR, mutant EGFR, or a fragment of either thereof).

[0103] EGFR susceptibility mutations include, but are not limited to, L858R, G719S, G719C, G719A, and / or L861Q. Drug-resistant EGFR mutants may have drug-resistant mutations including, but are not limited to, T790M, T854A, L718Q, C797S, or D761Y.

[0104] Selectivity between wild-type EGFR and EGFR containing one or more of the mutations described herein can also be measured using a cell proliferation assay in which cell proliferation is dependent on kinase activity. For example, murine Ba / F3 cells transfected with a suitable 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. Proliferation assays are performed at various inhibitor concentrations (10 μM, 3 μM, 1.1 μM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and the EC 50 is calculated.

[0105] Another method for measuring the effect on EGFR activity is to assay EGFR phosphorylation. Wild-type or mutant (L858R / T790M, L858R / C797S, L858R / T790M / C797S, L858R / T790M / I941R, or L858R / T790M / L718Q) EGFR can be introduced into NIH-3T3 cells (which typically do not express endogenous EGFR), and the ability of inhibitors (using the concentrations listed above) to inhibit EGFR phosphorylation can be assayed. Cells are exposed to increasing concentrations of inhibitor for 6 hours and then stimulated with EGF for 10 minutes. The effect on EGFR phosphorylation is assayed by Western blotting using a phospho-specific (Y1068) EGFR antibody.

[0106] In yet another aspect, the present disclosure provides a method for inhibiting epidermal growth factor receptor (EGFR), 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 method further comprises administering a second active agent, wherein the second active agent prevents EGFR dimerization. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents 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.

[0107] In another aspect, provided herein are methods for treating or preventing a disease, the methods 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 or near a position corresponding to Cys797 of EGFR, including such positions in 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 prevents kinase dimerization. In some embodiments, the second active agent that prevents kinase dimerization is an antibody. In further embodiments, the second active agent prevents EGFR dimerization. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In a further embodiment, 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.

[0108] In some embodiments, the disease is EGFR-mediated (e.g., EGFR plays a role in the initiation or development of the disease). In some embodiments, the disease is Her kinase-mediated. In further embodiments, the HER kinase is HER1, HER2, or HER4.

[0109] In certain embodiments, the disease 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 disease is associated with an activating mutation of EGFR. In certain embodiments, a diagnostic test is performed to determine whether the disease is associated with EGFR having an activating mutation and / or a drug-resistance mutation. Activating mutations include, but are not limited to, L858R, G719S, G719C, G719A, L718Q, and / or L861Q. Drug-resistant EGFR mutants may have drug-resistance mutations including, but not limited to, T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests may include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those skilled in the art that can detect nucleotide sequences.

[0110] In certain embodiments, the disease is cancer or a proliferative disease.

[0111] In a further embodiment, 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, 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 a further embodiment, the disease is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer. In yet another embodiment, the disease is non-small cell lung cancer.

[0112] In certain embodiments, the disease 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 disease is associated with an activating mutation of EGFR. In certain embodiments, a diagnostic test is performed to determine whether the disease is associated with EGFR having an activating mutation and / or a drug-resistance mutation. Activating mutations include, but are not limited to, L858R, G719S, G719C, G719A, L718Q, and / or L861Q. Drug-resistant EGFR mutants may have drug-resistance mutations including, but not limited to, T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests may include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those skilled in the art that can detect nucleotide sequences.

[0113] In yet another aspect, provided herein are methods for 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. In some embodiments, the compound is an inhibitor of HER1, HER2, or HER4. In other embodiments, the subject is administered an additional therapeutic agent. In other embodiments, the compound and the additional therapeutic agent are administered simultaneously or sequentially.

[0114] In another aspect, the present disclosure provides a method of treating a kinase-mediated disorder, 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 dimerization. In some embodiments, the compound is a HER1, HER2, or HER4 inhibitor. In other embodiments, the subject is administered an additional therapeutic agent. In other embodiments, the compound, the second active agent that prevents EGFR dimerization, and the additional therapeutic agent are administered simultaneously or sequentially. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents 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.

[0115] In another embodiment, the disease is cancer. In a further embodiment, 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 a further embodiment, the disease is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer. In yet another embodiment, the disease is non-small cell lung cancer.

[0116] In another aspect, provided herein is a method of treating cancer in which the cancer cells contain activated EGFR, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0117] In another aspect, provided herein is a method for treating cancer in which cancer cells contain activated EGFR, 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 dimerization. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents 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.

[0118] In certain embodiments, the EGFR activation is selected from EGFR mutation, EGFR amplification, EGFR expression, and ligand-mediated activation of EGFR.

[0119] In a further embodiment, the EGFR mutation is selected from G719S, G719C, G719A, L858R, T790M, and L861Q.

[0120] In yet another aspect, provided herein is a method of treating cancer in a subject, wherein the subject is identified as being in need of EGFR inhibition for the treatment of the cancer, the method comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0121] In certain embodiments, subjects identified as needing EGFR inhibition are 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 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 mutants may have drug-resistant mutations including, but not limited to, T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests may include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those skilled in the art that can detect nucleotide sequences.

[0122] In one aspect, provided herein is a method of preventing resistance to a known EGFR inhibitor (including but not limited to, gefitinib, erlotinib, or osimertinib) in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0123] In another aspect, provided herein are methods for preventing resistance to known EGFR inhibitors (including but not limited to gefitinib, erlotinib, or osimertinib) in a disease, the methods 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 a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab.

[0124] In one embodiment of the methods disclosed herein, the subject is a human.

[0125] 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 is involved.

[0126] 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, immune-mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone-related diseases, allergies, asthma, and Alzheimer's disease. In other embodiments, the condition is selected from a proliferative disorder and a neurodegenerative disorder.

[0127] One aspect of the present disclosure provides compounds useful for treating 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, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, colorectal cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, bone marrow disorders, lymphatic system disorders, Hodgkin's cancer, hairy cell carcinoma, cancer of the mouth and pharynx (oral cancer), lip cancer, tongue cancer, oral cancer, pharynx cancer, small intestine cancer, colon cancer, rectum cancer, large intestine cancer, rectum cancer, brain and central nervous system, chronic myeloid leukemia (CML), and leukemia. The term "cancer" includes, but is not limited to, myeloma, lymphoma, or a cancer selected from gastric cancer, renal cancer, head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, hepatocellular carcinoma, non-Hodgkin's lymphoma, and lung cancer.

