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] 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.

[0002] Related Applications This application claims priority to U.S. Provisional Application No. 62 / 864,914, filed June 21, 2019, No. 62 / 877,093, filed July 22, 2019, and No. 63 / 027,734, filed May 20, 2020, the contents of which are incorporated by reference in their entireties. [Background technology]

[0003] The epidermal growth factor receptor (EGFR, Erb-B1) belongs to the family of receptor tyrosine kinases that mediate the proliferation, differentiation and survival of normal and malignant cells (Arteaga, CL, J. Clin. Oncol. 19, 2001, pp. 32-40). Deregulation of EGFR has been implicated in many types of human cancer, with the receptor overexpressed in at least 70% of human cancers (Seymour, LK, Curr. Drug Targets 2, 2001, pp. 117-133), including non-small cell lung cancer, breast cancer, glioma, head and neck squamous cell carcinoma, and prostate cancer (Raymond, E. et al., Drugs 60(Suppl. 1), 2000, pp. 15-23, discussion pp. 41-2; Salomon, DS et al., Crit. Rev. Oncol. Hematol. 19, 1995, pp. 183-232; Voldborg BR et al., Ann. Oncol. 8, 1997, pp. 1197-1206). Therefore, EGFR has become known as an attractive target for the design and development of diagnostic and therapeutic agents that can specifically bind and inhibit the tyrosine kinase activity and signal transduction pathway of the receptor 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 have also been approved, including lapatinib and IRESSA®.

[0004] Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are an effective clinical treatment for patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) (Mok, TS et al., N. Engl. J. Med. 361, 2009, pp. 947-57; Paez, JG et al., Science 304, 2004, pp. 1497-500; Lynch, TJ et al., N. Engl. J. Med. 350, 2004, pp. 2129-39; Rosell, R. et al., Lancet Oncol. 13, 2012, pp. 239-46). Randomized clinical trials have demonstrated that EGFR TKIs are more effective than chemotherapy when used as initial systemic treatment for advanced EGFR-mutated NSCLC, as assessed by response rate (RR) and progression-free survival (PFS) (Mok, TS et al., N. Engl. J. Med. 361, 2009, pp. 947-57; Rosell, R. et al., Lancet Oncol. 13, 2012, pp. 239-46; Sequest, LV et al., J. Clin. Oncol. 31, 2013, pp. 3327-34; Wu, YL et al., Lancet Oncol. 15, 2014, pp. 213-22; Maemondo, M. et al., N. Engl. J. Med. 362, 2010, pp. 2380-8; Zhou, C. et al., Lancet Oncol. 12, 2011, pp. 735-42; Mitsudomi, T. et al., Lancet Oncol. 11, 2010, pp. 121-8). However, the majority of patients will develop disease progression after successful treatment with EGFR TKIs. The most common mechanism of acquired resistance, detected in 60% of patients, is a secondary mutation at position T790 in EGFR (T790M) (Yu, HA et al., Clin. Cancer Res. 19, 2013, pp. 2240-7). This mutation leads to an increased affinity of ATP, which makes 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, pp. 2070-5).

[0005] Covalent EGFR inhibitors have become known to inhibit cancers containing EGFR T790M. However, in lung cancer patients, only afatinib is effective in EGFR TKI-naive EGFR-mutated cancers, with less than 10% RR in patients with NSCLC that has acquired resistance to gefitinib or erlotinib (Miller, VA et al., Lancet Oncol. 13, 2012, pp. 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, limiting the ability to up-titrate afatinib to the dose required to inhibit EGFR T790M in patients. Irreversible pyrimidine EGFR inhibitors, including the tool compound WZ4002 and the clinical compounds CO-1686 and AZD9291, overcome many of the limitations of afatinib (Zhou, W. et al., Nature 462, 2009, pp. 1070-4; Walter, AO et al., Cancer Discov. 3, 2013, pp. 1404-15; Cross, DAE et al., Cancer Discov. 4, 2014, pp. 1046-61). Not only are they more potent against EGFR T790M, but they also inhibit the mutant more selectively than WT EGFR, leading to higher clinical efficacy and lower toxicity compared to afatinib (Zhou, W. et al.; Walter AO et al., Cross, DAE et al.). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Arteaga, CL, J. Clin. Oncol. 19, 2001, pp. 32-40. [Non-Patent Document 2] Seymour, LK, Curr. Drug Targets 2, 2001, pp. 117-133. [Non-Patent Document 3] Raymond, E. et al., Drugs 60 (Suppl. 1), 2000, pp. 15 - 23, discussion pp. 41 - 2

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[0007] However, all current EGFR TKIs target the ATP site, and while third-generation irreversible inhibitors can overcome T790M, they are all rendered powerless by the C797S mutation that already occurs in treated patients. The anti-EGFR antibody cetuximab, which interferes with receptor dimerization, is not effective in EGFR-mutated NSCLC, because the mutational activation of the kinase is effectively "downstream" of receptor dimerization. Therefore, alternative strategies to inhibit EGFR are required. At present, suitable compounds with alternative mechanisms of action that target mutant EGFR are not available. Thus, potent small molecule EGFR inhibitors with alternative mechanisms of action that target mutant EGFR are needed. [Means for solving the problem]

[0008] Provided herein are compounds of formula I:

[0009] [ka]

[0010] or a pharma- ceutically acceptable salt thereof. (In the formula, A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; W and W a are independently CH, CR 6 or N, X and B are each independently N, CH, CF, or C-(C1-C3 alkyl); Y and Z each independently represent N, CH, or CR 2 and with the proviso that at least one of X, Y, Z or B is CH; R 1 is phenyl or pyridinyl, where phenyl or pyridinyl is optionally independently R 7 is substituted once or twice with R 2each occurrence independently represents halo, 6- to 10-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 4- to 7-membered heterocycloalkyl, OR 4 , N.R. 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein 6-10 membered aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl, and 3-6 membered cycloalkyl are optionally selected from the group consisting of R 3 and each of C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with R 4 is substituted once, twice or three times by R 3 are halo, -OH, -SH, -CN, -NO2, -NH2, OR 4 , N.R. 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl and 4-7 membered heterocycle, wherein the 4-7 membered heterocycle is optionally substituted with C1-C4 alkyl, C1-C4 alkyl-OH, halo and =O; R 4 are independently for each occurrence: hydrogen, (CH2) 0~3 -(3 to 7 membered cycloalkyl), (CH2) 0~3 -(4-7 membered cycloalkenyl), (CH2) 0~3 -(6-10 membered aryl), (CH2) 0~3 -(5-6 membered heteroaryl) or (CH2) 0~3-(4- to 7-membered heterocycloalkyl), wherein the 6- to 10-membered aryl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl is each optionally selected from the group consisting of R 5 is substituted once, twice or three times by R 5 is independently selected for each occurrence from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, COOH, C(O)O(C1-C6 alkyl), O(CH2) 1~3 OH, NH2, OH, CN, (CH2) 0~3 (6-10 membered aryl), (CH2) 0~3 (5-6 membered heteroaryl) and (CH2) 0~3 (4-7 membered heterocycloalkyl), where the 6-10 membered aryl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are optionally selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, SO2NH2, (CH2) 1~2 OH, C(O)(CH2) 1~2 substituted with one or more substituents independently selected from OH and C(O)O(C1-C6 alkyl); R 6 is independently at each occurrence C1-C6 alkyl or halo; R 7 is independently selected at each occurrence from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halo, OH, SH, NO2, NH2, (CH2) 1~4 OH, S(O) 0~2 H, S(O) 0~2 NH2 or CN).

[0011] In one embodiment, the compound of formula I is

[0012] [Table 1A]

[0013] [Table 1B]

[0014] [Table 1C]

[0015] [Table 1D]

[0016] [Table 1E]

[0017] [Table 1F]

[0018] [Table 1G]

[0019] [Table 1H]

[0020] [Table 1I]

[0021] or a pharma- ceutically acceptable salt thereof.

[0022] In another aspect, provided herein is a pharmaceutical composition comprising any compound disclosed herein, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier.

[0023] In yet another aspect, provided herein is a method of inhibiting a kinase, comprising administering to a subject in need thereof an effective amount of a compound of formula I or a pharmaceutical composition comprising a compound of formula I and a pharma- ceutically acceptable carrier. In one embodiment, the kinase inhibited is epidermal growth factor receptor (EGFR). In a further embodiment, the EGFR inhibited contains one or more mutations. In yet a further embodiment, the EGFR inhibited contains one or more mutations selected from the group consisting of T790M, L718Q, L844V, V948R, L858R, I941R, C797S, and Del. In another embodiment, the compound of formula I exhibits at least 5-fold greater inhibition of EGFR containing one or more mutations compared to wild-type EGFR. In another embodiment, the method further comprises administering to the subject a second active agent that prevents EGFR dimerization. In another embodiment, the subject is a human.

[0024] In yet another aspect, provided herein is a method for treating or preventing a kinase-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound of formula I or a pharmaceutical composition comprising a compound of formula I and a pharma- ceutically acceptable carrier. In one embodiment, the kinase-mediated disorder is resistant to an EGFR-targeted therapy. In a further embodiment, the EGFR treatment therapy is selected from the group consisting of gefitinib, erlotinib, osimertinib, CO-1686, and WZ4002. In one embodiment, the method further comprises administering to the subject a second active agent that prevents EGFR dimerization. In another embodiment, the method further comprises an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib. In another embodiment, the subject is a human.

[0025] In one aspect, provided herein is a method for treating cancer or a proliferative disease, comprising administering to a subject in need thereof an effective amount of a compound of formula I or a pharmaceutical composition comprising a compound of formula I and a pharma- ceutically acceptable carrier. In one embodiment, the cancer is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer. In another embodiment, the method further comprises administering to the subject a second active agent that prevents EGFR dimerization. In another embodiment, the subject is a human.

[0026] The present disclosure also provides a kit comprising a compound capable of inhibiting EGFR activity, selected from the compound of formula I or a pharma- ceutically acceptable salt thereof, and instructions for use in the treatment of cancer. In one embodiment, the kit further comprises components for carrying out a test to determine whether a subject has an activating or drug-resistant mutation in EGFR. In another embodiment, the kit further comprises a second active agent that prevents dimerization of EGFR.

[0027] The present disclosure also relates to prodrugs of the compounds of formula I. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] 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 otherwise limited in specific instances, either individually or as part of a larger group.

[0029] 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 known and commonly employed in the art.

[0030] 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, use of the term "including" as well as other forms such as "include," "includes," and "included" are not limiting.

[0031] As used herein, the term "about" will be understood by those of skill in the art and will vary to some extent depending on the context in which it is used. When used herein when referring to a measurable value, such as an amount, duration in time, etc., the term "about" is meant to encompass variations of ±20% or ±10% from the stated value, including ±5%, ±1%, and ±0.1%, as long as such variations are appropriate to perform the disclosed method.

[0032] As used herein, terms such as "administration" refer to providing a therapeutic agent to a subject. There are multiple techniques in the art for administering therapeutic agents, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ophthalmic administration, pulmonary administration, and topical administration.

[0033] As used herein, terms such as "co-administration" or "co-administration" are meant to encompass the administration of more than one selected therapeutic agent to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[0034] The terms "treat," "treated," "treating," or "treatment" include the diminishment or alleviation of at least one symptom associated with or caused by the condition, disorder, or disease being treated. In certain embodiments, treatment involves contacting wild-type or mutant EGFR with an effective amount of a compound disclosed herein for a condition related to cancer.

[0035] As used herein, the term "prevent" or "prevention" refers to the absence of onset of a disorder or disease if none occurs, or the absence of further onset of a disorder or disease if onset of a disorder or disease is already present. It may also refer to the ability to prevent some or all of the symptoms associated with a disorder or disease.

[0036] As used herein, the terms "patient," "individual," or "subject" refer to a human or non-human mammal. Non-human mammals include, for example, livestock and pet animals, such as ovine, bovine, porcine, canine, feline, and marine mammals. Preferably, the patient, subject, or individual is a human.

[0037] As used herein, the terms "effective amount," "pharmacologically effective amount," and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to produce a desired biological result. This 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 can be determined by one of skill in the art using routine experimentation.

[0038] As used herein, the term "pharmaceutical acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of a compound and is relatively non-toxic, i.e., that can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any components in the composition in which it is contained.

[0039] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound has been modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the parent compound, e.g., salts formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing a basic or acid moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two (generally non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred). The phrase "pharmaceutically acceptable salts" is not limited to mono- or 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.

[0040] As used herein, the term "prodrug" refers to a precursor compound that undergoes metabolic activation in vivo to yield an active drug. Thus, for example, a prodrug of a compound of formula I, when administered to a subject, will undergo metabolic activation to produce the compound of formula I.

[0041] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the present disclosure and a pharma- ceutical carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. There are multiple techniques in the art for administering the compound, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ophthalmic administration, pulmonary administration, and topical administration.

