Allosteric EGFR inhibitors and methods of use thereof

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 for treating or preventing kinase-mediated disorders, including cancer and other proliferative diseases.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 036,622, filed June 9, 2020, and U.S. Provisional Application No. 63 / 111,429, filed November 9, 2020, the entire contents of which are incorporated herein by reference.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. R01 CA201049 awarded by the National Institutes of Health (NIH). 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). Deregulation of EGFR has been implicated in many types of human cancer, with overexpression of the receptor occurring in at least 70% of human cancers (Seymour, LK, Curr. Drug Targets 2, 2001, 117-133), including non-small cell lung cancer, breast cancer, glioma, squamous cell carcinoma of the head and neck, 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. For example, the EGFR tyrosine kinase (EGFR-TK) reversible inhibitor TARCEVA® has been approved by the FDA for the treatment of NSCLC and advanced pancreatic cancer. Other anti-EGFR targeting molecules, including lapatinib and IRESSA®, have also been approved.

[0004] Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are an effective clinical therapy 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). Several randomized clinical trials have demonstrated that EGFR TKIs are more effective than chemotherapy when used as initial systemic treatment for advanced EGFR mutant NSCLC, as measured by response rate (RR) and progression-free survival (PFS) (Mok, TS, et al., N. Engl. J. Med. 361, 2009, 947-57; Rosell, R., et al., Lancet Oncol. 13, 2012, 239-46; Sequest, LV et al., J. Clin. Oncol. 31, 2013, 3327-34; Wu, YL, et al., Lancet Oncol. 15, 2014, 213-22; Maemondo, M., et al., N. Engl. J. Med. 362, 2010, 2380-8; Zhou, C., et al., Lancet Oncol. 12, 2011, 735-42; Mitsudomi, T., et al., Lancet Oncol. 11, 2010, 121-8). However, the majority of patients will experience disease progression after successful treatment with EGFR TKIs. The most common mechanism of acquired resistance, detected in 60% of patients, is a secondary mutation of EGFR at position T790 (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 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] Covalent EGFR inhibitors have emerged to inhibit EGFR T790M-containing cancers. However, in lung cancer patients, afatinib is only effective in EGFR TKI-naive EGFR mutant cancers, and has a RR of less than 10% in patients with NSCLC who have developed resistance to gefitinib or erlotinib (Miller, VA, et al., Lancet Oncol. 13, 2012, 528-38). Afatinib is a potent inhibitor of both mutant and wild-type (WT) EGFR. Inhibition of WT EGFR leads to toxicities, including skin rash and diarrhea, which limits the ability to titrate afatinib doses in patients to those required to inhibit EGFR T790M. Irreversible pyrimidine EGFR inhibitors, including the tool compound WZ4002 and the clinical compounds CO-1686 and AZD9291, have overcome many of the limitations of afatinib (Zhou, W., et al., Nature 462, 2009, 1070-4; Walter, AO, et al., Cancer Discov. 3, 2013, 1404-15; Cross, DAE, et al., Cancer Discov. 4, 2014, 1046-61). They are not only more potent against EGFR T790M but also selectively inhibit the mutant over WT EGFR, which should result in increased clinical efficacy and lower toxicity compared to afatinib (Zhou, W., et al., Walter AO, et al., Cross, DAE, et al.).

[0006] However, all current EGFR TKIs target the ATP site, and although third-generation irreversible inhibitors can overcome T790M, they are all rendered ineffective by the C797S mutation, which already occurs in treated patients. Cetuximab, an anti-EGFR antibody that inhibits receptor dimerization, is ineffective in EGFR-mutant NSCLC because mutational activation of the kinase is actually "downstream" of receptor dimerization.

[0007] Currently, suitable compounds with alternative mechanisms of action that target mutant EGFR are not available. Thus, there is a need for potent small molecule EGFR inhibitors with alternative mechanisms of action that target mutant EGFR. Summary of the Invention

[0008] In one aspect, provided herein are compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, [ka] represents an optional double bond, A and A' are each independently CH, CR 8 , or N, W is N or C; Z is selected from the group consisting of S, O, N, NH, N-Me, CH, CH, C-halo, C—(C-C alkyl), or C—(C-C alkoxy); X and Y are each independently S, O, N, CH, or NR 3 , or CR 3 and provided that at least one of X, Y, or Z is CH; R 1 is C(O)NHR 9 , 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from the group consisting of one, two, or three R 8 optionally replaced by R 2 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which may be selected from one, two, or three R 6 optionally replaced by R3 independently at each occurrence, a halogen, OR 4 , N.R. 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , NHC(O)R 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, each of which is optionally selected from the group consisting of alkyl, alkenyl, or alkynyl; 4 aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R 5 is substituted 1, 2, or 3 times with R 4 is independently at each occurrence 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 -(5-6 membered heteroaryl), and (CH2) 0~3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl are each optionally selected from the group consisting of R 5 is substituted 1, 2, or 3 times with R 5 is independently, at each occurrence, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3-10 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 10aryl), (CH2) 0~3 -(5-6 membered heteroaryl), and (CH2) 0~3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl are each optionally selected from the group consisting of R 7 is substituted 1, 2, or 3 times with Or two R's 5 can be taken together with the atom to which they are attached to form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl, all of which can optionally be joined by R 7 can be substituted one, two, or three times with R 6 is independently, at each occurrence, 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; Or two R's 6 can be taken together with the atom to which they are attached to form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 7 is independently, at each occurrence, 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); Or two R's 7can be taken together with the atom to which they are attached to form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 8 is independently, at each occurrence, 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 NH2, or CN; R 9 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which may be selected from one, two, or three R 8 is optionally replaced by

[0009] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0010] In yet another aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I.

[0011] In yet another aspect, provided herein is 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 formula I.

[0012] In one aspect, provided herein is a method of treating or preventing a kinase-mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I. DETAILED DESCRIPTION OF THE INVENTION

[0013] definition Listed 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 limited in specific instances individually or as part of a larger group.

[0014] 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 used in the art.

[0015] 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. By way of example, "an element" means one element or more than one element. Furthermore, the use of the term "including" as well as other forms such as "include," "includes," and "including" is not limiting.

[0016] The term "about," as used herein, will be understood by one 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, such as an amount, length of time, etc., the term "about" is intended to encompass variations of ±20% or ±10%, e.g., ±5%, ±1%, and ±0.1%, from the specified value, since such variations are appropriate in performing the disclosed methods.

[0017] As used herein, the term "administering" and the like refers to providing a therapeutic agent to a subject. Multiple techniques for administering a therapeutic agent exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, intraocular, intrapulmonary, and topical administration.

[0018] 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, for cancer-related conditions, treatment involves contacting a wild-type or mutant EGFR with an effective amount of a compound disclosed herein.

[0019] As used herein, the term "prevent" or "prevention" refers to the absence of a disorder or disease occurring if none existed, or the absence of a further disorder or disease occurring if a disorder or disease has already occurred. Also considered is the ability to prevent some or all of the symptoms associated with a disorder or disease.

[0020] As used herein, the terms "patient," "individual," or "subject" refer to a human or non-human mammal. Non-human mammals include, for example, farm animals and pets, such as sheep, cattle, pigs, dogs, cats, and marine mammals. Preferably, the patient, subject, or individual is a human.

[0021] 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 a reduction or alleviation of the signs, symptoms, or causes of a disease, or any 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.

[0022] As used herein, the term "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that can be administered to an individual without abolishing the biological activity or properties of the compound, and that is relatively non-toxic, i.e., does not cause undesired biological effects or interact in a deleterious manner with any of the components of the composition in which it is contained.

[0023] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound has been modified by converting an acidic or basic moiety present therein into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. 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. Pharmaceutically acceptable salts of the present disclosure can be synthesized from parent compounds 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 simple salts, i.e., 1:1 salts. For example, "pharmaceutically acceptable salts" also includes bis salts, such as 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.

[0024] As used herein, the term "prodrug" refers to a precursor compound that will undergo metabolic activation in vivo to produce an active drug. Thus, for example, a prodrug of a compound provided herein, when administered to a subject, will undergo metabolic activation to produce the compound.

[0025] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful in the present disclosure and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple methods of administering a compound exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, intraocular, intrapulmonary, and topical administration.

[0026] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combination of two or more active ingredients, including both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both active ingredients, e.g., a compound of the present disclosure and a co-agent, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that both active ingredients, e.g., a compound of the present disclosure and a co-agent, are administered to a patient simultaneously, in parallel, or sequentially as separate entities without specific time restrictions, such that administration provides therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0027] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, 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 useful compound within the disclosure into or to a patient so that it may perform its intended function. Generally, such constructs are carried or transported from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the useful compound within the disclosure, and not harmful to the patient. Some examples of substances which can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as 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 materials used in pharmaceutical formulations.

[0028] As used herein, "pharmaceutically acceptable carrier" also 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 in the present disclosure and are physiologically acceptable to the patient. Supplementary active compounds can also be added to the compositions. "Pharmaceutically acceptable carriers" can also include pharmaceutically acceptable salts of the compounds disclosed herein. Other additional ingredients that can be included in pharmaceutical compositions are well 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.

[0029] As used herein, the term "EGFR" refers to the epidermal growth factor receptor (alternatively called ErbB-1 or HER1), and may refer to the wild-type receptor or a receptor containing one or more mutations.

[0030] As used herein, the term "HER" or "Her" refers to members of the ErbB receptor tyrosine kinase family, which includes EGFR, ERBB2, HER3, and HER4.

[0031] As used herein, the term "allosteric site" refers to a site on EGFR other than the ATP-binding site, for example, a site characterized in the crystal structure of EGFR. An "allosteric site" can be a site close to the ATP-binding site, for example, a site 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.

[0032] 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 "activator" 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.

[0033] 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., C1-C6 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 C1-C6 alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0034] As used herein, the term "haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halo substituents, where alkyl and halo are as defined herein. Haloalkyl includes, for example, chloromethyl, trifluoromethyl, bromoethyl, chlorofluoroethyl, and the like.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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 with at least one carbon-carbon double bond. An alkenyl group may or may not be the 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.

[0039] 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 with at least one carbon-carbon triple bond. An alkynyl group may or may not be the 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.

[0040] The terms “halo” or “halogen,” as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, and more preferably fluorine or chlorine.

[0041] As used herein, the term "cycloalkyl" refers to a fully saturated, non-aromatic carbocyclic ring system having one, two, or three rings, which rings may be fused. The term "fused" means that a second ring is present (i.e., linked or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. Cycloalkyl also includes bicyclic structures that may be bridged or spirocyclic in nature, with each individual ring in the bicyclic structure having between three and eight atoms. 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.

[0042] As used herein, the term "cycloalkenyl" means a partially saturated non-aromatic carbocyclic ring system having one, two, or three rings, which rings may be fused, and at least one ring is an aryl group. 2 Contains 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.

[0043] As used herein, the term "heterocyclyl" means a non-aromatic carbocyclic ring system having one, two, or three rings containing one, two, three, or four heteroatoms independently selected from N, O, and S, and which rings may be fused, where fusion is defined above. Heterocyclyl also includes bicyclic structures which may be bridged or spirocyclic in nature, where each individual ring within the bicycle varies from 3 to 8 atoms 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-aza-bicyclo[3.1.1]heptanyl, and the like. butanyl, 2-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo-[3.1.0]hexanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 3-oxa-7-azabicyclo[3.3.1]-nonanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, 2-oxa-5- These include azabicyclo[2.2.1]heptanyl, 6-oxa-3-aza-bicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxaspiro-[3.3]heptanyl, 2-oxaspiro[3.5]nonanyl, 3-oxaspiro[5.3]nonanyl, and 8-oxabicyclo[3.2.1]octanyl.

[0044] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring containing one or more polyunsaturated rings and having aromatic character (i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer).

[0045] As used herein, the term "aryl" refers to an aromatic carbocyclic ring system containing one, two, or three rings, which may be fused (fused as defined above). If the 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.

[0046] The term "heteroaryl," as used herein, refers to 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, which may be fused (fused as defined above). The term "heteroaryl" includes, but is not limited to, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridin ... [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.

