Allosteric EGFR Inhibitors and Methods of Using Them

Abstract

The present disclosure relates to a compound acting as an allosteric inhibitor of the epidermal growth factor receptor (EGFR); a pharmaceutical composition comprising the compound; and a method for treating or preventing kinase-mediated disorders, including cancer and other proliferative diseases.

Description

Technology Field

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 036,622 filed June 9, 2020 and U.S. Provisional Application No. 63 / 111,429 filed November 9, 2020, the entire contents of which are incorporated herein by reference.

[0003] Statements regarding federally funded research or development

[0004] This invention was made with government support under Project No. R01 CA201049 awarded by the National Institutes of Health (NIH). The government holds specific rights to this invention. Background Technology

[0005] background

[0006] 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, 32-40). EGFR deregulation is associated with non-small cell lung carcinoma, breast cancer, glioma, squamous cell carcinoma of the head and neck, and prostate cancer (Raymond, E., et al. Drugs 60 (Suppl. 1), 2000, 15-23, discussion 41-2; Salomon, D.S., etc.; Crit Rev. Oncol. Hematol . 19, 1995, 183-232; Voldborg BR, et al.; Ann. Oncol . At least 70% of human cancers (Seymour, LK, 8, 1997, 1197-1206) including Curr Drug TargetsMany types of human cancer are implicated with the overexpression of receptors present in 2, 2001, 117-133). Therefore, EGFR has emerged as an attractive target for the design and development of diagnostic and therapeutic agents capable of specifically binding to and inhibiting the receptor's tyrosine kinase activity and signaling pathways in cancer cells. For example, the EGFR tyrosine kinase (EGFR-TK) reversible inhibitor TARCEVA® has been approved by the FDA for the treatment of NSCLC and advanced pancreatic cancer. Other anti-EGFR targeted molecules, including lapatinib and IRESSA®, have also been approved.

[0007] Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) EGFR It is an effective clinical therapy for patients with mutant advanced non-small cell lung cancer (NSCLC) (Mok, TS, et al. N. Engl . J. Med . 361, 2009, 947-57; Paez, JG, et al., Science 304, 2004, 1497-500; Lynch, TJ, et al., N. Engl . J. Med . 350, 2004, 2129-39; Rosell, R., et al., Lancet Oncol . 13, 2012, 239-46). In several randomized clinical trials, EGFR TKIs progressive EGFR It has been proven that when used as an initial systemic treatment for mutant NSCLC, it is more effective than chemotherapy as measured by response rate (RR) and progression-free survival (PFS) (Mok, TS, et al. N. Engl . J. Med . 361, 2009, 947-57; Rosell, R., et al., Lancet Oncol . 13, 2012, 239-46; Sequest, LV et al., J. Clin . Oncol . 31, 2013, 3327-34; Wu, YL, et al., Lancet Oncol . 15, 2014, 213-22; Maemondo, M., et al., N. Engl . J. Med . 362, 2010, 2380-8; Zhou, C., et al., Lancet Oncol . 12, 2011, 735-42; Mitsudomi, T., et al., Lancet Oncol . 11, 2010, 121-8). However, disease progression develops in the majority of patients after successful treatment with EGFR TKIs. The most common mechanism of acquired resistance, detected in 60% of patients, is at position T790 (T790M). EGFR It is a secondary mutation of (Yu, HA, etc. Clin Cancer Res. 19, 2013, 2240-7). This mutation increases ATP affinity, making it more difficult for the reversible EGFR TKIs gefitinib and erlotinib to bind to the EGFR TKI domain (Yun CH, et al., Proc . Natl . Acad . Sci USA 105, 2008, 2070-5).

[0008] Shared EGFR inhibitors EGFR It has been highlighted for inhibiting cancers containing T790M. However, in lung cancer patients, apatinib is an EGFR TKI naive EGFRIt is effective only for mutant cancers, and the RR is less than 10% in NSCLC patients who have developed resistance to gefitinib or erlotinib (Miller, VA, et al., Lancet Oncol . 13, 2012, 528-38). Apatinib is a potent inhibitor of both mutant and wild-type (WT) EGFR. Inhibition of WT EGFR causes toxicity, including skin rash and diarrhea, which limits the patient's ability to increase the apatinib dose to the level required to inhibit EGFR T790M. Irreversible pyrimidine EGFR inhibitors, including instrumental compound WZ4002 and clinical compounds CO-1686 and AZD9291, overcome many of the limitations of apatinib (Zhou, W., et al. Nature 462, 2009, 1070-4; Walter, AO, et al., Cancer Discov . 3, 2013, 1404-15; Cross, DAE, et al., Cancer Discov . 4, 2014, 1046-61). Since these are not only more potent against EGFR T790M but also selectively inhibit mutants compared to WT EGFR, they should have increased clinical efficacy and lower toxicity compared to apatinib (Zhou, W., et al; Walter AO, et al; Cross, DAE, et al.).

[0009] However, all current EGFR TKIs target the ATP site, and while third-generation irreversible inhibitors can overcome T790M, they are all neutralized by the C797S mutation already present in treated patients. Cetuximab, an anti-EGFR antibody that blocks receptor dimerization, is not effective in EGFR-mutant NSCLC because the mutational activation of the kinase is effectively located "downstream" of receptor dimerization.

[0010] Currently, suitable compounds with alternative mechanisms of action targeting mutant EGFR are not available. Therefore, potent small molecule EGFR inhibitors with alternative mechanisms of action targeting mutant EGFR are needed.

[0011] In one embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof is provided herein:

[0012]

[0013] During the meal:

[0014] represents an optional double bond;

[0015] A and A' are independently CH, CR 8 or N and;

[0016] W is N or C;

[0017] Z is selected from the group consisting of S, O, N, NH, N-Me, CH2, CH, C-halo, C-(C1-C3alkyl), or C-(C1-C3alkoxy);

[0018] X and Y are independently S, O, N, CH, NR 3 or CR 3 And;

[0019] However, at least one of X, Y, or Z is CH;

[0020] R 1 is C(O)NHR 9 , selected from the group consisting of 6-10-membered aryls, 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, wherein the aryls, heteroaryls, cycloalkyls, and heterocycloalkyls optionally have 1, 2, or 3 Rs 8 Replaced with;

[0021] R 2is selected from the group consisting of 6-10-membered aryls, 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, all of which have 1, 2, or 3 Rs 6 Optionally replaced with;

[0022] R 3 is independently, in each case, halogen, OR 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , NHC(O)R 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 Selected from the group consisting of aryl, 5-6-membered heteroaryl, and 5-7-membered heterocyclil, wherein the alkyl, alkenyl, or alkynyl are each R 4 It is optionally substituted 1, 2, or 3 times, and the aryl, heteroaryl, or heterocyclil are each R 5 Optionally substituted 1, 2, or 3 times;

[0023] R 4 is independently, in each case, H, C1-C6 alkyl, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -( C6-C 10 Aril), (CH2) 0-3 -(5-6-membered heteroaryl), and (CH2) 0-3 Selected from the group consisting of -(5-7-membered heterocyclils), wherein the aryl, heteroaryl, or heterocyclil is each R 5 Optionally substituted 1, 2, or 3 times;

[0024] R 5Independently, in each case, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3-10 cycloalkyl, halogen, COOH, C(O)O(C1-C6 alkyl), O(CH2) 1-3 -OH, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, OH, CN, (CH2) 0-3 -( C6-C 10 Aril), (CH2) 0-3 -(5-6-membered heteroaryl), and (CH2) 0-3 Selected from the group consisting of -(5-7-membered heterocyclils), wherein the aryl, heteroaryl, or heterocyclil is each R 7 Optionally substituted 1, 2, or 3 times;

[0025] Alternatively, 2 Rs 5 They can form 5-10 member heteroaryls, 6-10 member aryls, 3-10 member heterocycloalkyls, or 3-10 member cycloalkyls together with the atoms to which they are attached, and all of these are R 7 Optionally substituted 1, 2, or 3 times;

[0026] R 6 are independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1- 4OH, S(O) 0-2 H, S(O) 0- Selected from the group consisting of 2NH2 or CN;

[0027] Alternatively, 2 Rs 6 They can form 5-10-membered heteroaryls, 6-10-membered aryls, 3-10-membered heterocycloalkyls, or 3-10-membered cycloalkyls together with the atoms to which they are attached;

[0028] R 7are independently, in each case, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, SO2NH2, SO2NH(C1-C6 alkyl), SO2N(C1-C6 alkyl)2, (CH2) 1-2 -OH, C(O)(CH2) 1-2 Selected from the group consisting of substituents independently selected from -OH, C(O)(C1-C6 alkyl), and C(O)O(C1-C6 alkyl);

[0029] Alternatively, 2 Rs 7 They can form 5-10-membered heteroaryls, 6-10-membered aryls, 3-10-membered heterocycloalkyls, or 3-10-membered cycloalkyls together with the atoms to which they are attached;

[0030] R 8 Independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1- 4OH, S(O) 0-2 H, S(O) 0- Selected from the group consisting of 2NH2 or CN;

[0031] R 9 is selected from the group consisting of 6-10-membered aryls, 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, all of which have 1, 2, or 3 Rs 8 It is optionally replaced with.

[0032] In another embodiment, a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier is provided herein.

[0033] In another aspect, a method for treating cancer in a subject requiring treatment for cancer is provided herein, comprising administering a therapeutically effective amount of a compound of formula I to the subject.

[0034] In another aspect, a method for inhibiting kinase in a subject requiring kinase inhibition is provided herein, comprising administering a therapeutically effective amount of a compound of formula I to the subject.

[0035] In one embodiment, a method for treating or preventing a kinase-mediated disorder in a subject requiring treatment or prevention of a kinase-mediated disorder is provided herein, comprising administering a therapeutically effective amount of a compound of Formula I to the subject. Specific details for implementing the invention

[0036] definition

[0037] Definitions of various terms used to describe the compounds and compositions disclosed in this specification are listed below. These definitions apply to terms used throughout this specification and claims, unless otherwise limited to individual cases or as part of a larger group.

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the relevant technical field. In general, the nomenclature and laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry used herein are widely known and commonly used in the art.

[0039] As used herein, the articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. For example, "element" means one element or more than one element. Furthermore, the use of the term "including" as well as other forms such as "include," "includes," and "included" is not limited.

[0040] As used herein, the term “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. As used herein when referring to measurable values ​​such as quantity, temporal duration, etc., the term “about” means encompassing a variation of ±20% or ±10% from the specified value, including ±5%, ±1%, and ±0.1%, and such variation is suitable for performing the disclosed method.

[0041] As used herein, terms such as "administration" refer to providing a therapeutic agent to a subject. Numerous techniques for administering therapeutic agents exist in the art, including but not limited to intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and local administration.

[0042] The terms “treat,” “treated,” “treating,” or “treatment” include the reduction or alleviation of at least one symptom associated with or caused by the condition, disorder, or disease being treated. In certain embodiments, treatment includes contacting an effective amount of the compound described herein with wild-type or mutant EGFR for a pathological condition associated with cancer.

[0043] As used herein, the terms “prevent” or “prevention” mean that if a disability or disease has not occurred, there has been no onset of the disability or disease, and if a disability or disease has already occurred, there has been no further onset of the disability or disease. Additionally, the ability to prevent some or all of the symptoms associated with the disability or disease is also taken into consideration.

[0044] As used herein, the terms “patient,” “entity,” or “subject” refer to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such as sheep, cattle, pigs, dogs, cats, and marine mammals. Preferably, the patient, subject, or entity is a human.

[0045] As used herein, the terms “effective dose,” “pharmaceutical effective dose,” and “therapeutic effective dose” refer to amounts of a formulation that are non-toxic but sufficient to provide a desired biological outcome. The outcome may be a reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desirable alteration of the biological system. In any individual case, the appropriate therapeutic dose may be determined by a person skilled in the art using routine experiments.