[0042] The term "pharmaceutical combination" as used herein means a product obtained by mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both active ingredients, e.g., the disclosed compound and a co-agent, are administered to a patient simultaneously in the form of a single entity or a single dosage. The term "non-fixed combination" means that both active ingredients, e.g., the disclosed compound and a co-agent, are administered to a patient as separate entities simultaneously, in parallel, or sequentially without specific time restrictions, such that such administration results in 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.

[0043] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or carrier, such as, for example, a liquid or solid filler, a stabilizer, a dispersant, a suspending agent, a diluent, an excipient, a thickener, a solvent or an encapsulating material, that is involved in carrying or transporting a compound useful within the present disclosure into or to a patient so that it can perform its intended function. Typically, such compositions are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the present disclosure, and not injurious to the patient. Some examples of materials which may serve as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; surface-active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic, compatible substances employed in pharmaceutical preparations.

[0044] 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 within the present disclosure and are physiologically acceptable to the patient. Supplementary active compounds can also be incorporated into the composition. "Pharmaceutically acceptable carrier" can further include pharmaceutically acceptable salts of the compounds disclosed herein. Other additional ingredients that can be included in pharmaceutical compositions are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0045] An "oral dosage form" includes a unit dosage form formulated or intended for oral administration. In certain embodiments of the combination pharmaceuticals provided herein, the EGFR inhibitors disclosed herein are administered as oral dosage forms.

[0046] As used herein, the term "EGFR" refers to the epidermal growth factor receptor (alternatively known as ErbB-1 or HER1), and may refer to a wild-type receptor or a receptor containing one or more mutations.

[0047] As used herein, the term "HER" or "Her" refers to members of the ErbB receptor tyrosine kinase family, including EGFR, ERBB2, HER3 and HER4.

[0048] As used herein, the term "allosteric site" refers to a site on EGFR other than the ATP binding site, as characterized in the crystal structure of EGFR. An "allosteric site" may be a site proximate to the ATP binding site, as characterized in the crystal structure of EGFR. For example, an 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.

[0049] 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 collides with the N-lobe of the "receiver" subunit. Examples of agents that prevent EGFR dimerization include, but are not limited to, cetuximab, cobimetinib, trastuzumab, panitumumab, and Mig6.

[0050] 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 designated 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, tert-butyl, pentyl, neopentyl, and hexyl. Other examples of C1-C6 alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0051] 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 defined herein. Haloalkyl includes, by way of example, chloromethyl, trifluoromethyl, bromoethyl, chlorofluoroethyl, and the like.

[0052] As used herein, the term "alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, and the like.

[0053] As used herein, the term "haloalkoxy" refers to an -O-haloalkyl group, where haloalkyl is as defined herein. Haloalkoxy includes, by way of example, chloromethoxy, trifluoromethoxy, bromoethoxy, chlorofluoroethoxy, and the like.

[0054] 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.

[0055] 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.

[0056] As used herein, the terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine or bromine, and more preferably fluorine or chlorine.

[0057] As used herein, the term "cycloalkyl" refers to a fully saturated non-aromatic carbocyclic ring system having one, two, or three rings, where such 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, where the individual rings within the bicyclic ring vary within the range of 3 to 8 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.

[0058] As used herein, the term "cycloalkenyl" means a partially saturated non-aromatic carbocyclic ring system having one, two or three rings, wherein such rings may be fused, and wherein at least one ring is a sp 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.

[0059] As used herein, the term "heterocyclyl" or "heterocycloalkyl" refers to a non-aromatic carbocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, and having 1, 2, or 3 rings, where such rings may be fused, where fusion is defined above. Heterocyclyl also includes bicyclic structures which may be bridged or spirocyclic in nature, where the individual rings within the bicycle vary in the range of 3-8 atoms and contain 0, 1, or 2 N, O, or S atoms. The term "heterocyclyl" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), specifically, epoxydyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, pyrazolidin ... Peridinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 2-azabicyclo-[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 6-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]-heptanyl, 3-aza-bicyclo[3.1.1]heptanyl, 2-azabicyclo[3. 1.1]heptanyl, 3-azabicyclo[3.1.0]-hexanyl, 2-azabicyclo-[3.1.0]hexanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 3-oxa-7-azabicyclo[3.3.1]-nonanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, 2-oxa-5-azabicyclo-[2.2.1 ]heptanyl, 6-oxa-3-aza-bicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxaspiro[3.3]-heptanyl, 2-oxaspiro[3.5]nonanyl, 3-oxaspiro[5.3]-nonanyl, and 8-oxabicyclo[3.2.1]octanyl.

[0060] 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.

[0061] As used herein, the term "aryl" refers to an aromatic carbocyclic ring system containing one, two or three rings, where such rings may be fused, where fusion is defined above. If the rings are fused, one of the rings must be fully unsaturated, and the fused rings 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.

[0062] As used herein, the term "heteroaryl" 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, where such rings may be fused, where fusion is defined above. The term "heteroaryl" refers to furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-cyclopenta-[c]pyridinyl, These include, but are not limited to, 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.

[0063] It should be understood that where an aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety may be attached to the indicated moiety through different ring atoms or may otherwise be attached (i.e., shown or described without a specific point of attachment indicated), all possible points are intended, whether through a carbon atom or, for example, through a trivalent nitrogen atom. For example, the term "pyridinyl" refers to 2-, 3-, or 4-pyridinyl, the term "thienyl" refers to 2- or 3-thienyl, etc.

[0064] As used herein, the term "substituted" means that an atom or group of atoms replaces a hydrogen as a substituent bonded to another group.

[0065] 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 groups, each independently selected from the groups described herein.

[0066] compound Provided herein are compounds that are allosteric inhibitors of the epidermal growth factor receptor (EGFR), useful in the treatment of disorders including kinase-mediated cancer and other proliferative diseases.

[0067] In one aspect, provided herein is a compound of formula I:

[0068] [ka]

[0069] or a pharma- ceutically acceptable salt thereof. (In the formula, A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; W and W a are independently CH, CR 6 or N, X and B are each independently N, CH, CF, or C-(C1-C3 alkyl); Y and Z each independently represent N, CH, or CR 2 and with the proviso that at least one of X, Y, Z or B is CH; R 1 is phenyl or pyridinyl, where phenyl or pyridinyl is optionally independently R 7is substituted once or twice with R 2 each occurrence independently represents halo, 6- to 10-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 5- to 7-membered heterocycloalkyl, OR 4 , N.R. 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, wherein 6-10 membered aryl, 5-10 membered heteroaryl, and 3-6 membered cycloalkyl are optionally selected from the group consisting of R 3 and each of C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with R 4 is substituted once, twice or three times by R 3 is selected from the group consisting of halo, -OH, -SH, -CN, -NO2, -NH2, and a 5-7 membered heterocycle, wherein the 5-7 membered heterocycle is optionally substituted with C1-C4 alkyl; R 4 are independently for each occurrence: hydrogen, (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) or (CH2) 0~3 -(5- to 7-membered heterocycloalkyl), wherein aryl, heteroaryl, or heterocycloalkyl is each optionally selected from the group consisting of R 5 is substituted once, twice or three times by R 5 is independently selected for each occurrence from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, COOH, C(O)O(C1-C6 alkyl), O(CH2) 1~3OH, NH2, OH, CN, (CH2) 0~3 (C6~C 10 Aryl), (CH2) 0~3 (5-6 membered heteroaryl) and (CH2) 0~3 (5-7 membered heterocycloalkyl), where C6-C 10 Aryl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocycloalkyl are optionally selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, SO2NH2, (CH2) 1~2 OH, C(O)(CH2) 1~2 substituted with one or more substituents independently selected from OH and C(O)O(C1-C6 alkyl); R 6 is independently at each occurrence C1-C6 alkyl or halo; R 7 is independently selected at each occurrence from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halo, OH, SH, NO2, NH2, (CH2) 1~4 OH, S(O) 0~2 H, S(O) 0~2 NH2 or CN).

[0070] In certain embodiments, the compound of formula I has formula II:

[0071] [ka]

[0072] or a pharma- ceutically acceptable salt thereof. (In the formula, A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; W and W a are independently CH, CR 6 or N, R 2is selected from the group consisting of absent, halo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered cycloalkyl, wherein the 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered cycloalkyl are optionally selected from the group consisting of R 3 is replaced by R 3 is selected from the group consisting of halo, -OH, -SH, -CN, -NO2, -NH2 and a 5-7 membered heterocycle, wherein the 5-7 membered heterocycle is optionally substituted with C1-C4 alkyl; R 6 is independently at each occurrence C1-C6 alkyl or halo; R 7 is selected from the group consisting of absent, halo, -OH, -SH, -CN, -NO2, and -NH2; n is 1 or 2).

[0073] In another embodiment, R 7 is absent. In yet another embodiment, R 7 In yet another embodiment, R 7 is fluoro.

[0074] In one embodiment, A is a 5-7 membered heteroaryl. In another embodiment, A is thiazole. In yet another embodiment, A is pyridine.

[0075] In yet another embodiment, R 2 is selected from the group consisting of absent, halo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered cycloalkyl, where the 6- to 10-membered aryl is optionally selected from the group consisting of R 4 In one embodiment, R 2 is halo. In another embodiment, R 2 In yet another embodiment, R 2 is fluoro. In yet another embodiment, R 2 is R 3 In one embodiment, R 3is a 6-membered heterocycle optionally substituted with C1-C4 alkyl. 3 is piperidine further substituted with methyl. 3 is piperazine further substituted with methyl. 3 is in para rank.

[0076] In another embodiment, the compound of formula I has formula III:

[0077] [ka]

[0078] or a pharma- ceutically acceptable salt thereof.

[0079] In yet another embodiment, the compound of formula I has formula V:

[0080] [ka]

[0081] or a pharma- ceutically acceptable salt thereof.

[0082] In yet another embodiment, the compound of formula I has formula VI:

[0083] [ka]

[0084] or a pharma- ceutically acceptable salt thereof.

[0085] In certain embodiments, the compound of formula I has formula VII:

[0086] [ka]

[0087] or a pharma- ceutically acceptable salt thereof.

[0088] In another embodiment, the compound of formula I has formula VIII:

[0089] [ka]

[0090] or a pharma- ceutically acceptable salt thereof.

[0091] In yet another embodiment, the compound of formula I is selected from the compounds in Table 1 or a pharma- ceutically acceptable salt thereof.

[0092] [Table 2A]

[0093] [Table 2B]

[0094] [Table 2C]

[0095] [Table 2D]

[0096] [Table 2E]

[0097] [Table 2F]

[0098] [Table 2G]

[0099]

Table 2H

[0100]

Table 2I

[0101]

Table 2J

[0102]

Table 2K

[0103]

Table 2L

[0104]

Table 2M

[0105]

Table 2N

[0106]

Table 2O

[0107]

Table 2P

[0108] Compounds disclosed herein can exist as tautomers and optical isomers (eg, enantiomers, diastereomers, diastereomeric mixtures, racemic mixtures, etc.).

[0109] Within the scope of this disclosure, it is generally known in the art that any compound that will be converted in vivo to provide a compound of Formulas I-VIII is a prodrug.

[0110] Provided herein are compounds and compositions that have improved pharmacokinetic profiles, particularly with respect to lipid solubility, compared to known EGFR inhibitors.

[0111] In another aspect, provided herein is a pharmaceutical composition comprising a compound of the present disclosure or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. In another aspect, the pharmaceutical composition further comprises a second active agent that prevents EGFR dimerization and a pharma- ceutically acceptable carrier. 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.

[0112] 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 combined with a second active agent that prevents EGFR dimerization, can modulate EGFR activity. In some embodiments, compounds of the present disclosure can inhibit or reduce EGFR activity without the use of 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 some embodiments, the second active agent can prevent EGFR dimerization and / or 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 further embodiments, the second active agent that prevents EGFR dimerization is cetuximab. In some embodiments, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0113] Treatment 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 of Formula I. 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).

[0114] 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 of Formula I. In certain embodiments, the kinase is EGFR.

[0115] In yet 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 formula I. In one embodiment, the kinase-mediated disorder is resistant to an EGFR-targeted therapy. In another embodiment, the EGFR treatment therapy is selected from the group consisting of gefitinib, erlotinib, osimertinib, CO-1686, and WZ4002.

[0116] In some embodiments, the compounds of the present disclosure can modulate (e.g., inhibit or reduce) the activity of EGFR containing one or more mutations. In 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, wherein the combination of mutations is 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, wherein the combination of mutations is 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, wherein the combination of mutations is selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M.

[0117] In some embodiments, the compounds 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 that contains one or more mutations. In some embodiments, the mutant EGFR contains one or more mutations selected from T790M, L718Q, L844V, V948R, L858R, I941R, C797S, and Del. In other embodiments, the mutant EGFR contains a combination of mutations, wherein the combination of mutations is 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, wherein the combination of mutations is 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, wherein the combination of mutations is 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 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 an 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, compounds of the disclosure can modulate (e.g., inhibit or reduce) the activity of EGFR containing one or more mutations, but do not affect the activity of wild-type EGFR.