[0047] Where an aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety can be bonded or otherwise connected to a designated moiety through different ring atoms (i.e., when shown or described without indicating a particular point of attachment), it is understood that all possible points are contemplated, whether through a carbon atom or, for example, through a trivalent nitrogen atom. For example, the term "pyridinyl" means 2-, 3-, or 4-pyridinyl, the term "thienyl" means 2- or 3-thioenyl, and so on.

[0048] 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 with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) 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 in the treatment of kinase-mediated disorders, including cancer and other proliferative diseases.

[0051] In one aspect, provided herein are compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, [ka] represents an optional double bond, A and A' are each independently CH, CR 8 , or N, W is N, C, or CH; Z is selected from the group consisting of S, O, N, NH, N-Me, CH, CH, C-halo, C—(C-C alkyl), or C—(C-C alkoxy); X and Y are each independently S, O, N, CH, or NR 3 , or CR 3 and However, at least one of X, Y, or Z is CH. R 1 is C(O)NHR 9, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from the group consisting of one, two, or three R 8 optionally replaced by R 2 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which may be selected from one, two, or three R 6 optionally replaced by R 3 independently at each occurrence, a halogen, OR 4 , N.R. 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , NHC(O)R 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, each of which is optionally selected from the group consisting of alkyl, alkenyl, or alkynyl; 4 aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R 5 is substituted 1, 2, or 3 times with R 4 is independently at each occurrence 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 -(5-6 membered heteroaryl), and (CH2) 0~3-(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl are each optionally selected from the group consisting of R 5 is substituted 1, 2, or 3 times with R 5 is independently, at each occurrence, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3-10 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 -(5-6 membered heteroaryl), and (CH2) 0~3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl are each optionally selected from the group consisting of R 7 is substituted 1, 2, or 3 times with Or two R's 5 can be taken together with the atom to which they are attached to form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl, all of which can optionally be joined by R 7 can be substituted one, two, or three times with R 6 is independently, at each occurrence, 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; Or two R's 6 can be taken together with the atom to which they are attached to form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 7 is independently, at each occurrence, 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); Or two R's 7 can be taken together with the atom to which they are attached to form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 8 is independently, at each occurrence, 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 NH2, or CN; R 9 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which may be selected from one, two, or three R 8 is optionally replaced by

[0052] In another aspect, provided herein are compounds of formula X: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, [ka] represents an optional double bond, A and A' are each independently CH, CR 8 , or N, Or A is absent, W is N, C, or CH; Z is selected from the group consisting of S, O, N, NH, N-Me, CH, CH, C-halo, C—(C-C alkyl), or C—(C-C alkoxy); X and Y are each independently S, O, N, CH, or NR 3 , or CR 3 and However, at least one of X, Y, or Z is CH. R 1 is C(O)NHR 9 , 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from the group consisting of one, two, or three R 8 optionally replaced by R 2 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which may be selected from one, two, or three R 6 optionally replaced by R 3 independently at each occurrence, a halogen, OR 4 , N.R. 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , NHC(O)R 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10aryl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, each of which is optionally selected from the group consisting of alkyl, alkenyl, or alkynyl; 4 aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R 5 is substituted 1, 2, or 3 times with R 4 is independently at each occurrence 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 -(5-6 membered heteroaryl), and (CH2) 0~3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl are each optionally selected from the group consisting of R 5 is substituted 1, 2, or 3 times with R 5 is independently, at each occurrence, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3-10 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 -(5-6 membered heteroaryl), and (CH2) 0~3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl are each optionally selected from the group consisting of R 7 is substituted 1, 2, or 3 times with Or two R's 5 can be taken together with the atom to which they are attached to form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl, all of which can optionally be joined by R7 can be substituted one, two, or three times with R 6 is independently, at each occurrence, 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; Or two R's 6 can be taken together with the atom to which they are attached to form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 7 is independently, at each occurrence, 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); Or two R's 7 can be taken together with the atom to which they are attached to form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 8 is independently, at each occurrence, 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) 0~2NH2, or CN; R 9 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which may be selected from one, two, or three R 8 is optionally replaced by

[0053] In one embodiment of Formula X, A and A' are each independently CH, CHR 8 , NH, or NR 8 and the remaining variables are defined herein.

[0054] In another aspect, provided herein are compounds of formula XX: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A and A' are each independently CH2, CHR 8 , NH, or NR 8 and Or A is absent, Z is selected from the group consisting of N, CH, C-halo, C—(C1-C3 alkyl), or C—(C1-C3 alkoxy); X and Y are each independently N, CH, or CR. 3 and However, at least one of X, Y, or Z is CH. R 1 is C(O)NHR 9 , 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from the group consisting of one, two, or three R 8 optionally replaced by R 2is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which may be selected from one, two, or three R 6 optionally replaced by R 3 independently at each occurrence, a halogen, OR 4 , N.R. 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , NHC(O)R 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, each of which is optionally selected from the group consisting of alkyl, alkenyl, or alkynyl; 4 aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R 5 is substituted 1, 2, or 3 times with R 4 is independently at each occurrence 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 -(5-6 membered heteroaryl), and (CH2) 0~3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl are each optionally selected from the group consisting of R 5 is substituted 1, 2, or 3 times with R 5is independently, at each occurrence, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3-10 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 -(5-6 membered heteroaryl), and (CH2) 0~3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl are each optionally selected from the group consisting of R 7 is substituted 1, 2, or 3 times with Or two R's 5 can be taken together with the atom to which they are attached to form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl, all of which can optionally be joined by R 7 can be substituted one, two, or three times with R 6 is independently, at each occurrence, 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; Or two R's 6 can be taken together with the atom to which they are attached to form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 7is independently, at each occurrence, 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); Or two R's 7 can be taken together with the atom to which they are attached to form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 8 is independently, at each occurrence, 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 NH2, or CN; R 9 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which may be selected from one, two, or three R 8 is optionally replaced by

[0055] In one embodiment, R 2 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, both of which may be joined by one, two, or three R 6 In another embodiment, R 2 is one, two, or three R 6 In yet another embodiment, R 2 is one, two, or three R 6In yet another embodiment, R 2 is one, two, or three R 6 In one embodiment, R 2 is one, two, or three R 6 and pyridyl optionally substituted with

[0056] In another embodiment, A and A' are each independently CH2 or CHR 8 is.

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

[0058] In yet another embodiment, the compound of formula II is a compound of formula IIa: [ka] or a pharmaceutically acceptable salt thereof.

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

[0060] In another embodiment, the compound of formula III is a compound of formula IIIa: [ka] or a pharmaceutically acceptable salt thereof.

[0061] In yet another embodiment, the compound of formula I is a compound of formula IV: [ka] or a pharmaceutically acceptable salt thereof.

[0062] In another embodiment, the compound of formula IV is a compound of formula IVa: [ka] or a pharmaceutically acceptable salt thereof.

[0063] In yet another embodiment, the compound of formula IV is a compound of formula IVb: [ka] or a pharmaceutically acceptable salt thereof.

[0064] In one embodiment of Formula IIa, IIIa, IVa, and IVb, R 1 is selected from the group consisting of benzimidazole, imidazopyridine, indole, triazole, pyrazole, imidazole, pyridinylamide, and thiazolylamide, all of which contain one, two, or three R 8 optionally replaced by R 6 is independently, at each occurrence, 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 is a C1-C3 alkyl, Each R 8 is independently at each occurrence selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, OH, and NH2.

[0065] In one embodiment, the compound of formula I is a compound of formula V: [ka] or a pharmaceutically acceptable salt thereof.

[0066] In another embodiment, the compound of formula I is a compound of formula VI: [ka] or a pharmaceutically acceptable salt thereof.

[0067] In yet another embodiment, the compound of formula I is a compound of formula VII: [ka] or a pharmaceutically acceptable salt thereof.

[0068] In another embodiment, the compound of formula I is a compound of formula VIII: [ka] or a pharmaceutically acceptable salt thereof.

[0069] In yet another embodiment, the compound of formula I is a compound of formula IX: [ka] or a pharmaceutically acceptable salt thereof.

[0070] In another embodiment, the compound of formula X is a compound of formula Xa: [ka] or a pharmaceutically acceptable salt thereof.

[0071] In yet another embodiment, the compound of formula X is a compound of formula Xb: [ka] or a pharmaceutically acceptable salt thereof.

[0072] In one embodiment, the compound of formula XX is a compound of formula XXa: [ka] or a pharmaceutically acceptable salt thereof.

[0073] In another embodiment, the compound of formula XXa can be a compound of formula XXb: [ka] or a pharmaceutically acceptable salt thereof.

[0074] In yet another embodiment, the compound of formula XXa is a compound of formula XXc: [ka] or a pharmaceutically acceptable salt thereof.

[0075] In one embodiment or in formulas XXb and XXc: R 1 is selected from the group consisting of benzimidazole, imidazopyridine, indole, triazole, pyrazole, imidazole, pyridinylamide, and thiazolylamide, all of which contain one, two, or three R 8 optionally replaced by R 6 is independently, at each occurrence, 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 is a C1-C3 alkyl, R 8 is independently at each occurrence selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, OH, and NH2.

[0076] In one embodiment, R 3 independently at each occurrence, a halogen, OR 4 , N.R. 4 R 4 , C(O)NHR 4 , C1-C6 alkyl, C2-C6 alkynyl, and C6-C 10 aryl, alkyl and alkynyl are selected from the group consisting of R 4 and aryl is optionally substituted one, two, or three times with R 5 is optionally substituted 1, 2, or 3 times with

[0077] In another embodiment, R 3 is OR 4 In yet another embodiment, R 3 is NR 4 R 4 In yet another embodiment, R 3 is R 4 In one embodiment, R is a C2-C6 alkynyl optionally substituted 1, 2, or 3 times with 3 is R 5 C6-C optionally substituted 1, 2, or 3 times with 10 In another embodiment, R 3 is C(O)NHR 4 is.

[0078] In yet another embodiment, R 3 is independently, at each occurrence, a halogen, methyl, [ka] is selected from the group consisting of:

[0079] In another embodiment, R 6 is independently, at each occurrence, 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 In yet another embodiment, R 6 is independently at each occurrence hydroxy or halo. In one embodiment, R 6 is chloro. In another embodiment, R 6 is fluoro. In yet another embodiment, R 6 is hydroxy.

[0080] In one embodiment, R 1 is selected from the group consisting of benzimidazole, imidazopyridine, indole, triazole, pyrazole, imidazole, pyridinylamide, and thiazolylamide, all of which contain one, two, or three R 8 is optionally replaced by

[0081] In another embodiment, R 1 teeth, [ka] is selected from the group consisting of All of these have one, two, or three R 8 is optionally replaced by

[0082] In yet another embodiment, R 1 teeth, [ka] is selected from the group consisting of All of these have one, two, or three R 8 is optionally replaced by

[0083] In another embodiment, R 1 teeth, [ka] is.

[0084] In yet another embodiment, R 1 teeth, [ka] is.

[0085] In yet another embodiment, R 1 teeth, [ka] is.

[0086] In one embodiment, R 7 is C1-C3 alkyl. In another embodiment, R 7 is methyl.

[0087] In yet another embodiment, R 8 is independently at each occurrence selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, OH, and NH2.

[0088] In one embodiment, the compound of formula I is selected from the group consisting of the compounds in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] or a pharmaceutically acceptable salt thereof.

[0089] In another embodiment, the compound of formula X is selected from the group consisting of the compounds in Table 2. [Table 2-1] [Table 2-2] or a pharmaceutically acceptable salt thereof.

[0090] In another embodiment, the compound of formula XX is selected from the group consisting of the compounds in Table 3. [Table 3]

[0091] Compounds disclosed herein can exist as tautomers and optical isomers (eg, enantiomers, diastereomers, diastereomeric mixtures, racemic mixtures, etc.).

[0092] It is generally known in the art that any compound that will be converted in vivo to provide a compound disclosed herein is a prodrug within the scope of this disclosure.

[0093] 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.

[0094] 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 dimerization in a 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.

[0095] 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 that 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.

[0096] Compounds that bind to an allosteric site in EGFR, such as compounds of the present disclosure (e.g., compounds of the formulae disclosed herein), optionally in combination with a second active agent, where the second active agent prevents EGFR dimerization, can modulate EGFR activity. In some embodiments, compounds of the present disclosure can inhibit or reduce EGFR activity without a second active agent (e.g., an antibody such as cetuximab, trastuzumab, or panitumumab). In other embodiments, compounds of the present disclosure are 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.