[0128] The term "cancer" also refers to any cancer caused by the proliferation of malignant cells (e.g., tumor, neoplasm, carcinoma, sarcoma, leukemia, lymphoma, etc.). For example, cancers include, but are not limited to, mesothelioma, leukemia, and lymphoma (e.g., cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, human T-cell lymphotropic virus (HTLV)-associated lymphoma (e.g., adult T-cell leukemia / lymphoma (ATLL)), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myeloid leukemia, lymphoma, and multiple myeloma, non-Hodgkin's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia-lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma). Further examples include pediatric solid tumors (e.g., brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcoma), common adult solid tumors (e.g., head and neck cancers (e.g., oral cavity, larynx, nasopharynx, and esophagus), genitourinary cancers (e.g., prostate, bladder, kidney, uterus, ovaries, and testes), lung cancer (e.g., small cell and non-small cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, gastric cancer, brain tumors, tumors associated with Gorlin syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer). Further examples of cancers that may be treated by the subject compounds include, but are not limited to, skeletal or smooth muscle cancer, gastric cancer, small intestine cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal gland cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0129] Additional cancers that the compounds described herein may be useful for preventing, treating, and studying include, for example, colorectal cancer, familial adenomatous polypoid cancer, and hereditary non-polypoid colorectal cancer, or melanoma. Further cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary and papillary), kidney cancer, renal parenchymal cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumor), gallbladder cancer, bronchial carcinoma, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma. In one aspect of the disclosure, the disclosure provides the use of one or more compounds of the disclosure in the manufacture of a medicament for the treatment of cancer (including but not limited to, the various types of cancer disclosed herein).

[0130] In some embodiments, compounds of the present disclosure are useful for treating cancer (e.g., colon cancer, thyroid cancer, breast cancer, and lung cancer) and myeloproliferative disorders (e.g., polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mast cell disease). In some embodiments, compounds of the present disclosure are useful for treating hematopoietic disorders, particularly acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute promyelocytic leukemia, and acute lymphoblastic leukemia (ALL).

[0131] The term "cancer cell" as provided herein includes a cell afflicted by any one of the above-defined conditions.

[0132] The present disclosure further provides methods for treating or preventing cell proliferative disorders (e.g., hyperplasia, dysplasia, and precancerous lesions). Dysplasia is the first form of precancerous lesion that is recognizable in a biopsy by a pathologist. The subject compounds can be administered to prevent the hyperplasia, dysplasia, or precancerous lesion from continuing to grow or from becoming cancerous. Examples of precancerous lesions can occur in the skin, esophageal tissue, breast, and cervical intraepithelial tissue.

[0133] Examples of neurodegenerative diseases include, but are not limited to, adrenoleukodystrophy (ALD), Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Voigt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, familial fatal insomnia, frontotemporal lobar degeneration, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, dementia with Lewy bodies, and neurological disorders. Neuroleptic malignancies include: spinocerebellar ataxia (SMA), Machado-Joseph disease (Spinocerebellar ataxia type 3), multiple system atrophy, multiple sclerosis, narcolepsy, Niemann-Pick disease, Parkinson's disease, Pelizaeus-Merzbach disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, Spielmeyer-Voght-Sjögren-Batten disease (also known as Batten disease), spinocerebellar ataxia (multiple types with varying features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, tabes dorsalis, and toxic encephalopathy.

[0134] Another aspect of the present disclosure provides a method for treating or reducing the severity of a disease selected from a proliferative or hyperproliferative disease or a neurodegenerative disease, the method comprising administering an effective amount of a compound or a pharmaceutically acceptable composition comprising the compound to a subject in need thereof. In other embodiments, the method further comprises administering a second active agent, wherein the second active agent prevents EGFR dimerization. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents 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.

[0135] The activity of the compounds and compositions of the present 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 the kinase activity or the ATPase activity of an activated kinase. Alternative in vitro assays can quantify the ability of an inhibitor to bind to a protein kinase by radiolabeling the inhibitor prior to binding, isolating the inhibitor / kinase complex, and determining the amount of bound radiolabel, or by performing a competition experiment in which new inhibitors are incubated with a kinase bound to a known radioligand. Detailed conditions for assaying the compounds utilized in the present disclosure as inhibitors of various kinases are described in the Examples below.

[0136] In accordance with the above, the present disclosure further provides a method for preventing or treating any of the above diseases or disorders in a subject in need thereof, 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 prevents EGFR dimer formation. In any of the above applications, the required dosage will vary depending on the mode of administration, the particular condition to be treated, and the desired effect.

[0137] In other embodiments, the compound and the second active agent that prevents EGFR dimerization are administered simultaneously or sequentially.

[0138] 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, liquid dosage forms may contain inert diluents commonly used in the art (e.g., water or other solvents), solubilizers and emulsifiers (e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan), and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants (e.g., wetting agents, emulsifying and suspending agents, sweeteners, flavorings, and perfumes).

[0139] Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) 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 non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic monoglycerides and diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0140] In order to prolong the effect of a drug, it is often desirable to slow down the absorption of the drug by subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of the drug then depends on the dissolution rate, which may also depend on the size and crystalline form of the crystal.Alternatively, the delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0141] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient or carrier (e.g., cocoa butter, polyethylene glycol, or a suppository wax) which is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0142] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0143] The active compound can also be in microencapsulated form with one or more excipients as described above. Tablets, sugar-coated tablets, capsules, pills, and other solid dosage forms can be prepared using coatings and shells (e.g., enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art). In such solid dosage forms, the active compound can be mixed with at least one inert diluent (e.g., sucrose, lactose, or starch). Such dosage forms may also contain additional substances other than inert diluents (e.g., tableting lubricants) and other tableting aids (e.g., magnesium stearate and microcrystalline cellulose), as is customary. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0144] 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 mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as required. Ophthalmic formulations, ear drops, eye ointments, powders, and solutions are also contemplated as being within the scope of the present disclosure.

[0145] The ointments, pastes, creams, and gels may contain, in addition to the active compounds of the present disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0146] Powders and sprays can contain, in addition to the compounds of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays can also contain conventional propellants such as chlorofluorohydrocarbons.

[0147] Transdermal patches have the additional advantage of controlling the delivery of compounds into the body. Such dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0148] According to the methods of treatment of the present disclosure, a disorder is treated or prevented in a subject (e.g., a human or other animal) by administering a therapeutically effective amount of a compound of the present disclosure to the subject, in such amounts and for such time as is necessary to achieve the desired result. As used herein, the term "therapeutically effective amount" of a compound of the present disclosure means a sufficient amount of the compound to reduce the symptoms of the disorder in the subject. As is well understood in the medical field, a therapeutically effective amount of a compound of the present disclosure will be at a reasonable benefit / risk ratio applicable to any medical treatment.

[0149] In general, the compounds of the present disclosure are administered in a therapeutically effective amount, either alone or in combination with one or more therapeutic agents, by any of the conventional and acceptable methods 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 used, and other factors. In general, satisfactory results are indicated to be obtained systemically at a daily dosage of about 0.03 to 2.5 mg / kg of body weight. The recommended daily dosage for large mammals (e.g., humans) ranges from about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses up to four times daily or in delayed form. Suitable unit dosage forms for oral administration contain about 1 to 50 mg of active ingredient.

[0150] In certain embodiments, the therapeutic amount or dose of a compound of the present disclosure may range from about 0.1 mg / kg to about 500 mg / kg, or alternatively from about 1 to about 50 mg / kg. Generally, treatment regimens according to the present disclosure involve administering to a patient in need of such treatment about 10 mg to about 1000 mg of a compound(s) of the present disclosure per day, in single or multiple doses. The therapeutic amount or dose will also vary depending on the route of administration and the possibility of co-administration with other drugs.