[0046] As used herein, the term “pharmaceuticalally acceptable” refers to a substance, such as a carrier or diluent, that is relatively non-toxic and does not compromise the biological activity or properties of the compound; that is, the substance may be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any component of the composition containing it.

[0047] As used herein, the term “pharmaceuticalally acceptable salt” refers to a derivative of the disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts of the present disclosure include, for example, conventional nontoxic salts of the parent compound formed from nontoxic inorganic or organic acids. Pharmaceutically acceptable salts of the present disclosure may be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts may be prepared by reacting the free acid or base form of such compound with a stoichiometric amount of a suitable base or acid in water or an organic solvent, or a mixture of both; generally, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred. The phrase “pharmaceuticalally acceptable salt” is not limited to mono or 1:1 salts. For example, “pharmaceuticalally acceptable salt” also includes bis-salts such as bis-hydrochloride. A list of suitable salts is provided in the literature [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.

[0048] As used herein, the term "prodrug" refers to a precursor compound that undergoes metabolic activation in vivo to produce an active drug. Accordingly, for example, the prodrug of the compound provided herein will undergo metabolic activation to produce the compound when administered to a subject.

[0049] As used herein, the terms “composition” or “pharmaceutical composition” refer to a mixture of at least one useful compound and a pharmaceutically acceptable carrier within this disclosure. A pharmaceutical composition facilitates the administration of a compound to a patient or subject. A number of techniques for administering a compound exist in the art, including but not limited to intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0050] As used herein, the term “pharmaceutical combination” means a product produced from a mixture or combination of one or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term “fixed combination” means that active ingredients, e.g., the compound of the present disclosure and a co-preparation, are administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that active ingredients, e.g., the compound of the present disclosure and a co-preparation, are both administered to a patient simultaneously, concurrently, or sequentially without specific time limits as separate entities, wherein such administration provides therapeutically effective levels of both compounds in the patient’s body. The latter also applies to cocktail therapy, e.g., administration of three or more active ingredients.

[0051] As used herein, the term “pharmaceuticalally acceptable carrier” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, which is involved in carrying or transporting a useful compound within or to the patient as disclosed herein so as to 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 that it is compatible with other components of a formulation containing a useful compound as disclosed herein and does not cause harm to the patient. Some examples of materials that serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; Excipients, e.g., cocoa butter and suppository wax; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, e.g., propylene glycol; polyols, e.g., glycerin, sorbitol, mannitol and polyethylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffers, e.g., magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-removing water; isotonic saline solution; Ringer's solution; ethyl alcohol; phosphate buffer solution; and other non-toxic compatible materials used in pharmaceutical formulations.

[0052] As used herein, “pharmaceuticalally acceptable carriers” also include any and all coatings, antimicrobial and antifungal agents, and absorption retardants, etc. that are compatible with the activity of the useful compounds within this disclosure and are physiologically acceptable to the patient. Additional active compounds may also be incorporated into the composition. “Pharmaceutically acceptable carriers” may further comprise pharmaceutically acceptable salts of the compounds disclosed herein. Other additional components that may be included in the pharmaceutical composition are known in the art and are described, for example, in the literature incorporated herein by reference [Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA].

[0053] As used herein, the term “EGFR” refers to the epidermal growth factor receptor (also called ErbB-1 or HER1) and may refer to the wild-type receptor or a receptor containing one or more mutations.

[0054] As used herein, the term “HER” or “Her” refers to a member of the ErbB receptor tyrosine kinase family, including EGFR, ERBB2, HER3, and HER4.

[0055] As used herein, the term “allosteric site” refers to a site on the EGFR other than an ATP binding site, such as one that characterizes the crystal structure of the EGFR. An “allosteric site” may be a site close to an ATP binding site, such as one that characterizes the crystal structure of the EGFR. For example, one allosteric site comprises one or more of the following amino acid residues of the epidermal growth factor receptor (EGFR): Lys745, Leu788, Ala743, Cys755, Leu777, Phe856, Asp855, Met766, Ile759, Glu762, and / or Ala763.

[0056] As used herein, the term “agents preventing EGFR dimer formation” or a repetition thereof refers to agents that prevent the formation of dimers in which the C-lobe of the “activator” subunit adversely affects the N-lobe of the “receptor” subunit. Examples of agents preventing EGFR dimer formation include, but are not limited to, cetuximab, trastuzumab, panitumumab, and Mig6.

[0057] As used herein, the term “alkyl” means a straight-chain or branched-chain hydrocarbon having a specified number of carbon atoms, either itself or as part of another substituent, unless otherwise mentioned (i.e., C1-C6 alkyl means an alkyl having 1 to 6 carbon atoms), and includes straight-chain and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Other examples of C1-C6 alkyls include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0058] As used herein, the term "haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halo substituents, wherein alkyl and halo are as defined herein. Haloalkyls include, for example, chloromethyl, trifluoromethyl, bromoethyl, chlorofluoroethyl, etc.

[0059] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein alkyl is defined as in this specification. Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, etc.

[0060] As used herein, the term "alkylamine" refers to an -NH-alkyl group, wherein alkyl is defined as in this specification. Alkylamines include, for example, methylamine, ethylamine, isopropylamine, n-propylamine, n-butylamine, sec-butylamine, t-butylamine, etc.

[0061] As used in this specification, the term "haloalkoxy" refers to an -O-haloalkyl group, wherein haloalkyl is defined as in this specification. Haloalkoxy includes, for example, chloromethoxy, trifluoromethoxy, bromoethoxy, chlorofluoroethoxy, etc.

[0062] As used herein, the term “alkenyl” refers to a monovalent group derived from a hydrocarbon moiety containing 2 to 6 or 2 to 8 carbon atoms having at least one carbon-carbon double bond in a specific embodiment. The alkenyl group may or may not be an attachment site for other groups. The term “alkenyl” includes, but is not limited to, ethenyl, 1-propenyl, 1-butenyl, heptenyl, octenyl, etc.

[0063] As used herein, the term “alkynyl” refers to a monovalent group derived from a hydrocarbon moiety containing 2 to 6 or 2 to 8 carbon atoms having at least one carbon-carbon triple bond in a specific embodiment. The alkynyl group may or may not be an attachment site for other groups. The term “alkynyl” includes, but is not limited to, ethinyl, 1-propynyl, 1-butynyl, heptinyl, octinyl, etc.

[0064] As used herein, the term “halo” or “halogen” means a fluorine, chlorine, bromine, or iodine atom, either alone or as part of another substituent, unless otherwise noted, preferably a fluorine, chlorine, or bromine atom, more preferably a fluorine or chlorine atom.

[0065] As used herein, the term “cycloalkyl” means a fully saturated non-aromatic carbon-cyclic system having one, two, or three rings, wherein these rings may be fused. The term “fused” means that a second ring is present (i.e. attached or formed) by having two adjacent atoms common (i.e. shared) with the first ring. Cycloalkyl also includes bicyclic structures that vary in number from three to eight atoms and may be naturally cross-linked with each individual ring within the bicycle or may be spirocyclic. 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.

[0066] As used herein, the term “cycloalkenyl” means a non-aromatic carbon-cyclic system having one, two, or three partially saturated rings, wherein these rings may be fused, and at least one ring is sp 2It contains carbon-carbon bonds. The term "cycloalkenyl" includes, but is not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, bicyclo[3.1.0]hexenyl, spiro[3.3]-heptanyl, and bicyclo[1.1.1]pentenyl.

[0067] As used herein, the terms “heterocyclile” or “heterocycloalkyl” mean a non-aromatic carboncyclic system having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having 1, 2, or 3 rings, wherein these rings may be fused, where fusion is defined above. Heterocycliles also comprise bicyclic structures that may be naturally cross-linked or spirocyclic with each individual ring in the bicycle, which varies from 3 to 8 atoms and contains 0, 1, or 2 N, O, or S atoms. The term "heterocyclil" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), and also specifically, epoxidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, mopolinyl, piperazinyl, thiomopolinyl, 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] Includes, but is not limited to, octanyl.

[0068] As used herein, the term “aromatic” refers to a carbocycle or heterocycle having one or more polyunsaturated rings and being aromatic, i.e., having (4n + 2) delocalized π (pi) electrons, where n is an integer.

[0069] As used herein, the term “aryl” means an aromatic carbon-cyclic system containing one, two, or three rings, such rings may be fused, and fusion is defined above. When rings are fused, one of the rings must be completely unsaturated, and the fused ring(s) may be completely saturated, partially unsaturated, or completely unsaturated. The term “aryl” includes, but is not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. In some embodiments, the aryl group has six carbon atoms. In some embodiments, the aryl group has six to ten carbon atoms. In some embodiments, the aryl group has six to sixteen carbon atoms.

[0070] As used herein, the term “heteroaryl” means an aromatic carbon-cyclic system having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having 1, 2, or 3 rings, wherein these 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, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-cyclopenta-[c]pyridinyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]-triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl, and 4,5,6,7-tetrahydro-2H-indazolyl.

[0071] Where an aryl, heteroaryl, cycloalkyl, or heterocyclil moiety can be bonded to or otherwise attached to a specified moiety through different ring atoms (i.e., shown or described without indicating a specific attachment point), any possible point through a carbon atom or, for example, a trivalent nitrogen atom is intended. For example, the term "pyridinyl" means 2-, 3-, or 4-pyridinyl, and the term "thienyl" means 2- or 3-thienyl, etc.

[0072] As used herein, the term "substituted" means that an atom or group of atoms has replaced hydrogen with a substituent attached to another group.

[0073] As used herein, the term “optionally substituted” means that the mentioned group may be substituted or unsubstituted. In one embodiment, the mentioned group is optionally substituted with zero substituents, that is, the mentioned group is unsubstituted. In another embodiment, the mentioned group is optionally substituted with one or more additional group(s) selected individually and independently from the group described herein.

[0074] compound

[0075] Compounds that are allosteric inhibitors of the epidermal growth factor receptor (EGFR), useful for the treatment of kinase-mediated disorders including cancer and other proliferative diseases, are provided herein.

[0076] In one embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof is provided herein:

[0077]

[0078] During the meal:

[0079] represents an optional double bond;

[0080] A and A' are independently CH, CR 8 or N and;

[0081] W is N, C, or CH;

[0082] Z is selected from the group consisting of S, O, N, NH, N-Me, CH2, CH, C-halo, C-(C1-C3alkyl), or C-(C1-C3alkoxy);

[0083] X and Y are independently S, O, N, CH, NR 3 or CR 3 And;

[0084] However, at least one of X, Y, or Z is CH;

[0085] R 1 is C(O)NHR 9 , selected from the group consisting of 6-10-membered aryls, 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, wherein the aryls, heteroaryls, cycloalkyls, and heterocycloalkyls have 1, 2, or 3 Rs 8 Optionally replaced with;

[0086] R 2 is selected from the group consisting of 6-10-membered aryls, 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, all of which have 1, 2, or 3 Rs 6 Optionally replaced with;

[0087] R 3 is independently, in each case, halogen, OR 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , NHC(O)R 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 Selected from the group consisting of aryl, 5-6-membered heteroaryl, and 5-7-membered heterocyclil, wherein the alkyl, alkenyl, or alkynyl are each R 4 It is optionally substituted 1, 2, or 3 times, and the aryl, heteroaryl, or heterocyclil are each R 5 Optionally substituted 1, 2, or 3 times;

[0088] R 4 is independently, in each case, H, C1-C6 alkyl, (CH2) 0-3-(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -( C6-C 10 Aril), (CH2) 0-3 -(5-6-membered heteroaryl), and (CH2) 0-3 Selected from the group consisting of -(5-7-membered heterocyclils), wherein the aryl, heteroaryl, or heterocyclil is each R 5 Optionally substituted 1, 2, or 3 times;

[0089] R 5 Independently, in each case, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3-10 cycloalkyl, halogen, COOH, C(O)O(C1-C6 alkyl), O(CH2) 1-3 -OH, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, OH, CN, (CH2) 0-3 -( C6-C 10 Aril), (CH2) 0-3 -(5-6-membered heteroaryl), and (CH2) 0-3 Selected from the group consisting of -(5-7-membered heterocyclils), wherein the aryl, heteroaryl, or heterocyclil is each R 7 Optionally substituted 1, 2, or 3 times;