[0097] Treatment method In one aspect, provided herein is a method of treating cancer in an individual in need thereof, 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).

[0098] In another aspect, provided herein is a method of inhibiting a kinase in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound provided herein. In one embodiment, the kinase is EGFR.

[0099] In another aspect, provided herein is a method for treating or preventing a kinase-mediated disorder in an individual in need thereof, 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-targeting therapy is selected from the group consisting of gefitinib, erlotinib, or osimertinib.

[0100] In some embodiments, compounds of the present disclosure can modulate (e.g., inhibit or reduce) 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, C797S, and Del. In other embodiments, the mutant EGFR contains a combination of mutations, the combinations being selected from Del / L718Q, Del / L844V, Del / T790M, Del / T790M / L718Q, Del / T790M / L844V, L858R / L718Q, L858R / L844V, L858R / T790M, L858R / T790M / I941R, Del / T790M, Del / T790M / C797S, L858R / T790M / C797S, and L858R / T790M / L718Q. In other embodiments, the mutant EGFR contains a combination of mutations selected from Del / L844V, L858R / L844V, L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M, Del / T790M / C797S, and L858R / T790M. In other embodiments, the mutant EGFR contains a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M.

[0101] In some embodiments, a compound of the present disclosure in combination with a second active agent that prevents EGFR dimerization can modulate (e.g., inhibit or reduce) the activity of an 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, C797S, and Del. In other embodiments, the mutant EGFR contains a combination of mutations, the combinations being selected from Del / L718Q, Del / L844V, Del / T790M, Del / T790M / L718Q, Del / T790M / L844V, L858R / L718Q, L858R / L844V, L858R / T790M, L858R / T790M / I941R, Del / T790M, Del / T790M / C797S, L858R / T790M / C797S, and L858R / T790M / L718Q. In other embodiments, the mutant EGFR contains a combination of mutations selected from Del / L844V, L858R / L844V, L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M. In other embodiments, the mutant EGFR contains a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M. 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.

[0102] In some embodiments, compounds of the present disclosure can modulate (eg, inhibit or reduce) the activity of EGFR containing one or more mutations, but do not affect the activity of wild-type EGFR.

[0103] In other embodiments, a compound of the present disclosure in combination with a second active agent that 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 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.

[0104] Modulation of EGFR containing one or more mutations, such as those described herein, rather than wild-type EGFR, 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.

[0105] In some embodiments, compounds of the present disclosure exhibit greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In various embodiments, compounds of the present disclosure exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In various embodiments, compounds of the present disclosure exhibit up to 10,000-fold greater inhibition of EGFR with a combination of mutations described herein (e.g., L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M) compared to wild-type EGFR.

[0106] In other embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In various embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In various embodiments, a compound of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibits up to 10,000-fold greater inhibition of EGFR with the mutation combinations described herein (e.g., L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M) compared to 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.

[0107] In some embodiments, compounds of the present disclosure exhibit about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In various embodiments, compounds of the present disclosure exhibit about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In various embodiments, compounds of the present disclosure exhibit about 100-fold to about 1000-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In various embodiments, compounds of the present disclosure exhibit about 1000-fold to about 10,000-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR.

[0108] In other embodiments, a compound of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibits about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In other embodiments, a compound of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibits about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In other embodiments, a compound of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibits about 100-fold to about 1000-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In another embodiment, a compound of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibits about 1,000- to about 10,000-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In another embodiment, 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.

[0109] In certain embodiments, compounds of the present disclosure exhibit at least two-fold greater inhibition of EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least three-fold greater inhibition of EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least 5-fold greater inhibition of EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least 10-fold greater inhibition of EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least 25-fold greater inhibition of EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least 50-fold greater inhibition of EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR.In certain embodiments, compounds of the present disclosure exhibit at least 100-fold greater inhibition of EGFRs with mutation combinations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR.

[0110] In certain embodiments, a compound of the present disclosure in combination with a second active agent, where the second active agent prevents EGFR dimerization, exhibits at least a two-fold greater inhibition of EGFRs with mutation combinations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure in combination with a second active agent, where the second active agent prevents EGFR dimerization, exhibit at least a three-fold greater inhibition of EGFRs with mutation combinations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure in combination with a second active agent, where the second active agent prevents EGFR dimerization, exhibit at least a 5-fold greater inhibition of EGFRs with a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, a compound of the present disclosure in combination with a second active agent, where the second active agent prevents EGFR dimerization, exhibits at least 10-fold greater inhibition of EGFRs with mutation combinations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, a compound of the present disclosure in combination with a second active agent, where the second active agent prevents EGFR dimerization, exhibits at least 25-fold greater inhibition of EGFRs with mutation combinations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR.In certain embodiments, a compound of the present disclosure in combination with a second active agent, where the second active agent prevents EGFR dimerization, exhibits at least 50-fold greater inhibition of EGFRs with mutation combinations selected from L L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, a compound of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibits at least 100-fold greater inhibition of EGFRs with mutation combinations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to 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.

[0111] In some embodiments, the inhibition of EGFR activity is 50 It is measured by

[0112] In some embodiments, the inhibition of EGFR activity is 50 It is measured by

[0113] In some embodiments, inhibition of EGFR by compounds of the present disclosure can be measured via biochemical assays. By way of illustrative and non-limiting example, a homogeneous time-resolved fluorescence (HTRF) assay can be used to determine inhibition of EGFR activity using the conditions and experimental parameters disclosed herein. HTRF assays can 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 >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 the 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 >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.

[0114] In some embodiments, compounds of the present disclosure bind to an allosteric site in 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.

[0115] In some embodiments, the present disclosure provides compounds comprising allosteric kinase inhibitors, which are more potent inhibitors of drug-resistant EGFR mutants than wild-type EGFR. For example, the compounds may be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent in inhibiting the kinase activity of drug-resistant EGFR mutants than 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, WZ4002, HKI-272, CL-387785, and osimertinib.

[0116] In some embodiments, the drug-resistant EGFR mutants include sensitizing mutations such as Del and L858R.

[0117] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor in combination with a second active agent, where 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. For example, a compound in combination with a second active agent that prevents EGFR dimerization may be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent in inhibiting kinase activity of drug-resistant EGFR mutants compared to wild-type EGFR. In some embodiments, the drug-resistant EGFR mutant is resistant to one or more known EGFR inhibitors, including, but not limited to, gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib. In some embodiments, the drug-resistant EGFR mutant contains a sensitizing mutation, such as Del or 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.

[0118] In some embodiments, the disclosure provides compounds comprising allosteric kinase inhibitors, which inhibit the kinase activity (e.g., IC) of drug-resistant EGFR mutants having sensitizing mutations (e.g., Del and L858R) and drug-resistance mutations (e.g., T790M, L718Q, C797S, and L844V) compared to EGFR mutants having the sensitizing mutations but not the drug-resistance mutations. 50In some embodiments, the difference in potency is less than about 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4-fold, 3-fold, or 2-fold.

[0119] In other embodiments, the 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 inhibits kinase activity (e.g., IC) of drug-resistant EGFR mutants that have sensitizing mutations (e.g., Del and L858R) and drug-resistance mutations (e.g., T790M, L718Q, C797S, and L844V) compared to EGFR mutants that have the sensitizing mutations but do not have the drug-resistance mutations. 50 (as measured by β-actinib). In some embodiments, the difference in potency is less than about 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4-fold, 3-fold, or 2-fold. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0120] In some embodiments, the present disclosure provides compounds comprising allosteric kinase inhibitors, wherein the compounds are more potent than one or more known EGFR inhibitors, including but not limited to, gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib, at inhibiting the activity of EGFRs containing one or more mutations described herein, such as T790M, L718Q, L844V, L858R, C797S, and Del. For example, the compounds are more potent than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib (e.g., IC 50 The compound may be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent (as measured by

[0121] 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 wherein the compound in combination with the second active agent is more potent at inhibiting the activity of EGFR containing one or more mutations described herein, such as T790M, L718Q, L844V, L858R, C797S, and Del, than one or more known EGFR inhibitors, including, but not limited to, gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib. For example, a compound in combination with a second active agent, where the second active agent prevents EGFR dimerization, is more effective at inhibiting the activity of EGFR containing one or more of the mutations described herein than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib (e.g., IC 50The second active agent may be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent (as measured by β-glucan). 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.

[0122] In some embodiments, the present disclosure provides compounds comprising allosteric kinase inhibitors, wherein the compounds are 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, WZ4002, HKI-272, CL-387785, and osimertinib. For example, the compounds are less potent at inhibiting the activity of wild-type EGFR than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib (e.g., IC 50 In some cases, the compound may be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold less potent (as measured by

[0123] In other embodiments, the present disclosure provides compounds comprising an allosteric kinase inhibitor in combination with a second active agent, where 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, WZ4002, HKI-272, CL-387785, and osimertinib. For example, the compound in combination with the second active agent, where the second active agent prevents EGFR dimerization, is more potent at inhibiting the activity of wild-type EGFR than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib (e.g., IC 50 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.

[0124] The efficacy of the inhibitors was evaluated by EC 50 A lower EC value, as determined under substantially similar conditions, can be determined by the 50 Compounds with higher EC 50 In some embodiments, the substantially similar conditions include determining EGFR-dependent phosphorylation levels in vitro or in vivo (e.g., in 3T3 cells expressing wild-type EGFR, mutant EGFR, or a fragment of either thereof).

[0125] Inhibitor efficacy is also measured by IC 50 A lower IC as determined under substantially similar conditions can be determined by the IC value. 50 Compounds with higher IC 50 In some embodiments, the substantially similar conditions include determining EGFR-dependent phosphorylation levels in vitro or in vivo (e.g., in 3T3 cells expressing wild-type EGFR, mutant EGFR, or a fragment of either thereof).

[0126] EGFR sensitizing mutations include, without limitation, L858R, G719S, G719C, G719A, L861Q, a deletion in exon 19, and / or an insertion in exon 20. Drug-resistant EGFR mutants can have drug-resistance mutations including, without limitation, T790M, T854A, L718Q, C797S, or D761Y.

[0127] The selectivity between wild-type EGFR and EGFR containing one or more mutations described herein can also be measured using cell proliferation assays when cell proliferation depends on kinase activity.For example, mouse Ba / F3 cells transfected with suitable version of wild-type EGFR (such as VIII, containing WT EGFR kinase domain) or Ba / F3 cells transfected with L858R / T790M, Del / T790M / L718Q, L858R / T790M / L718Q, L858R / T790M / C797S, Del / T790M / C797S, L858R / T790M / I941R, or exon 19 deletion / T790M can be used. Proliferation assays were 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 EC 50 is calculated.

[0128] An alternative method for measuring the effect on EGFR activity is to assay EGFR phosphorylation. Wild-type or mutant (L858R / T790M, Del / T790M, Del / T790M / L718Q, L858R / T790M / C797S, Del / T790M / C797S, L858R / T790M / I941R, or L858R / T790M / L718Q) EGFR can be transfected into NIH-3T3 cells (which do not normally express endogenous EGFR) and the ability of 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.

[0129] In another aspect, the present disclosure relates to compounds that bind to an allosteric site in EGFR, wherein the compounds exhibit greater than 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, 100-fold, or 1000-fold inhibition of EGFR containing one or more mutations described herein (e.g., L858R / T790M, Del / T790M, Del / T790M / L718Q, L858R / T790M / C797S, Del / T790M / C797S, L858R / T790M / I941R, or L858R / T790M / L718Q) compared to wild-type EGFR.

[0130] In other embodiments, the disclosure provides compounds that bind to an allosteric site in EGFR in combination with a second active agent, where the second active agent prevents EGFR dimerization, and the compound in combination with the second active agent exhibits greater than 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, 100-fold, or 1000-fold inhibition of EGFR containing one or more mutations described herein (e.g., L858R / T790M, Del / T790M, Del / T790M / L718Q, Del / T790M / C797S, L858R / T790M / C797S, L858R / T790M / I941R, or L858R / T790M / L718Q) compared to wild-type EGFR. 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.

[0131] In yet another aspect, the disclosure provides a method of 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 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.