[0151] When the condition of the subject improves, the maintenance dose of the compound, composition or combination of the present disclosure can be administered as needed.Subsequently, the dosage or administration frequency or both can be reduced according to symptoms to a level that maintains the improved condition.When the condition is alleviated to a desired level, treatment should be discontinued.However, the subject may need to be treated intermittently for a long period of time when any disease symptoms recur.

[0152] However, it will be understood that the total daily usage amount of the compounds and compositions of the present disclosure can be determined by the attending physician within the scope of sound medical judgment.The specific inhibitory dose for a specific patient will vary depending on various factors (for example, the disorder to be treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex and diet; the time of administration, route of administration and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or simultaneously with the specific compound used; and similar factors well known in the medical field).

[0153] The present disclosure also provides pharmaceutical combinations (e.g., kits) comprising: a) a first agent that is a compound disclosed herein in free form or a pharmaceutically acceptable salt form; and b) at least one co-agent. The kit may include instructions for its administration.

[0154] In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents, for example, agents that prevent EGFR dimerization, chemotherapeutic agents, or other anti-proliferative agents may be combined with the compounds of the present disclosure to treat proliferative diseases and cancer.

[0155] Some examples of substances that can function as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins (e.g., human serum albumin); buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate); partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes (e.g., protamine sulfate); disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene polyoxypropylene block polymers; wool fat; sugars (e.g., lactose, glucose, and sucrose). starches (e.g., corn starch and potato starch); cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate); powdered tragacanth; malt; gelatin; talc; excipients (e.g., cocoa butter and suppository wax); oils (peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil); glycols (e.g., propylene glycol and polyethylene glycol); esters (e.g., ethyl oleate and ethyl laurate); agar; buffers (e.g., magnesium hydroxide and aluminum hydroxide); alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer. Additionally, non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), coloring agents, release agents, coating agents, sweeteners, flavorings, perfuming agents, preservatives, and antioxidants can also be present in the composition, according to the discretion of the formulator. The protein kinase inhibitors or pharmaceutical salts thereof can be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions, which comprise an amount of the protein inhibitor effective to treat or prevent a protein kinase-mediated condition and a pharmaceutically acceptable carrier, are other embodiments of the present disclosure.

[0156] kit In one aspect, provided herein is a kit comprising a compound capable of inhibiting kinase activity selected from one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and instructions for use in treating cancer. In certain embodiments, the kit further comprises components for performing a test to determine whether a subject has an activating mutation and / or drug resistance mutation in EGFR.

[0157] 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.

[0158] In another aspect, the present disclosure provides a kit comprising a compound capable of inhibiting kinase activity selected from one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof; a second active agent, wherein the second active agent prevents EGFR dimerization; and instructions for use in treating cancer. In certain embodiments, the kit further comprises components for performing a test to determine whether a subject has an activating mutation and / or drug resistance mutation in EGFR. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab.

[0159] 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, and a second active agent, wherein the second active agent prevents EGFR dimerization. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents 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.

[0160] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate particular embodiments and that the scope of the present disclosure is not limited thereby. Furthermore, it should be understood that reliance may be placed on various other embodiments, modifications thereof, and equivalents that may occur to those skilled in the art without departing from the spirit of the present disclosure and / or the scope of the appended claims. [Example]

[0161] The present application is further illustrated by the following examples, which should not be construed as further limiting. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, within the skill of the art.

[0162] Abbreviation ACN Acetonitrile DCM dichloromethane DIEA Diisopropylethylamine DMF Dimethylformamide DMSO dimethyl sulfoxide EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc ethyl acetate HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU 3-[bis(dimethylamino)methylimyl]-3H-benzotriazole-1-oxide hexafluorophosphate MeOH Methanol TFA trifluoroacetic acid RT room temperature THF tetrahydrofuran

[0163] Example 1: Synthetic Procedure Scheme 1. Synthesis of Compound 001 [ka] Methyl (E)-4-chloro-2-(2-ethoxyvinyl)-6-fluorobenzoate A mixture of methyl 2-bromo-4-chloro-6-fluorobenzoate (1.00 g, 3.74 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (741 mg, 3.74 mmol), K2CO3 (1.55 mg, 11.22 mmol), water (3 mL), and dioxane (30 mL) in a sealed vial was degassed and refilled with nitrogen three times. Pd2dba3 (171 mg, 0.187 mmol) and tricyclohexylphosphine (209 mg, 0.748 mmol) were added, the vial was resealed, refilled with nitrogen, and heated to 80 °C for 20 min. After cooling, the reaction was poured into saturated brine (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with water and saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with 0-15% EtOAc / hexanes) to give the title compound (674 mg, 70%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.55 (d, 1H) 7.45 (d, 1H) 7.29 (dd, 1H) 5.76 (d, 1H) 3.93 (q, 2H) 3.99 (s, 3H) 1.25 (t, 3H); MS (m / z): [M+1] + , 259.24.

[0164] Methyl (E)-3-(2-ethoxyvinyl)-5-fluoro-4'-(1-methylpiperidin-4-yl)-[1,1'-biphenyl]-4-carboxylate A mixture of methyl (E)-4-chloro-2-(2-ethoxyvinyl)-6-fluorobenzoate (348 mg, 1.34 mmol), Pd(OAc) (30 mg, 0.134 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (813 mg, 2.69 mmol), S-Phos (110 mg, 0.269 mmol), CsCO (1.75 g, 5.38 mmol), and CuCl (27 mg, 0.269 mmol) in DMF (20 mL) in a sealed vial was degassed and refilled with N three times. The mixture was stirred at 80 °C for 1 h, cooled, filtered, and purified directly by reverse-phase HPLC (eluting with 0–80% ACN / HO (TFA modifier, 0.0375%)) to afford the title compound (446 mg, 65%) as the TFA salt. 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.45 (br s, 1H) 7.77 (d, 2H) 7.67 (d, 1H) 7.47 (d, 1H) 7.39 (d, 1H) 7.36 (d, 2H) 5.86 (d, 1H) 3.95 (q, 2H) 3.89 (s, 3H) 3.54 (d, 2H) 3.10 (m, 2H) 2.87 (m, 1H) 2.84 (d, 3H) 2.05 (d, 2H) 1.87 (m, 2H); MS (m / z): [M+1] + , 398.17.

[0165] Lithium (E)-3-(2-ethoxyvinyl)-5-fluoro-4'-(1-methylpiperidin-4-yl)-[1,1'-biphenyl]-4-carboxylate A mixture of methyl (E)-3-(2-ethoxyvinyl)-5-fluoro-4'-(1-methylpiperidin-4-yl)-[1,1'-biphenyl]-4-carboxylate (TFA salt, 440 mg, 0.86 mmol) and LiOH·HO (100 mg, 2.43 mmol) in THF (3 mL), MeOH (3 mL), and water (3 mL) was heated at 50 °C for 5 h. The solvent was removed under reduced pressure, and the residue was dried under vacuum at 60 °C overnight and used without further purification. MS (m / z): [M+1] + ,384.14.