[0119] In other embodiments, the compounds 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 do not affect the activity of wild-type EGFR. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab. In some embodiments, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0120] Modulation of EGFR containing one or more mutations such as those described herein, rather than modulation of 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.

[0121] In some embodiments, the 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, the 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, the 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 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.

[0122] In other embodiments, the 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, the 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, the 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, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization show up to 10,000-fold greater inhibition of EGFR with the combinations 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. 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 certain embodiments, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0123] In some embodiments, the 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, the 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, the 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, the compounds of the present disclosure exhibit about 1000-fold to about 10000-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR.

[0124] In other embodiments, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization 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 other embodiments, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization 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 other embodiments, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization 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 other embodiments, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit about 1000-fold to about 10000-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 an embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0125] In certain embodiments, compounds of the present disclosure exhibit at least 2-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, as compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least 3-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, as compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least 5-fold greater inhibition against EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M, as compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least 10-fold greater inhibition against EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M, as compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least 25-fold greater inhibition against EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M, as compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least 50-fold greater inhibition against EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M, as compared to wild-type EGFR.In certain embodiments, compounds of the disclosure exhibit at least 100-fold greater inhibition against EGFR 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.

[0126] In certain embodiments, compounds of the disclosure in combination with a second active agent that prevents EGFR dimerization exhibit at least 2-fold greater inhibition against EGFR 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, compounds of the disclosure in combination with a second active agent that prevents EGFR dimerization exhibit at least 3-fold greater inhibition against EGFR 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, compounds of the disclosure in combination with a second active agent that prevents EGFR dimerization exhibit at least 5-fold greater inhibition against EGFR 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, compounds of the disclosure in combination with a second active agent that prevents EGFR dimerization exhibit at least 10-fold greater inhibition against EGFR 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, compounds of the disclosure in combination with a second active agent that prevents EGFR dimerization exhibit at least 25-fold greater inhibition against EGFR 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, compounds of the disclosure in combination with a second active agent that prevents EGFR dimerization exhibit at least 50-fold greater inhibition against EGFR 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, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization show at least 100-fold greater inhibition against EGFR 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 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 certain embodiments, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0127] In some embodiments, the inhibition of activity of EGFR is 50 It is measured by.

[0128] In some embodiments, inhibition of EGFR activity is 50 It is measured by.

[0129] In some embodiments, the inhibition of EGFR by the disclosed compounds can be measured by biochemical assays. By way of illustrative and non-limiting example, homogenous time-resolved fluorescence (HTRF) assays can be used to determine the inhibition of EGFR activity using the conditions and experimental parameters disclosed herein. HTRF assays can employ, 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. Disclosed compounds screened under these conditions have an IC 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 In certain embodiments, the disclosed compounds screened under the above conditions for inhibition of EGFR having a mutation or combination of mutations selected from L858R / T790M, L858R and T790M exhibit IC values ​​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 Indicates the value.

[0130] In some embodiments, the compounds of the present disclosure bind to an allosteric site in EGFR. In some embodiments, the compounds of the present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Lys745, Leu788, and Ala743. In other embodiments, the compounds of the present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Cys755, Leu777, Phe856, and Asp855. In other embodiments, the compounds of the present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Met766, Ile759, Glu762, and Ala763. In other embodiments, the compounds of the present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Lys745, Leu788, and Ala743; at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Cys755, Leu777, Phe856, and Asp855; and at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Met766, Ile759, Glu762, and Ala763. In other embodiments, the compounds of the present disclosure do not interact with any amino acid residue of epidermal growth factor receptor (EGFR) selected from Met793, Gly796, and Cys797.

[0131] In some embodiments, the present disclosure provides compounds that include allosteric kinase inhibitors, which are more potent inhibitors of drug-resistant EGFR mutants than wild-type EGFR. For example, the compounds can 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.

[0132] In some embodiments, drug-resistant EGFR mutations include sensitizing mutations such as Del and L858R.

[0133] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor in combination with a second active agent that prevents EGFR dimerization, the compound being a more potent inhibitor of drug-resistant EGFR mutants than wild-type EGFR. For example, the 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 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. In some embodiments, the drug-resistant EGFR mutants include sensitizing mutations such as Del and L858R. 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 an embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0134] In some embodiments, the disclosure provides compounds, including allosteric kinase inhibitors, that are capable of increasing the kinase activity of drug-resistant EGFR mutants that carry sensitizing mutations (e.g., Del and L858R) and drug-resistance mutations (e.g., T790M, L718Q, C797S, and L844V) by potency (e.g., IC 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.

[0135] In other embodiments, the disclosure provides compounds comprising an allosteric kinase inhibitor in combination with a second active agent that prevents EGFR dimerization, and that increase the kinase activity of drug-resistant EGFR mutants that carry sensitizing mutations (e.g., Del and L858R) and drug-resistance mutations (e.g., T790M, L718Q, C797S, and L844V) compared to EGFR mutants that carry sensitizing mutations but do not carry drug-resistance mutations, by increasing potency (e.g., IC 50 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 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 some embodiments, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0136] In some embodiments, the disclosure provides compounds, including allosteric kinase inhibitors, that are more potent in inhibiting the activity of EGFR containing one or more mutations described herein, e.g., 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, the compounds are at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent (e.g., IC 30-fold, IC 31-fold, IC 32-fold, IC 33-fold, IC 34-fold, IC 35-fold, IC 36-fold, IC 37-fold, IC 38-fold, IC 39 ... 50 (measured by

[0137] In other embodiments, the disclosure provides compounds comprising an allosteric kinase inhibitor in combination with a second active agent that prevents EGFR dimerization, the compounds in combination with the second active agent being more potent in inhibiting the activity of EGFR containing one or more of the mutations described herein, e.g., 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, the compounds in combination with a second active agent that prevents EGFR dimerization are at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent (e.g., IC 50In 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 certain embodiments, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0138] In some embodiments, the disclosure provides compounds, including allosteric kinase inhibitors, that are less potent in inhibiting wild-type EGFR activity 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 at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold less potent (e.g., IC50-100) in inhibiting wild-type EGFR activity than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib. 50 (measured by

[0139] In other embodiments, the disclosure provides compounds comprising an allosteric kinase inhibitor in combination with a second active agent that prevents EGFR dimerization, the compounds in combination with the second active agent being less potent in inhibiting wild-type EGFR activity 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 in combination with a second active agent that prevents EGFR dimerization are at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold less potent (e.g., IC 50In 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 certain embodiments, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0140] The potency of the inhibitors was determined by the EC 50 The EC value determined under substantially similar conditions can be used to determine the 50 Compounds with low values ​​have EC 50 A compound having a higher phosphorylation level is a more potent inhibitor than a compound having a higher phosphorylation level. In some embodiments, substantially similar conditions include determining the level of EGFR-dependent phosphorylation in vitro or in vivo (e.g., in 3T3 cells expressing wild-type EGFR, mutant EGFR, or any fragment thereof).

[0141] The potency of the inhibitor is expressed as IC 50 It can also be determined by IC values ​​determined under substantially similar conditions. 50 Compounds with low IC 50 A compound having a higher phosphorylation level is a more potent inhibitor than a compound having a higher phosphorylation level. In some embodiments, substantially similar conditions include determining the level of EGFR-dependent phosphorylation in vitro or in vivo (e.g., in 3T3 cells expressing wild-type EGFR, mutant EGFR, or any fragment thereof).

[0142] EGFR sensitizing mutations include, but are not limited to, L858R, G719S, G719C, G719A, L861Q, a deletion in exon 19 and / or an insertion in exon 20. Drug-resistant EGFR mutants may have drug-resistant mutations including, but are not limited to, T790M, T854A, L718Q, C797S, or D761Y.

[0143] The selectivity between wild-type EGFR and EGFR containing one or more mutations described herein can also be measured using a cell proliferation assay in which cell proliferation depends on kinase activity. For example, mouse Ba / F3 cells transfected with a suitable version of wild-type EGFR (e.g., 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 the EC 50 is calculated.

[0144] An alternative method to measure the effect on EGFR activity is to assay the phosphorylation of EGFR. 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 to inhibit EGFR phosphorylation can be assayed (using the concentrations listed above). Cells are exposed to increasing concentrations of inhibitor for 6 hours and stimulated with EGF for 10 minutes. The effect on EGFR phosphorylation is assayed by Western blot using a phosphorylation site (Y1068) specific EGFR antibody.

[0145] In another aspect, the disclosure relates to compounds that bind to an allosteric site within EGFR and 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.

[0146] In other embodiments, the disclosure provides compounds that bind to an allosteric site in EGFR in combination with a second active agent that prevents EGFR dimerization, and that 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, 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 an embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0147] In yet another aspect, the disclosure provides a method of inhibiting epidermal growth factor receptor (EGFR), comprising administering an effective amount of a compound disclosed herein or a pharma- ceutically acceptable salt thereof to a subject in need thereof. In some embodiments, the method further comprises administering 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 some embodiments, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0148] In another aspect, provided herein is a method for treating or preventing a disease, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the disease is kinase-mediated. 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 Cys797 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 that 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 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.

[0149] In some embodiments, the disease is EGFR-mediated (e.g., EGFR contributes to the initiation or development of the disease). In some embodiments, the disease is Her-kinase-mediated. In further embodiments, the Her-kinase is HER1, HER2, or HER4.

[0150] In certain embodiments, the disease is resistant to known EGFR inhibitors, including but not limited to gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002. In certain embodiments, diagnostic tests are performed to determine whether the disease is associated with an activating mutation in EGFR. In certain embodiments, diagnostic tests are performed to determine whether the disease is associated with EGFR carrying an activating mutation and / or a drug-resistant mutation. Activating mutations include, but are not limited to, L858R, G719S, G719C, G719A, L718Q, L861Q, a deletion in exon 19, and / or an insertion in exon 20. Drug-resistant EGFR mutants may have drug-resistant mutations, including but not limited to, T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests may include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those skilled in the art capable of detecting nucleotide sequences.

[0151] In certain embodiments, the disease is cancer or a proliferative disease.

[0152] In further embodiments, the disease is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, squamous cell carcinoma of the head and neck, 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.

[0153] In certain embodiments, the disease is resistant to known EGFR inhibitors, including but not limited to gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002. In certain embodiments, diagnostic tests are performed to determine whether the disease is associated with an activating mutation in EGFR. In certain embodiments, diagnostic tests are performed to determine whether the disease is associated with EGFR carrying an activating mutation and / or a drug-resistant mutation. Activating mutations include, but are not limited to, L858R, G719S, G719C, G719A, L718Q, L861Q, a deletion in exon 19, and / or an insertion in exon 20. Drug-resistant EGFR mutants may have drug-resistant mutations, including but not limited to, T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests may include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those skilled in the art capable of detecting nucleotide sequences.

[0154] In yet another aspect, provided herein is a method for treating a kinase-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is an inhibitor of HER1, HER2, or HER4. In other embodiments, an additional therapeutic agent is administered to the subject. In other embodiments, the compound and the additional therapeutic agent are administered simultaneously or sequentially.

[0155] 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 pharma- ceutically acceptable salt thereof and a second active agent that prevents EGFR dimerization. In some embodiments, the compound is an inhibitor of HER1, HER2, or HER4. In other embodiments, an additional therapeutic agent is administered to the subject. In other embodiments, the compound, the second active agent that prevents EGFR 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 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 some embodiments, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0156] In other embodiments, the disease is cancer. In further embodiments, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, squamous cell carcinoma of the head and neck, 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.

[0157] In another aspect, provided herein is a method of treating cancer in which the cancer cells contain activated EGFR, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0158] In another aspect, provided herein is a method of treating cancer in which the cancer cells contain activated EGFR, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharma- ceutically 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 some embodiments, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0159] In certain embodiments, EGFR activation is selected from EGFR mutation, EGFR amplification, EGFR expression, and a ligand that mediates EGFR activation.

[0160] 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.

[0161] In yet another aspect, provided herein is a method of treating cancer in a subject identified as in need of inhibition of EGFR for the treatment of cancer, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0162] In certain embodiments, the subject identified as needing inhibition of EGFR is resistant to known EGFR inhibitors, including but not limited to gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002. In certain embodiments, a diagnostic test is performed to determine whether the subject has an activating mutation in EGFR. In certain embodiments, a diagnostic test is performed to determine whether the subject has an EGFR carrying an activating mutation and / or a drug-resistant mutation. Activating mutations include, but are not limited to, L858R, G719S, G719C, G719A, L718Q, L861Q, a deletion in exon 19, and / or an insertion in exon 20. Drug-resistant EGFR mutants may have drug-resistant mutations, including, but not limited to, T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests may include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those skilled in the art capable of detecting nucleotide sequences.