[0132] In another aspect, provided herein are methods of 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 equivalent to Cys 797 in 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 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.

[0133] In some embodiments, the disease is mediated by EGFR (e.g., EGFR plays a role in the initiation or development of the disease). In some embodiments, the disease is mediated by a Her-kinase. In further embodiments, the Her-kinase is HER1, HER2, or HER4.

[0134] 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 in EGFR. In certain embodiments, a diagnostic test is performed to determine whether the disease is associated with an EGFR having an activating mutation and / or a drug-resistance mutation. Activating mutations include, without limitation, L858R, G719S, G719C, G719A, L718Q, L861Q, a deletion in exon 19, and / or an insertion in exon 20. Drug-resistant EGFR mutants can have drug-resistance mutations including, without limitation, T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests can include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those skilled in the art that can detect nucleotide sequences.

[0135] In certain embodiments, the disease is cancer or a proliferative disease.

[0136] In further embodiments, the disease is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, renal cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, or a solid tumor. In further embodiments, the disease is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer. In yet further embodiments, the disease is non-small cell lung cancer.

[0137] 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 in EGFR. In certain embodiments, a diagnostic test is performed to determine whether the disease is associated with an EGFR having an activating mutation and / or a drug-resistance mutation. Activating mutations include, without limitation, L858R, G719S, G719C, G719A, L718Q, L861Q, a deletion in exon 19, and / or an insertion in exon 20. Drug-resistant EGFR mutants can have drug-resistance mutations including, without limitation, T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests can include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those skilled in the art that can detect nucleotide sequences.

[0138] In yet another aspect, provided herein are methods of treating a kinase-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof. 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.

[0139] In another aspect, the disclosure provides a method of treating a kinase-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a second active agent, wherein the second active agent prevents EGFR dimerization. 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, 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.

[0140] In other embodiments, the disease is cancer. In further embodiments, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, renal cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, or a solid tumor. In further embodiments, the disease is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer. In yet further embodiments, the disease is non-small cell lung cancer.

[0141] In another aspect, provided herein is a method of treating cancer, wherein the cancer cells contain activated EGFR, comprising administering to a subject in need of treatment an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0142] In another aspect, provided herein is a method of treating cancer, wherein cancer cells contain activated EGFR, comprising administering to a subject in need of treatment 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 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.

[0143] In certain embodiments, the EGFR activation is selected from EGFR mutation, EGFR amplification, EGFR expression, and ligand-mediated activation of EGFR.

[0144] In further embodiments, the EGFR mutation is selected from G719S, G719C, G719A, L858R, L861Q, an exon 19 deletion mutation, and an exon 20 insertion mutation.

[0145] 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, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0146] 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 a subject has an activating mutation in EGFR. In certain embodiments, a diagnostic test is performed to determine whether a subject has an EGFR with an activating mutation and / or a drug-resistant mutation. Activating mutations include, without limitation, L858R, G719S, G719C, G719A, L718Q, L861Q, a deletion in exon 19, and / or an insertion in exon 20. Drug-resistant EGFR mutants can have drug-resistant mutations including, without limitation, T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests can include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those skilled in the art that can detect nucleotide sequences.

[0147] In one aspect, provided herein is a method of preventing resistance to known EGFR inhibitors (including but not limited to gefitinib, erlotinib, or osimertinib) in a subject, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0148] In another aspect, provided herein is a method of preventing resistance to known EGFR inhibitors (including, but not limited to, gefitinib, erlotinib, or osimertinib) in a disease, 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 a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab.

[0149] In one embodiment of the methods disclosed herein, the subject is a human.

[0150] In another aspect, the present disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating or preventing a disease in which EGFR plays a role.

[0151] In one aspect, provided herein is a method of treating or preventing a condition selected from the group consisting of autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immunologically mediated diseases, bone diseases, metabolic diseases, 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.

[0152] 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, the following cancers: breast, ovarian, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, colorectal, adenoma, pancreatic, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract, kidney cancer, bone marrow disorders, lymphatic system disorders, Hodgkin's disease, hairy cell, buccal cavity and pharynx (oral cavity), lip, tongue, mouth, pharynx, small intestine, colon, rectum, large intestine, rectum, brain and central nervous system, chronic myeloid leukemia (CML), and leukemia. The term "cancer" includes, but is not limited to, the following cancers: myeloma, lymphoma, or cancer selected from gastric, renal, head and neck, oropharyngeal, non-small cell lung cancer (NSCLC), endometrial, liver cancer, non-Hodgkin's lymphoma, and lung.

[0153] The term "cancer" refers to any cancer caused by the proliferation of malignant new cells, such as a tumor, neoplasm, carcinoma, sarcoma, leukemia, lymphoma, etc. For example, cancer includes, but is not limited to, mesothelioma, leukemia, and lymphoma, e.g., cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotropic virus (HTLV), e.g., adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphoma, and multiple myeloma, non-Hodgkin'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 myelogenous leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndromes, pediatric solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcomas, common adult solid tumors such as head and neck cancer (e.g., oral cavity, larynx, nasopharynx, and esophagus), genitourinary cancer (e.g., prostate, bladder, kidney, uterus, ovaries, 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. Additional exemplary forms of cancer that may be treated by the compounds include, but are not limited to, skeletal or smooth muscle cancer, gastric cancer, cancer of the small intestine, rectal cancer, salivary gland cancer, endometrial cancer, adrenal gland cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0154] Additional cancers for which the compounds described herein may be useful in the prevention, treatment, and research are, for example, colon cancer, familial adenomatous polyposis, and hereditary nonpolyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, labia cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumor, gallbladder cancer, bronchial carcinoma, multiple myeloma, basaloma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma. In one aspect of the present disclosure, the present disclosure provides use of one or more compounds of the present disclosure in the manufacture of a medicament for the treatment of cancer, including, without limitation, the various types of cancer disclosed herein.

[0155] In some embodiments, compounds of the present disclosure are useful for treating cancers such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer, and myeloproliferative disorders such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mast cell disease. In some embodiments, compounds of the present disclosure are useful for treating hematopoietic disorders, particularly acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute promyelocytic leukemia, and acute lymphocytic leukemia (ALL).

[0156] The term "cancer cell" as provided herein includes a cell afflicted by any one of the above-identified conditions.

[0157] The present disclosure further provides a method for treating or preventing cell proliferative disorders, such as hyperplasia, dysplasia, and precancerous lesions. Dysplasia is the earliest form of precancerous lesion that can be recognized in a biopsy by a pathologist. The compound can be administered to prevent the hyperplasia, dysplasia, or precancerous lesion from continuing to grow or becoming cancerous. Examples of precancerous lesions can occur in the skin, esophageal tissue, breast, and cervical intraepithelial tissue.

[0158] Examples of neurodegenerative diseases include, without limitation, adrenoleukodystrophy (ALD), Alexander disease, Alpers disease, Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), ataxia-telangiectasia, Batten disease (also known as Spillmeyer-Voigt-Sjogren-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, neuroborreliosis, Machado syndrome, and the like. -Joseph's disease (Spinocerebellar ataxia type 3), multiple system atrophy, multiple sclerosis, narcolepsy, Niemann-Pick disease, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy, Refsum's disease, Sandhoff's disease, Schilder's disease, subacute combined spinal degeneration, secondary pernicious anemia, Spillmeyer-Voigt-Sjögren-Batten disease (also known as Batten disease), spinocerebellar degeneration (multiple forms with different characteristics), spinal muscular atrophy, Steele-Richardson-Olzewski disease, tabes dorsalis, and toxic encephalopathy.

[0159] 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, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable composition comprising a compound. 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.

[0160] 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 ATPase activity of an activated kinase. Alternative in vitro assays quantitate the ability of an inhibitor to bind to a protein kinase, which can be measured either 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 a new inhibitor is incubated with the 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.

[0161] In accordance with the foregoing, the present disclosure further provides a method for preventing or treating any of the above-mentioned diseases or disorders in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and optionally a second active agent, wherein the second active agent prevents EGFR dimer formation. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition being treated, and the desired effect.

[0162] In other embodiments, the compound and the second active agent that prevents EGFR dimerization are administered simultaneously or sequentially.

[0163] 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 can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as 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 can also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0164] 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 bland fixed oil can be used, including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid can be used in the preparation of injectables.

[0165] In order to prolong the effect of drugs, it is often desirable to delay the absorption of drugs from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with low water solubility.In this case, the absorption rate of the drug depends on its dissolution rate, which in turn depends on the crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0166] 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 such as 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.

[0167] 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.

[0168] The active compound can also be in micro-encapsulated form with one or more of the above-mentioned excipients.Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation field.In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch.According to common practices, such dosage forms can also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose.In the case of capsules, tablets, and pills, dosage forms can also contain buffering agents.

[0169] 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.

[0170] 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.

[0171] 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 additionally contain conventional propellants, such as chlorofluorohydrocarbons.

[0172] Transdermal patches have the additional advantage of providing controlled delivery of compounds to 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 across the skin.The rate can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0173] According to the therapeutic methods of the present disclosure, disorders are treated or prevented in a subject, such as a human or other animal, by administering to the subject a therapeutically effective amount of a compound of the present disclosure in an amount and for a time necessary to achieve the desired result. The term "therapeutically effective amount" of a compound of the present disclosure, as used herein, means an amount of the compound sufficient to reduce the symptoms of 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.

[0174] In general, the compounds of the present disclosure will be administered in a therapeutically effective amount, either alone or in combination with one or more therapeutic agents, via any of the conventional and acceptable methods known in the art. Therapeutically effective amounts 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. Generally, favorable results are indicated to be obtained systemically at a daily dosage of about 0.03 to 2.5 mg / kg of body weight. Recommended daily dosages for larger mammals, e.g., humans, range from about 0.5 mg to about 100 mg, conveniently administered in divided doses, e.g., up to four times daily, or in delayed form. Suitable unit dosage forms for oral administration contain about 1 to 50 mg of the active ingredient.

[0175] 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, a treatment regimen according to the present disclosure involves administration of about 10 mg to about 1000 mg of a compound of the present disclosure per day to a patient in need of such treatment, 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.

[0176] 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.Then, the dosage or frequency of administration, or both, can be reduced according to the symptoms to a level at which the improved condition is maintained, and when the symptoms are reduced to a desired level, treatment should be discontinued.However, the subject may need intermittent treatment on a long-term basis when the symptoms of the disease recur.

[0177] However, it will be understood that the total daily usage amount of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific inhibitory dose for a particular patient will depend on a variety of factors, including the disorder being 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 administration time, 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.

[0178] The present disclosure also provides pharmaceutical combinations, e.g., kits, comprising: a) a first agent that is a compound of the present disclosure disclosed herein, in free form or in pharmaceutically acceptable salt form; and b) at least one auxiliary agent. The kit can include instructions for its administration.

[0179] 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 antiproliferative agents may be combined with the compounds of the present disclosure to treat proliferative diseases and cancer.

[0180] Some examples of materials that can function as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates, glycine, sorbic acid, or potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene polyoxypropylene block polymers; wool fat; sugars, such as lactose, glucose, and sucrose; starches, such as Examples include corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solution. Additionally, non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings, and perfuming agents, preservatives, and antioxidants can also be present in the composition, according to the discretion of the formulator. The protein kinase inhibitor or pharmaceutical salts thereof can be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions, comprising 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.

[0181] 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 and / or drug resistance mutation in EGFR.

[0182] 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.

[0183] 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 that 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 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 a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab.

[0184] 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 that 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.

[0185] 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 disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It should be further understood that resort to various other embodiments, modifications, and equivalents thereof, which may suggest themselves to those skilled in the art, may be made without departing from the spirit of the present disclosure and / or the scope of the appended claims. [Example]

[0186] 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. [Table 4]

[0187] Example 1: Preparation of 2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxopyrrolo[2,1-f][1,2,4]-triazin-3(4H)-yl)-2-phenyl-N-(thiazol-2-yl)acetamide hydrochloride (001) [ka] 2-(6-bromo-4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)-2-phenylacetic acid methyl ester [ka] A mixture of 6-bromopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (321 mg, 1.5 mmol), methyl 2-bromo-2-phenylacetate (378 mg, 1.65 mmol), CsCO (975 mg, 3.0 mmol), and DMF (3 mL) was stirred at 50 °C for 1.5 h. Another aliquot of methyl 2-bromo-2-phenylacetate (147 mg, 0.65 mmol) was added, and the reaction mixture was heated for an additional 1 h. After cooling, the reaction mixture was poured into saturated brine (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with saturated brine, dried over NaSO, filtered, concentrated under reduced pressure, and purified by normal-phase flash chromatography (0–75% EtOAc / hexanes) to give the title compound (445 mg, 82%).