[0090] Alternatively, 2 Rs 5 They can form 5-10 member heteroaryls, 6-10 member aryls, 3-10 member heterocycloalkyls, or 3-10 member cycloalkyls together with the atoms to which they are attached, and all of these are R 7 Optionally substituted 1, 2, or 3 times;

[0091] R 6 are independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2)1- 4OH, S(O) 0-2 H, S(O) 0- Selected from the group consisting of 2NH2 or CN;

[0092] Alternatively, 2 Rs 6 They can form 5-10-membered heteroaryls, 6-10-membered aryls, 3-10-membered heterocycloalkyls, or 3-10-membered cycloalkyls together with the atoms to which they are attached;

[0093] R 7 are independently, in each case, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, SO2NH2, SO2NH(C1-C6 alkyl), SO2N(C1-C6 alkyl)2, (CH2) 1-2 -OH, C(O)(CH2) 1-2 Selected from the group consisting of substituents independently selected from -OH, C(O)(C1-C6 alkyl), and C(O)O(C1-C6 alkyl);

[0094] Alternatively, 2 Rs 7 They can form 5-10-membered heteroaryls, 6-10-membered aryls, 3-10-membered heterocycloalkyls, or 3-10-membered cycloalkyls together with the atoms to which they are attached;

[0095] R 8 Independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1- 4OH, S(O) 0-2 H, S(O) 0- Selected from the group consisting of 2NH2 or CN;

[0096] R 9is selected from the group consisting of 6-10-membered aryls, 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, all of which have 1, 2, or 3 Rs 8 It is optionally replaced with.

[0097] In another embodiment, a compound of formula X or a pharmaceutically acceptable salt thereof is provided herein:

[0098]

[0099] During the meal:

[0100] represents an optional double bond;

[0101] A and A' are independently CH, CR 8 or N and;

[0102] Alternatively, A is absent;

[0103] W is N, C, or CH;

[0104] Z is selected from the group consisting of S, O, N, NH, N-Me, CH2, CH, C-halo, C-(C1-C3alkyl), or C-(C1-C3alkoxy);

[0105] X and Y are independently S, O, N, CH, NR 3 or CR 3 And;

[0106] However, at least one of X, Y, or Z is CH;

[0107] R 1 is C(O)NHR 9 , selected from the group consisting of 6-10-membered aryls, 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, wherein the aryls, heteroaryls, cycloalkyls, and heterocycloalkyls have 1, 2, or 3 Rs 8 Optionally replaced with;

[0108] R 2is selected from the group consisting of 6-10-membered aryls, 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, all of which have 1, 2, or 3 Rs 6 Optionally replaced with;

[0109] R 3 is independently, in each case, halogen, OR 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , NHC(O)R 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 Selected from the group consisting of aryl, 5-6-membered heteroaryl, and 5-7-membered heterocyclil, wherein the alkyl, alkenyl, or alkynyl are each R 4 It is optionally substituted 1, 2, or 3 times, and the aryl, heteroaryl, or heterocyclil are each R 5 Optionally substituted 1, 2, or 3 times;

[0110] R 4 is independently, in each case, H, C1-C6 alkyl, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -( C6-C 10 Aril), (CH2) 0-3 -(5-6-membered heteroaryl), and (CH2) 0-3 Selected from the group consisting of -(5-7-membered heterocyclils), wherein the aryl, heteroaryl, or heterocyclil is each R 5 Optionally substituted 1, 2, or 3 times;

[0111] R 5Independently, in each case, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3-10 cycloalkyl, halogen, COOH, C(O)O(C1-C6 alkyl), O(CH2) 1-3 -OH, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, OH, CN, (CH2) 0-3 -( C6-C 10 Aril), (CH2) 0-3 -(5-6-membered heteroaryl), and (CH2) 0-3 Selected from the group consisting of -(5-7-membered heterocyclils), wherein the aryl, heteroaryl, or heterocyclil is each R 7 Optionally substituted 1, 2, or 3 times;

[0112] Alternatively, 2 Rs 5 They can form 5-10 member heteroaryls, 6-10 member aryls, 3-10 member heterocycloalkyls, or 3-10 member cycloalkyls together with the atoms to which they are attached, and all of these are R 7 Optionally substituted 1, 2, or 3 times;

[0113] R 6 are independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1- 4OH, S(O) 0-2 H, S(O) 0- Selected from the group consisting of 2NH2 or CN;

[0114] Alternatively, 2 Rs 6 They can form 5-10-membered heteroaryls, 6-10-membered aryls, 3-10-membered heterocycloalkyls, or 3-10-membered cycloalkyls together with the atoms to which they are attached;

[0115] R 7are independently, in each case, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, SO2NH2, SO2NH(C1-C6 alkyl), SO2N(C1-C6 alkyl)2, (CH2) 1-2 -OH, C(O)(CH2) 1-2 Selected from the group consisting of substituents independently selected from -OH, C(O)(C1-C6 alkyl), and C(O)O(C1-C6 alkyl);

[0116] Alternatively, 2 Rs 7 They can form 5-10-membered heteroaryls, 6-10-membered aryls, 3-10-membered heterocycloalkyls, or 3-10-membered cycloalkyls together with the atoms to which they are attached;

[0117] R 8 Independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1- 4OH, S(O) 0-2 H, S(O) 0- Selected from the group consisting of 2NH2 or CN;

[0118] R 9 is selected from the group consisting of 6-10-membered aryls, 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, all of which have 1, 2, or 3 Rs 8 It is optionally replaced with.

[0119] In one embodiment of chemical formula X, A and A' are each independently CH2, CHR 8 , NH, or NR 8 and; here, the remaining variables are defined in this specification.

[0120] In another embodiment, a compound of formula XX or a pharmaceutically acceptable salt thereof is provided herein:

[0121]

[0122] During the meal:

[0123] A and A' are independently CH2, CHR 8 , NH, or NR 8 And;

[0124] Alternatively, A is absent;

[0125] Z is selected from the group consisting of N, CH, C-halo, C-(C1-C3alkyl), or C-(C1-C3alkoxy);

[0126] X and Y are each independently N, CH, or CR 3 And;

[0127] However, at least one of X, Y, or Z is CH;

[0128] R 1 is C(O)NHR 9 , selected from the group consisting of 6-10-membered aryls, 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, wherein the aryls, heteroaryls, cycloalkyls, and heterocycloalkyls have 1, 2, or 3 Rs 8 Optionally replaced with;

[0129] R 2 is selected from the group consisting of 6-10-membered aryls, 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, all of which have 1, 2, or 3 Rs 6 Optionally replaced with;

[0130] R 3 is independently, in each case, halogen, OR 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R4 , C(O)OR 4 , C(O)NHR 4 , NHC(O)R 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 Selected from the group consisting of aryl, 5-6-membered heteroaryl, and 5-7-membered heterocyclil, wherein the alkyl, alkenyl, or alkynyl are each R 4 It is optionally substituted 1, 2, or 3 times, and the aryl, heteroaryl, or heterocyclil are each R 5 Optionally substituted 1, 2, or 3 times;

[0131] R 4 is independently, in each case, H, C1-C6 alkyl, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -( C6-C 10 Aril), (CH2) 0-3 -(5-6-membered heteroaryl), and (CH2) 0-3 Selected from the group consisting of -(5-7-membered heterocyclils), wherein the aryl, heteroaryl, or heterocyclil is each R 5 Optionally substituted 1, 2, or 3 times;

[0132] R 5 Independently, in each case, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3-10 cycloalkyl, halogen, COOH, C(O)O(C1-C6 alkyl), O(CH2) 1-3 -OH, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, OH, CN, (CH2) 0-3 -( C6-C 10 Aril), (CH2) 0-3 -(5-6-membered heteroaryl), and (CH2) 0-3Selected from the group consisting of -(5-7-membered heterocyclils), wherein the aryl, heteroaryl, or heterocyclil is each R 7 Optionally substituted 1, 2, or 3 times;

[0133] Alternatively, 2 Rs 5 They can form 5-10 member heteroaryls, 6-10 member aryls, 3-10 member heterocycloalkyls, or 3-10 member cycloalkyls together with the atoms to which they are attached, and all of these are R 7 Optionally substituted 1, 2, or 3 times;

[0134] R 6 are independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1- 4OH, S(O) 0-2 H, S(O) 0- Selected from the group consisting of 2NH2 or CN;

[0135] Alternatively, 2 Rs 6 They can form 5-10-membered heteroaryls, 6-10-membered aryls, 3-10-membered heterocycloalkyls, or 3-10-membered cycloalkyls together with the atoms to which they are attached;

[0136] R 7 are independently, in each case, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, SO2NH2, SO2NH(C1-C6 alkyl), SO2N(C1-C6 alkyl)2, (CH2) 1-2 -OH, C(O)(CH2) 1-2 Selected from the group consisting of substituents independently selected from -OH, C(O)(C1-C6 alkyl), and C(O)O(C1-C6 alkyl);

[0137] Alternatively, 2 Rs 7They can form 5-10-membered heteroaryls, 6-10-membered aryls, 3-10-membered heterocycloalkyls, or 3-10-membered cycloalkyls together with the atoms to which they are attached;

[0138] R 8 Independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1- 4OH, S(O) 0-2 H, S(O) 0- Selected from the group consisting of 2NH2 or CN;

[0139] R 9 is selected from the group consisting of 6-10-membered aryls, 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, all of which have 1, 2, or 3 Rs 8 It is optionally replaced with.

[0140] In one embodiment, R 2 is a 6-10-membered aryl or a 5-10-membered heteroaryl, and both of these have 1, 2, or 3 R 6 It is optionally replaced with. In another implementation, R 2 is 1, 2, or 3 R 6 It is a 6-10 aryl optionally substituted with . In another embodiment, R 2 is 1, 2, or 3 R 6 It is a 5-10-membered heteroaryl optionally substituted with. In another embodiment, R 2 is 1, 2, or 3 R 6 It is a phenyl selectively substituted with . In another embodiment, R 2 is 1, 2, or 3 R 6 It is pyridil that has been selectively substituted with.

[0141] In another embodiment, A and A' are each independently CH2 or CHR8 am.

[0142] In another embodiment, the compound of Formula I is a compound of Formula II or a pharmaceutically acceptable salt thereof:

[0143] .

[0144] In another embodiment, the compound of Formula II is the compound of Formula IIa below or its pharmaceutically acceptable salt:

[0145] .

[0146] In another embodiment, the compound of Formula I is a compound of Formula III or a pharmaceutically acceptable salt thereof:

[0147] .

[0148] In another embodiment, the compound of Formula III is the compound of Formula IIIa below or its pharmaceutically acceptable salt:

[0149] .

[0150] In another embodiment, the compound of Formula I is a compound of Formula IV or a pharmaceutically acceptable salt thereof:

[0151] .

[0152] In another embodiment, the compound of Formula IV is the compound of Formula IVa below or its pharmaceutically acceptable salt:

[0153] .

[0154] In another embodiment, the compound of formula IV is the compound of formula IVb or its pharmaceutically acceptable salt:

[0155] .

[0156] In one embodiment of chemical formulas IIa, IIIa, IVa and IVb,

[0157] R 1 is selected from the group consisting of benzimidazole, imidazopyridine, indole, triazole, pyrazole, imidazole, pyridinylamide, and thiazolylamide, all of which have 1, 2, or 3 R 8 Optionally replaced with;

[0158] R 6 are independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 Selected from the group consisting of NH2 or CN;

[0159] R 7 is a C1-C3 alkyl;

[0160] Each R 8 In each case, it is independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, OH, and NH2.

[0161] In one embodiment, the compound of formula I is a compound of formula V or a pharmaceutically acceptable salt thereof:

[0162] .