[0163] In one aspect, provided herein is a method of preventing resistance in a subject to a known EGFR inhibitor (including but not limited to gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002), comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0164] In another aspect, provided herein is a method of preventing resistance in a disease to known EGFR inhibitors (including but not limited to gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002), comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharma- ceutically 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.

[0165] In certain embodiments of the methods disclosed herein, the subject is a human.

[0166] In another aspect, the disclosure provides a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment or prevention of a disease in which EGFR plays a contributing role.

[0167] In certain aspects, provided herein are methods of treating or preventing a condition selected from the group consisting of autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immune-mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone-related diseases, allergies, asthma, and Alzheimer's disease, hi other embodiments, the condition is selected from proliferative disorders and neurodegenerative disorders.

[0168] One aspect of the present disclosure provides compounds useful for the treatment of diseases, disorders and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, proliferative or hyperproliferative diseases and neurodegenerative diseases. Examples of proliferative and hyperproliferative diseases include, but are not limited to, cancer. The term "cancer" includes, but is not limited to, the following cancers: breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, colorectal cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, bone marrow disorders, lymphatic system disorders, Hodgkin's disease, hairy cell, buccal and pharyngeal (oral) cancer, lip cancer, tongue cancer, mouth cancer, pharyngeal cancer, small intestine cancer, colon cancer, rectal cancer, large intestine cancer, rectal cancer, brain cancer and central nervous system cancer, chronic myeloid leukemia (CML), and leukemia. The term "cancer" includes, but is not limited to, the following cancers: myeloma, lymphoma, or a cancer selected from gastric cancer, renal cancer, head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, hepatocellular carcinoma, non-Hodgkin's lymphoma, and lung cancer.

[0169] The term "cancer" refers to any cancer resulting from the proliferation of malignant new cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, and the like. For example, cancers include, but are not limited to, mesothelioma, leukemias and lymphomas, such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphomas associated with human T-cell lymphotropic virus (HTLV) such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphoma, and multiple myeloma, non-Hodgkin's lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndromes, pediatric solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcomas, solid tumors common in adults 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's syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer. Further exemplary forms of cancer that may be treated by the subject compounds include, but are not limited to, skeletal or smooth muscle cancer, gastric cancer, cancer of the small intestine, rectal cancer, cancer of the salivary glands, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0170] Further cancers in which the compounds described herein may be useful in the prevention, treatment and study are, for example, colon cancer, familial polyposis coli cancer and hereditary non-polyposis colorectal cancer, or melanoma. Further, cancer includes, but is not limited to, carcinoma of the labia, larynx, hypopharynx, tongue, salivary gland, stomach, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, gallbladder cancer, bronchial carcinoma, multiple myeloma, basal cell tumor, 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 the use of one or more compounds of the present disclosure in the manufacture of a medicament for the treatment of cancer, including, but not limited to, the various types of cancer disclosed herein.

[0171] In some embodiments, the compounds of the present disclosure are useful for the treatment of cancer, such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer, as well as myeloproliferative disorders, such as polycythemia vera, thrombocythemia, myelofibrosis-associated myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis. In some embodiments, the compounds of the present disclosure are useful for the treatment of hematopoietic disorders, specifically acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute promyelocytic leukemia, and acute lymphocytic leukemia (ALL).

[0172] As provided herein, the term "cancerous cell" includes a cell damaged by any one of the above-identified conditions.

[0173] The present disclosure further provides a method for treating or preventing cell proliferation disorders such as hyperplasia, dysplasia, and precancerous lesions. Metaplasia is the earliest form of precancerous lesion that is recognizable in a biopsy by a pathologist. The subject compounds may be administered for the purpose of preventing said hyperplasia, dysplasia, or precancerous lesion from continuing to expand or becoming cancerous. Examples of precancerous lesions may occur in tissues of the skin, esophagus, breast, and cervical intraepithelium.

[0174] Examples of neurodegenerative diseases include adrenoleukodystrophy (ALD), Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, fatal familial insomnia, frontotemporal lobar degeneration, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, dementia with Lewy bodies, neuroborreliosis, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple system atrophy, multiple sclerosis, narcolepsy, Niemann-Pick disease, Parkinson's disease, Pelizaeus disease, and others. These include, but are not limited to, Merzbach disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, Spielmeyer-Vogt-Sjogren-Batten disease (also known as Batten disease), spinocerebellar ataxias (several types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, spinal fistula, and toxic encephalopathy.

[0175] Another aspect of the 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 pharma- ceutically acceptable composition comprising the compound. In other embodiments, the method further comprises administering 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 some embodiments, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0176] 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 the inhibition of either the kinase activity or the ATPase activity of the activated kinase. An alternative in vitro assay quantifies the ability of an inhibitor to bind to a protein kinase, which can be measured either by radiolabeling the inhibitor before binding and separating the inhibitor / kinase complex to determine the amount of radiolabel bound, or by performing a competition experiment in which a new inhibitor is incubated with a kinase bound to a known radioligand. Detailed conditions for assaying the compounds utilized in the present disclosure as inhibitors of various kinases are set forth in the Examples below.

[0177] In accordance with the above, the present disclosure further provides a method for preventing or treating any of the above diseases or disorders in a subject in need of such treatment, comprising administering to said subject a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, and optionally a second active agent that prevents EGFR dimerization.For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated, and the desired effect.

[0178] In other embodiments, the compound and the second active agent that prevents EGFR dimerization are administered simultaneously or sequentially.

[0179] Administration / Dosage / Formulation Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active compounds, liquid dosage forms may 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 may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and aromatics.

[0180] 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, such as, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, USP and isotonic saline. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0181] In order to prolong the effect of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material that is poorly soluble in water. In this case, the rate of absorption of the drug depends on its rate of dissolution, which may depend on the size and crystalline form of the crystals. Alternatively, delayed absorption of a parenterally administered drug form can be accomplished by dissolving or suspending the drug in an oil vehicle.

[0182] 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 room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity to liberate the active compound.

[0183] 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.

[0184] The active compound may also be in microencapsulated form with one or more of the above-mentioned excipients. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings and other coatings known in the pharmaceutical formulation art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose or starch. 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, as is common practice. In the case of capsules, tablets and pills, the dosage forms can also contain buffering agents.

[0185] The 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 pharma- ceutically acceptable carrier and any necessary preservatives or buffers as required.Ophthalmic preparations, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of the present disclosure.

[0186] The ointments, pastes, creams and gels may contain, in addition to the active compounds of this disclosure, excipients such as animal or vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0187] 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 further contain customary propellants such as chlorofluorohydrocarbons.

[0188] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable 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.

[0189] According to the treatment method of the present disclosure, a disorder is treated or prevented in a subject, such as a human or other animal, by administering to the subject a therapeutically effective amount of a compound of the present disclosure in an amount and for a 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 arts, a therapeutically effective amount of a compound of the present disclosure will have a reasonable benefit / risk ratio applicable to any medical treatment.

[0190] 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, by any conventional and accepted manner known in the art. The therapeutically effective amount can vary widely, depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. In general, good results have been shown to be obtained systemically at a daily dosage of about 0.03 to 2.5 mg / kg of body weight. Indicated daily dosages in larger mammals, such as humans, range from about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses up to four times a day, or in retard form. A suitable unit dosage form for oral administration contains about 1 to 50 mg of active ingredient.

[0191] In certain embodiments, the therapeutic amount or dose of the disclosed compound may range from about 0.1 mg / Kg to about 500 mg / Kg, or from about 1 to about 50 mg / Kg. In general, treatment regimens according to the present disclosure include administration of about 10 mg to about 1000 mg of the disclosed compound per day in a single dose or multiple doses to a patient in need of such treatment. The therapeutic amount or dose will also vary depending on the route of administration and possible co-administration with other drugs.

[0192] When the subject's condition improves, a maintenance dose of the disclosed compound, composition or combination can be administered if necessary. Thereafter, the dose or frequency of administration, or both, should be reduced as a function of symptoms to a level at which the improved condition is maintained, and treatment should be terminated when symptoms have been alleviated to a desired level. However, subjects may require intermittent treatment on a long-term basis upon the recurrence of any disease symptoms.

[0193] However, it will be understood that the total daily usage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment.The specific inhibitory dose for any particular patient will depend on various factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, weight, general health, sex and diet of the patient; the timing, route of administration and excretion rate of the specific compound employed; the duration of treatment; drugs used in combination or simultaneously with the specific compound employed; and similar factors known in the medical field.

[0194] The present disclosure also provides a combination pharmaceutical, such as a kit, comprising a) a first agent that is a compound disclosed herein in free form or in pharma- ceutical acceptable salt form, and b) at least one co-medicinal agent. The kit may include instructions for administration thereof.

[0195] In certain embodiments, these compositions may optionally further comprise one or more additional therapeutic agents. For example, agents that prevent EGFR dimerization, chemotherapeutic agents, or other anti-proliferative agents may be combined with the compounds of the present disclosure to treat proliferative diseases and cancer.

[0196] Some examples of materials which may serve as pharma- ceutically acceptable carriers include ion exchangers; alumina; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffer substances such as phosphate, 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; lactose, glucose, and sucrose; corn starch and potatoes. Examples of suitable cellulose derivatives include, but are not limited to, starches such as moderxch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solutions. In addition, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants, as well as non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, can be present in the composition at 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, which comprise an amount of the protein inhibitor effective to treat or prevent a protein kinase-mediated condition, and a pharma- ceutically acceptable carrier, are other embodiments of the present disclosure.

[0197] kit In certain aspects, provided herein is a kit comprising a compound capable of inhibiting kinase activity, selected from one or more compounds disclosed herein, or a pharma- ceutically acceptable salt thereof, and instructions for use in the treatment of cancer. In certain embodiments, the kit further comprises components for performing a test to determine whether a subject has an activating and / or drug resistance mutation in EGFR.

[0198] In another aspect, the disclosure provides a kit comprising a compound capable of inhibiting EGFR activity selected from the compounds disclosed herein or a pharma- ceutically acceptable salt thereof.

[0199] 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 pharma- ceutically 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 further embodiments, the second active agent that prevents EGFR dimerization is cetuximab.

[0200] 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 pharma- ceutically 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 some embodiments, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib. EXAMPLES

[0201] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate specific embodiments, and no limitations are intended thereby on the scope of the present disclosure. It should also be further understood that resort may be made to various other embodiments, modifications, and their equivalents, which may suggest themselves to those skilled in the art, without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0202] Abbreviation AC Acetonitrile AcOH Acetic acid DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DIEA / DIPEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Et2O Diethyl ether EtOAc Ethyl acetate HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate Hex Hexanes HOBt Hydroxybenzotriazole MeOH Methanol OAc Acetate TFA Trifluoroacetic acid THF Tetrahydrofuran

[0203] Example 1 Preparation of Compounds of Formula I and Intermediates Compound 001 was prepared according to the reaction protocol in Scheme 1. Scheme 1

[0204] [ka]

[0205] 2-(7-Bromo-4-oxoquinazolin-3(4H)-yl)-2-phenylacetic acid methyl ester 1

[0206] [ka]

[0207] A mixture of 7-bromoquinazolin-4(3H)-one (1.0 g, 4.44 mmol), methyl 2-bromo-2-phenylacetate (0.92 mL, 4.67 mmol) and cesium carbonate (2.9 g, 8.89 mmol) in DMF (3 mL) was heated to 50° C. After 2 h and another 1 h, an additional portion of methyl 2-bromo-2-phenylacetate (0.10 mL, 0.51 mmol) was added and the mixture was stirred for another 30 min. The reaction mixture was added to water and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and the residue was purified by silica chromatography (0-35% EtOAc in Hex) to give the title compound as a white solid (1.09 g, 66%). 1H NMR (500 MHz, CDCl3-d) δ 8.19 (d, 1H) 7.89 (s, 1H) 7.88 (d, 1H) 7.63 (dd, 1H) 7.47 (m, 3H) 7.38 (m, 2H) 6.74 (s, 1H) 3.88 (s, 3H); MS (m / z): 375.0 [M+1] + . 2-(7-Bromo-4-oxoquinazolin-3(4H)-yl)-2-phenylacetic acid (acid 1)

[0208] [ka]

[0209] A mixture of methyl 2-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-phenylacetate (1.09 g, 2.9 mmol) and lithium hydroxide (1.2 g, 29 mmol) in THF (4 mL), MeOH (4 mL) and water (4 mL) was stirred for 20 min. The organic solvent was removed under reduced pressure, water was added and the solution was acidified with 6N HCl. The resulting precipitate was filtered and dried in vacuo to give the title compound as a white solid (0.28 g, 27%). 1 H NMR (500 MHz, d6-DMSO) δ 8.19 (s, 1H) 8.09 (d, 1H) 7.84 (d, 1H) 7.68 (dd, 1H) 7.38 (m, 2H) 7.33 (m, 2H) 7.27 (m, 1H) 6.30 (s, 1H); MS (m / z): 358.9 [M+1] + . Compound 001: 2-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-phenyl-N-(thiazol-2-yl)acetamide

[0210] [ka]

[0211] To a mixture of 2-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-phenylacetic acid (0.28 g, 0.78 mmol) and HATU (0.59 g, 1.6 mmol) in DMF (3 mL) was added diisopropylethylamine (0.68 mL, 3.9 mmol). The reaction mixture was stirred at 60° C. for 2 h and then poured into water. The mixture was extracted with EtOAc, the organic phase was washed with brine, dried (MgSO4), filtered and the residue was purified by silica chromatography (0-50% EtOAc in Hex) to give the title compound as a white solid (198 mg, 58%). 1 H NMR (500 MHz, d6-DMSO) δ 8.11 (d, 1H) 7.94 (d, 1H) 7.87 (s, 1H) 7.77 (dd, 1H) 7.51 (m, 4H) 7.44 (m, 2H) 7.32 (d, 1H) 6.84 (s, 1H); MS (m / z): 442.9 [M+1] + .