[0188] 2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-2-phenylacetic acid [ka] A mixture of methyl 2-(6-bromo-4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)-2-phenyl-acetate (100 mg, 0.0.28 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)piperidine (92 mg, 0.3 mmol), NaCO (89 mg, 0.84 mmol), Pd(dppf)Cl-DCM (46 mg, 0.056 mmol) in dioxane (1.5 mL) and HO (0.5 mL) under N in a sealed vial was heated at 95 °C for 16 h. The mixture was allowed to cool, filtered through a syringe filter, and purified by reverse-phase HPLC eluting with 0-80% ACN / H2O (0.038% TFA modifier) ​​to give the title compound (125 mg, 78%). 1 H NMR(500MHz,DMSO-d6)δ 9.40(br s,1H)8.17(d,1H)7.82(s,1H)7.74(d,2H)7.51(m,r2H)7.46(m,3H)7.43(d,1H)7.26(d, 2H)6.46(s,1H)3.53(d,2H)3.08(m,2H)2.83(d,3H)2.81(m,1H)2.03(d,2H)1.84(m,2H).

[0189] 2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)-2-phenyl-N-(thiazol-2-yl)acetamide hydrochloride (001) [ka] A mixture of 2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-2-phenylacetic acid (60 mg, 0.14 mmol), 2-aminothiazole (20 mg, 0.20 mmol), HATU (103 mg, 0.27 mmol), and DIEA (71 μL, 0.41 mmol) in DMF (2 mL) was stirred at 50 °C for 1.5 h. After cooling, the reaction mixture was purified by reverse-phase HPLC, eluting with 0-80% ACN / HO (0.038% TFA modifier). The crude product was further purified by silica chromatography (0-10% 7N methanolic NH in DCM). The residue was dissolved in MeOH (5 mL), treated with 4N HCl / dioxane (0.5 mL), and concentrated under reduced pressure. The residue was triturated with Et2O, filtered and dried to give the title compound (57 mg, 79%). 1 H NMR(500MHz,DMSO-d6)δ 9.33(br s,1H)8.19(d,1H)7.75(d,2H)7.57(s,1H)7.51(m,4H)7.44(m,3H)7.33(d,1H)7.26(d,1 H)6.81(s,1H)3.53(d,2H)3.08(m,2H)2.84(d,3H)2.81(m,1H)2.03(m,2H)1.83(m,2H).

[0190] The following examples were prepared by a method similar to Example 1 from methyl 2-bromo-2-phenylacetate and the corresponding bicyclic starting material. [Table 5]

[0191] Example 2: Preparation of 3-((1H-benzo[d]imidazol-2-yl)(phenyl)methyl)-6-(4-(1-methylpiperidin-4-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one hydrochloride (002) [ka] N-(2-aminophenyl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxopyrrolo[2,1-f][1,2,4]-triazin-3(4H)-yl)-2-phenylacetamide [ka] A mixture of 2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-2-phenylacetic acid (60 mg, 0.14 mmol), benzene-1,2-diamine (75 mg, 0.69 mmol), HATU (174 mg, 0.46 mmol), and DIEA (120 μL, 0.69 mmol) in DMF (3 mL) was stirred at 50 °C for 1 h. After cooling, the mixture was purified by reverse-phase HPLC eluting with 0-80% ACN / HO (0.038% TFA modifier) ​​to give the title compound (80 mg, 65%). 1 H NMR(500MHz,DMSO-d6)δ 9.97(s,1H)9.32(br s,1H)8.17(d,1H)7.75(d,2H)7.63(s,1H)7.53(m,4H)7.48(m,1H)7.46(d,1H)7.26(d,2H)7.23(dd,1H)6.98(m,1 H)6.82(s,1H)6.78(dd,1H)6.61(m,1H)3.53(d,2H)3.08(m,2H)2.83(d,3H)2.81(m,1H)2.03(d,2H)1.83(m,2H).

[0192] 3-((1H-benzo[d]imidazol-2-yl)(phenyl)methyl)-6-(4-(1-methylpiperidin-4-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one hydrochloride (002) [ka] A solution of N-(2-aminophenyl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-2-phenylacetamide (80 mg, 0.15 mmol) and AcOH (3 mL) was heated to 100 °C for 1 h. Excess AcOH was removed under reduced pressure. The residue was dissolved in EtOAc (5 mL) and washed with 1 N NaOH (5 mL), water (5 mL), and saturated brine (5 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica chromatography (0-5% 7 N methanol / NH3 / DCM), and the product was dissolved in MeOH (5 mL), treated with 4 N HCl in dioxane (1 mL), and concentrated under pressure. The resulting solid was triturated with Et2O, filtered and dried to give the title compound (19 mg, 25%). 1 H NMR(500MHz,DMSO-d6)δ 10.09(br s,1H)8.21(d,1H)8.08(s,1H)7.75(d,2H)7.64(m,2H)7.51(s,1H)7.48(m,4H)7.44(m,2 H)7.30(m,2H)7.26(d,2H)3.50(d,2H)3.06(m,2H)2.80(m,1H)2.79(d,3H)1.96(m,4H).

[0193] The following examples were prepared by a method similar to Example 2 from methyl 2-bromo-2-phenylacetate and the corresponding bicyclic starting materials. [Table 6]

[0194] Example 3: Preparation of 2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-phenyl-N-(thiazol-2-yl)acetamide (003) [ka] 2-(6-bromo-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-phenylacetic acid methyl ester [ka] A mixture of 6-bromothieno[3,2-d]pyrimidin-4(3H)-one (250 mg, 1.08 mmol), methyl 2-bromo-2-phenylacetate (296 mg, 1.29 mmol), and CsCO (543 mg, 1.5 mmol) in DMF (3 mL) was stirred at 50 °C for 2 h. After cooling, the reaction mixture was poured into saturated brine (ca. 30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were dried over NaSO, filtered, concentrated under reduced pressure, and purified by normal-phase flash chromatography, eluting (0–50% EtOAc / hexanes) to give the title compound (250 mg, 61%). 1 H NMR(500MHz,DMSO-d6)δ 8.47(s,1H)8.37(s,1H)7.52(m,2H)7.45(m,3H)6.64(s,1H)3.77(s,3H).

[0195] 2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-phenylacetate methyl [ka] A mixture of methyl 2-(6-bromo-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-phenylacetate (250 mg, 0.83 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-piperidine (275 mg, 0.91 mmol), Pd(dppf)Cl-DCM (68 mg, 0.083 mmol), and NaCO (264 mg, 2.89 mmol) in dioxane (3.0 mL) and water (1.0 mL) was heated in a sealed vial under N at 100 °C for 1 h. After cooling, the reaction mixture was filtered through a syringe filter and purified by reverse-phase HPLC eluting with 0-80% ACN / H2O (0.038% TFA modifier) ​​to give the title compound (65 mg, 16%).

[0196] 2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-phenylacetic acid [ka] A mixture of methyl 2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-phenylacetate (65 mg, 0.14 mmol), LiOH—HO (24 mg, 0.72 mmol), THF (1.0 mL), MeOH (1 mL), and water (1 mL) was stirred for 60 min. The solvent was removed under reduced pressure, and the residue was dissolved in water (5 mL). The pH of the solution was adjusted to pH 5 (pH paper) with 1.5 N HCl. The precipitate was triturated with water (2 × 5 mL), filtered, and dried overnight at 60 °C under high vacuum to give the title compound (64 mg, quantitative), which was used in the subsequent step without further purification.

[0197] 2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-phenyl-N-(thiazol-2-yl)acetamide (003) [ka] This compound was prepared in a similar manner to compound 001 from the acid above and purified by reverse-phase HPLC eluting with 0-80% ACN / HO (0.038% TFA modifier) ​​to give the title compound (43 mg, 94%).

[0198] Example 4: 5-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-6,7-dihydrothieno[3,2-c]pyridin-4-one dihydrochloride (012) [ka] Step 1. Methyl 2-(2-bromo-4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5-yl)-2-(5-fluoro-2-methoxy-phenyl)acetate [ka] To a solution of 2-bromo-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (0.300 g, 1.29 mmol) in THF (6 mL) was added sodium hydride (0.077 g, 1.93 mmol, 60% in mineral oil) at 0 °C. After stirring at the same temperature for 0.5 h, a solution of 2-bromo-2-(5-fluoro-2-methoxyphenyl)-methyl acetate (0.714 g, 2.58 mmol) in THF (4 mL) was added dropwise to the reaction mixture. After stirring at room temperature for 2 h, the reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.552 g, quantitative). MS m / z: 428.0 [M+1] + .

[0199] Step 2. 2-(2-Bromo-4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5-yl)-2-(5-fluoro-2-methoxy-phenyl)acetic acid [ka] To a solution of methyl 2-(2-bromo-4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5-yl)-2-(5-fluoro-2-methoxy-phenyl)acetate (0.552 g, 1.28 mmol) in THF / water (20 mL, 1 / 1) was added lithium hydroxide (0.092 g, 3.84 mmol). After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure and the resulting residue was adjusted to pH 3 with HCl (1 M). The resulting solid was collected by filtration and washed with water to give the title compound (0.45 g, 85%). 1H NMR(DMSO-d6)δ:7.35(s,1H),7.16-7.25(m,1H),7.06-7.14(m,1H),6.97-7.05(m,1H) ,6.17(s,1H),3.76(s,3H),3.61-3.70(m,1H),3.25-3.27(m,1H),2.77-3.05(m,2H);MS m / z:414.1[M+1] + .

[0200] Step 3. 5-[1H-benzimidazol-2-yl-(5-fluoro-2-methoxy-phenyl)methyl]-2-bromo-6,7-dihydrothieno[3,2-c]pyridin-4-one [ka] To a solution of 2-(2-bromo-4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5-yl)-2-(5-fluoro-2-methoxy-phenyl)acetic acid (0.450 g, 1.08 mmol), 1,2-diaminobenzene (0.174 g, 1.61 mmol), and HATU (0.612 g, 1.61 mmol) in DMF (8 mL) was added DIPEA (0.562 mL, 3.23 mmol). After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate and washed twice with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the amide intermediate, which was used in the next reaction without further purification. MS m / z: 504.0 [M+1] + .

[0201] To the above amide intermediate was added acetic acid (10 mL). After stirring at 80° C. for 1 hour, the solvent was removed under reduced pressure. The crude product was purified by C18 column chromatography eluting with 0-100% ACN / water containing 10 mM ammonium acetate to give the title compound (0.4 g, 77%). 1H NMR(DMSO-d6)δ:12.59(br MS m / z:486.1[M+1] + .

[0202] Step 4. 5-[1H-benzimidazol-2-yl-(5-fluoro-2-methoxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-6,7-dihydrothieno[3,2-c]pyridin-4-one [ka] A mixture of 5-[1H-benzimidazol-2-yl-(5-fluoro-2-methoxy-phenyl)methyl]-2-bromo-6,7-dihydrothieno[3,2-c]pyridin-4-one (0.200 g, 0.411 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (0.148 g, 0.493 mmol), Pd(dppf)Cl (0.030 g, 0.041 mmol), and sodium carbonate (0.130 g, 1.23 mmol) in dioxane / water (9:1, 6 mL) was heated at 100 °C for 2 h under nitrogen. After cooling, the reaction mixture was filtered and the filtrate was concentrated and purified by silica gel flash chromatography eluting with 0-15% methanol in dichloromethane to give the title compound (0.2 g, 84%). 1 H NMR(400MHz,DMSO-d6)δ:12.56(s,1H),7.56-7.64(m,4H),7.41-7.49(m,1H),7.10-7.31(m,7H),6.83-6.90(m,1H),3.66-3 .82(m,4H),3.40-3.46(m,1H),2.90-3.17(m,4H),2.52-2.56(m,1H),2.30(s,3H),2.04-2.21(m,2H),1.64-1.81(m,4H).MS m / z:581.5[M+1] + .