[0163] In another embodiment, the compound of Formula I is a compound of Formula VI or a pharmaceutically acceptable salt thereof:

[0164] .

[0165] In another embodiment, the compound of Formula I is the compound of Formula VII or its pharmaceutically acceptable salt:

[0166] .

[0167] In another embodiment, the compound of Formula I is a compound of Formula VIII or a pharmaceutically acceptable salt thereof:

[0168] .

[0169] In another embodiment, the compound of Formula I is the compound of Formula IX below or a pharmaceutically acceptable salt thereof:

[0170] .

[0171] In another embodiment, the compound of formula X is a compound of formula Xa or a pharmaceutically acceptable salt thereof:

[0172] .

[0173] In another embodiment, the compound of formula X is a compound of formula Xb or a pharmaceutically acceptable salt thereof:

[0174] .

[0175] In one embodiment, the compound of formula XX is a compound of formula XXa or a pharmaceutically acceptable salt thereof:

[0176] .

[0177] In another embodiment, the compound of formula XXa is the compound of formula XXb or its pharmaceutically acceptable salt:

[0178] .

[0179] In another embodiment, the compound of formula XXa is the compound of formula XXc or its pharmaceutically acceptable salt:

[0180] .

[0181] In one embodiment of chemical formulas XXb and XXc,

[0182] R 1is selected from the group consisting of benzimidazole, imidazopyridine, indole, triazole, pyrazole, imidazole, pyridinylamide, and thiazolylamide, all of which have 1, 2, or 3 R 8 Optionally replaced with;

[0183] R 6 are independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 Selected from the group consisting of NH2 or CN;

[0184] R 7 is a C1-C3 alkyl;

[0185] R 8 In each case, it is independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, OH, and NH2.

[0186] In one embodiment, R 3 is independently, in each case, halogen, OR 4 , NR 4 R 4 , C(O)NHR 4 , C1-C6 alkyl, C2-C6 alkynyl, and C6-C 10 Selected from the group consisting of aryls, wherein alkyl and alkynyl are R 4 It is optionally substituted 1, 2, or 3 times, and the aryl is R 5 It is optionally substituted 1, 2, or 3 times.

[0187] In another implementation example, R 3 is OR 4 is. In another implementation, R 3 NR 4 R 4 is. In another implementation, R 3 is R 4It is a C2-C6 alkynyl selectively substituted 1, 2, or 3 times. In one embodiment, R 3 is R 5 C6-C that is optionally substituted 1, 2, or 3 times 10 It is Aril. In another implementation example, R 3 is C(O)NHR 4 am.

[0188] In another implementation example, R 3 is independently, in each case, halogen, methyl,

[0189]

[0190] and It is selected from a group consisting of.

[0191] In another implementation example, R 6 are independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1- 4OH, S(O) 0-2 H, S(O) 0- It is selected from the group consisting of 2NH2 or CN. In another embodiment, R 6 is independently, in each case, a hydroxy or a halo. In one embodiment, R 6 is chloro. In another embodiment, R 6 is a fluoro. In another embodiment, R 6 It is a hydroxyl group.

[0192] In one embodiment, R 1 is selected from the group consisting of benzimidazole, imidazopyridine, indole, triazole, pyrazole, imidazole, pyridinylamide, and thiazolylamide, all of which have 1, 2, or 3 R 8 It is optionally replaced with.

[0193] In another implementation example, R 1is selected from a group consisting of the following; all of them are 1, 2, or 3 R 8 Optionally replaced with:

[0194]

[0195]

[0196] and .

[0197] In another implementation example, R 1 is selected from a group consisting of the following; all of them are 1, 2, or 3 R 8 Optionally replaced with:

[0198]

[0199] and .

[0200] In another implementation example, R 1 is the following:

[0201] .

[0202] In another implementation example, R 1 is the following:

[0203] .

[0204] In another implementation example, R 1 is the following:

[0205] .

[0206] In one embodiment, R 7 is a C1-C3 alkyl. In another embodiment, R 7 It is methyl.

[0207] In another implementation example, R 8 In each case, it is independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, OH, and NH2.

[0208] In one embodiment, the compound of formula I is selected from the group consisting of the compounds of Table 1 or their pharmaceutically acceptable salts.

[0209]

[0210]

[0211]

[0212] In another embodiment, the compound of formula X is selected from the group consisting of the compounds of Table 2 or their pharmaceutically acceptable salts.

[0213]

[0214] In another embodiment, the compound of chemical formula XX is selected from the group consisting of compounds in Table 3.

[0215]

[0216] The compounds disclosed in this specification may exist as tautomers and optical isomers (e.g., enantiomers, diastereomers, mixtures of diastereomers, racemic mixtures, etc.).

[0217] It is generally well known in the art that any compound to be converted in vivo to provide the compound disclosed in this specification is a prodrug within the scope of this disclosure.

[0218] In one embodiment, a pharmaceutical composition is provided herein comprising any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0219] In one embodiment, the composition further comprises a second activator. In another embodiment, the second activator is selected from the group consisting of MEK inhibitors, PI3K inhibitors, and mTor inhibitors. In another embodiment, the second activator prevents EGFR dimer formation in the subject. In another embodiment, the second activator is selected from the group consisting of cetuximab, trastuzumab, and panitumumab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0220] In another aspect, a pharmaceutical composition comprising the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier is provided herein. In another aspect, the pharmaceutical composition further comprises a second activator that prevents EGFR dimer formation and a pharmaceutically acceptable carrier. In some embodiments, the second activator that prevents EGFR dimer formation is an antibody. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab.

[0221] A compound that binds to an allosteric site of EGFR, selectively combined with a second activator that prevents EGFR dimer formation, e.g., a compound of the present disclosure (e.g., a compound of the formula disclosed herein), can modulate EGFR activity. In some embodiments, the compound of the present disclosure can inhibit or reduce EGFR activity without a second activator (e.g., an antibody such as cetuximab, trastuzumab, or panitumumab). In other embodiments, the compound of the present disclosure is combined with a second activator. In one embodiment, the second activator can prevent EGFR dimer formation and / or inhibit or reduce EGFR activity. In some embodiments, the second activator that prevents EGFR dimer formation is an antibody. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In an additional embodiment, the second activator that prevents EGFR dimer formation is cetuximab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0222] Treatment methods

[0223] In one embodiment, a method for treating cancer in an individual requiring treatment for cancer is provided herein, comprising administering a therapeutically effective amount of the compound of the present disclosure to the individual. 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).

[0224] In another aspect, a method for inhibiting a kinase in an individual requiring kinase inhibition is provided herein, comprising administering a therapeutically effective amount of the compound provided herein to the individual. In one embodiment, the kinase is EGFR.

[0225] In another aspect, a method for treating or preventing a kinase-mediated disorder in an individual requiring treatment or prevention of the kinase-mediated disorder is provided herein, comprising administering a therapeutically effective amount of the compound of the present disclosure to the individual. In one embodiment, the kinase-mediated disorder is resistant to EGFR targeted therapy. In another embodiment, the EGFR therapeutic regimen is selected from the group consisting of gefitinib, erlotinib, or osimertinib.

[0226] In some embodiments, the compounds of the present disclosure may regulate (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 another embodiment, the mutant EGFR contains a combination of mutations, wherein the combination 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 another embodiment, the mutant EGFR contains a combination of mutations, wherein the combination 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 another embodiment, the mutant EGFR contains a combination of mutations, wherein the combination is selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M.

[0227] In some embodiments, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation can regulate (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 another embodiment, the mutant EGFR contains a combination of mutations, wherein the combination 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 another embodiment, the mutant EGFR contains a combination of mutations, wherein the combination is selected from Del / L844V, L858R / L844V, L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M. In another embodiment, the mutant EGFR contains a combination of mutations, wherein the combination is selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M. In some embodiments, the second activator that prevents EGFR dimer formation is an antibody. In additional embodiments, the second activator that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In additional embodiments, the second activator that prevents EGFR dimer formation is cetuximab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor.In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib.

[0228] In some embodiments, the compounds of the present disclosure may regulate (e.g., inhibit or reduce) the activity of EGFR containing one or more mutations, but do not affect the activity of wild-type EGFR.

[0229] In another embodiment, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation can modulate (e.g., inhibit or reduce) the activity of EGFR containing one or more mutations and does not affect the activity of wild-type EGFR. In some embodiments, the second activator that prevents EGFR dimer formation is an antibody. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In yet another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0230] Modulation of EGFR containing one or more mutations such as those described herein, rather than wild-type EGFR, provides an approach for the treatment, prevention, or improvement of diseases including but not limited to cancer and metastasis, inflammation, arthritis, systemic lupus erythematosus, skin-related disorders, lung disorders, cardiovascular diseases, ischemia, neurodegenerative disorders, liver diseases, gastrointestinal 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.

[0231] In some embodiments, the compounds of the present disclosure exhibit greater inhibition of EGFR containing one or more mutations as described herein compared to wild-type EGFR. In certain embodiments, the compounds of the present disclosure exhibit at least 2, 3, 5, 10, 25, 50, or 100 greater inhibition of EGFR containing one or more mutations as described herein compared to wild-type EGFR. In various embodiments, the compounds of the present disclosure exhibit up to 1,000 greater inhibition of EGFR containing one or more mutations as described herein compared to wild-type EGFR. In various embodiments, the compounds of the present disclosure exhibit up to 10,000 times greater inhibition of EGFR having combinations of the 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.

[0232] In another embodiment, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation exhibits greater inhibition of EGFR containing one or more mutations as described herein compared to wild-type EGFR. In a specific embodiment, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation exhibits at least 2, 3, 5, 10, 25, 50, or 100 greater inhibition of EGFR containing one or more mutations as described herein compared to wild-type EGFR. In various embodiments, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation exhibits up to 1,000 greater inhibition of EGFR containing one or more mutations as described herein compared to wild-type EGFR. In various embodiments, the compounds of the present disclosure combined with a second activator that prevents EGFR dimer formation exhibit up to 10,000-fold greater inhibition of EGFR having combinations of the 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 activator that prevents EGFR dimer formation is an antibody. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0233] In some embodiments, the compounds of the present disclosure exhibit about 2 to about 10 times greater inhibition of EGFR containing one or more mutations as described herein compared to wild-type EGFR. In various embodiments, the compounds of the present disclosure exhibit about 10 to about 100 times greater inhibition of EGFR containing one or more mutations as described herein compared to wild-type EGFR. In various embodiments, the compounds of the present disclosure exhibit about 100 to about 1000 times greater inhibition of EGFR containing one or more mutations as described herein compared to wild-type EGFR. In various embodiments, the compounds of the present disclosure exhibit about 1000 to about 10000 times greater inhibition of EGFR containing one or more mutations as described herein compared to wild-type EGFR.

[0234] In another embodiment, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation exhibits inhibition of EGFR containing one or more mutations as described herein, which is about 2 to about 10 times greater than wild-type EGFR. In another embodiment, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation exhibits inhibition of EGFR containing one or more mutations as described herein, which is about 10 to about 100 times greater than wild-type EGFR. In another embodiment, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation exhibits inhibition of EGFR containing one or more mutations as described herein, which is about 100 to about 1000 times greater than wild-type EGFR. In another embodiment, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation exhibits inhibition of EGFR containing one or more mutations as described herein, which is about 1,000 to about 10,000 times greater than that of wild-type EGFR. In another embodiment, the second activator that prevents EGFR dimer formation is an antibody. In a further embodiment, the second activator that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second activator that prevents EGFR dimer formation is cetuximab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0235] In a specific embodiment, the compound of the present disclosure exhibits at least 2 times greater inhibition of EGFR having a combination of L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and mutations selected from L858R / T790M compared to wild-type EGFR. In a specific embodiment, the compound of the present disclosure exhibits at least 3 times greater inhibition of EGFR having a combination of L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and mutations selected from L858R / T790M compared to wild-type EGFR. In a specific embodiment, the compound of the present disclosure exhibits at least 5 times greater inhibition of EGFR having a combination of L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and mutations selected from L858R / T790M compared to wild-type EGFR. In a specific embodiment, the compound of the present disclosure exhibits at least 10 times greater inhibition of EGFR having a combination of L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and mutations selected from L858R / T790M compared to wild-type EGFR. In a specific embodiment, the compound of the present disclosure exhibits at least 25 times greater inhibition of 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.In a specific embodiment, the compound of the present disclosure exhibits at least 50 times greater inhibition of EGFR having a combination of mutants selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In a specific embodiment, the compound of the present disclosure exhibits at least 100 times greater inhibition of EGFR having a combination of mutants selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR.