[0166] Ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(8-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-1-oxoisoquinolin-2(1H)-yl)acetate Lithium (E)-3-(2-ethoxyvinyl)-5-fluoro-4'-(1-methylpiperidin-4-yl)-[1,1'-biphenyl]-4-carboxylate (214 mg, 0.55 mmol) in DMF (1 mL) was treated with HBTU (229 mg, 0.61 mmol), and the mixture was stirred at room temperature for 1 h. A solution of ethyl 2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate trifluoroacetate (240 mg, 0.74 mmol) in DMF (1 mL) was added, and the reaction mixture was stirred at room temperature for 10 min. Most of the DMF was evaporated under a stream of N2, and the residue was partitioned between water (30 mL) and DCM (30 mL). The aqueous layer was further extracted with DCM (2 × 30 mL), and the combined organic extracts were dried over Na2SO4 and filtered. The filtrate was treated with 4 N HCl in dioxane (2 mL) and allowed to stand for 5 min, after which the solvent was removed under reduced pressure. The residue was purified by reverse-phase HPLC using 0-80% ACN / HO (TFA modifier) ​​to give the title compound (196 mg, 55%) as the TFA salt. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.56 (br s, 1 H) 8.74 (br s, 1 H) 7.86 (d, 1 H) 7.83 (d, 2H) 7.64 (dd, 1 H) 7.52 (d, 1 H) 7.40 (d, 2 H) 6.78 (dd, 1 H) 6.53 (s, 1 H) 4.24 (q, 2 H) 4.21 (m, 2H) 3.55 (d, 2H) 3.10 (m, 2 H) 2.89 (m, 2H) 2.85 (d, 3H) 2.80 (m, 1H) 2.56 (m, 2 H) 2.06 (d, 2H) 1.88 (m, 2 H) 1.21 (t, 3 H); MS (m / z): [M+1] + , 528.99.

[0167] 2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(8-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-1-oxoisoquinolin-2(1H)-yl)acetic acid A solution of ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(8-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-1-oxoisoquinolin-2(1H)-yl)acetate (TFA salt, 192 mg, 0.3 mmol) in THF / MeOH / water (1:1:1, 4.5 mL) was treated with LiOH·HO (62 mg, 1.5 mmol) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (7 mL) and treated with 1 N HCl to pH 2. The water was removed under reduced pressure, and the residue was dried to give the title compound, which was used in the next step without further purification. MS (m / z): [M+1] + ,501.15.

[0168] Example 1 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(8-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-1-oxoisoquinolin-2(1H)-yl)-N-(thiazol-2-yl)acetamide A mixture of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(8-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-1-oxoisoquinolin-2(1H)-yl)acetic acid (obtained in the previous step, 0.3 mmol), HATU (125 mg, 0.33 mmol), 2-aminothiazole (45 mg, 0.45 mmol), and diisopropylethylamine (208 mL, 1.2 mmol) in DMF (3.5 mL) was stirred at room temperature for 1.5 hours. An additional portion of HATU (125 mg, 0.33 mmol) and 2-aminothiazole (45 mg, 0.45 mmol) was added, and the mixture was stirred at 50 °C for 2 hours. After cooling to room temperature, the reaction mixture was purified by reverse-phase HPLC (eluting with 0-80% ACN / H2O (TFA modifier)) to give the title compound as the TFA salt (110 mg, 53% over two steps). 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.46 (br s, 1 H) 7.86 (m, 1 H) 7.85 (d, 2H) 7.64 (dd, 1 H) 7.53 (d, 1 H) 7.40 (d, 2 H) 7.32 (d, 1 H) 7.30 (s, 1H) 6.78 (s, 1 H) 6.72 (dd, 1 H) 4.17 (m, 2 H) 3.55 (d, 2 H) 3.10 (m, 2 H) 2.89 (m, 2H) 2.85 (s, 3H) 2.80 (m, 1H) 2.56 (m, 2 H) 2.07 (d, 2 H) 1.87 (m, 2H); MS (m / z): [M+1] + , 583.23.

[0169] Ethyl 2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate Ethyl 2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate was prepared according to the procedure described in WO2020 / 002487.

[0170] Compound 2 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(8-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-1-oxoisoquinolin-2(1H)-yl)-N-(thiazol-2-yl)acetamide Compound 2 was prepared in the same manner as compound 1 from lithium (E)-3-(2-ethoxyvinyl)-5-fluoro-4'-(1-methylpiperidin-4-yl)-[1,1'-biphenyl]-4-carboxylate and ethyl 2-amino-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate. MS (m / z): [M+1] + ,601.26.

[0171] Ethyl 2-amino-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate Ethyl 2-amino-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate was prepared according to the procedure described in WO2020 / 002487.

[0172] Scheme 2 - Synthesis of Compound 3 [ka] Methyl 3-bromo-5-(4-(1-methylpiperidin-4-yl)phenyl)thiophene-2-carboxylate Tetrakis(triphenylphosphine)palladium(0) (533 mg, 0.462 mmol) was added to a mixture of methyl 3,5-dibromothiophene-2-carboxylate (690 mg, 2.31 mmol), KCO (957 mg, 6.92 mmol), and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (764 mg, 2.54 mmol) in toluene (10 mL) and water (1 mL). The reaction vial was degassed with nitrogen, and the mixture was stirred at 80 °C for 3 days. The solvent was removed under reduced pressure, and the residue was dissolved in DMSO and filtered. The filtrate was purified by reverse-phase HPLC (eluting with 0–80% ACN / water (TFA modifier)) to give the title compound (412 mg, 35%) as the TFA salt. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.77 (d, 2H) 7.75 (s, 1H) 7.36 (d, 2H) 3.85 (s, 3H) 3.55 (m, 2H) 3.08 (m, 2H) 2.86 (m, 1H) 2.84 (d, 3H) 2.04 (m, 2H) 1.84 (m, 2H); MS (m / z): [M+1] + 394.01.

[0173] Methyl (E)-3-(2-ethoxyvinyl)-5-(4-(1-methylpiperidin-4-yl)phenyl)thiophene-2-carboxylate Pd(dba) (102 mg, 0.056 mmol) and PCy (63 mg, 0.223 mmol) were added to a mixture of methyl 3-bromo-5-(4-(1-methylpiperidin-4-yl)phenyl)thiophene-2-carboxylate (TFA salt, 440 mg, 0.87 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (243 mg, 1.23 mmol), and KCO (462 mg, 3.35 mmol) in dioxane (8 mL) and water (0.8 mL). The reaction vial was degassed with nitrogen, and the mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled, filtered, and the filtrate was purified by reverse-phase HPLC (eluting with 0-80% ACN / water (TFA modifier)) to give the title compound (182 mg, 42%) as the TFA salt. MS (m / z): [M+1] + 387.18.

[0174] Lithium (E)-3-(2-ethoxyvinyl)-5-(4-(1-methylpiperidin-4-yl)phenyl)thiophene-2-carboxylate A mixture of methyl (E)-3-(2-ethoxyvinyl)-5-(4-(1-methylpiperidin-4-yl)phenyl)thiophene-2-carboxylate (TFA salt, 250 mg, 0.50 mmol) and LiOH monohydrate (82 mg, 1.95 mmol) in THF / MeOH / water (1:1:1, 3.0 mL) was stirred at 60° C. for 3.5 hours. The solvent was removed under reduced pressure, and the residue was dried under high vacuum overnight. This material was used in the next step without further purification. MS (m / z): [M+1] + ,372.14.