[0203] Step 5. 5-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-6,7-dihydrothieno[3,2-c]pyridin-4-one dihydrochloride [ka] To a solution of 5-[1H-benzimidazol-2-yl-(5-fluoro-2-methoxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-6,7-dihydrothieno[3,2-c]pyridin-4-one (0.200 g, 0.344 mmol) in dichloromethane (10 mL) at 0 °C was added boron tribromide (0.859 g, 3.43 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with dichloromethane and poured into ice water. The aqueous phase was extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC eluting with 0–100% ACN / water (0.05% HCl modifier) ​​to give the title compound (0.107 g, 55%). 1 H NMR(400MHz,DMSO-d6)δ:10.06-10.82(m,2H),7.69-7.78(m,2H),7.60-7.67(m,3H),7.39-7.53(m,2H),7.29(d,2H), MS m / z:567.5[M+1] + .

[0204] The following examples were prepared by a method similar to Example 4 from methyl 2-bromo-2-(5-fluoro-2-methoxyphenyl)acetate and the corresponding bicyclic starting materials. [Table 7-1] [Table 7-2]

[0205] Example 5 Preparation of 6-[(R)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]thieno[2,3-c]pyridin-7-one and 6-[(S)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]thieno[2,3-c]pyridin-7-one (015 and 016) [ka] 6-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxyphenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]thieno[2,3-c]pyridin-7-one dihydrochloride (009, 0.300 g, 0.470 mmol) was purified to separate the enantiomers by preparative SFC at 40 °C using a Chiral Technologies Chiralpak IA (5 micron 250 × 10 mm) column eluted with 50% (0.3% TEA in MeOH) / 50% CO at 10 MPa. The absolute configuration of the chiral center for each isolated enantiomer is unknown. The first eluting peak (015) (93 mg, 35% yield, 99.6:0.4 er), [α] 20 D +58.2 (c=0.91, MeOH), 1 H NMR(DMSO-d6)δ:12.79(br s,1H),10.01(br s,1H),7.70-7.80(m,3H),7.65(s,1H),7.46-7.61(m,2H),7.32-7.40(m,3H),7.16-7.25(m,2H),7.05-7.14(m,1H),6.85-6.93 MS m / z:565.2[M+1]+ The second eluting peak (016) (95 mg, 36% yield, 99.4:0.6er), [α] 20 D -52.5 (c=0.92, MeOH), 1 H NMR(DMSO-d6)δ:12.79(br s,1H),10.02(br s,1H),7.70-7.78(m,3H),7.65(s,1H),7.44-7.60(m,2H),7.33-7.40(m,3H),7.15-7.24(m,2H),7.06-7.13(m,1H),6.86-6.93 MS m / z:565.2[M+1] + .

[0206] Example 6: 5-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-6H-thieno[2,3-c]pyrrol-4-one dihydrochloride (013) [ka] Step 1. 2-Bromo-4-fluoro-1-(methoxymethoxy)benzene [ka] To a solution of 2-bromo-4-fluorophenol (100 g, 523 mmol) in THF (1 L) was added sodium hydride (23.0 g, 575 mmol, 60% in mineral oil) at 0 °C for 4 h, followed by the addition of methoxymethyl chloride (44.9 mL, 601 mmol). After stirring at room temperature for 10 h, the reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 1–10% ethyl acetate in petroleum ether to give the title compound (80 g, 65%).1 H NMR(400MHz, CDCl3)δ:7.30(dd,1H),7.12(dd,1H),6.97(m,1H),5.07-5.24(m,2H),3.46-3.62(m,3H).

[0207] Step 2. Ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-oxo-acetate [ka] To a solution of 2-bromo-4-fluoro-1-(methoxymethoxy)benzene (80.0 g, 340 mmol) in THF (1 L) at −78° C. was added n-butyllithium (2.5 M in hexanes, 142 mL, 357 mmol) dropwise. After stirring at −78° C. for 1 hour, the reaction mixture was cannulated into a pre-cooled (−78° C.) solution of diethyl oxalate (74.4 g, 510 mmol) in THF (500 mL). After the addition was complete, the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 10% ethyl acetate in petroleum ether to give the title compound (70 g, 80%). 1 H NMR(400MHz,CDCl3)δ:7.57(dd,1H),7.26-7.31(m,1H),7.18-7.23(m,1H),5.15(s,2H),4.37-4.43(m,2H),3.46-3.50(m,3H),1.35-1.41(m,3H).

[0208] Step 3. Ethyl-2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-hydroxyimino-acetate [ka] To a solution of hydroxylamine hydrochloride (37.9 g, 546 mmol) in ethanol (500 mL) was added ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-oxo-acetate (70.0 g, 273 mmol) and sodium acetate (44.7 g, 132 mmol). After stirring at 80° C. for 2.5 hours, the solvent was removed under reduced pressure and the resulting residue was partitioned between water and dichloromethane. The aqueous phase was extracted with additional dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (68 g, 92%). 1 H NMR(400MHz,CDCl3)δ:9.76(br s,1H),7.17-7.23(m,1H),7.07-7.14(m,2H),5.10(s,2H),4.31-4.39(m,2H),3.44-3.48(m,3H),1.35-1.40(m,3H).

[0209] Step 4. Ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate [ka] To a solution of Raney Ni (1.46 g, 25.0 mmol) in EtOH / THF (650 mL, 4 / 1) was added ethyl-2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-hydroxyimino-acetate (34.0 g, 125 mmol). The flask was evacuated and backfilled with hydrogen, and the reaction mixture was stirred at 70° C. under an atmosphere of hydrogen (50 psi) for 24 hours. The reaction mixture was filtered through a pad of Celite, which was washed several times with ethanol. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with 33% ethyl acetate in petroleum ether to give the title compound (30.6 g, 48%). 1 H NMR(400MHz,DMSO-d6)δ:7.23(dd,1H),7.04-7.08(m,2H),5.14-5.18(m,2H),4.66(s,1H),3.92-4.12(m,2H),3.37(s,3H),1.06-1.22(m,3H).

[0210] Step 5. Methyl 5-bromo-2-[[[2-ethoxy-1-[5-fluoro-2-(methoxymethoxy)phenyl]-2-oxo-ethyl]amino]methyl]thiophene-3-carboxylate [ka] To a solution of ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (0.409 g, 1.59 mmol) and methyl 5-bromo-2-(bromomethyl)thiophene-3-carboxylate (0.500 g, 1.59 mmol) in DMF (15 mL) was added DIPEA (0.789 mL, 4.77 mmol). The reaction mixture was heated at 80° C. for 3 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-25% ethyl acetate in petroleum ether to give the title compound (0.32 g, 41%). MS m / z: 491.8 [M+1]

[0211] Step 6. Ethyl 2-(2-bromo-4-oxo-6H-thieno[2,3-c]pyrrol-5-yl)-2-[5-fluoro-2-(methoxymethoxy)-phenyl]acetate [ka] To a solution of methyl 5-bromo-2-[[[2-ethoxy-1-[5-fluoro-2-(methoxymethoxy)phenyl]-2-oxo-ethyl]amino]methyl]thiophene-3-carboxylate (0.610 g, 1.24 mmol) in toluene (20 mL) was added trimethylaluminum in toluene (2 M, 1.86 mL, 3.72 mmol). The reaction mixture was heated at 110 °C for 4 h. After cooling to room temperature, the reaction mixture was poured into saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 1-10% ethyl acetate in petroleum ether to give the title compound (0.13 g, 23%). MS m / z: 458.0 [M+1] + .

[0212] Step 7. 2-(2-Bromo-4-oxo-6H-thieno[2,3-c]pyrrol-5-yl)-2-[5-fluoro-2-(methoxymethoxy)-phenyl]acetic acid [ka] To a solution of ethyl 2-(2-bromo-4-oxo-6H-thieno[2,3-c]pyrrol-5-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (0.130 g, 0.283 mmol) in THF / water (8 mL, 1 / 1) was added lithium hydroxide (0.021 g, 0.849 mmol). After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure and the resulting residue was adjusted to pH 4 with HCl (1 M). The resulting solid was collected by filtration and washed with water to give the title compound (0.09 g, 74%). MS m / z: 429.9 [M+1] + .

[0213] Step 8. 5-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-2-bromo-6H-thieno[2,3-c]pyrrol-4-one [ka] To a solution of 2-(2-bromo-4-oxo-6H-thieno[2,3-c]pyrrol-5-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetic acid (0.090 g, 0.209 mmol), 1,2-diaminobenzene (0.027 g, 0.250 mmol), and HATU (0.103 g, 0.271 mmol) in DMF (3 mL) was added DIPEA (0.103 mL, 0.627 mmol). After stirring at room temperature for 4 hours, the reaction mixture was diluted with ethyl acetate and washed twice with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the amide intermediate, which was used in the next reaction without further purification. MS m / z: 519.9 [M+1] + .

[0214] To the above amide intermediate was added acetic acid (8 mL). After stirring at 80° C. for 1 hour, the solvent was removed under reduced pressure. The crude product was purified by C18 column chromatography eluting with 0-100% ACN / water containing 10 mM ammonium acetate to give the title compound (0.07 g, 73%). MS m / z: 502.0 [M+1] + .

[0215] Step 9. 5-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-6H-thieno[2,3-c]pyrrol-4-one [ka] A mixture of 5-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-2-bromo-6H-thieno[2,3-c]pyrrol-4-one (0.070 g, 0.139 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (0.050 g, 0.166 mmol), Pd(dppf)Cl (0.010 g, 0.014 mmol), and sodium carbonate (0.046 g, 0.416 mmol) in dioxane / water (4:1, 3 mL) was heated at 100 °C for 4 h under nitrogen. After cooling, the reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel flash chromatography eluting with 0-10% methanol in dichloromethane to give the title compound (0.05 g, 60%). MS m / z: 597.2 [M+1] + .

[0216] Step 10. 5-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-6H-thieno[2,3-c]pyrrol-4-one dihydrochloride [ka] 5-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-6H-thieno[2,3-c]pyrrol-4-one (0.050 g, 0.084 mmol) was added to HCl in methanol (1.25 M, 2 mL, 2.50 mmol). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure. The crude product was purified by reverse-phase HPLC eluting with 0-100% ACN / water (0.05% HCl modifier) ​​to give the title compound (0.01 g, 22%). 1H NMR (400MHz, methanol-d4) δ:7.63-7.75(m,4H),7.50-7.59(m,3H),7.37(d,2H),7.12-7.20(m,2H),7.07(s,1H),6.95- 7.01(m,1H),4.90-4.99(m,2H)4.46(d,1H),3.66-3.78(m,2H),3.12-3.24(m,2H),2.93(s,3H),1.93-2.21(m,4H);MS m / z:553.1[M+1] + .

[0217] The following examples were prepared by a method similar to that of Example 6 from ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate and the corresponding starting materials. [Table 8]

[0218] Example 7: Preparation of Compounds 019 and 020 [ka] Step 1. 2-Bromo-4-fluorothieno[2,3-c]pyridin-7(6H)-one [ka] A mixture of 2-bromothieno[2,3-c]pyridin-7(6H)-one (233 mg, 1 mmol), Selectfluor (354 mg, 1 mmol), and dimethylacetamide (3 mL) was heated to 150 °C with stirring in a sealed microwave vial for 15 min. After cooling to room temperature, the entire reaction mixture was purified by RP-HPLC eluting with 0-80% ACN / water (0.038% TFA) to give the title compound (47 mg, 19%). NMR MS m / z: 247.8 [M+1] + .

[0219] Step 2. Methyl 2-(2-bromo-4-fluoro-7-oxothieno[2,3-c]pyridin-6(7H)-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate [ka] A mixture of 2-bromo-4-fluorothieno[2,3-c]pyridin-7(6H)-one (140 mg, 0.59 mmol), methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate (218 mg, 0.71 mmol), cesium carbonate (391 mg, 1.08 mmol), and DMF (2 mL) was heated to 30° C. for 6 h. After cooling, the entire reaction mixture was purified by flash chromatography eluting with 0-50% EtOAc / hexanes to give the title compound (107 mg, 38%). 1 H NMR(500MHz,CDCl3)δ:7.34(s,1H),7.22(dd,1H),7.14(dd,1H),7.10(d,1H),7.07(dd,1H)6.93(s,1H),5.15(s,2H),3.86(s,3H),3.39(s,3H);MS m / z:475.8[M+1] + .