[0236] In a specific embodiment, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation exhibits at least 2 times greater inhibition of 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. In a specific embodiment, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation exhibits at least three times greater inhibition of 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. In a specific embodiment, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation exhibits at least 5 times greater inhibition of 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. In a specific embodiment, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation exhibits at least 10 times greater inhibition of 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.In a specific embodiment, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation exhibits at least 25 times greater inhibition of 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. In a specific embodiment, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation exhibits at least 50 times greater inhibition of EGFR having a combination of mutants selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In a specific embodiment, the compound of the present disclosure combined with a second activator that prevents EGFR dimer formation exhibits at least 100-fold greater inhibition of 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. In some embodiments, the second activator that prevents EGFR dimer formation is an antibody. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0237] In some embodiments, inhibition of EGFR activity is IC 50 It is measured by.

[0238] In some embodiments, inhibition of EGFR activity is EC 50 It is measured by.

[0239] In some embodiments, inhibition of EGFR by the compounds of the present disclosure may be measured by biochemical assays. As an exemplary and non-limiting example, inhibition of EGFR activity may be determined using homogeneous time-resolved fluorescence (HTRF) assays using the conditions and experimental parameters disclosed herein. The HTRF assay may utilize, for example, a concentration of about 1 μM of a substrate (e.g., a biotin-Lck-peptide substrate); a concentration of about 0.2 nM to about 40 nM of EGFR (mutant or WT); and a concentration of about 0.000282 μM to about 50 μM of an inhibitor. Compounds of the present disclosure screened under these conditions may be, 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 of IC 50 Values ​​may be represented. In certain embodiments, compounds of the present disclosure screened under the above conditions for inhibition of EGFR having a mutation or combination of mutations selected from L858R / T790M, L858R, and T790M have, for example, ICs of about 1 nM to >1 μM; about 1 nM to about 400 nM; about 1 nM to about 150 nM; about 1 nM to about 75 nM; about 1 nM to about 40 nM; about 1 nM to about 25 nM; about 1 nM to about 15 nM; or about 1 nM to about 10 nM. 50 Can represent a value.

[0240] In some embodiments, the compound of the present disclosure binds to an allosteric site of EGFR. In some embodiments, the compound of the present disclosure interacts with at least one amino acid residue of the epidermal growth factor receptor (EGFR) selected from Lys745, Leu788, and Ala743. In other embodiments, the compound of the present disclosure interacts with at least one amino acid residue of the epidermal growth factor receptor (EGFR) selected from Cys755, Leu777, Phe856, and Asp855. In other embodiments, the compound of the present disclosure interacts with at least one amino acid residue of the epidermal growth factor receptor (EGFR) selected from Met766, Ile759, Glu762, and Ala763. In other embodiments, the compound of the present disclosure interacts with at least one amino acid residue of the epidermal growth factor receptor (EGFR) selected from Lys745, Leu788, and Ala743; It interacts with at least one amino acid residue of the epidermal growth factor receptor (EGFR) selected from Cys755, Leu777, Phe856, and Asp855; and at least one amino acid residue of the epidermal growth factor receptor (EGFR) selected from Met766, Ile759, Glu762, and Ala763. In another embodiment, the compound of the present disclosure does not interact with any of the amino acid residues of the epidermal growth factor receptor (EGFR) selected from Met793, Gly796, and Cys797.

[0241] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor, wherein the compound is a more potent inhibitor of a drug-resistant EGFR mutant compared to wild-type EGFR. For example, the compound may be at least about 2, 3, 5, 10, 25, 50, or about 100 times more potent in inhibiting the kinase activity of a drug-resistant EGFR mutant compared to wild-type EGFR. In some embodiments, the drug-resistant EGFR mutant is resistant to one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib.

[0242] In some embodiments, drug-resistant EGFR mutants include sensitization mutants such as Del and L858R.

[0243] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor combined with a second activator that prevents EGFR dimer formation, wherein the compound is a more potent inhibitor of a drug-resistant EGFR mutant compared to wild-type EGFR. For example, the compound combined with the second activator that prevents EGFR dimer formation may be at least about 2, 3, 5, 10, 25, 50, or about 100 times more potent in inhibiting the kinase activity of a drug-resistant EGFR mutant compared to wild-type EGFR. In some embodiments, the drug-resistant EGFR mutant is resistant to one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib. In some embodiments, drug-resistant EGFR mutants include sensitization mutations such as Del and L858R. In some embodiments, a secondary activator that prevents EGFR dimer formation is an antibody. In additional embodiments, the secondary activator that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In additional embodiments, the secondary activator that prevents EGFR dimer formation is cetuximab. In one embodiment, the secondary activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0244] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor, wherein the compound does not possess drug resistance mutations but compared to an EGFR mutant possessing sensitization mutations (e.g., IC 50(When measured as) inhibits the kinase activity of sensitized mutants (e.g., Del and L858R) and drug-resistant mutants (e.g., T790M, L718Q, C797S, and L844V) carrying drug-resistant EGFR mutants with a difference in efficacy of less than 10 times. In some embodiments, the difference in efficacy is about 9 times, 8 times, 7 times, 6 times, 5 times, 4 times, 3 times, or less than 2 times.

[0245] In another embodiment, the present disclosure provides a compound comprising an allosteric kinase inhibitor combined with a second activator, wherein the second activator prevents the formation of EGFR dimers, and wherein the compound combined with the second activator is compared to an EGFR mutant that does not possess drug resistance mutations but possesses sensitization mutations (e.g., IC 50 (When measured as) inhibits the kinase activity of sensitized mutants (e.g., Del and L858R) and drug-resistant mutants (e.g., T790M, L718Q, C797S, and L844V) harboring drug-resistant EGFR mutants with a difference in efficacy of less than 10-fold. In some embodiments, the difference in efficacy is about 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4-fold, 3-fold, or less than 2-fold. In some embodiments, the secondary activator preventing EGFR dimer formation is an antibody. In additional embodiments, the secondary activator preventing EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In additional embodiments, the secondary activator preventing EGFR dimer formation is cetuximab. In one embodiment, the secondary activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0246] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor, wherein the compound is more potent than one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib, in inhibiting the activity of EGFR containing one or more mutations as described herein, e.g., T790M, L718Q, L844V, L858R, C797S, and Del. For example, the compound is more potent than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib (e.g., IC 50 (When measured as) it can be at least about 2, 3, 5, 10, 25, 50, or about 100 times more powerful.

[0247] In another embodiment, the present disclosure provides a compound comprising an allosteric kinase inhibitor combined with a second activator that prevents EGFR dimer formation, and the compound combined with the second activator is more potent than one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib, when inhibiting the activity of EGFR containing one or more mutations as described herein, e.g., T790M, L718Q, L844V, L858R, C797S, and Del. For example, compounds combined with a second activator that prevents EGFR dimer formation, compared to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib (e.g., IC 50(When measured as) it may be at least about 2, 3, 5, 10, 25, 50, or about 100 times more potent. In some embodiments, the secondary activator preventing EGFR dimer formation is an antibody. In additional embodiments, the secondary activator preventing EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In additional embodiments, the secondary activator preventing EGFR dimer formation is cetuximab. In one embodiment, the secondary activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0248] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor, wherein the compound is less potent than one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib, when inhibiting the activity of wild-type EGFR. For example, the compound is less potent than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib (e.g., IC 50 (When measured as) it may be at least about 2, 3, 5, 10, 25, 50, or about 100 times less powerful.

[0249] In another embodiment, the present disclosure provides a compound comprising an allosteric kinase inhibitor combined with a second activator that prevents EGFR dimer formation, wherein the compound combined with the second activator is less potent than one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib, when inhibiting the activity of wild-type EGFR. For example, the compound combined with the second activator that prevents EGFR dimer formation is less potent than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib when inhibiting the activity of wild-type EGFR (e.g., IC 50 (When measured as) it may be at least about 2, 3, 5, 10, 25, 50, or about 100 times less potent. In some embodiments, the secondary activator preventing EGFR dimer formation is an antibody. In additional embodiments, the secondary activator preventing EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In additional embodiments, the secondary activator preventing EGFR dimer formation is cetuximab. In one embodiment, the secondary activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0250] The efficacy of the inhibitor is EC 50 It can be determined as a value. As determined under substantially similar conditions, EC 50 Compounds with lower values ​​are EC 50 It is a more potent inhibitor compared to compounds with higher values. In some embodiments, substantially similar conditions include determining EGFR-dependent phosphorylation levels in vitro or in vivo (e.g., in 3T3 cells expressing wild-type EGFR, mutant EGFR, or any fragment thereof).

[0251] The efficacy of inhibitors is also IC 50 It can be determined by the value. As determined under substantially similar conditions, IC 50 Compounds with lower IC values 50 It is a more potent inhibitor compared to compounds with higher values. In some embodiments, substantially similar conditions include determining EGFR-dependent phosphorylation levels in vitro or in vivo (e.g., in 3T3 cells expressing wild-type EGFR, mutant EGFR, or any fragment thereof).

[0252] EGFR sensitization mutations include, without restriction, L858R, G719S, G719C, G719A, L861Q, deletions in exon 19 and / or insertions in exon 20. Drug-resistant EGFR mutants may have drug-resistant mutations including, without restriction, T790M, T854A, L718Q, C797S, or D761Y.

[0253] Selectivity between wild-type EGFR containing one or more mutations as described herein and EGFR can also be measured using a cell proliferation assay in which cell proliferation depends on kinase activity. For example, murine Ba / F3 cells transfected with a suitable version of wild-type EGFR (e.g., VIII; containing the WT EGFR kinase domain), or Ba / F3 cells transfected with L858R / T790M, Del / T790M / L718Q, L858R / T790M / L718Q, L858R / T790M / C797S, Del / T790M / C797S, L858R / T790M / I941R, or exon 19 deletion / T790M may be used. Proliferation assays were performed in the inhibitor concentration range (10 μM, 3 μM, 1.1 μM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and EC 50 This is calculated.

[0254] An alternative method to measure the effect on EGFR activity is to test EGFR phosphorylation. Wild-type or mutant (L858R / T790M, Del / T790M, Del / T790M / L718Q, L858R / T790M / C797S, Del / T790M / C797S, L858R / T790M / I941R, or L858R / T790M / L718Q) EGFR can be transfected into NIH-3T3 cells (which do not normally express endogenous EGFR), and the ability of inhibitors (using the concentrations mentioned above) to inhibit EGFR phosphorylation can be tested. Cells are exposed to increasing concentrations of the inhibitor for 6 hours and stimulated with EGF for 10 minutes. The effect on EGFR phosphorylation is tested by Western blotting using a phospho-specific (Y1068) EGFR antibody.

[0255] In another aspect, the present disclosure relates to a compound that binds to an allosteric site of EGFR, wherein the compound exhibits inhibition of EGFR containing one or more mutations as described herein (e.g., L858R / T790M, Del / T790M, Del / T790M / L718Q, L858R / T790M / C797S, Del / T790M / C797S, L858R / T790M / I941R, or L858R / T790M / L718Q) greater than 2, 3, 5, 10, 25, 50, 100, or 1000 times compared to wild-type EGFR.