[0212] The following compounds in Table 2 were prepared from the corresponding carboxylic acid and 2-aminothiazole or 2-aminopyridine by a method similar to compound 001.

[0213] [Table 3A]

[0214] [Table 3B]

[0215] [Table 3C]

[0216] [Table 3D]

[0217] The following compounds in Table 3 were prepared from the corresponding carboxylic acid and 2-aminothiazole or 2-aminopyridine in a manner similar to compound 001.

[0218] [Table 4A]

[0219] [Table 4B]

[0220] The following esters in Table 4 were prepared by a method similar to ester 1 from the corresponding starting material and methyl 2-bromo-2-phenylacetate or methyl 2-amino-2-(3-fluorophenyl)acetate.

[0221] [Table 5A]

[0222] [Table 5B]

[0223] [Table 5C]

[0224] [Table 5D]

[0225] [Table 5E]

[0226] Scheme 2

[0227] [ka]

[0228] 3-Bromo-2-fluoro-N-hydroxybenzamide

[0229] [ka]

[0230] A suspension of 3-bromo-2-fluorobenzoic acid (1 g, 4.6 mmol) in DCM (15 mL) at 0° C. was treated with oxalyl chloride (474 ​​μL, 5.5 mmol) dropwise over 2 min. DMF (2 drops) was added and the reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure to give crude 3-bromo-2-fluorobenzoyl chloride, which was used immediately without further purification.

[0231] To a vigorously stirred suspension of EtOAc (36 mL), water (18 mL) and K2CO3 (1.27 g, 9.2 mmol) was added dropwise a solution of crude 3-bromo-2-fluorobenzoyl chloride in EtOAc (10 mL) at 0 °C. The reaction mixture was stirred overnight at room temperature. The phases were separated and the aqueous phase was extracted with EtOAc (2x30 mL). The combined organic extracts were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (700 mg, 65%). 1 H NMR (500 MHz, d6-DMSO) δ 11.10 (s, 1H) 9.33 (s, 1H) 7.83 (m, 1H) 7.53 (m, 1H) 7.24 (m, 1H). 3-Bromo-2-fluoro-N-(pivaloyloxy)benzamide

[0232] [ka]

[0233] To a solution of 3-bromo-2-fluoro-N-hydroxybenzamide (700 mg, 3.0 mmol) and DIEA (572 μL, 3.3 mmol) in anhydrous THF (9 mL) was added pivaloyl chloride (407 μL, 3.3 mmol) dropwise. The reaction mixture was stirred for 1 h and then concentrated under reduced pressure. The residue was dissolved in EtOAc (15 mL), washed with 1N HCl (15 mL) and saturated brine (15 mL), dried over Na2SO4, filtered, and purified by silica chromatography (0-65% EtOAc / hexanes) to give the title compound (850 mg, 89%). 1 H NMR (500 MHz, d6-DMSO) δ 7.93 (m, 1H) 7.64 (m, 1H) 7.30 (m, 1H) 1.29 (s, 9H). 7-Bromo-8-fluoroisoquinolin-1(2H)-one

[0234] [ka]

[0235] A mixture of 3-bromo-2-fluoro-N-(pivaloyloxy)benzamide (318 mg, 1.0 mmol), penta-methylcyclopentadienyl rhodium dichloride (6 mg, 0.01 mmol), Cs(OAc) (58 mg, 0.3 mmol), vinyl acetate (131 μL, 1.5 mmol) and methanol (8 mL) was stirred at 45° C. overnight under N2. An additional aliquot of pentamethylcyclopentadienyl rhodium dichloride (6 mg, 0.01 mmol) and vinyl acetate (131 μL, 1.5 mmol) was added and the reaction was stirred at 45° C. for an additional 48 h. The solvent was removed under reduced pressure and the residue was triturated with 10 mL of 10% MeOH in Et2O. The solid was collected and purified by reverse phase HPLC eluting with 0-80% ACN / H2O (0.038% TFA modifier) ​​to give the title compound (116 mg, 48%). 1H NMR (500 MHz, d6-DMSO) δ 11.41 (br s, 1H) 7.93 (dd, 1H) 7.45 (d, 1H) 7.24 (d, 1H) 6.56 (dd, 1H). 2-Amino-2-(3-fluorophenyl)acetic acid methyl ester

[0236] [ka]

[0237] To a mixture of 2-amino-2-(3-fluorophenyl)acetic acid (6.0 g, 0.035 mol) in methanol (100 mL) was added thionyl chloride (7.72 mL, 0.106 mol) dropwise at 0° C. The reaction was stirred at room temperature for 30 min and then at 60° C. for 16 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (150 mL). The organic phase was washed with saturated brine and saturated NaHCO3, dried (Na2SO4) and concentrated to give the title compound, which was used without further purification (6.49 g). 1 H NMR (500 MHz, d6-DMSO) δ 7.35 (m, 1H) 7.20 (d, 1H) 7.15 (d, 1H) 7.03 (m, 1H) 3.74 (s, 3H). Ester 19: 2-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(3-fluorophenyl)acetate methyl

[0238] [ka]

[0239] To a mixture of 7-bromoquinazolin-4(3H)-one (1.00 g, 4.44 mmol) and methyl 2-amino-2-(3-fluorophenyl)acetate (977 mg, 5.33 mmol) in CH3CN (20 mL) was added DBU (1.00 mL, 6.66 mmol) and HATU (2.53 g, 6.66 mmol) and the reaction was stirred at 60 °C for 18 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated NH4Cl solution. The organic phase was dried (Na2SO4) and the residue was purified by silica chromatography (0-5% MeOH in DCM) to give the title compound (517 mg, 30%). 1 H NMR (500 MHz, d6-DMSO) δ 8.37 (s, 1H) 8.10 (d, 1H) 7.95 (d, 1H) 7.77 (dd, 1H) 7.47 (m, 1H) 7.43 (m, 1H) 7.36 (d, 1H) 7.28 (m, 1H) 6.59 (s, 1H); MS (m / z): 392.97 [M+1] + .

[0240] Esters 20, C and D in Table 5 were prepared in a similar manner to ester 19 from 6-bromoquinazolin-4(3H)-one and methyl 2-amino-2-(3-fluorophenyl)acetate.

[0241] [Table 6]

[0242] 7-Bromo-2-methyl-4H-benzo[d][1,3]oxazin-4-one

[0243] [ka]

[0244] A mixture of 2-amino-4-bromobenzoic acid (1.50 g, 6.94 mmol) and acetic anhydride (10 mL, 106 mmol) was heated to reflux for 3 h. The reaction mixture was cooled and the resulting solid was filtered, washed with 2 mL of acetic anhydride, and dried to give the title compound (750 mg, 45%). 7-Bromo-2-methylquinazolin-4(3H)-one

[0245] [ka]

[0246] A mixture of 7-bromo-2-methyl-4H-benzo[d][1,3]oxazin-4-one (500 mg, 2.09 mmol) and 30% aqueous ammonia (6 mL) was heated in a sealed pressure tube at 80° C. for 2 h. After cooling to room temperature, the solid was filtered, washed with water, and dried to give the title compound (240 mg, 47%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.98 (d, 1H) 7.78 (d, 1H) 7.62 (m, 1H) 2.36 (s, 3H); MS (m / z): 238.9 [M+1] + .

[0247] Scheme 3

[0248] [ka]

[0249] 4-Bromo-5-fluoro-2-nitrobenzoic acid

[0250] [ka]

[0251] To a solution of 4-bromo-3-fluorobenzoic acid (20.0 g, 91 mmol) in concentrated sulfuric acid (70 mL) was added potassium nitrate (9.69 g, 96 mmol) in small portions. The reaction solution was stirred for 3 hours and then carefully poured into 250 mL of crushed ice. The mixture was stirred for 10 minutes, filtered, washed with water, and dried to give the title compound (21 g, 87%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.51 (d, 1 H) 7.90 (m, 1 H). 2-Amino-4-bromo-5-fluorobenzoic acid

[0252] [ka]

[0253] To a suspension of 4-bromo-5-fluoro-2-nitrobenzoic acid (9.4 g, 35.6 mmol) in 6N HCl (140 mL) was added stannous chloride dihydrate (24 g, 107 mmol). The mixture was stirred at 100° C. for 3 h and then cooled. The resulting solid was filtered, washed with water, and dried to give the title compound (7.68 g, 92%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.50 (d, 1H) 7.09 (d, 1H); MS (m / z): 233.9 [M+1] + . 7-Bromo-6-fluoroquinazolin-4(3H)-one

[0254] [ka]

[0255] A mixture of 2-amino-4-bromo-5-fluorobenzoic acid (4.6 g, 20 mmol) and formamide (23 mL) was heated at 160° C. for 6 h under nitrogen. The mixture was cooled and poured into about 200 mL of ice water. The solid was filtered, washed with water, and dried to give the title compound (3.44 g, 71%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.12 (d, 1 H) 8.06 (d, 1 H) 7.91 (d, 1 H); MS (m / z): 242.9 [M+1] + . 6-Bromo-5-fluoroquinazolin-4(3H)-one

[0256] [ka]

[0257] A mixture of 6-amino-3-bromo-2-fluorobenzoic acid (500 mg, 2.1 mmol) and formamide (10 mL) was heated at 160° C. for 8 h. After cooling, the reaction mixture was added to 100 mL of water. The solid was filtered, washed with water, and dried to give the title compound (250 mg, 48%). 1 H NMR (500 MHz, CDCl3-d) δ ppm 8.05 (s, 1H) 7.93 (dd, 1H) 7.49 (dd, 1H). MS (m / z): 242.9 [M+1] + . 6-Bromo-4-fluoroisoquinolin-1(2H)-one

[0258] [ka]

[0259] A mixture of 6-bromoisoquinolin-1(2H)-one (365 mg, 1.63 mmol), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)[Selectfluor] (576 mg, 1.63 mmol) and dimethylacetamide (3.5 mL) was heated in a microwave for 15 min at 150 °C. This was repeated three more times. The four runs were combined and partitioned between EtOAc (100 mL) and water (100 mL). The aqueous phase was extracted with EtOAc (2x100 mL) and the combined organic extracts were washed with brine, dried (Na2SO4), concentrated and the residue was purified by silica chromatography (0-50% EtOAc in Hex) to give the title compound (230 mg, 25%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.30 (br s, 1 H) 8.12 (dd, 1 H) 7.91 (d, 1 H) 7.78 (dd, 1 H) 7.47 (m, 1 H); MS (m / z): 241.9 [M+1] + . 7-Bromo-4-fluoroisoquinolin-1(2H)-one

[0260] [ka]

[0261] 7-Bromo-4-fluoroisoquinolin-1(2H)-one was prepared from 7-bromoisoquinolin-1(2H)-one following a procedure similar to that for 6-bromo-4-fluoroisoquinolin-1(2H)-one. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.30 (m, 1H) 8.01 (m, 1H) 7.71 (d, 1H) 7.46 (d, 1H). 3,6-Dibromoisobenzofuran-1(3H)-one

[0262] [ka]

[0263] A mixture of 6-bromoisobenzofuran-1(3H)-one (1.0 g, 4.69 mmol), N-bromosuccinimide (958 mg, 5.38 mmol) and chloroform (25 mL) was heated to reflux for 2.5 h. After cooling, the reaction was quenched with saturated aqueous NaHCO3 (25 mL). The organic phase was washed with water and brine, dried (Na2SO4), concentrated and the residue was purified by silica chromatography (5-10% EtOAc in Hex) to give the title compound (350 mg, 26%). 1 H NMR (500 MHz, CDCl3-d) δ ppm 7.99 (d, 1H) 7.83 (m, 1H) 7.44 (d, 1H) 7.29 (s, 1H). 7-Bromophthalazin-1(2H)-one

[0264] [ka]

[0265] A mixture of 3,6-dibromoisobenzofuran-1(3H)-one (350 mg, 1.2 mmol) and hydroxylamine hydrate (300 μL, 6 mmol) in ethanol (15 mL) was heated to reflux for 1.5 h. After cooling to room temperature, 20 mL of ice water was added. The resulting precipitate was filtered, washed with water, and dried to give the title compound (250 mg, 93%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.40 (s, 1H) 8.32 (d, 1H) 8.13 (m, 1H) 7.92 (d, 1H); MS (m / z): 224.9 [M+1] + .