[0220] Step 3. 2-(4-Fluoro-2-(4-(1-methylpiperidin-4-yl)phenyl)-7-oxothieno[2,3-c]pyridin-6(7H)-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetic acid [ka] A mixture of methyl 2-(2-bromo-4-fluoro-7-oxothieno[2,3-c]pyridin-6(7H)-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate (100 mg, 0.21 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (67 mg, 0.63 mmol), Na2CO3 (67 mg, 0.63 mmol), dioxane (3 mL), and water (1 mL) was degassed twice under vacuum and backfilled with N2. PdCl2dppf-dcm (19 mg, 0.023 mmol) was added, and the Rxn mixture was backfilled with N2. The Rxn mixture was heated to 95 °C for 6 h. The entire reaction mixture was purified by RP-HPLC eluting with 0-80% ACN / water (0.038% TFA) to afford the title compound (40 mg, 52%). 1 H NMR(500MHz,DMSO-d6)δ:9.46(br s,1H),7.88(m,3H),7.45(d,1H),7.39(d,2H),7.28(dd,1H),7.26(dd,1H),7.21(dd,1H),6.70(s,1H),5.23(d, MS m / z:555.1[M+1] + .

[0221] Step 4. 2-(4-fluoro-2-(4-(1-methylpiperidin-4-yl)phenyl)-7-oxothieno[2,3-c]pyridin-6(7H)-yl)-2-(5-fluoro-2-hydroxyphenyl)-N-(thiazol-2-yl)acetamide (019) [ka] A mixture of 2-(4-fluoro-2-(4-(1-methylpiperidin-4-yl)phenyl)-7-oxothieno[2,3-c]pyridin-6(7H)-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetic acid (20 mg, 0.036 mmol), HATU (27 mg, 0.072 mmol), 2-aminothiazole (5.4 mg, 0.072 mmol), DIEA (19 mL, 0.108 mmol), and DMF (2 mL) was stirred at room temperature overnight. The entire reaction mixture was purified by RP-HPLC eluting with 0-80% ACN / water (0.038% TFA). MS m / z: 637.2 [M+1] + .

[0222] This material was treated with DCM:TFA (1:1, 4 mL) for 30 min. The solvent was removed under reduced pressure, and the entire reaction mixture was purified by RP-HPLC eluting with 0-80% ACN / water (0.038% TFA) to give the title compound (4.8 mg, 22% over two steps). 1 H NMR(500MHz,DMSO-d6)δ:10.17(s,1H),9.41(br s,1H),7.90(m,3H),7.51(d,1H),7.39(d,2H),7.30(d,1H),7.21(m,1H),7.15(d,1H),6.96(dd,1H),6.9 5(s,1H),6.88(dd,1H),3.55(d,2H),3.10(m,2H),2.88(m,1H),2.83(d,3H),2.05(d,2H),1.86(m,2H);MS m / z:593.1[M+1] + .

[0223] Step 5. 6-((1H-benzo[d]imidazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-4-fluoro-2-(4-(1-methylpiperidin-4-yl)phenyl)thieno[2,3-c]pyridin-7(6H)-one (020) [ka] A mixture of 2-(4-fluoro-2-(4-(1-methylpiperidin-4-yl)phenyl)-7-oxothieno[2,3-c]pyridin-6(7H)-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetic acid (20 mg, 0.036 mmol), HATU (27 mg, 0.072 mmol), 1,2-phenylenediamine (8 mg, 0.072 mmol), DIEA (19 mL, 0.108 mmol), and DMF (2 mL) was stirred at room temperature overnight. The entire reaction mixture was purified by RP-HPLC eluting with 0-80% ACN / water (0.038% TFA). MS m / z: 645.4 [M+1] + .

[0224] This material was dissolved in AcOH (3 mL) and the solution was heated to 100° C. for 1 h. The solvent was removed under reduced pressure. MS m / z: 627.1 [M+1] + .

[0225] This material was treated with DCM:TFA (1:1, 4 mL) for 30 min. The solvent was removed under reduced pressure, and the entire reaction mixture was purified by RP-HPLC eluting with 0-80% ACN / water (0.038% TFA) to give the title compound (5.7 mg, 27% over 3 steps). 1 H NMR(500MHz,DMSO-d6)δ:10.12(brs,1H),9.46(br s,1H),7.91(s,1H),7.88(d,2H),7.61(s,1H),7.58(m,2H),7.47(d,1H),7.39(d,2H),7.24(m,2H),7.15(m,1H) MS m / z:583.2[M+1] + .

[0226] The following examples were prepared in a similar manner to compound 019 from methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding starting materials. [Table 9]

[0227] The following examples were prepared in a similar manner to compound 020 from methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding starting materials. [Table 10]

[0228] [ka] 2-Bromo-N-(pivaloyloxy)thiazole-5-carboxamide [ka] Oxalyl chloride (15 mL, 30 mmol, 2 M solution in DCM) was added dropwise over 20 min to a suspension of 2-bromothiazole-5-carboxylic acid (4.2 g, 20 mmol) and anhydrous DMF (4 drops) in DCM (20 mL). The reaction was stirred at room temperature for 3 days and the solvent was removed under reduced pressure to give the acid chloride.

[0229] Hydroxylamine hydrochloride (1.39 g, 20 mmol) was added to a biphasic mixture of K2CO3 (5.52 g, 20 mmol) in a 2:1 mixture of EtOAc (40 mL) and water (20 mL). The resulting solution was cooled to 0 °C, followed by the dropwise addition of the crude acid chloride in EtOAc (12 mL) over 20 min. The reaction was allowed to warm to room temperature, resulting in a thick white suspension. After 4 h, pivaloyl chloride (2.46 mL, 20 mmol) was added dropwise over approximately 10 min. After 2 h, additional pivaloyl chloride (0.5 mL) was added, and the reaction was stirred for 16 h. The mixture was diluted with water (125 mL) and extracted with EtOAc (2 × 125 mL). The combined organic extracts were washed with water and saturated brine, dried (Na2SO4), filtered, and the residue was purified by flash chromatography 0–35% EtOAc / hexanes to afford 2.44 g (40%) of a white solid. 1H NMR(500MHz,DMSO-d6)δ:8.22(s,1H),1.28(s,9H);MS m / z:308.8[M+1] + .

[0230] 2-Bromothiazolo[5,4-c]pyridin-4(5H)-one [ka] 2-Bromo-N-(pivaloyloxy)thiazole-5-carboxamide (233 mg, 1 mmol), CsCO3 (58 mg, 0.3 mmol), [Cp * A mixture of [RhCl2]2 (12 mg, 0.02 mmol) was degassed and filled with N2 twice. Vinyl acetate (131 mL, 1.5 mmol) was added and the mixture was heated to 45 °C for 60 h. The entire reaction mixture was purified by RP-HPLC eluting with 0-80% ACN / water (0.038% TFA) to give the title compound (16 mg, 7%). MS m / z: 232.8 [M+1] + .

[0231] [ka] 2-(5-fluoro-2-methoxyphenyl)acetic acid methyl ester [ka] Thionyl chloride (5.8 mL, 81.3 mmol) was added dropwise over 15 min to a solution of 2-(5-fluoro-2-methoxyphenyl)acetic acid (5.0 g, 27.1 mmol) in MeOH (3 mL) at 0 °C. The mixture was heated at 60 °C for 16 h, and the solvent was removed under reduced pressure. EtOAc (100 mL) and saturated brine (100 mL) were added, and the pH was adjusted to 9 with saturated NaHCO solution. The organic layer was washed with brine, dried (NaSO), and concentrated to give the title compound (5.13 g, 95%), which was used without further purification. 1H NMR(500MHz,CDCl3)δ:6.96(m,2H),6.81(m,1H),3.81(s,3H),3.72(s,3H),3.63(s,2H).

[0232] 2-(5-fluoro-2-hydroxyphenyl)acetic acid methyl ester [ka] BBr3 (77 mL, 1 M in DCM) was added dropwise over 45 min to a solution of methyl 2-(5-fluoro-2-methoxyphenyl)acetate in DCM (100 mL) at −78° C., and the mixture was stirred for 1 h. The reaction was quenched with water (50 mL). DCM (100 mL) and water (50 mL) were added, and the pH was adjusted to 8 with saturated NaHCO3 solution. The organic layer was washed with brine, dried (Na2SO4), and concentrated to give the title compound (4.38 g, 92%), which was used without further purification. 1 H NMR(500MHz,CDCl3)δ:7.16(s,1H),6.90(dd,1H),6.85(dd,1H),3.79(s,3H),3.66(s,2H),3.67(s,2H).

[0233] 2-(5-fluoro-2-(methoxymethoxy)phenyl)acetic acid methyl ester [ka] Diisopropylethylamine (12.4 mL, 71.4 mmol) and chloromethyl methyl ether (4.52 mL, 59.5 mmol) methyl 2-(5-fluoro-2-hydroxyphenyl)acetate were added to a solution of methyl 2-(5-fluoro-2-hydroxyphenyl)acetate (4.38 g, 23.8 mmol) in DCM (150 mL). The reaction mixture was stirred for 20 h. DCM (100 mL) and brine (100 mL) were added, the organic layer was washed with brine, dried (NaSO), and the residue was purified by silica chromatography (0-20% EtOAc in Hex) to give the title compound (4.78 g, 88%). 1H NMR(500MHz,CDCl3)δ:7.07(dd,1H),6.96(dd,1H),6.94(m,1H),5.16(s,2H),3.72(s,3H),3.66(s,2H),3.48(s,3H).

[0234] 2-Bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetic acid methyl ester [ka] NBS (3.05 g, 17.1 mmol) and benzoyl peroxide (396 mg, 1.63 mmol) were added to a solution of methyl 2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate (3.72 g, 16.3 mmol) in CCl (80 mL). The reaction mixture was stirred at 80 °C for 20 h. EtOAc (150 mL) and brine (100 mL) were added, the organic layer was washed with brine, dried (NaSO), and the residue was purified by silica chromatography (0-10% EtOAc in Hex) to give the title compound (3.59 g, 72%). 1 H NMR(500MHz,CDCl3)δ:7.41(dd,1H),7.09(dd,1H),7.02(m,1H),5.85(s,1H),5.22(d,1H),5.21(d,1H),3.82(s,3H),3.51(s,3H).

[0235] Example 8 Preparation of 6-((1H-benzo[d]imidazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl-d)-2-(4-(1-methylpiperidin-4-yl)phenyl)thieno[2,3-c]pyridin-7(6H)-one (024) [ka] A solution of 6-((1H-benzo[d]imidazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-2-(4-(1-methylpiperidin-4-yl)phenyl)thieno[2,3-c]pyridin-7(6H)-one (0.09, 20 mg, 0.035 mmol), deuterium oxide (350 mL, 19.3 mmol), DIEA (38 mL, 6.3 mmol), and anhydrous THF (1 mL) was stirred at 70 °C for 60 h. The entire reaction mixture was purified by RP-HPLC eluting with 0-80% ACN / HO (0.038% TFA modifier) ​​to give the title compound (12 mg, 62%). NMR (500 MHz, DMSO-d) δ: 1 H 10.06(br s,1H),9.39(br s,1H),7.80(d,2H),7.77(s,1H),7.57(m,2H),7.38(m,3H),7.24(m,2H),7.13(m,1H),6.92(dd,1H),6.78(d,1H), 6.69(dd,1H),3.54(m,2H),3.09(m,2H),2.87(m,1H),2.84(d,3H),2.06(d,2H),1.85(m,2H).MS,m / z566.15,[M+1] + .