[0175] Ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(2-(4-(1-methylpiperidin-4-yl)phenyl)-7-oxothieno[2,3-c]pyridin-6(7H)-yl)acetate HBTU (271 mg, 0.72 mmol) was added to a suspension of crude lithium (E)-3-(2-ethoxyvinyl)-5-(4-(1-methylpiperidin-4-yl)phenyl)thiophene-2-carboxylate obtained in the previous step in DMF (3 mL) and stirred at room temperature for 1 h. A solution of ethyl 2-amino-2-(3a,4,5,6-tetrahydrocyclopenta[c]pyrrol-1-yl)acetate (210 mg, 0.65 mmol) in DMF (1 mL) was added, and the reaction was stirred at room temperature for 1.5 h. Most of the DMF was evaporated under a stream of N2, and the residue was partitioned between water (30 mL) and DCM (30 mL). The aqueous layer was further extracted with DCM (2 × 30 mL), and the combined organic extracts were dried over Na2SO4 and filtered. The filtrate was treated with 4 N HCl in dioxane (2 mL) and allowed to stand for 5 min, after which the solvent was removed under reduced pressure. The residue was purified by reverse-phase HPLC (0-80% ACN / HO (TFA modifier)) to give the title compound (100 mg, 32% over two steps) as the TFA salt. MS (m / z): [M+1] + ,517.19.

[0176] 2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(2-(4-(1-methylpiperidin-4-yl)phenyl)-7-oxothieno[2,3-c]pyridin-6(7H)-yl)acetic acid A mixture of ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(2-(4-(1-methylpiperidin-4-yl)phenyl)-7-oxothieno[2,3-c]pyridin-6(7H)-yl)acetate (TFA salt, 100 mg, 0.16 mmol), LiOH monohydrate (37 mg, 0.9 mmol), THF (1 mL), MeOH (1 mL), and water (1 mL) was stirred at room temperature for 2 hours. The organic solvent was removed under reduced pressure, water (5 mL) was added, and the residue was treated with 1N HCl to pH 3-4. The solvent was removed under reduced pressure, and the residue was dried under high vacuum overnight. This material was used in the next step without further purification. MS (m / z): [M+1] + ,488.92.

[0177] Compound 3 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(2-(4-(1-methylpiperidin-4-yl)phenyl)-7-oxothieno[2,3-c]pyridin-6(7H)-yl)-N-(thiazol-2-yl)acetamide A mixture of crude 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(2-(4-(1-methylpiperidin-4-yl)phenyl)-7-oxothieno[2,3-c]pyridin-6(7H)-yl)acetic acid (0.16 mmol) obtained in the previous step, HATU (61 mg, 0.16 mmol), 2-aminothiazole (33 mg, 0.33 mmol), DIEA (83 mL), and DMF (3.5 mL) was stirred at room temperature for 1 hour. An additional portion of HATU (61 mg), 2-aminothiazole (33 mg), and DIEA (83 mL) was added, and the reaction was heated at 50° C. for 1 hour. After cooling, the entire reaction mixture was purified by reverse-phase HPLC (eluting with 0-80% ACN / HO (TFA modifier)) to give the title compound (70 mg, 77% over two steps) as the TFA salt. MS (m / z): [M+1] + ,571.02.

[0178] Compound 4 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(2-(4-(1-methylpiperidin-4-yl)phenyl)-7-oxothieno[2,3-c]pyridin-6(7H)-yl)-N-(thiazol-2-yl)acetamide Compound 4 was prepared in the same manner as compound 3 from lithium (E)-3-(2-ethoxyvinyl)-5-(4-(1-methylpiperidin-4-yl)phenyl)thiophene-2-carboxylate and ethyl 2-amino-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate. MS (m / z): [M+1] + ,589.19.

[0179] Scheme 3 - Synthesis of Compound 5 [ka] Ethyl 2-(2-amino-5-bromobenzamido)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate A mixture of 2-amino-5-bromobenzoic acid (500 mg, 2.31 mmol), ethyl 2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (500 mg, 2.39 mmol), HOBt (400 mg, 2.96 mmol), EDCI (500 mg, 2.61 mmol), and diisopropylethylamine (808 mL, 4.64 mmol) in DMF (3.5 mL) was degassed and purged with N, and the mixture was stirred under N at 20 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (15 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, EtOAc:MeOH=10 / 1) to give the title compound (890 mg, 94% yield) as a yellow solid.

[0180] Ethyl 2-(6-bromo-4-oxoquinazolin-3(4H)-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate A mixture of ethyl 2-[(2-amino-5-bromobenzoyl)amino]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (500 mg, 1.23 mmol) in trimethyl orthoformate (5 mL) was degassed and purged with N, and the mixture was stirred under N at 110 °C for 12 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, EtOAc:methanol = 1:0 to 10:1) to give the title compound (426 mg, crude) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (m, 2H) 8.02 (dd, 1H) 7.65 (d, 1H) 7.63 (s, 1H) 6.41 (s, 1H) 4.21 (m, 1H) 4.19 (m, 1H) 4.02 (m, 2H) 2.81 (m, 1H) 2.69 (m, 1H) 2.56 (m, 2H) 1.18 (t, 3H).

[0181] 2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)acetic acid Pd(dppf)Cl (66 mg, 0.09 mmol) and KCO (249 mg, 1.80 mmol) were added to a solution of ethyl 2-(6-bromo-4-oxo-quinazolin-3-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (376 mg, 0.90 mmol) and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (299 mg, 0.99 mmol) in dioxane (4 mL) and water (0.4 mL). The mixture was stirred at 120 °C under N for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions, column: Waters Xbridge BEH C18 100*30mm*10mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 5% to 35%, 8 min) to give the title compound (120 mg, 27% yield) as a white solid. MS (m / z): [M+1] + ,484.3.

[0182] Compound 5 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)acetamide A mixture of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-4-oxoquinazolin-3-yl]acetic acid (25 mg, 0.05 mmol), thiazol-2-amine (16 mg, 0.16 mmol), diisopropylethylamine (22 mL, 0.13 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (27 mg, 0.06 mmol) in DMF (1 mL) was degassed and purged with N, and the mixture was stirred under N at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions, column: Phenomenex Luna C18 75*30mm*3mm; mobile phase: [water (FA)-ACN]; B%: 1% to 40%, 8 min) to give the title compound (4 mg, 14% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (d, 1H) 8.23 ​​(s, 1H) 8.17 (m, 1H) 7.78 (d, 1H) 7.72 (d, 2H) 7.68 (s, 1H) 7.50 (d, 1H) 7.39 (d, 2H) 7.27 (d, 1H) 6.76 (s, 1H) 4.01 (m, 2H) 2.98 (d, 2H) 2.82 (m, 1H) 2.56 (m, 4H) 2.30 (s, 3H) 2.16 (m, 2H) 1.79 (m, 2H) 1.73 (m, 2H); MS (m / z): [M+1] + , 566.2.