[0266] Acids 2-17, A and B in Table 6 were prepared from the corresponding methyl esters in a manner similar to that of acid 1.

[0267] [Table 7A]

[0268] [Table 7B]

[0269] [Table 7C]

[0270] [Table 7D]

[0271] Compound 012: 2-(7-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-phenyl-N-(thiazol-2-yl)acetamide

[0272] [ka]

[0273] A mixture of 2-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-phenyl-N-(thiazol-2-yl)acetamide (70 mg, 0.16 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-piperidine (72 mg, 0.24 mmol), Pd(dppf)Cl2.DCM (26 mg, 0.03 mmol) and sodium carbonate (50 mg, 0.48 mmol) in dioxane:water (4:1, 3.5 mL) was stirred at 100° C. for 3 h. The reaction mixture was filtered and purified by reverse phase HPLC eluting with 0-80% ACN / water to give the title compound (21 mg, 25%). 1H NMR (500 MHz, d6-DMSO) δ 9.39 (br s, 1H) 8.26 (d, 1H) 7.95 (d, 1H) 7.92 (dd, 1H) 7.87 (s, 1H) 7.83 (d, 2H) 7.52 (m, 4H) 7.45 (m, 2H) 7.40 (d, 2H) 7.32 (d, 1H) 6.89 (s, 1H) 3.54 (d, 2H) 3.10 (m, 2H) 2.88 (m, 1H) 2.83 (d, 3H) 2.07 (d, 2H) 1.86 (m, 2H); MS (m / z): 539.2 [M+1] + .

[0274] The following compounds were prepared from the corresponding starting materials in a similar manner to compound 012.

[0275] [Table 8A]

[0276] [Table 8B]

[0277] [Table 8C]

[0278] [Table 8D]

[0279] [Table 8E]

[0280] [Table 8F]

[0281] [Table 8G]

[0282] [Table 8H]

[0283] [Table 8I]

[0284] [Table 8J]

[0285] 2-(6-bromo-5-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(pyridin-2-yl)-N-(thiazol-2-yl)acetamide

[0286] [ka]

[0287] Step 1: A mixture of ethyl 2-(6-bromo-5-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(pyridin-2-yl)acetate (83 mg, 0.2 mmol), LiOH-HO (17 mg, 0.4 mmol), MeOH (2 mL) and water (0.5 mL) was stirred at room temperature for 30 min. The solvent was removed under reduced pressure and the residue was dried under vacuum at 60° C. overnight. This material was used in the next step without further purification.

[0288] Step 2: A mixture of the material from step 1, HOBt-HO (46 mg, 0.3 mmol), EDC (57 mg, 0.3 mmol), DIEA (52 μL, 0.3 mmol), 2-aminothiazole (20 mg, 0.2 mmol) and degassed DMF (3 mL) was stirred at room temperature for 1 h. HATU (116 mg, 0.3 mmol) was added and the reaction was continued for an additional 1.5 h. The reaction mixture was purified by reverse-phase HPLC eluting with 0-80% ACN / HO (0.038% TFA modifier) ​​to give the title compound (15 mg, 16%, 2 steps). 1 H NMR (500 MHz, d6-DMSO) δ 8.32 (dd, 1H) 8.19 (s, 1H) 8.14 (dd, 1H) 7.95 (m, 1H) 7.64 (d, 1H) 7.49 (m, 3H) 7.30 (d, 1H) 7.08 (s, 1H). Compound 040: 2-(6-(3-fluoro-4-(1-methylpiperidin-4-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-phenyl-N-(thiazol-2-yl)acetamide

[0289] Compound 040 was prepared according to the procedure in Scheme 4. Scheme 4

[0290] [ka]

[0291] 2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid ethyl ester

[0292] [ka]

[0293] A mixture of ethyl 2-amino-2-phenylacetate (1.0 g, 4.6 mmol), di-tert-butyl dicarbonate (1.2 g, 5.5 mmol), DCM (20 mL) and DIEA (0.8 mL, 4.6 mmol) was stirred at room temperature for 1 h. The reaction mixture was poured into ethyl acetate (100 mL) and washed with ice-cold 0.1 N HCl (40 mL), saturated Na2CO3 (40 mL), water (40 mL) and brine (40 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to give the title compound (1.3 g, 100%). 1 H NMR (500 MHz, CDCl3-d) δ ppm 9.04 (d, 1H) 8.79 (d, 1H) 8.16 (s, 1H) 7.48 (m, 1H) 7.19 (s, 2H) 7.11 (m, 1H) 4.39 (m, 2H) 1.57 (s, 9H) 1.35 (t, 3H). 2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid

[0294] [ka]

[0295] 2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid was prepared similarly to acid 1 from ethyl 2-((tert-butoxycarbonyl)amino)-2-phenylacetate (1.3 g, 4.7 mmol) to give 550 mg in 47% yield. tert-Butyl (2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)carbamate

[0296] [ka]

[0297] tert-Butyl (2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)carbamate was prepared similarly to Example 1 from 2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (550 mg, 2.2 mmol) to give 670 mg, 92% yield.1 H NMR (500 MHz, CDCl3-d) δ ppm 7.48 (d, 1H) 7.39 (m, 5H) 7.02 (d, 1H) 5.70 (br s, 1H) 5.48 (br s, 1H) 1.46 (s, 9H). 2-Amino-2-phenyl-N-(thiazol-2-yl)acetamide hydrochloride

[0298] [ka]

[0299] A solution of tert-butyl (2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)carbamate (670 mg, 2 mmol) in DCM (2.5 mL) and trifluoroacetic acid (2.5 mL) was stirred at room temperature for 15 minutes and then concentrated under reduced pressure. The residue was dissolved in DCM (25 mL) and treated with 4N HCl in dioxane (5 mL). The resulting precipitate was collected by filtration, washed with DCM, and dried to give the title compound, which was used without further purification. 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.03 (br s, 3H) 7.59 (dd, 2H) 7.46 (m, 4H) 7.31 (d, 1H) 5.25 (m, 1H). 7-Fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)quinazolin-4(3H)-one

[0300] [ka]

[0301] A mixture of 6-bromo-7-fluoroquinazolin-4(3H)-one (100 mg, 0.4 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (187 mg, 0.6 mmol), Pd(dppf)Cl2.DCM (67 mg, 0.08 mmol) and sodium carbonate (131 mg, 1.2 mmol) in dioxane:water (4:1, 4 mL) was degassed and backfilled with nitrogen three times. The mixture was heated at 100 °C for 3 h. After cooling, the reaction mixture was filtered, concentrated and the residue was purified by reverse phase HPLC eluting with 0-80% ACN / water (0.035% TFA modifier). The product was dissolved in ethyl acetate, washed with saturated Na2CO3 and saturated brine, dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (24 mg, 17%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.17 (d, 1H) 8.15 (s, 1H) 7.55 (m, 3H) 7.40 (d, 2H) 2.88 (d, 2H) 2.21 (s, 3H) 1.98 (m, 2H) 1.78 (m,2H) 1.70 (m, 2H) One proton is masked by the solvent peak. Compound 040: 2-(6-(3-fluoro-4-(1-methylpiperidin-4-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-phenyl-N-(thiazol-2-yl)acetamide

[0302] [ka]

[0303] Compound 040 was prepared similarly to ester 19 from 2-amino-2-phenyl-N-(thiazol-2-yl)acetamide hydrochloride and 7-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-quinazolin-4(3H)-one. 1H NMR (500 MHz, d6-DMSO) δ 9.37 (br s, 1H) 8.26 (d, 1H) 7.91 (s, 1H) 7.67 (d, 1H) 7.64 (d, 2H) 7.52 (m, 4H) 7.46 (m, 2H) 7.42 (d, MS (m / z): 554.2 [M+1] + . Preparation of compound 056: 2-(7-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxopyrido-[3,2-d]pyrimidin-3(4H)-yl)-2-phenyl-N-(thiazol-2-yl)acetamide

[0304] Compounds 056-060 were prepared by the following methods. Scheme 5 below shows an example of the synthesis of compound 056. Scheme 5

[0305] [ka]

[0306] Acid X: 2-(7-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-phenylacetic acid

[0307] [ka]

[0308] A mixture of methyl 2-(7-bromo-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-phenylacetate (100 mg, 0.27 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (88 mg, 0.29 mmol), Pd(dppf)Cl2.DCM (44 mg, 0.054 mmol) and sodium carbonate (85 mg, 0.81 mmol) in dioxane:water (4:1, 2 mL) was degassed and backfilled with nitrogen three times. The mixture was heated at 100 °C under nitrogen for 4 h. After cooling, the reaction mixture was filtered and purified by reverse phase HPLC eluting with 0-80% ACN / water (0.035% TFA modifier) ​​to give the title compound (70 mg, 57%). MS(m / z):454.9[M+1] + . Compound 056: 2-(7-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-phenyl-N-(thiazol-2-yl)acetamide

[0309] [ka]

[0310] A mixture of 2-(7-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-phenylacetic acid (70 mg, 0.15 mmol), thiazol-2-amine (23 mg, 0.23 mmol), HATU (117 mg, 0.31 mmol), DIEA (80 μL, 0.46 mmol) and degassed DMF (2 mL) was heated to 60° C. for 2.5 h. The reaction mixture was purified by reverse phase HPLC eluting with 0-80% ACN / water (0.035% TFA modifier) ​​to give the title compound (44 mg, 53%). 1H NMR (500 MHz, d6-DMSO) δ 9.55 (br s, 1H) 9.22 (d, 1H) 8.39 (d, 1H) 7.95 (s, 1H) 7.93 (d, 2H) 7.53 (m, 4H) 7.48 (m, 2H) 7.44 (d, 2H) 7.33 (d, 1H) 6.92 (s, 1H) 3.56 (d, 2H) 3.11 (m, 2H) 2.91 (m, 1H) 2.85 (d, 3H) 2.07 (d, 2H) 1.89 (m, 2H); MS (m / z): 537.4 [M+1] + .

[0311] The following compounds in Table 8 were prepared from the corresponding carboxylic acids and 2-aminothiazoles in a manner similar to compound 056.

[0312] [Table 9A]

[0313] [Table 9B]

[0314] [Table 9C]

[0315] [Table 9D]

[0316] [Table 9E]

[0317] Acids 18-21 and C-O in Table 9 were prepared from the corresponding starting materials by methods similar to acid X.

[0318] [Table 10A]

[0319] [Table 10B]

[0320] [Table 10C]

[0321] [Table 10D]

[0322] [Table 10E]

[0323] Scheme 6

[0324] [ka]

[0325] 3-Amino-6-bromopicolinic acid methyl ester

[0326] [ka]

[0327] c. To a suspension of methyl 3-aminopicolinate (652 mg, 4.27 mmol) in 13 mL of water containing H2SO4 (207 μL, 4.0 mmol) was added a solution of bromine (220 μL, 4.27 mmol) in AcOH (800 μL) dropwise over 1 min. The reaction mixture was stirred for 15 min and then basified to pH 6 with 10 N NaOH. The reaction mixture was extracted with EtOAc (3x30 mL). The combined organic extracts were washed with saturated brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by normal phase flash chromatography (0-60% EtOAc / hexanes) to give the title compound (600 mg, 61%). 1 H NMR (500 MHz, d6-DMSO) δ 7.45 (d, 1H) 7.22 (d, 1H) 6.89 (s, 2H) 3.82 (s, 3H). 3-Amino-6-bromopicolinic acid

[0328] [ka]

[0329] A mixture of methyl 3-amino-6-bromopicolinate (600 mg, 2.6 mmol), LiOH-HO (600 mg, 5.5 mmol), THF (6 mL), MeOH (1.5 mL) and water (1.5 mL) was stirred for 45 min. The solvent was removed under reduced pressure and the residue was dissolved in water (20 mL). The pH of the solution was adjusted to pH 6 with 2N HCl (pH paper). The resulting solid was filtered, washed with cold water (ca. 10 mL) and dried to give 302 mg of the title compound. The mother liquor was acidified as above to give an additional 98 mg of the title compound, for a total yield of 400 mg, 71%. 1 H NMR (500 MHz, d6-DMSO) δ 7.43 (d, 1H) 7.20 (d, 1H). 2-(3-amino-6-bromopicolinamido)-2-(3-fluorophenyl)acetic acid ethyl ester (Amide A)

[0330] [ka]

[0331] A solution of 3-amino-6-bromopicolinic acid (217 mg, 1.0 mmol), 2-amino-2-(3-fluorophenyl)ethyl acetate hydrochloride (280 mg, 1.2 mmol), HATU (760 mg, 2.0 mmol), DIEA (1 mL, 5.75 mmol) and degassed DMF (2 mL) was stirred at 60 °C for 1 h. After cooling, the reaction mixture was poured into saturated brine (ca. 20 mL) and extracted with EtOAc (2x30 mL). The combined organic extracts were washed with saturated brine, dried over Na2SO4, filtered, concentrated under reduced pressure and purified by normal phase flash chromatography (0-55% EtOAc / hexanes) to give the title compound (340 mg, 86%). 2-(6-bromo-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(3-fluorophenyl)acetic acid ethyl ester (ester E)

[0332] [ka]

[0333] A mixture of ethyl 2-(3-amino-6-bromopicolinamido)-2-(3-fluorophenyl)acetate (320 mg, 0.8 mmol) and triethyl orthoformate (4 mL) in a sealed tube was exposed to MW irradiation at 210° C. for 70 min. Excess triethyl orthoformate was removed under reduced pressure. The residue was purified by normal phase flash chromatography (0-65% EtOAc / hexanes) to give the title compound (340 mg, quantitative). 1 H NMR (500 MHz, d6-DMSO) δ 8.44 (s, 1H) 8.08 (m, 2H) 7.50 (m, 1H) 7.43 (m, 1H) 7.37 (d, 1H) 7.29 (m, 1H) 6.60 (s, 1H) 4.26 (m, 2H) 1.19 (t, 3H).