[0256] In another embodiment, the present disclosure provides a compound that binds to an allosteric site in an EGFR combined with a second activator that prevents EGFR dimer formation, and the compound combined with the second activator exhibits inhibition of more than 2, 3, 5, 10, 25, 50, 100, or 1000 times of an EGFR containing one or more mutations as 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 secondary activator that prevents EGFR dimer formation is an antibody. In additional embodiments, the secondary activator that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In additional embodiments, the secondary activator that prevents EGFR dimer formation is cetuximab. In one embodiment, the secondary activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0257] In another aspect, the present disclosure provides a method for inhibiting the epidermal growth factor receptor (EGFR), the method comprising administering an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject requiring such method. In some embodiments, the method further comprises administering a second activator, wherein the second activator prevents EGFR dimer formation. In some embodiments, the second activator preventing EGFR dimer formation is an antibody. In further embodiments, the second activator preventing EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second activator preventing EGFR dimer formation is cetuximab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0258] In another aspect, a method for treating or preventing a disease is provided herein, comprising administering an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject requiring treatment or prevention of the disease. In some embodiments, the disease is mediated by a kinase. In further embodiments, the kinase comprises a mutated cysteine ​​residue. In further embodiments, the mutated cysteine ​​residue is located at or near a position equivalent to Cys 797 in EGFRs including these positions in Jak3, Blk, Bmx, Btk, HER2 (ErbB2), HER4 (ErbB4), Itk, Tec, and Txk. In some embodiments, the method further comprises administering a second activator, said second activator prevents the formation of a kinase dimer. In some embodiments, the second activator preventing the formation of a kinase dimer is an antibody. In further embodiments, the second activator prevents the formation of an EGFR dimer. In additional embodiments, the second activator that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In additional embodiments, the second activator that prevents EGFR dimer formation is cetuximab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0259] In some embodiments, the disease is mediated by EGFR (e.g., EGFR plays a role in the initiation or development of the disease). In some embodiments, the disease is mediated by Her-kinase. In additional embodiments, the Her-kinase is HER1, HER2, or HER4.

[0260] In certain embodiments, the disease is resistant to known EGFR inhibitors, including but not limited to gefitinib, erlotinib, or osimertinib. In certain embodiments, a diagnostic test is performed to determine whether the disease is associated with an activating mutation of EGFR. In certain embodiments, a diagnostic test is performed to determine whether the disease is associated with an EGFR having an activating mutation and / or a drug-resistant mutation. Activating mutations include, without limitation, L858R, G719S, G719C, G719A, L718Q, L861Q, deletions in exon 19 and / or insertions in exon 20. Drug-resistant EGFR mutants may have drug-resistant mutations including, without limitation, 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.

[0261] In a specific embodiment, the disease is cancer or a proliferative disease.

[0262] In an additional embodiment, the disease is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, gastric cancer, skin cancer, bone cancer, stomach cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, or solid tumor. In an additional embodiment, the disease is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer. In another embodiment, the disease is non-small cell lung cancer.

[0263] In certain embodiments, the disease is resistant to known EGFR inhibitors, including but not limited to gefitinib, erlotinib, or osimertinib. In certain embodiments, a diagnostic test is performed to determine whether the disease is associated with an activating mutation of EGFR. In certain embodiments, a diagnostic test is performed to determine whether the disease is associated with an EGFR having an activating mutation and / or a drug-resistant mutation. Activating mutations include, without limitation, L858R, G719S, G719C, G719A, L718Q, L861Q, deletions in exon 19 and / or insertions in exon 20. Drug-resistant EGFR mutants may have drug-resistant mutations including, without limitation, 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.

[0264] In another aspect, a method for treating a kinase-mediated disorder is provided herein, comprising administering an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject in need. In some embodiments, the compound is an inhibitor of HER1, HER2, or HER4. In other embodiments, the subject receives an additional therapeutic agent. In other embodiments, the compound and the additional therapeutic agent are administered simultaneously or sequentially.

[0265] In another aspect, the present disclosure provides a method for treating a kinase-mediated disorder, the method comprising administering an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a second activator that prevents EGFR dimer formation to a subject requiring treatment. In some embodiments, the compound is an inhibitor of HER1, HER2, or HER4. In other embodiments, the subject receives an additional therapeutic agent. In other embodiments, the compound, the second activator that prevents EGFR dimer formation, and the additional therapeutic agent are administered simultaneously or sequentially. In some embodiments, the second activator that prevents EGFR dimer formation is an antibody. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0266] In another embodiment, the disease is cancer. In an additional embodiment, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, gastric cancer, skin cancer, bone cancer, stomach cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, or solid tumor. In an additional embodiment, the disease is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer. In yet another embodiment, the disease is non-small cell lung cancer.

[0267] In another embodiment, a method for treating cancer is provided herein, wherein cancer cells contain activated EGFR, and the method comprises administering an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment.

[0268] In another aspect, a method for treating cancer is provided herein, wherein cancer cells contain activated EGFR, and the method comprises administering an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a second activator that prevents EGFR dimer formation to a subject requiring treatment. In some embodiments, the second activator that prevents EGFR dimer formation is an antibody. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0269] In a specific embodiment, EGFR activation is selected from mutation of EGFR, amplification of EGFR, expression of EGFR, and ligand-mediated activation of EGFR.

[0270] In an additional embodiment, mutations of EGFR are selected from G719S, G719C, G719A, L858R, L861Q, exon 19 deletion mutations, and exon 20 insertion mutations.

[0271] In another aspect, the present specification provides a method for treating cancer in a subject identified as requiring EGFR inhibition for cancer treatment, the method comprising administering an effective amount of the compound disclosed in the present specification, or a pharmaceutically acceptable salt thereof, to the subject.

[0272] In a specific embodiment, a subject identified as requiring EGFR inhibition is resistant to a known EGFR inhibitor, including but not limited to gefitinib, erlotinib, or osimertinib. In a specific embodiment, a diagnostic test is performed to determine whether the subject has an activating mutation in the EGFR. In a specific embodiment, a diagnostic test is performed to determine whether the subject has an EGFR harboring an activating mutation and / or a drug-resistant mutation. Activating mutations include, without limitation, L858R, G719S, G719C, G719A, L718Q, L861Q, deletions in exon 19, and / or insertions in exon 20. Drug-resistant EGFR mutants may have drug-resistant mutations including, without limitation, 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.

[0273] In one embodiment, a method for preventing resistance to a known EGFR inhibitor (including but not limited to gefitinib, erlotinib, or osimertinib) in a subject is provided herein, and the method comprises administering an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a subject who requires it.

[0274] In another aspect, a method for preventing resistance to a known EGFR inhibitor (including but not limited to gefitinib, erlotinib, or osimertinib) in a disease is provided herein, and the method comprises administering an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a second activator that prevents EGFR dimer formation to a subject requiring such a method. In some embodiments, the second activator that prevents EGFR dimer formation is an antibody. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab.

[0275] In an embodiment of the method disclosed in this specification, the subject is a human.

[0276] In another aspect, the present disclosure provides a compound disclosed herein or a pharmaceutically acceptable salt thereof for use in the manufacture of a drug for treating or preventing a disease in which EGFR plays a role.

[0277] In one embodiment, a method for treating or preventing a pathological condition selected from the group consisting of autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immunologically mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone-related diseases, allergies, asthma, and Alzheimer's disease is provided herein. In another embodiment, the pathological condition is selected from proliferative disorders and neurodegenerative disorders.

[0278] One aspect of the present disclosure provides a compound useful for the treatment of diseases, disorders, and pathological 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, glioblastoma, gastric cancer, skin cancer, keratocanceroma, lung cancer, epidermal 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 carcinoma, liver carcinoma and gallbladder carcinoma, renal carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's cancer, hair cell carcinoma, buccal cancer and pharyngeal cancer (oral), lip cancer, tongue cancer, oral cancer, pharyngeal cancer, small intestine cancer, colon cancer, rectal cancer, colorectal cancer, rectal cancer, brain and central nervous system, chronic myeloid leukemia (CML), and Leukemia. The term "cancer" includes, but is not limited to, the following cancers: multiple myeloma, lymphoma, or gastric cancer, renal cancer, head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, hepatocarcinoma, non-Hodgkin lymphoma, and selected cancers from the lung.

[0279] The term "cancer" refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, etc. For example, cancer includes, but is not limited to, mesothelioma, leukemias, and lymphomas such as cutaneous T-cell lymphoma (CTCL), extracutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotropic virus (HTLV) such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphoma, and multiple myeloma, non-Hodgkin lymphoma, acute lymphotropic leukemia (ALL), chronic lymphotropic leukemia (CLL), Hodgkin lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Additional examples include myelodysplastic syndrome, childhood solid tumors such as brain tumors, glial cell tumors, retinoblastoma, Wilms tumor, bone tumors, and soft tissue sarcomas, common adult solid tumors such as head and neck cancers (e.g., oral, laryngeal, nasopharyngeal, and esophageal), genitourinary cancers (e.g., prostate, bladder, kidney, uterus, ovary, testis), lung cancer (e.g., small cell and non-small cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, gastrointestinal cancer, brain tumors, tumors associated with Gorlin syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer. Additional exemplary forms of cancer that can be treated by the compound include, but are not limited to, cancer of the skeleton or smooth muscle, gastrointestinal cancer, small intestine cancer, rectal carcinoma, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0280] Additional cancers for which the compounds described herein may be useful for prevention, treatment, and research include, for example, colorectal carcinoma, familial adenomatous polyposis carcinoma, congenital non-polyposis colorectal cancer, or melanoma. In addition, cancer includes, but is not limited to, labial carcinoma, laryngeal carcinoma, hypopharyngeal carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), renal carcinoma, renal parenchymal carcinoma, cervical carcinoma, uterine trunk carcinoma, endometrial carcinoma, choriocarcinoma, testicular carcinoma, urinary tract carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gallbladder carcinoma, bronchial carcinoma, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing 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 drug for treating cancer, including but not limited to various types of cancer disclosed herein.

[0281] In some embodiments, the compounds of the present disclosure are useful for the treatment of cancers, e.g., colorectal cancer, thyroid cancer, breast cancer, and lung cancer; and myeloproliferative disorders, e.g., polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, eosinophilia syndrome, pediatric myelomonocytic leukemia, and systemic mast cell disease. In some embodiments, the compounds of the present disclosure are useful for the treatment of hematopoietic disorders, particularly acute-myeloid leukemia (AML), chronic-myeloid leukemia (CML), acute-promyeloid leukemia, and acute lymphoblastic leukemia (ALL).

[0282] The term "cancer cell" as provided in this specification includes a cell affected by any one of the identified pathological conditions.

[0283] The present disclosure further provides a method for treating or preventing cell proliferative disorders such as hyperplasia, dysplasia, and precancerous lesions. Dysplasia is the earliest form of precancerous lesion that a pathologist can recognize in a biopsy. The compound may be administered to prevent said proliferation, dysplasia, or precancerous lesion from continuing to expand or becoming cancerous. Examples of precancerous lesions may occur in the skin, esophageal tissue, breast, and cervical intraepithelial tissue.

[0284] Examples of neurodegenerative diseases are, without limitation, adrenoleukodystrophy (ALD), Alexander disease, Alpers disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), ataxia vasodilation, Batten disease (also known as Spielmeier-Vogt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, familial fatal insomnia, frontotemporal degeneration, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe disease, Lewy body dementia, neuroborreliosis, Macaudo-Joseph disease (spinocerebellar ataxia type 3), multiple system atrophy, multiple sclerosis, narcolepsy, Niemann-Pick disease, Parkinson's disease, Pelizeus-Merzbacher disease, Pick disease, primary lateral sclerosis, prion disease, progressive supranuclear palsy, Refsum disease, Includes Sandhoff disease, Schielder disease, secondary pernicious anemia of the spinal cord with subacute combined degeneration, Spielmeier-Vogt-Sjögren-Watten disease (also known as Batten disease), spinocerebellar ataxia (several types with varying characteristics), spinal muscular atrophy, Still-Richardson-Olszewski disease, spinal syphilis, and toxic encephalopathy.