[0236] Example 9 Preparation of 6-((1H-indol-2-yl)(phenyl)methyl)-2-(4-(1-methylpiperidin-4-yl)phenyl)thieno[2,3-c]pyridin-7(6H)-one (025) [ka] Step 1. tert-Butyl 2-formyl-1H-indole-1-carboxylate [ka] A solution of triethylamine (0.6 mL, 4.0 mmol), DMAP (41 mg, 0.34 mmol), 1H-indole-2-carbaldehyde (0.5 g, 3.4 mmol), and THF (15 mL) was cooled to 0 °C. Di-tert-butyl dicarbonate (0.87 g, 4.0 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, and the residue was partitioned between water (30 mL) and EtOAc (30 mL). The aqueous solution was later extracted with EtOAc, and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica chromatography (0–30% EtOAc / hexanes) to give the title compound (570 mg, 68%). 1 H NMR(500MHz,CDCl3)δ:10.46(s,1H),8.19(d,1H),7.70(d,1H),7.51(t,1H),7.46(s,1H),7.33(t,1H),1.74(s,9H).

[0237] Step 2. tert-Butyl 2-(hydroxy(phenyl)methyl)-1H-indole-1-carboxylate [ka] Phenylmagnesium bromide (1 M in THF, 2.79 mL, 2.79 mmol) was added dropwise to a solution of tert-butyl 2-formyl-1H-indole-1-carboxylate (0.57 g, 2.32 mmol) in anhydrous THF at 0 °C. The reaction was stirred at 0 °C for 30 min and quenched with saturated aqueous NH Cl (10 mL). The mixture was extracted with EtOAc (2 × 20 mL), dried (Na SO ), filtered, and concentrated under reduced pressure. The residue was purified by silica chromatography (0–30% EtOAc / hexanes) to give the title compound (500 mg, 67%). 1 H NMR(500MHz,CDCl3)δ:7.99(d,1H),7.45(d,3H),7.39(m,2H),7.34(m,1H),7.31(m,1H),7.23(t,1H),6.23(s,1H),6.21(d,1H),4.71(br d,1H),1.67(s,9H).

[0238] Step 3. tert-Butyl 2-(((methylsulfonyl)oxy)(phenyl)methyl)-1H-indole-1-carboxylate [ka] Mesyl chloride (143 mL, 1.86 mmol) was added dropwise to a solution of tert-butyl 2-(hydroxy(phenyl)methyl)-1H-indole-1-carboxylate (300 mg, 0.93 mmol), DIEA (647 mL, 3.72 mmol), and anhydrous DCM (10 mL) at 0° C. The reaction was stirred at 0° C. for 15 min and at room temperature for 1 h, then diluted with DCM (10 mL) and quenched with ice-water (20 mL). The organic layer was collected, dried (NaSO), filtered, and concentrated under reduced pressure to give the crude mesylate salt, which was used in the next step without further purification.

[0239] Step 4. 6-((1H-indol-2-yl)(phenyl)methyl)-2-bromothieno[2,3-c]pyridin-7(6H)-one [ka] The material from Step 3 was dissolved in DMF (3 mL) and added dropwise to a suspension of 2-bromothieno[2,3-c]pyridin-7(6H)-one (193 mg, 0.81 mmol) and CsCO (673 mg, 1.86 mmol) in DMF (8 mL). The reaction mixture was heated at 36 °C for 6 h. After cooling, the reaction mixture was poured into ice-water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with saturated brine (20 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by silica chromatography (0–30% EtOAc / hexanes) to give the title compound (120 mg, 30% over two steps). 1 H NMR(500MHz,CDCl3)δ:9.81(s,1H),7.62(s,1H),7.58(d,1H),7.39(m,4H),7 .33(m,2H),7.23(m,2H),7.13(t,1H),7.09(s,1H),6.50(d,1H),6.31(s,1H),

[0240] Step 4. 6-((1H-indol-2-yl)(phenyl)methyl)-2-(4-(1-methylpiperidin-4-yl)phenyl)thieno[2,3-c]pyridin-7(6H)-one [ka] A mixture of 6-((1H-indol-2-yl)(phenyl)methyl)-2-bromothieno[2,3-c]pyridin-7(6H)-one (120 mg, 0.27 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (90 mg, 0.3 mmol), Na2CO3 (86 mg, 0.81 mmol), dioxane (3 mL), and water (1 mL) was degassed and backfilled with N2 twice. PdCl2dppf-dcm (44 mg, 0.054 mmol) was added, and the mixture was degassed and backfilled with N2. The reaction mixture was heated to 95 °C for 20 min. After cooling, the entire reaction mixture was purified by RP-HPLC eluting with 0-80% ACN / HO (0.038% TFA) to give the title compound (54 mg, 38%). NMR (500 MHz, DMSO-d) δ: 1 H 11.42(s,1H),9.43(br s,1H),7.80(d,2H),7.77(s,1H),7.50(d,2H),7.44(m,2H),7.38(m,3H),7.31(m,4H),7.11(t,1H),7.00(t,1H) ),6.78(d,1H),6.09(s,1H),3.54(d,2H),3.10(m,2H),2.87(m,1H),2.84(d,3H),2.06(d,2H),1.86(m,2H).MS m / z:530.25[M+1] + .

[0241] Example 10: HTRF-based EGFR biochemical assay EGFR biochemical activity measurements were performed using a homogeneous time-resolved fluorescence (HTRF) assay (Cisbio). Inhibitors and DMSO normalizers were first 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 (10 μL final volume) contained 1 μM tyrosine kinase peptide-biotin substrate and mutant EGFR in reaction buffer (50 mM HEPES pH 7.0, 5 mM MgCl2, 1 mM MnCl2, 0.01% BSA, 2 mM TCEP, 0.1 mM NaVO4). Enzyme concentrations were adjusted to accommodate different kinase activities (L858R 0.1 nM, L858R / T790M 0.02 nM). The enzyme reaction solution (2x concentration, 5 μL) was added to the compound-containing 384-well plate and incubated for 30 minutes. The enzyme reaction was initiated by adding 5 μL of ATP to a final concentration of 100 μM and allowed to react for 20 minutes. The reaction was quenched by adding 10 μL of phospho-tyrosine antibody-europium(III) cryptate (1:180 volume ratio) and streptavidin-XL665 (46.7 nM) in EDTA-containing detection buffer, then incubated at room temperature for 1 hour and read on a PHERAstar plate reader (excitation = 337 nm, emission = 620 nm and 665 nm). IC 50 Values ​​were determined in triplicate by inhibition curve fitting (11-point curve from 1.0 μM to 0.130 nM, or 23-point curve from 1.0 μM to 0.130 pM) using nonlinear least-squares fitting in GraphPad Prism 7.0d. The data obtained are shown in Table 4 below. [Table 11]

[0242] Example 11: Ba / F3 cell proliferation model EGFR mutant L858R and L858R / T790M Ba / F3 cells have been 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 via site-directed mutagenesis using the Quick Change Site-Directed Mutagenesis Kit (Stratagene; La Jolla, CA) according to the manufacturer's instructions. All constructs were verified 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 previously described (Zhou, et al., Nature 2009). Stable clones were obtained by selection in puromycin (2 μg / ml).

[0243] Proliferation and proliferation inhibition were assessed by the Cell Titer Glo assay (Promega, Madison, WI) and performed according to the manufacturer's instructions. The Cell Titer Glo assay is a luminescence-based method used to determine the number of viable cells based on the quantification of ATP present, which is directly proportional to the amount of metabolically active cells present. Ba / F3 cells of different EGFR genotypes were exposed to compounds as single agents or in combination with 1 μg / mL cetuximab 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 graphed 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 in Table 5 below. [Table 12]

[0244] The disclosed subject matter should not be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. These modifications are intended to be included within the scope of the appended claims.

[0245] All references (e.g., publications or 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 or 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, During the ceremony, 【Chemistry 2】 represents a single or double bond, A and A' are each independently CH, CR ８ , or N, W is N or C; Z is S, O, N, NH, N-Me, CH ２ , CH, C-halo, C-(C １ ~C ３ alkyl), or C—(C １ ~C ３ alkoxy), X is S, O, N, CH, NR ３ , or CR ３ and Y is CR 3 ; However, at least one of X or Z is CH, R １ is a 5- to 10-membered heteroaryl, C(O)NHR ９ , 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, wherein the heteroaryl, cycloalkyl, and heterocycloalkyl are selected from the group consisting of 1, 2, or 3 R ８ optionally replaced by R ２ But one, two, or three R ６ is phenyl optionally substituted with R ３ but, 【Transformation 3】 and R ６ But independently, in each occurrence, 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; Or, two R ６ can be taken together with the atoms to which they are attached to form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R ７ But C １ to C3 alkyl, R ８ But independently, in each occurrence, 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, 3-6 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 or CN; R ９ is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, each of which is selected from one, two, or three R ８ or a pharmaceutically acceptable salt thereof, optionally substituted with

2. wherein said compound of formula I is Compound of Formula II: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, Compounds of Formula IIIa: 【Transformation 5】 or a pharmaceutically acceptable salt thereof, Compound of Formula IV: 【Transformation 6】 or a pharmaceutically acceptable salt thereof, or Compound of Formula V: 【Transformation 7】 or a pharmaceutically acceptable salt thereof, 2. The compound of claim 1, wherein:

3. R ６ 3. The compound of claim 1 or 2, wherein, independently at each occurrence, is hydroxy or halo.

4. R １ is selected from the group consisting of benzimidazole, imidazopyridine, indole, triazole, pyrazole, imidazole, pyridinylamide, and thiazolylamide, each of which contains one, two, or three R ８ The compound of any one of claims 1 to 3, optionally substituted with

5. R 1 is 【Transformation 8】 is selected from the group consisting of A compound according to any one of claims 1 to 4, each of which is optionally substituted with 1, 2 or 3 R 8 .

6. R １ but, 【Chemistry 9】 is selected from the group consisting of All of these have one, two, or three R ８ The compound of any one of claims 1 to 5, optionally substituted with

7. R ７ The compound according to any one of claims 1 to 6, wherein is CH3.

8. R ８ But independently, in each occurrence, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, halogen, OH, and NH ２ The compound according to any one of claims 1 to 7, selected from the group consisting of:

9. wherein said compound of formula I is 【Chemistry 10-1】 【Chemistry 10-2】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

10. The compound of formula I may be a compound of formula IVb: 【Chemistry 11】 And, R 6 is independently at each occurrence hydroxy or halo; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1 -C 3 alkyl.

11. R 1 is 【Chemistry 12】 The compound according to any one of claims 1 to 8 and 10,

12. The compound of formula I is 【Chemistry 13】 12. The compound of any one of claims 1, 10 and 11, wherein:

13. The compound of formula I is 【Chemistry 14】 13. The compound of any one of claims 1, 10, 11 and 12, wherein:

14. The compound of formula I, 【Chemistry 15】 The compound according to any one of claims 1, 11 to 13,

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15, wherein the composition further comprises a second active agent.

17. The pharmaceutical composition of claim 16, wherein the second active agent is selected from the group consisting of a MEK inhibitor, a PI3K inhibitor, and an mTor inhibitor.

18. The pharmaceutical composition of claim 16, wherein the second active agent prevents EGFR dimer formation in a subject.

19. The pharmaceutical composition of claim 18, wherein the second active agent is selected from the group consisting of cetuximab, trastuzumab, and panitumumab.

20. The pharmaceutical composition of claim 16, wherein the second active agent is an ATP-competitive EGFR inhibitor.

21. The pharmaceutical composition of claim 20, wherein the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib.

22. 22. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 15 to 21, in the manufacture of a medicament for treating cancer in a subject in need thereof.

23. Use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, in combination with a second active agent in the manufacture of a medicament for the treatment of cancer in a subject in need thereof.

24. Use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof, wherein the subject is receiving a second active agent.

25. The use of claim 23 or 24, wherein the second active agent is selected from the group consisting of a MEK inhibitor, a PI3K inhibitor, and an mTor inhibitor.

26. The use of claim 23 or 24, wherein the second active agent is selected from the group consisting of cetuximab, trastuzumab, and panitumumab.

27. The use of claim 23 or 24, wherein the second active agent is an ATP-competitive EGFR inhibitor.

28. The use of claim 27, wherein the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib.

29. The use according to any one of claims 22 to 28, 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.

30. 30. The use of claim 29, wherein the lung cancer is non-small cell lung cancer (NSCLC).

31. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 15 to 21, in the manufacture of a medicament for inhibiting EGFR kinase in a subject having a disease or disorder associated with overexpression of EGFR kinase.

Images