[0334] Esters FK in Table 10 were prepared from the corresponding starting materials by methods similar to ester E.

[0335] [Table 11A]

[0336] [Table 11B]

[0337] Amides BG in Table 11 were prepared from the corresponding starting materials by methods similar to those for amide A.

[0338] [Table 12A]

[0339] [Table 12B]

[0340] Scheme 7

[0341] [ka]

[0342] 2-Bromo-2-(2-fluoro-6-methoxyphenyl)acetic acid methyl ester

[0343] [ka]

[0344] To a solution of methyl 2-(2-fluoro-6-methoxyphenyl)acetate (4.30 g, 21.7 mmol) in CCl4 (120 mL) was added N-bromosuccinimide (4.05 g, 22.7 mmol) and benzoyl peroxide (524 mg, 2.16 mmol) and the reaction mixture was heated at 80° C. for 24 h. After cooling, dichloromethane (150 mL) was added and the organic phase was washed with saturated brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica chromatography (0-10% EtOAc in Hex) to give the title compound (3.93 g, 65%). 1 H NMR (500 MHz, CDCl3) δ CDCl37.30 (m, 1H) 6.73 (m, 2H) 6.01 (s, 1H) 3.90 (s, 3H) 3.80 (s, 3H). 2-(6-bromo-4-oxoquinazolin-3(4H)-yl)-2-(2-fluoro-6-methoxyphenyl)acetic acid methyl ester

[0345] [ka]

[0346] To a solution of 6-bromoquinazolin-4(3H)-one (1.0 g, 4.44 mmol) in DMF (20 mL) was added NaH (60% in mineral oil, 356 mg) at 0° C. and the mixture was stirred at room temperature for 1 h. A solution of 2-bromo-2-(2-fluoro-6-methoxyphenyl)methyl acetate (1.5 g, 5.33 mmol) in DMF (5 mL) was added dropwise. The reaction was stirred overnight and ethyl acetate (100 mL) was added. The mixture was washed with saturated brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica chromatography (0-60% EtOAc in Hex) to give the title compound (1.42 g, 76%). 1H NMR (500 MHz, d6-DMSO) δ 8.30 (s, 1H) 8.05 (dd, 1H) 8.04 (s, 1H) 7.67 (d, 1H) 7.55 (m, 1H) 7.07 (d, 1H) 6.98 (m, 1H) 6.87 (s, 1H) 3.87 (s, 3H) 3.76 (s, 3H); MS (m / z): 423.09. Preparation of compound 061: 2-(4-oxo-6-(pyridin-3-ylethynyl)quinazolin-3(4H)-yl)-2-phenyl-N-(thiazol-2-yl)acetamide

[0347] [ka]

[0348] A mixture of 2-(6-iodo-4-oxoquinazolin-3(4H)-yl)-2-phenyl-N-(thiazol-2-yl)acetamide (100 mg, 0.2 mmol), triphenylphosphine (11 mg, 0.04 mmol), 3-ethynylpyridine (32 mg, 0.3 mmol) and triethylamine (85 uL, 0.6 mmol) in DMF (2 mL) was degassed and backfilled with nitrogen. Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and Cu(I)I (4 mg, 0.02 mmol) were added and the reaction mixture was heated at 100 °C for 4 h. After cooling, the reaction mixture was purified by reverse phase HPLC eluting with 0-80% ACN / water (TFA modifier) ​​to give the title compound (7.6 mg, 8%). 1 H NMR (500 MHz, d6-DMSO) δ 8.84 (m, 1H) 8.62 (dd, 1H) 8.35 (d, 1H) 8.07 (m, 1H) 8.03 (dd, 1H) 7.90 (s, 1H) 7.76 (d, 1H) 7.52 (m, 5H) 7.45 (m, 2H) 7.32 (d, 1H) 6.88 (s, 1H); MS (m / z): 463.8 [M+1] + . Preparation of 2-(5-fluoro-2-hydroxyphenyl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-N-(pyridin-2-yl)acetamide; hydrochloride salt (082) Scheme 8

[0349] [ka]

[0350] 2-Bromo-4-fluoro-1-(methoxymethoxy)benzene

[0351] [ka]

[0352] To a solution of 2-bromo-4-fluoro-phenol (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, 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 (400 MHz, 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). 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-oxo-ethyl acetate

[0353] [ka]

[0354] To a solution of 2-bromo-4-fluoro-1-(methoxymethoxy)benzene (80.0 g, 340 mmol) in THF (1 L) was added n-butyllithium (2.5 M in hexanes, 142 mL, 357 mmol) dropwise at −78° C. After stirring at −78° C. for 1 h, the reaction mixture was cannulated into a pre-cooled (−78° C.) solution of diethyl oxalate (74.4 g, 510 mmol) in THF (500 mL). Upon completion of the addition, 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 (400 MHz, 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). 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-hydroxyiminoethyl acetate

[0355] [ka]

[0356] To a solution of hydroxylamine hydrochloride (37.9 g, 546 mmol) in ethanol (500 mL) were added 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-oxo-ethyl acetate (70.0 g, 273 mmol) and sodium acetate (44.7 g, 132 mmol). After stirring at 80° C. for 2.5 h, the solvent was removed under reduced pressure and the resulting residue was partitioned between water and dichloromethane. The aqueous phase was extracted with further 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%). 1H NMR (400 MHz, 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). 2-Amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]ethyl acetate

[0357] [ka]

[0358] To a solution of Raney Ni (1.46 g, 25.0 mmol) in EtOH / THF (650 mL, 4 / 1) was added 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-hydroxyimino-ethyl acetate (34.0 g, 125 mmol). The flask was evacuated and backfilled with hydrogen, and the reaction mixture was allowed to stir under hydrogen atmosphere (50 psi) at 70° C. for 24 h. The reaction mixture was filtered through a pad of Celite that was washed multiple times with ethanol. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography eluting with 33% ethyl acetate in petroleum ether to give the title compound (30.6 g, 48%). 1 H NMR (400 MHz, 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). 2-[(2-amino-5-bromo-benzoyl)amino]-2-[5-fluoro-2-(methoxymethoxy)phenyl]ethyl acetate

[0359] [ka]

[0360] To a solution of ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (10.0 g, 38.8 mmol) and 6-bromo-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione (10.3 g, 42.6 mmol) in THF (80 mL) was added triethylamine (7.85 g, 77.6 mmol). After stirring at 40° C. for 3 h, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 25% ethyl acetate in petroleum ether to give the title compound (5 g, 28%). 1 H NMR (400 MHz, DMSO-d6) δ: 8.95 (d, 1H), 7.77 (d, 1H), 7.29 (dd, 1H), 7.15-7.22 (m, 3H), 6.69 (d, 1H), 6.57 (s, 2H), 5.99 (d, 1H), 5.19-5.27 (m, 2H), 4.09-4.18 (m, 2H), 3.38 (s, 3H), 1.14-1.18 (m, 3H). 2-(6-bromo-4-oxo-quinazolin-3-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]ethyl acetate

[0361] [ka]

[0362] A solution of ethyl 2-[(2-amino-5-bromo-benzoyl)amino]-2-[5-fluoro-2-(methoxymethoxy)-phenyl]acetate (5.25 g, 11.5 mmol) in triethoxymethane (20 mL) was stirred at 110° C. for 22 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 10-33% ethyl acetate in petroleum ether to give the title compound (2.2 g, 41%). 1H NMR (400 MHz, DMSO-d6) δ: 8.25-8.29 (m, 2H), 8.02 (dd, 1H), 7.66 (d, 1H), 7.26-7.37 (m, 2H), 7.14-7.21 (m, 1H), 6.68 (s, 1H), 5.17-5.25 (m, 2H), 4.22-4.30 (m, 2H), 3.26 (s, 3H) 1.15-1.25 (m, 3H). 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-4-oxo-quinazolin-3-yl]ethyl acetate

[0363] [ka]

[0364] A mixture of ethyl 2-(6-bromo-4-oxo-quinazolin-3-yl)-2-[5-fluoro-2-(methoxymethoxy)-phenyl]acetate (2.2 g, 4.72 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (1.98 g, 6.60 mmol), potassium carbonate (1.96 g, 14.1 mmol) and dioxane / water (20 mL, 4 / 1) was degassed with nitrogen gas. [1,1'bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (0.690 g, 0.944 mmol) was added and the reaction was degassed once more under nitrogen. The reaction mixture was heated at 105° 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 brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-15% methanol in dichloromethane to give the title compound (1.8 g, 68%). MS m / z: 560.4 [M+1] + . 2-[5-Fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-4-oxo-quinazolin-3-yl]acetic acid

[0365] [ka]

[0366] To a solution of ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)-phenyl]-4-oxo-quinazolin-3-yl]acetate (1.80 g, 3.21 mmol) in THF / MeOH / water (30 mL, 1 / 1 / 1) was added lithium hydroxide monohydrate (0.404 g, 9.62 mmol). After stirring at room temperature for 3 h, the solvent was removed under reduced pressure and the resulting residue was adjusted to pH 3 with HCl (1M). The resulting solid was collected by filtration and washed with water to give the title compound (1.5 g, 88%). MS m / z: 532.1 [M+1] + . 2-[5-Fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-4-oxo-quinazolin-3-yl]-N-(2-pyridyl)acetamide

[0367] [ka]

[0368] To a solution of 2-[5-fluoro-2-(methoxymethoxy)-phenyl]-2-[6-[4-(1-methyl-4-piperidyl)-phenyl]-4-oxo-quinazolin-3-yl]acetic acid (0.600 g, 1.12 mmol), 2-aminopyridine (0.158 g, 1.68 mmol) and HATU (0.638 g, 1.68 mmol) in DMF (10 mL) was added DIPEA (0.434 g, 3.36 mmol). After stirring at room temperature for 10 h, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-10% methanol in dichloromethane to give the title compound (0.20 g, 29%). MS m / z: 608.5 [M+1] + . 2-(5-Fluoro-2-hydroxyphenyl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-N-(pyridin-2-yl)acetamide; Hydrochloride (082)

[0369] [ka]

[0370] To a solution of 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-4-oxo-quinazolin-3-yl]-N-(2-pyridyl)acetamide (0.200 g, 0.329 mmol) in dichloromethane (5 mL) was added HCl in dioxane (4 M, 0.102 mL, 0.408 mmol). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure. Diethyl ether was added to the residue and the resulting solid was isolated by filtration to give the title compound (130 mg, 68%). 1H NMR (DMSO-d6) δ: 8.40 (d, 1H), 8.34-8.39 (m, 1H), 8.19 (m, 1H), 8.06-8.14 (m, 1H), 7.83-7.90 (m, 2H), 7.75-7.81 (m, 3H), 7.40 (d, 2H), 7.14-7.25 (m, 2H), 6.95-7.06 (m, 3H), 3.44-3.54 (m, 2H), 3.02-3.17 (m, 2H), 2.83-2.94 (m, 1H), 2.78 (d, 3H), 1.94-2.15 (m, 4H). MS m / z: 564.3 [M+1] + .