[0183] Compound 6 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(5-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)acetamide Compound 6 was prepared in a similar manner to compound 5 from 6-amino-3-bromo-2-fluorobenzoic acid and ethyl 2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (m, 1H) 7.96 (t, 1H) 7.68 (s, 1H) 7.59 (d, 1H) 7.53 (d, 2H) 7.49 (d, 1H) 7.38 (d, 2H) 7.27 (d, 1H) 6.68 (s, 1H) 4.01 (m, 2H) 2.91 (d, 2H) 2.82 (m, 1H) 2.56 (m, 4H) 2.23 (s, 3H) 2.04 (m, 2H) 1.77 (m, 2H) 1.72 (m, 2H); MS (m / z): [M+1] + , 584.1.

[0184] Scheme 4 - Synthesis of Compound 7 [ka] 2-(6-Bromo-4-oxoquinazolin-3(4H)-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid LiOH·HO (107 mg, 2.54 mmol) was added to a solution of ethyl 2-(6-bromo-4-oxo-quinazolin-3-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (530 mg, 1.27 mmol) in EtOH (3 mL) and water (1 mL). The mixture was stirred at 25 °C for 12 h and then concentrated to give a residue. Water (10 mL) was added and the pH was adjusted to 2. The mixture was filtered and concentrated under reduced pressure to give the title compound (450 mg, 91% yield) as a pale yellow solid, which was used without further purification.

[0185] 2-(6-Bromo-4-oxoquinazolin-3(4H)-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide HATU (234 mg, 0.616 mmol) and diisopropylethylamine (448 mL, 2.57 mmol) were added to a solution of 2-(6-bromo-4-oxo-quinazolin-3-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (200 mg, 0.513 mmol) and thiazol-2-amine (129 mg, 1.28 mmol) in DMF (2 mL). The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, ethyl acetate / methanol = 1 / 0 to 10 / 1) to give the title compound (120 mg, yield 50%) as a yellow solid.

[0186] Compound 7 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(4-methylpiperazin-1-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)acetamide Pd(dppf)Cl (8 mg, 0.010 mmol) and KCO (29 mg, 0.212 mmol) were added to a solution of 2-(6-bromo-4-oxo-quinazolin-3-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide (50 mg, 0.106 mmol) and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (34 mg, 0.111 mmol) in dioxane (1 mL) and water (0.1 mL). The mixture was stirred at 110 °C for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA condition, column: Phenomenex Luna C18 75*30 mm*3 mm; mobile phase: [water (FA)-ACN]; B%: 10%~40%, 8 min) to give the title compound (2 mg, yield 3%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.30 (d, 1H) 8.20 (s, 1H), 8.17 (s, 1H) 8.13 (dd, 1H) 7.74 (d, 1H) 7.68 (s, 1H) 7.65 (d, 2H) 7.50 (d, 1H) 7.27 (d, 1H) 7.06 (d, 2H) 6.76 (s, 1H) 4.01 (m, 2H) 3.20 (m, 2H) 2.81 (m, 1H) 2.23 (s, 3H), 9 protons masked by solvent; MS (m / z): [M+1] + , 567.1.

[0187] Scheme 5 - Synthesis of Example 8 [ka] Ethyl 2-(5-bromo-2-hydroxybenzamido)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate A mixture of 5-bromo-2-hydroxybenzoic acid (500 mg, 2.30 mmol), ethyl 2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (HCl salt, 623 mg, 2.53 mmol), HATU (1.05 g, 2.76 mmol), and DIEA (1.20 mL, 6.91 mmol) in DMF (5 mL) was degassed and purged with N2 three times, then stirred at room temperature for 16 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc. The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the title compound (410 mg) as a yellow solid.

[0188] Ethyl 2-(6-bromo-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate A mixture of ethyl 2-[(5-bromo-2-hydroxybenzoyl)amino]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (50 mg, 0.122 mmol), diiodomethane (10 μL, 0.122 mmol), and CsCO (68 mg, 0.208 mmol) in DMF (1 mL) was stirred at 110 °C for 1 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (4 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the title compound (70 mg) as a brown solid.

[0189] 2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)acetic acid A mixture of ethyl 2-(6-bromo-4-oxo-2H-1,3-benzoxazin-3-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (25 mg, 0.06 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (20 mg, 0.065 mmol), Pd(dppf)Cl (4.3 mg, 0.006 mmol), and KCO (16.4 mg, 0.012 mmol) in dioxane (1 mL) and water (0.1 mL) was degassed, purged with N three times, and stirred at 120 °C under N for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions, column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (FA)-ACN]; B%: 5%-30%, 8 min) to give the title compound (18 mg, 29% yield) as a white solid. MS (m / z): [M+1] + 487.2.

[0190] Example 8 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-N-(thiazol-2-yl)acetamide A mixture of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-4-oxo-2H-1,3-benzoxazin-3-yl]acetic acid (13 mg, 27 μmol), thiazol-2-amine (3 mg, 29 μmol), HATU (12 mg, 32 μmol), and DIEA (14 μL, 80 μmol) in DMF (1 mL) was degassed, purged with N three times, and stirred under N at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions, column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 35%~65%, 8 min) to give the title compound (2 mg, 13% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, 1H), 7.83 (dd, 1H), 7.60 (m, 3H), 7.47 (d, 1H), 7.33 (d, 2H), 7.24 (br d, 1H), 7.13 (d, 1H), 6.38 (s, 1H), 5.54 (d, 1H), 5.34 (d, 1H), 4.00 (m, 2H), 2.87 (d, 2H), 2.76 (m, 1H), 2.19 (s, 3H), 1.97 (m, 2H), 1.74 (m, 2H), 1.67 (m, 2H), four protons masked by solvent. MS(m / z):[M+1] + 569.3.

[0191] Example 2: HTRF-based EGFR biochemical assay EGFR biochemical activity measurements were performed using a homogeneous time-resolved fluorescence (HTRF) assay (Cisbio). First, inhibitors and DMSO standardization were dispensed into empty black low-volume 384-well plates (Corning) using a D300 digital liquid dispenser (HP). All reactions were performed at room temperature, and solutions were added to the plates using a Multidrop Combi reagent dispenser (ThermoFisher). The reaction mixture (final volume 10 μL) 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). Enzyme concentrations were adjusted to various kinase activities (L858R 0.1 nM, L858R / T790M 0.02 nM). The enzyme reaction solution (5 μL, 2x concentration) was added to the compound-containing 384-well plate and incubated for 30 minutes. 5 μL of ATP was added to a final concentration of 100 μM to initiate the enzyme reaction, which was allowed to proceed for 20 minutes. The reaction was quenched by adding 10 μL of phosphotyrosine antibody-europium(III) cryptate (1:180 volume ratio) and streptavidin XL665 (46.7 nM) in EDTA-containing detection buffer. The reaction was then incubated at room temperature for 1 hour and read on a PHERAstar plate reader (excitation = 337 nm, emission = 620 nm and 665 nm). Triplicate inhibition curves (11-point curve from 1.0 μM to 0.130 nM or 23-point curve from 1.0 μM to 0.130 pM) were fitted using nonlinear least-squares in GraphPad Prism 7.0d. IC values ​​were calculated. 50 The data obtained are shown in Table 2 below, with "-" indicating an IC of 5 nM or greater. 50 values, and "+" indicates IC<5 nM 50 values ​​and "++" indicates IC<1 nM 50 values, and "+++" indicates IC<0.5 nM 50 Indicates the value. [Table 2]

[0192] Example 3: Ba / F3 cell proliferation model EGFR mutant L858R and L858R / T790M Ba / F3 cells were previously described (Zhou, W., et al. Nature 462, 2009, 1070-1074). All cell lines were maintained in RPMI 1640 (Cellgro; Mediatech Inc., Herndon, CA) supplemented with 10% FBS, 100 units / mL penicillin, and 100 units / mL streptomycin. The EGFR I941R mutation was introduced by 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. Constructs were shuttled 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 standard protocols as described above (Zhou, et al., Nature 2009). Stable clones were obtained by selection with puromycin (2 μg / ml).