[0285] Another aspect of the present disclosure provides a method for alleviating or treating the severity of a disease selected from proliferative or hyperproliferative diseases or neurodegenerative diseases, the method comprises administering an effective amount of a compound or a pharmaceutically acceptable composition containing the compound to a subject in need thereof. In another embodiment, the method further comprises administering a second activator, said second activator prevents EGFR dimer formation. In some embodiments, the second activator preventing EGFR dimer formation is an antibody. In further embodiments, the second activator preventing EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second activator preventing EGFR dimer formation is cetuximab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0286] The activity of the compounds and compositions of the present disclosure as EGFR kinase inhibitors may be tested in vitro, in vivo, or in cell lines. In vitro tests include tests that determine the inhibition of kinase activity or ATPase activity of an activated kinase. Alternative in vitro tests may be measured by quantifying the ability of an inhibitor to bind to a protein kinase, radiolabeling the inhibitor before binding, isolating the inhibitor / kinase complex, determining the amount of the bound radiolabel, or by performing a competitive experiment in which a new inhibitor is incubated with a kinase bound to a known radioligand. Detailed conditions for testing the compounds used in the present disclosure as inhibitors of various kinases are described in the following examples.

[0287] According to the foregoing, the present disclosure further provides a method for preventing or treating any of the diseases or disorders described above in a subject requiring treatment, the method comprising administering to the subject a therapeutically effective amount of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and optionally a second activator that prevents EGFR dimer formation. For the said use, the required dosage varies depending on the mode of administration, the specific pathological condition to be treated, and the desired effect.

[0288] In another embodiment, the compound and the second activator that prevents EGFR dimer formation are administered simultaneously or sequentially.

[0289] Administration / Dosage / Formulation

[0290] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may contain, for example, 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 (particularly cottonseed, peanut, corn, germ, olive, castor, and sesame oils), fatty acid esters of glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan, and mixtures thereof, and inert diluents commonly used in the art. In addition to inert diluents, the oral composition may also include adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0291] Injectable formulations (e.g., sterile injectable aqueous or oil-based suspensions) may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable formulations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, e.g., solutions in 1,3-butanediol. Acceptable vehicles and solvents available include water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile fixatives are typically used as solvents or dispersion media. For this purpose, any non-irritating fixative, including synthetic mono- or diglycerides, may be used. Furthermore, fatty acids such as oleic acid are used in the preparation of injectable formulations.

[0292] To prolong the effect of a drug, it is often desirable to slow its absorption via subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. The rate of drug absorption depends on the rate of dissolution, which can vary depending on crystal size and crystal form. Alternatively, delayed absorption of parenterally administered drug forms is achieved by dissolving or suspending the drug in an oil vehicle.

[0293] A composition for rectal or vaginal administration is preferably a suppository that can be prepared by mixing the compound of the present disclosure with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity to release the active compound.

[0294] Similar types of solid compositions can also be used as fillers for soft and hard filled gelatin capsules using excipients such as lactose or lactose, as well as high molecular weight polyethylene glycol.

[0295] The active compound may also be in a microencapsulated form with one or more excipients as mentioned above. Solid dosage forms of tablets, coated tablets, capsules, pills, and granules may be manufactured with coatings and shells such as enteric coatings, controlled-release coatings, and other coatings widely known in pharmaceutical formulation technology. In these solid dosage forms, the active compound may be mixed with one or more inert diluents such as sucrose, lactose, or starch. These dosage forms may also include additional substances other than the inert diluent, such as tableted lubricants and other tableted preparations such as magnesium stearate and microcrystalline cellulose, as in normal practice. In the case of capsules, tablets, and pills, the dosage forms may also include a buffer.

[0296] Forms of administration for topical or transdermal administration of the compounds of the present disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. Ophthalmic formulations, ear drops, eye ointments, powders, and solutions are also considered to be within the scope of the present disclosure.

[0297] Ointments, pastes, creams, and gels may contain, in addition to the active compound of the present disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, and zinc oxide, or mixtures thereof.

[0298] In addition to the compounds of the present disclosure, the powders and sprays may contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder or mixtures of such materials. The sprays may further contain conventional propellants such as chlorofluorohydrocarbons.

[0299] Transdermal patches have the additional advantage of providing controlled delivery of compounds to the body. These dosage forms can be prepared by dissolving or dispersing 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 providing a rate-regulating membrane or by dispersing the compound in a polymer matrix or gel.

[0300] 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 a therapeutically effective amount of the compound of the present disclosure to the subject in an amount necessary to obtain a desired result and for a necessary period of time. As used herein, the term “therapeutically effective amount” of the compound of the present disclosure means an amount of the compound sufficient to reduce the symptoms of the disorder in the subject. As is well understood in the medical field, the therapeutically effective amount of the compound of the present disclosure will be a reasonable benefit / harm ratio applicable to any medical treatment.

[0301] Generally, the compounds of the present disclosure will be administered at a therapeutically effective dose, either alone or in combination with one or more therapeutic agents, via any of the ordinary and acceptable methods known in the art. The therapeutically effective dose may vary significantly depending on the severity of the disease, the age and relative health of the subject, the efficacy of the compounds used, and other factors. Generally, satisfactory systemic results are shown at a daily dose of about 0.03 to 2.5 mg / kg of body weight. In larger mammals, e.g., humans, the prescribed daily dose ranges from about 0.5 mg to about 100 mg and is conveniently administered, for example, in up to four divided doses per day or in a delayed form. Suitable unit dosage forms for oral administration contain about 1 to 50 mg of the active ingredient.

[0302] In certain embodiments, the therapeutic dose or dosage of the compounds of the present disclosure may be in the range of about 0.1 mg / kg to about 500 mg / kg, or alternatively about 1 to about 50 mg / kg. Generally, a therapeutic regimen according to the present disclosure comprises administering about 10 mg to about 1000 mg of the compounds of the present disclosure in a single or multiple doses per day to a patient requiring such treatment. The therapeutic dose or dosage will also vary depending on the route of administration and the possibility of co-use with other agents.

[0303] When the subject's condition improves, a maintenance dose of the compound, composition, or combination of the present disclosure may be administered if necessary. Consequently, the dosage or frequency of administration, or both, may be reduced as a function of symptoms to a level where the improved condition is maintained; and treatment should be discontinued when symptoms are relieved to a desired level. However, the subject may require intermittent treatment over a long period of time depending on any recurrence of disease symptoms.

[0304] However, it will be understood that the total daily use 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 suppression 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 used; the specific composition used; the patient's age, weight, general health, gender, and diet; the time of administration, route of administration, and elimination rate of the specific compound used; the duration of treatment; drugs used together with or simultaneously with the specific compound used; and factors well known in the medical field.

[0305] The present disclosure also provides a pharmaceutical combination, e.g., a kit, comprising a) a first formulation which is a compound of the present disclosure as disclosed herein in a free form or in a pharmaceutically acceptable salt form, and b) at least one co-formulation. The kit may include administration instructions.

[0306] In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. For example, agents that prevent EGFR dimer formation, chemotherapy agents, or other antiproliferative agents may be combined with the compounds of the present disclosure to treat proliferative diseases and cancer.

[0307] Some examples of substances that can serve as pharmaceutically acceptable carriers include ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, e.g., human serum albumin; buffer substances, e.g., phosphates, glycine, sorbic acid, or potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water; salts or electrolytes, e.g., protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; wool fats; sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., 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; non-pyrogenous water; isotonic saline solution; Ringer's solution; ethyl alcohol; and phosphate buffer solution are included but not limited thereto. Additionally, at the discretion of the formulationr, non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives, and antioxidants may be present in the composition. Protein kinase inhibitors or pharmaceutical salts thereof may be formulated into pharmaceutical compositions for administration to animals or humans. This pharmaceutical composition, comprising an amount of protein inhibitor effective for treating or preventing protein kinase-mediated pathology and a pharmaceutically acceptable carrier, is another embodiment of the present disclosure.

[0308] Kit

[0309] In one embodiment, a kit is provided herein comprising one or more compounds disclosed herein, or a compound capable of inhibiting kinase activity selected from pharmaceutically acceptable salts thereof, and instructions for use in cancer treatment. In a specific embodiment, the kit further comprises a component for performing a test to determine whether a subject has an activating and / or drug-resistant mutation in EGFR.

[0310] In another aspect, the present disclosure provides a kit comprising a compound capable of inhibiting EGFR activity selected from the compounds disclosed herein or pharmaceutically acceptable salts thereof.

[0311] 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 pharmaceutically acceptable salts thereof; a second activator that prevents EGFR dimer formation; and instructions for use in cancer treatment. In certain embodiments, the kit further comprises components for performing a test to determine whether a subject has an activating and / or drug-resistant mutation in EGFR. In some embodiments, the second activator that prevents EGFR dimer formation is an antibody. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab.

[0312] In another aspect, the present disclosure provides a kit comprising: a compound capable of inhibiting EGFR activity selected from the compounds disclosed herein or pharmaceutically acceptable salts thereof; and a second activator that prevents EGFR dimer formation. In some embodiments, the second activator that prevents EGFR dimer formation is an antibody. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second activator that prevents EGFR dimer formation is cetuximab. In one embodiment, the second activator is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0313] The present disclosure is further illustrated by the following examples and synthesis schemes, which should not be construed as limiting the scope or intent of the specific procedures described herein. Examples are provided to illustrate specific embodiments and should be understood that the scope of the present disclosure is not limited by this. It should be further understood that reliance may be placed on various other embodiments, modifications, and equivalents that may be proposed to those skilled in the art without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0314] Examples

[0315] Applications are further illustrated by the following examples, which should not be construed as additional limitations. Unless otherwise indicated, the practice of this disclosure will utilize the ordinary techniques of organic synthesis, cell biology, cell culture, and molecular biology within the art.

[0316] abbreviation

[0317] AcOH acetic acid

[0318] ACN Acetonitrile

[0319] DCM dichloromethane

[0320] DIEA Diisopropylethylamine

[0321] DMF dimethylformamide

[0322] DMSO dimethyl sulfoxide

[0323] Et2O diethyl ether

[0324] EtOAc ethyl acetate

[0325] HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0326] MeOH methanol

[0327] TFA trifluoroacetic acid

[0328] THF Tetrahydrofuran

[0329] Example 1: 2 -(6-(4-(1- Methylpiperidine -4-il)phenyl)-4- Oxopyrolo [2,1-f][1,2,4]-triazine-3(4H)-yl)-2-phenyl-N-(thiazole-2-yl)acetamide;hydrochloride ( 001 )of manufacturing

[0330] Reaction Equation 1.

[0331]

[0332] methyl 2-(6- Bromo -4- Oxopyrrolo[2,1- f ][1,2,4]Triazine -3(4 H )-day)-2- Phenyl acetate

[0333]

[0334] 6-bromopyrrolo[2,1- f ][1,2,4]Triazine-4(3 HA mixture of )-one (321 mg, 1.5 mmol), methyl 2-bromo-2-phenylacetate (378 mg, 1.65 mmol), Cs2CO3 (975 mg, 3.0 mmol), and DMF (3 mL) was stirred at 50°C for 1.5 hours. Another aliquot of methyl 2-bromo-2-phenylacetate (147 mg, 0.65 mmol) was added, and the reaction mixture was heated for an additional time. After cooling, the reaction mixture was poured into saturated brine (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extract was washed with saturated brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by normal-phase flash chromatography (0-75% EtOAc / hexane) to obtain the title compound (445 mg, 82%).