[0371] Compounds 083 and 084 were prepared from the corresponding MOM-protected intermediates following the procedure used to prepare compound 082. 2-(5-fluoro-2-hydroxyphenyl)-2-(5-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)acetamide (083)

[0372] [ka]

[0373] 1 H NMR (500 MHz, d6-DMSO) δ 10.24 (s, 1H) 9.37 (br s, 1H) 7.97 (m, 1H) 7.90 (s, 1H) 7.60 (d, 3H) 7.52 (d, 1H) 7.39 (d, 2H) 7.32 (d, 1H) 7.21 (m, 1H) 6.96 (dd, 1H) 6.93 (dd, 1H) 6.86 (s, 1H) 3.55 (d, 2H) 3.12 (m, 2H) 2.87 (m, 1H) 2.83 (d, 3H) 2.07 (m, 2H) 1.86 (m, 2H); MS (m / z): 588.28. 2-(5-Fluoro-2-hydroxyphenyl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-N-(thiazol-2-yl)acetamide (084)

[0374] [ka]

[0375] 1 H NMR (500 MHz, d6-DMSO) δ 10.23 (s, 1H) 9.32 (br s, 1H) 8.46 (d, 1H) 8.22 (d, 3H) 7.99 (s, 1H) 7.53 (d, 1H) 7.45 (d, 2H) 7.33 (d, MS (m / z): 571.31. 2-(2-Fluoro-6-hydroxyphenyl)-2-(6-(4-(4-methylpiperazin-1-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)acetamide (085)

[0376] [ka]

[0377] To a solution of trifluoroacetoacetate 2-(2-fluoro-6-methoxyphenyl)-2-(6-(4-(4-methylpiperazin-1-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)acetamide (191 mg, 0.273 mmol) in dichloromethane (50 mL) was added a solution of BBr3 (1 M in DCM, 1.37 mL, 1.37 mmol) at -78 °C and the reaction was stirred at room temperature overnight. It was cooled again to -78 °C and further solution of BBr3 (1 M in DCM, 2.73 mL, 2.73 mmol) was added and the mixture was stirred at room temperature overnight. Dichloromethane (100 mL) and saturated brine (100 mL) were added and the pH was adjusted to 7 by addition of NaHCO3. The mixture was extracted with dichloromethane (3x50mL) and the combined organic phase was washed with saturated brine. The solvent was removed and the residue was purified by reverse phase HPLC eluting with 1-60% ACN / H2O (0.038% TFA modifier) ​​to give the title compound (47mg). 1 H NMR (500 MHz, d6-DMSO) δ 10.82 (s, 1H) 9.80 (br s, 1H) 8.36 (d, 1H) 8.18 (dd, 1H) 7.97 (s, 1H) 7.77 (d, 1H) 7.75 (d, 2H) 7.48 (d, 1H) 7.39 (m, 1H) 7.26 (d, 1H) 7.16 (d, 2H) 7.06 (s, 1H) 6.80 (d, 1H) 6.79 (m, 1H) 3.98 (d, 2H) 3.54 (m, 2H) 3.19 (m, 2H) 3.05 (m, 2H) 2.88 (s, 3H); MS (m / z): 571.28.

[0378] The following compounds were prepared similarly to compound 085: 2-(2-Fluoro-6-hydroxyphenyl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)acetamide (086)

[0379] [ka]

[0380] 1 H NMR (500 MHz, d6-DMSO) δ 10.84 (s, 1H) 9.52 (br s, 1H) 8.42 (d, 1H) 8.20 (dd, 1H) 8.00 (s, 1H) 7.80 (m, 3H) 7.57 (m, 1H) 7.48 (d, 1H) 7.40 (d, 2H) 7.38 (m, 1H) 7.26 (d, 1H) 7.06 (s, 1H) 6.81 (d, 1H) 6.79 (m, 1H) 3.54 (d, 2H) 3.11 (m, 2H) 2.88 (m, 1H) 2.84 (d, 3H) 2.07 (m, 2H) 1.89 (m, 2H); MS (m / z): 570.25.

[0381] (Example 2) HTRF EGFR biochemistry Biochemical activity measurements of EGFR were performed using a homogeneous time-resolved fluorescence (HTRF) assay (Cisbio). First, inhibitors and DMSO normalization were dispensed into an empty black low-volume 384-well plate (Corning) using a D300 digital liquid dispenser (HP). All reactions were performed at room temperature, and solutions were added to the plate using a Multidrop Combi reagent dispenser (ThermoFisher). The reaction mixture (final volume 10 μl) contained 1 μM of 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 for different kinase activities (L858R 0.1 nM, L858R / T790M 0.02 nM). Enzyme reaction solution (2x concentration, 5 μL) was added to the 384-well plate containing the compounds and incubated for 30 min. The enzyme reaction was started by adding 5 μL of ATP to a final concentration of 100 μM and allowed to react for 20 min. The reaction was quenched by adding 10 μL of phosphotyrosine antibody-europium(III) cryptate (1:180 volume ratio) and streptavidin-XL665 (46.7 nM) in detection buffer containing EDTA, then incubated for 1 h at room temperature and read on a PHERAstar plate reader (excitation = 337 nm, emission = 620 nm and 665 nm). IC 50 Values ​​were determined by inhibition curves in triplicate (11-point curves from 1.0 μM to 0.130 nM or 23-point curves from 1.0 μM to 0.130 pM) using nonlinear least-squares fitting in GraphPad Prism 7.0d. The results of the HTRF-based EGFR biochemical assay are summarized in Table 12 below.

[0382] [Table 13A]

[0383] [Table 13B]

[0384] [Table 13C]

[0385] Example 3 Ba / F3 cell proliferation model EGFR mutants L858R, Del E746_A750, L858R / T790M, Del E746_A750 / T790M, L858R / T790M / C797S and Del / T790M / C797S in Ba / F3 cells have been described previously (Zhou, W. et al., Nature 462, 2009, pp. 1070-1074). All cell lines were maintained in RPMI 1640 (Cellgro; Mediatech, Herndon, CA) supplemented with 10% FBS, 100 units / mL penicillin, 100 units / mL streptomycin. The I941R mutation in EGFR was introduced by site-directed mutagenesis using the Quick Change site-directed mutagenesis kit (Stratagene; La Jolla, CA) according to the manufacturer's instructions. All constructs were verified by DNA sequencing. The 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 following standard protocols as previously described (Zhou et al., Nature 2009). Stable clones were obtained by selection in puromycin (2 μg / ml).

[0386] Proliferation and growth inhibition were assessed by 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 for viable cell number determination based on 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 placed in triplicate in 384-well plates, and all experiments were repeated at least three times. Luminescence signals were detected using a spectrometer, and data were displayed graphically using GraphPad Prism version 5.0 for Windows (GraphPad software; www.graphpad.com). Curves were fitted using a nonlinear regression model with a sigmoidal dose-response. IC 50 The measured values ​​are shown in Table 13 below.

[0387] [Table 14A]

[0388] [Table 14B]

[0389] [Table 14C]

[0390] The subject matter of the present disclosure is not limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the present disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to be within the scope of the appended claims.

[0391] 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. Formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof (In the formula, A is thiazole or pyridine; W and W a are independently CH, CR 6 or N, X and B are each independently N, CH, CF or C-(C 1 ~C 3 alkyl), Y and Z each independently represent CH or CR 2 and with the proviso that at least one of X, Y, Z or B is CH; R 1 is phenyl or pyridinyl, where phenyl or pyridinyl is optionally independently R 7 is substituted once or twice with R 2 is independently selected from each occurrence of halo, 6- to 10-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 4- to 7-membered heterocycloalkyl, OR 4 , N.R. 4 R 4 , S.O. 2 R 4 , S.O. 2 NHR 4 , N.H.S.O. 2 R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl and C 2 ~C 6 alkynyl, wherein 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 7-membered heterocycloalkyl, and 3- to 6-membered cycloalkyl are optionally selected from the group consisting of R 3 is replaced by C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl or C 2 ~C 6 Each alkynyl is optionally R 4 is substituted once, twice or three times by R 3 are halo, -OH, -SH, -CN, -NO 2 , -NH 2 , OR 4 , N.R. 4 R 4 , S.O. 2 R 4 , S.O. 2 NHR 4 , N.H.S.O. 2 R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, 6- to 10-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, and 4- to 7-membered heterocycle, wherein the 4- to 7-membered heterocycle is optionally selected from the group consisting of C 1 ~C 4 Alkyl, C 1 ~C 4 substituted with alkyl-OH, halo and =O; R 4 are independently for each occurrence hydrogen, (CH 2 ) 0～3 -(3- to 7-membered cycloalkyl), (CH 2 ) 0～3 -(4- to 7-membered cycloalkenyl), (CH 2 ) 0～3 -(6-10 membered aryl), (CH 2 ) 0～3 -(5-6 membered heteroaryl) or (CH 2 ) 0～3 -(4- to 7-membered heterocycloalkyl), wherein the 6- to 10-membered aryl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl are each optionally selected from the group consisting of R 5 is substituted once, twice or three times by R 5 independently for each occurrence, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, Halo, COOH, C(O)O(C 1 ~C 6 alkyl), O(CH 2 ) 1～3 OH, NH 2 , OH, CN, (CH 2 ) 0～3 (6-10 membered aryl), (CH 2 ) 0～3 (5-6 membered heteroaryl) and (CH 2 ) 0～3 (4- to 7-membered heterocycloalkyl), wherein the 6- to 10-membered aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are optionally selected from the group consisting of C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, Halo, NH 2 , NH(C 1 ~C 6 alkyl), N(C 1 ~C 6 Alkyl) 2 , S.O. 2 NH 2 , (CH 2 ) 1～2 OH, C(O)(CH 2 ) 1～2 OH and C(O)O(C 1 ~C 6 alkyl), R 6 C 1 ~C 6 alkyl or halo; R 7 independently for each occurrence, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, Halo, OH, SH, NO 2 , N.H. 2 , (CH 2 ) 1～4 OH, S(O) 0～2 H, S(O) 0～2 NH 2 or CN).

2. The compound of formula I has formula II: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof. (In the formula, A is thiazole or pyridine; W and W a are independently CH, CR 6 or N, R 2 is selected from the group consisting of absent, halo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered cycloalkyl, where the 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered cycloalkyl are optionally selected from the group consisting of R 3 is replaced by R 3 are halo, -OH, -SH, -CN, -NO 2 , -NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, 6- to 10-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, and 4- to 7-membered heterocycle, wherein the 4- to 7-membered heterocycle is optionally selected from the group consisting of C 1 ~C 4 Alkyl, C 1 ~C 4 substituted with alkyl-OH, halo and =O; R 7 are halo, -OH, -SH, -CN, -NO 2 and -NH 2 is selected from the group consisting of m is 0, 1 or 2; n is 1 or 2).

3. R 7 3. The compound of claim 1 or 2, wherein is absent or is halo.

4. R 7 The compound of claim 1 or 2, wherein is fluoro.

5. 5. The compound of claim 1, wherein A is thiazole.

6. 5. The compound according to claim 1, wherein A is pyridine.

7. R 2 is absent, halo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered cycloalkyl, where the 6- to 10-membered aryl is optionally selected from the group consisting of R 4 7. The compound of claim 1 , substituted with

8. R 2 The compound of any one of claims 1 to 7, wherein is halo.

9. R 2 9. The compound according to any one of claims 1 to 8, wherein is bromo or fluoro.

10. R 2 R 3 8. The compound of claim 1, wherein the phenyl is further substituted with

11. R 3 In some cases, C 1 ~C 4 11. The compound of any one of claims 1 to 10, which is a 6-membered heterocycle substituted with alkyl.

12. R 3 12. The compound according to claim 10 or 11, wherein R 3 is piperidine further substituted with methyl, or R 3 is piperazine further substituted with methyl, wherein R 3 is in the para position.

13. The compound of formula I is of formula III, formula IV, formula V, formula VI, formula VII or formula VIII: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

14. The following: 【Table 1A】 【Table 1B】 【Table 1C】 【Table 1D】 【Table 1E】 【Table 1F】 【Table 1G】 【Table 1H】 or a pharma- ceutically acceptable salt thereof.

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

16. The pharmaceutical composition of claim 15, further comprising a second active agent that prevents EGFR dimer formation in a subject, the second active agent being selected from the group consisting of a MEK inhibitor, a PI3K inhibitor and an mTor inhibitor, or the second active agent being an ATP-competitive EGFR inhibitor.

17. 17. The pharmaceutical composition of claim 16, wherein the second active agent is selected from the group consisting of cetuximab, trastuzumab and panitumumab.

18. 17. The pharmaceutical composition of claim 16, wherein the ATP-competitive EGFR inhibitor is osimertinib.

19. A composition for treating cancer in a subject in need thereof, 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. The composition of any one of claims 15 to 18.

20. 20. The composition of claim 19, wherein the cancer is non-small cell lung cancer (NSCLC).

21. A composition for inhibiting a kinase in a subject in need thereof, comprising the composition of any one of claims 15 to 18, wherein the kinase is EGFR.

22. A composition for treating or preventing a kinase-mediated disorder in a subject in need thereof, wherein the kinase-mediated disorder is resistant to EGFR targeted therapy, and the EGFR treatment therapy is selected from the group consisting of gefitinib, erlotinib, and osimertinib.

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