[0193] Growth and growth inhibition were assessed using 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 viable cell number based on the amount of ATP present, which 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 per experiment was determined empirically as previously established (Zhou, et al., Nature 2009). All experimental points were set up in triplicate in a 384-well plate, and all experiments were repeated at least three times. Luminescence signals were detected using a spectrometer, and data were displayed graphically using GraphPad Prism version 5.0 for Windows (GraphPad Software, www.graphpad.com). Curves were fitted using a nonlinear regression model with a sigmoidal dose-response. The results of this assay for the compounds disclosed herein are shown below in Table 3, where a "+" indicates an IC of less than 5 uM. 50 values, and "++" indicates IC<0.5uM 50 values, and "+++" indicates IC<0.1uM 50 Indicates the value. [Table 3]

[0194] The disclosed subject matter is not 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 skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

[0195] All references (e.g., publications, patents, or patent applications) cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual reference (e.g., publication, patent, or patent application) was 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. Compounds of Formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (In the formula, 【Chemistry 2】 represents a single or double bond, A and A' are each independently CH, CR １０ , C.H. ２ , O, or N; W and Z are each independently N or CR ９ 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 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 selected from one, two, or three R ８ optionally replaced by Each R ２ But C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, C １ -C ３ Alkylamine, halogen, OH, NO ２ , N.H. ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , (CH ２ ) １－４ OH, S(O) ０－２ H, S (O) ０－２ NH ２ , CN, and 3- to 10-membered cycloalkyl; Or, two R ２ together with the atom to which they are attached form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycloalkyl; R ３ is, in each occurrence, independently a halogen, OR ４ , N.R. ４ R ４ , S.O. ２ R ４ , S.O. 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 4- to 7-membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl is selected from the group consisting of R ４ and optionally substituted one, two, or three times with aryl, heteroaryl, or heterocyclyl, respectively, R ５ optionally substituted one, two, or three times by R ４ In each occurrence, independently, H, C １ -C ６ Alkyl, (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 -(4- to 7-membered heterocyclyl), wherein said aryl, heteroaryl, or heterocyclyl is each selected from the group consisting of R ６ optionally substituted one, two, or three times by R ５ but, in each occurrence, independently, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, C １ -C ３ Alkylamine, 3-10 membered cycloalkyl, halogen, COOH, C(O)O(C １ -C ６ alkyl), O(CH ２ ) １－３ -OH, NH ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , OH, CN, (CH ２ ) ０－３ -(C ６ -C １０ aryl), (CH ２ ) ０－３ -(5- to 6-membered heteroaryl), and (CH ２ ) ０－３ -(4- to 7-membered heterocyclyl), wherein said aryl, heteroaryl, or heterocyclyl is each selected from the group consisting of R ７ optionally substituted one, two, or three times by R ６ but, in each occurrence, independently, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, C １ -C ３ Alkylamine, halogen, OH, NO ２ , N.H. ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , (CH ２ ) １－４ OH, S(O) ０－２ H, S (O) ０－２ NH ２ or CN; R ７ but, in each occurrence, independently, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, halogen, NH ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , S.O. ２ NH ２ , S.O. ２ NH (C １ -C ６ alkyl), SO ２ N (C １ -C ６ alkyl) ２ , (CH ２ ) １－２ -OH, C(O)(CH ２ ) １－２ -OH, C(O)(C １ -C ６ alkyl), and C(O)O(C １ -C ６ alkyl); R ８ but, in each occurrence, independently, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, C １ -C ３ Alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO ２ , N.H. ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , (CH ２ ) １－４ OH, S(O) ０－２ H, S (O) ０－２ NH ２ and CN; R ９ may, in each occurrence independently, be H, halo, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, and C １ -C ３ alkoxy; R １０ but, in each occurrence, independently, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, C １ -C ３ Alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO ２ , N.H. ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , (CH ２ ) １－４ OH, S(O) ０－２ H, S (O) ０－２ NH ２ and CN; n is 0, 1, 2, or 3).

2. A is CH ２ 2. The compound of claim 1, wherein:

3. 2. The compound of claim 1, wherein A is CH. 【Request Item 4】 【Chemistry 3】 The compound according to claim 1 , wherein represents a single bond. 【Request Item 5】 【Chemistry 4】 The compound of claim 1 , wherein represents a double bond.

6. R １ But one, two, or three R ８ The compound of any one of claims 1 to 5, wherein the heteroaryl is a 5- to 10-membered heteroaryl optionally substituted with

7. R １ is thiazolyl or pyridinyl, both of which contain one, two, or three R ８ The compound of any one of claims 1 to 6, optionally substituted with

8. R １ but, 【Transformation 5】 selected from the group consisting of Both of these can be 1, 2, or 3 R ８ The compound of any one of claims 1 to 7, optionally substituted with

9. The compound of formula I may be a compound of formula Ia: 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

10. When the compound of formula I is a compound of formula Ib: 【Transformation 7】 or a pharmaceutically acceptable salt thereof.

11. The compound of formula I may be a compound of formula Id: 【Transformation 8】 or a pharmaceutically acceptable salt thereof.

12. X is CR ３ 12. The compound of any one of claims 1 to 11, wherein when

13. Y is CR ３ 12. The compound of any one of claims 1 to 11, wherein when

14. The compound of any one of claims 1 to 3 and 5 to 13, wherein A' is N.

15. The compound of any one of claims 1 to 3 and 5 to 13, wherein A' is C--H.

16. A' is CH ２ The compound according to any one of claims 1 to 4 and 6 to 13,

17. The compound of any one of claims 1 to 4 and 6 to 13, wherein A' is O.

18. 18. The compound of any one of claims 1 to 8 and 12 to 17, wherein Z is CH or C-halo.

19. R ２ is halogen or C １ -C ３ The compound of any one of claims 1 to 18, which is alkyl.

20. R ３ But one or two R ５ The compound of any one of claims 1 to 19, wherein the aryl is 6 to 10 membered substituted with

21. R ５ But, R ７ 21. The compound of any one of claims 1 to 20, wherein the heterocyclyl is 4 to 7 membered, optionally substituted 1, 2 or 3 times by

22. R ３ but, 【Chemistry 9】 The compound according to any one of claims 1 to 21,

23. R ７ But C １ -C ６ The compound of any one of claims 1 to 22, which is alkyl.

24. The compound according to any one of claims 1 to 23, wherein n is 0 or 1. 【Request Item 25】 【Chemistry 10】 represents a single or double bond, A and A' are each independently CH, CH ２ , O, or N; W and Z are each independently CH or CR ９ and X and Y are each independently CH or CR ３ and R １ But one, two, or three R ８ is a 5- to 10-membered heteroaryl optionally substituted with R ２ is halogen or C １ -C ３ is alkyl, Or, two R ２ together with the atom to which they are attached form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycloalkyl; R ３ But one or two R ５ is a 6- to 10-membered aryl substituted with R ５ But, R ７ and 4- to 7-membered heterocyclyl optionally substituted 1, 2, or 3 times by R ７ But C １ -C ６ is alkyl, R ８ but, in each occurrence, independently, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, C １ -C ３ Alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO ２ , N.H. ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , (CH ２ ) １－４ OH, S(O) ０－２ H, S (O) ０－２ NH ２ and CN; R ９ may, in each occurrence independently, be a halo, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, and C １ -C ３ alkoxy; 2. The compound of claim 1, wherein n is 0 or 1.

26. The compound of formula I is 【Chemistry 11】 26. The compound of any one of claims 1 to 25, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

27. Compound of Formula II: 【Chemistry 12】 or a pharmaceutically acceptable salt thereof, A and A' are each independently CH, CR １０ , or N, R １ 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 selected from one, two, or three R ８ optionally replaced by Each R ２ But C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, C １ -C ３ Alkylamine, halogen, OH, NO ２ , N.H. ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , (CH ２ ) １－４ OH, S(O) ０－２ H, S (O) ０－２ NH ２ , CN, and 3- to 10-membered cycloalkyl; Or, two R ２ together with the atom to which they are attached form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycloalkyl; R ３ is, in each occurrence, independently a halogen, OR ４ , N.R. ４ R ４ , S.O. ２ R ４ , S.O. 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 4- to 7-membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl is selected from the group consisting of R ４ and optionally substituted one, two, or three times with aryl, heteroaryl, or heterocyclyl, respectively, R ５ optionally substituted one, two, or three times by R ４ In each occurrence, independently, H, C １ -C ６ Alkyl, (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 -(4- to 7-membered heterocyclyl), wherein said aryl, heteroaryl, or heterocyclyl is each selected from the group consisting of R ６ optionally substituted one, two, or three times by R ５ but, in each occurrence, independently, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, C １ -C ３ Alkylamine, 3-10 membered cycloalkyl, halogen, COOH, C(O)O(C １ -C ６ alkyl), O(CH ２ ) １－３ -OH, NH ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , OH, CN, (CH ２ ) ０－３ -(C ６ -C １０ aryl), (CH ２ ) ０－３ -(5- to 6-membered heteroaryl), and (CH ２ ) ０－３ -(4- to 7-membered heterocyclyl), wherein said aryl, heteroaryl, or heterocyclyl is each selected from the group consisting of R ７ optionally substituted one, two, or three times by R ６ but, in each occurrence, independently, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, C １ -C ３ Alkylamine, halogen, OH, NO ２ , N.H. ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , (CH ２ ) １－４ OH, S(O) ０－２ H, S (O) ０－２ NH ２ or CN; R ７ but, in each occurrence, independently, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, halogen, NH ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , S.O. ２ NH ２ , S.O. ２ NH (C １ -C ６ alkyl), SO ２ N (C １ -C ６ alkyl) ２ , (CH ２ ) １－２ -OH, C(O)(CH ２ ) １－２ -OH, C(O)(C １ -C ６ alkyl), and C(O)O(C １ -C ６ alkyl); R ８ but, in each occurrence, independently, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, C １ -C ３ Alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO ２ , N.H. ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , (CH ２ ) １－４ OH, S(O) ０－２ H, S (O) ０－２ NH ２ and CN; R １０ but, in each occurrence, independently, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, C １ -C ３ Alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO ２ , N.H. ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , (CH ２ ) １－４ OH, S(O) ０－２ H, S (O) ０－２ NH ２ and CN; n is 0, 1, 2, or 3).

28. R １ But one, two, or three R ８ 28. The compound of claim 27, wherein the heteroaryl is a 5-10 membered heteroaryl optionally substituted with

29. R １ is thiazolyl or pyridinyl, both of which contain one, two, or three R ８ 29. The compound of claim 27 or 28, optionally substituted with

30. R １ but, 【Chemistry 13】 selected from the group consisting of Both of these can be 1, 2, or 3 R ８ 30. The compound of any one of claims 27 to 29, optionally substituted with

31. The compound of formula II may be a compound of formula IIa: 【Chemistry 14】 or a pharmaceutically acceptable salt thereof.

32. The compound of any one of claims 27 to 31, wherein A' is N.

33. The compound of any one of claims 27 to 31, wherein A' is CH.

34. R ２ The compound according to any one of claims 27 to 33, wherein is halogen.

35. R ３ But one or two R ５ The compound of any one of claims 27 to 34, wherein the aryl is 6 to 10 membered substituted with

36. R ５ But, R ７ 36. The compound of any one of claims 27 to 35, wherein the heterocyclyl is 4 to 7 membered, optionally substituted 1, 2 or 3 times by

37. R ３ but, 【Chemistry 15】 The compound according to any one of claims 27 to 36,

38. R ７ But C １ -C ６ The compound of any one of claims 27 to 37, which is alkyl.

39. The compound according to any one of claims 27 to 38, wherein n is 0 or 1.

40. A and A' are each independently CH or N; R １ But one, two, or three R ８ is a 5- to 10-membered heteroaryl optionally substituted with R ２ is a halogen, Or, two R ２ together with the atom to which they are attached form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycloalkyl; R ３ But one or two R ５ is a 6- to 10-membered aryl substituted with R ５ But, R ７ and 4- to 7-membered heterocyclyl optionally substituted 1, 2, or 3 times by R ７ But C １ -C ６ is alkyl, R ８ but, in each occurrence, independently, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, C １ -C ３ Alkylamine, halogen, OH, NH ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , (CH ２ ) １－４ OH, S(O) ０－２ H, S (O) ０－２ NH ２ and CN; 28. The compound of claim 27, wherein n is 0 or 1.

41. The compound of formula II is 【Chemistry 16】 41. The compound of any one of claims 27 to 40, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

42. 42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

43. 43. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any of claims 1-41 or a pharmaceutical composition of claim 42.

44. 44. The method of claim 43, 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.

45. 44. The method of claim 43, wherein the cancer is non-small cell lung cancer (NSCLC).

46. 46. ​​The method of any one of claims 43 to 45, wherein the method further comprises administering a second active agent.

47. 43. A method of inhibiting a kinase in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any of claims 1-41 or a pharmaceutical composition of claim 42.

48. 48. The method of claim 47, wherein the kinase is EGFR.

49. 43. A method of treating a kinase-mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any of claims 1-41 or a pharmaceutical composition of claim 42.

50. 50. The method of claim 49, wherein the kinase-mediated disorder is an EGFR-mediated disorder.

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