[0335] 2-(6-(4-(1- Methylpiperidine -4-il)phenyl)-4- Oxopyrrolo[2,1- f ][1,2,4]Triazine -3(4 H )-1)-2-phenylacetic acid

[0336]

[0337] Methyl 2-(6-bromo-4-oxopyrrol[2,1- in dioxane (1.5 mL) and H2O (0.5 mL) f ][1,2,4]Triazine-3(4 HA mixture of )-yl)-2-phenyl-acetate (100 mg, 0.0.28 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)piperidine (92 mg, 0.3 mmol), Na2CO3 (89 mg, 0.84 mmol), and Pd(dppf)Cl2-DCM (46 mg, 0.056 mmol) was heated at 95°C for 16 hours in a sealed vial under N2. The mixture was allowed to cool, filtered through a syringe filter, and purified by reverse-phase HPLC eluting with 0-80% ACN / H2O (0.038% TFA modifier) ​​to obtain the title compound (125 mg, 78%). 1 ¹H NMR (500 MHz, DMSO- d 6) δ 9.40 (br s, 1H) 8.17 (d, 1H) 7.82 (s, 1H) 7.74 (d, 2H) 7.51 (m, 2H) 7.46 (m, 3H) 7.43 (d, 1H) 7.26 (d, 2H) 6.46 (s, 1H) 3.53 (d, 2H) 3.08 (m, 2H) 2.83 (d, 3H) 2.81 (m, 1H) 2.03 (d, 2H) 1.84 (m, 2H).

[0338] 2-(6-(4-(1- Methylpiperidine -4-il)phenyl)-4- Oxopyrrolo[2,1- f ][1,2,4]Triazine -3(4 H )-yl)-2-phenyl- N -(thiazole-2-yl)acetamide; hydrochloride (001)

[0339]

[0340] 2-(6-(4-(1-methylpiperidine-4-yl)phenyl)-4-oxopyrrolo[2,1- in DMF (2 mL) f ][1,2,4]Triazine-3(4 HA mixture of )-yl)-2-phenylacetic acid (60 mg, 0.14 mmol), 2-aminothiazole (20 mg, 0.20 mmol), HATU (103 mg, 0.27 mmol), and DIEA (71 μL, 0.41 mmol) was stirred at 50°C for 1.5 hours. After cooling, the reaction mixture was purified by reverse-phase HPLC eluted with 0-80% ACN / H2O (0.038% TFA modifier). The unrefined product was further purified by silica chromatography (0-10% 7N methanolic NH3 in DCM). The residue was dissolved in MeOH (5 mL), treated with 4 N HCl / dioxane (0.5 mL), and concentrated under reduced pressure. The residue was ground with Et2O, filtered, and dried to obtain the title compound (57 mg, 79%). 1 ¹H NMR (500 MHz, DMSO- d 6) δ 9.33 (br s, 1H) 8.19 (d, 1H) 7.75 (d, 2H) 7.57 (s, 1H) 7.51 (m, 4H) 7.44 (m, 3H) 7.33 (d, 1H) 7.26 (d, 1H) 6.81 (s, 1H) 3.53 (d, 2H) 3.08 (m, 2H) 2.84 (d, 3H) 2.81 (m, 1H) 2.03 (m, 2H) 1.83 (m, 2H).

[0341] The following examples from methyl 2-bromo-2-phenylacetate and the corresponding cyclic starting material Example 1 Manufactured using a method similar to:

[0342]

[0343] Examples 2: 3 -((1H- benzo[d]imidazole -2-il)(phenyl) methyl )-6-(4-(1- Methylpiperidine -4-yl)phenyl)pyrrolo [2,1-f][1,2,4]triazine-4(3H)-one;hydrochloride ( 002 Manufacturing of )

[0344] Reaction Equation 2.

[0345]

[0346] N -(2- aminophenyl )-2-(6-(4-(1- Methylpiperidine -4-yl)phenyl)-4-oxopyrrol[2,1- f ][1,2,4]-Triazine-3(4 H )-yl)-2-phenylacetamide

[0347]

[0348] 2-(6-(4-(1-methylpiperidine-4-yl)phenyl)-4-oxopyrrolo[2,1- in DMF (3 mL) f ][1,2,4]Triazine-3(4 H A mixture of )-yl)-2-phenylacetic acid (60 mg, 0.14 mmol), benzene-1,2-diamine (75 mg, 0.69 mmol), HATU (174 mg, 0.46 mmol), and DIEA (120 μL, 0.69 mmol) was stirred at 50°C for 1 hour. After cooling, the mixture was purified by reverse-phase HPLC eluting with 0-80% ACN / H2O (0.038% TFA modifier) ​​to obtain the title compound (80 mg, 65%). 1 ¹H NMR (500 MHz, DMSO- d 6) δ 9.97 (s, 1H) 9.32 (br s, 1H) 8.17 (d, 1H) 7.75 (d, 2H) 7.63 (s, 1H) 7.53 (m, 4H) 7.48 (m, 1H) 7.46 (d, 1H) 7.26 (d, 2H) 7.23 (dd, 1H) 6.98 (m, 1H) 6.82 (s, 1H) 6.78 (dd, 1H) 6.61 (m, 1H) 3.53 (d, 2H) 3.08 (m, 2H) 2.83 (d, 3H) 2.81 (m, 1H) 2.03 (d, 2H) 1.83 (m, 2H).

[0349] 3-((1 H - Benzo[ d ]Imidazole -2-il)(phenyl) methyl )-6-(4-(1- Methylpiperidine -4-il)phenyl)pyrrole [2,1- f ][1,2,4]Triazine-4(3 H )- On; hydrochloride (002)

[0350]

[0351] N -(2-aminophenyl)-2-(6-(4-(1-methylpiperidine-4-yl)phenyl)-4-oxopyrrolo[2,1- f ][1,2,4]Triazine-3(4 H A solution of )-yl)-2-phenylacetamide (80 mg, 0.15 mmol) and AcOH (3 mL) was heated to 100°C for 1 hour. Excess AcOH was removed under reduced pressure. The residue was dissolved in EtOAc (5 mL) and washed with 1 N NaOH (5 mL), water (5 mL), and saturated brine (5 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica chromatography (0-5% 7N methanolic NH3 / DCM), dissolved in the product MeOH (5 mL), treated with 4N HCl (1 mL) in dioxane, and concentrated under pressure. The resulting solid was ground with Et2O, filtered, and dried to obtain the title compound (19 mg, 25%). 1 ¹H NMR (500 MHz, DMSO- d 6) δ 10.09 (br s, 1H) 8.21 (d, 1H) 8.08 (s, 1H) 7.75 (d, 2H) 7.64 (m, 2H) 7.51 (s, 1H) 7.48 (m, 4H) 7.44 (m, 2H) 7.30 (m, 2H) 7.26 (d, 2H) 3.50 (d, 2H) 3.06 (m, 2H) 2.80 (m, 1H) 2.79 (d, 3H) 1.96 (m, 4H).

[0352] The following examples from methyl 2-bromo-2-phenylacetate and the corresponding cyclic starting material Example 2 Manufactured in a similar manner to:

[0353]

[0354] Examples 3: 2 -(6-(4-(1- Methylpiperidine -4-il)phenyl)-4- Oxotieno[3,2-d]pirimi Din-3(4H)-yl)-2-phenyl-N-(thiazole-2-yl)acetamide ( 003 Manufacturing of )

[0355] Reaction Equation 3.

[0356]

[0357] Methyl 2-(6-bromo-4-oxothienno[3,2-d]pyrimidine-3(4H)-yl)-2-phenylacetate

[0358]

[0359] 6-bromothieno[3,2- in DMF (3 mL) d ]Pyrimidine-4(3 H A mixture of )-one (250 mg, 1.08 mmol), methyl 2-bromo-2-phenylacetate (296 mg, 1.29 mmol), and Cs2CO3 (543 mg, 1.5 mmol) was stirred at 50°C for 2 hours. After cooling, the reaction mixture was poured into saturated brine (~30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extract was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica chromatography eluted with (0-50% EtOAc / hexane) to obtain the title compound (250 mg, 61%). 1 ¹H NMR (500 MHz, DMSO- d 6) δ 8.47 (s, 1H) 8.37 (s, 1H) 7.52 (m, 2H) 7.45 (m, 3H) 6.64 (s, 1H) 3.77 (s, 3H).

[0360] methyl 2-(6-(4-(1- Methylpiperidine -4-il)phenyl)-4- Oxothieno[3,2-d]pyrimidine -3(4H)-yl)-2-phenylacetate

[0361]

[0362] Methyl 2-(6-bromo-4-oxothienno[3,2- in dioxane (3.0 mL) and water (1.0 mL) d ]Pyrimidine-3(4 H A mixture of )-yl)-2-phenylacetate (250 mg, 0.83 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-piperidine (275 mg, 0.91 mmol), Pd(dppf)Cl2-DCM (68 mg, 0.083 mmol), and Na2CO3 (264 mg, 2.89 mmol) was heated at 100°C for 1 hour in a sealed vial under N2. After cooling, the reaction mixture was filtered through a syringe filter and purified by reverse-phase HPLC eluting with 0-80% ACN / H2O (0.038% TFA modifier) ​​to obtain the title compound (65 mg, 16%).

[0363] 2-(6-(4-(1- Methylpiperidine -4-il)phenyl)-4- Oxothieno[3,2-d]pyrimidine -3(4H)-yl)-2-phenylacetic acid

[0364]

[0365] methyl 2-(6-(4-(1-methylpiperidine-4-yl)phenyl)-4-oxothieno[3,2- d ]Pyrimidine-3(4 HA mixture of )-yl)-2-phenylacetate (65 mg, 0.14 mmol), LiOH-H2O (24 mg, 0.72 mmol), THF (1.0 mL), MeOH (1 mL), and water (1 mL) was stirred for 60 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in water (5 mL). The pH of the solution was adjusted to pH 5 (pH paper) with 1.5 N HCl. The precipitate was ground with water (2 x 5 mL), filtered, and dried overnight at 60°C under hi-vac to obtain the title compound (64 mg, quant), which was used in subsequent steps without further purification.

[0366] 2-(6-(4-(1- Methylpiperidine -4-il)phenyl)-4- Oxotieno[3,2- d ]Pyrimidine -3(4 H )-yl)-2-phenyl- N -(thiazole-2-yl)acetamide (003)

[0367]

[0368] This compound from the above acid Compound 001 The title compound (43 mg, 94%) was obtained by preparing it in a similar manner and purifying it with reverse-phase HPLC eluting with 0-80% ACN / H2O (0.038% TFA modifier).

[0369] Examples 4: 5-[1H-benzimidazole-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-6,7-dihydrothieno[3,2-c]pyridin-4-one;dihydrochloride ( 012 )

[0370] Reaction Equation 4

[0371]

[0372] Step 1. methyl 2-(2- Bromo -4-Oxo-6,7- dihydrothieno[3,2-c]pyridine -5-yl)-2-(5-fluoro-2-methoxy-phenyl)acetate

[0373]

[0374] Sodium hydride (0.077 g, 1.93 mmol, 60% in mineral oil) was added at 0°C to a solution of 2-bromo-6,7-dihydrothieno[3,2-c]pyridine-4(5H)-one (0.300 g, 1.29 mmol) in THF (6 mL). After stirring for 0.5 hours at the same temperature, a solution of methyl 2-bromo-2-(5-fluoro-2-methoxyphenyl)-acetate (0.714 g, 2.58 mmol) in THF (4 mL) was added dropwise to the reaction mixture. After stirring for 2 hours at room temperature, the reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.552 g, quant.). MS m / z : 428.0 [M+1] + .

[0375] Step 2. 2-(2- Bromo -4-Oxo-6,7- dihydrothieno[3,2-c]pyridine -5-day)-2-(5- fluoro -2-methoxy-phenyl)acetic acid

[0376]

[0377] Lithium hydroxide (0.092 g, 3.84 mmol) was added to a solution of methyl 2-(2-bromo-4-oxo-6,7-dihydrothieno[3,2-c]pyridine-5-yl)-2-(5-fluoro-2-methoxy-phenyl)acetate (0.552 g, 1.28 mmol) in THF / water (20 mL, 1 / 1). After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure, and the resulting residue was adjusted to pH 3 with HCl (1 M). The resulting solid was collected by filtration and washed with water to obtain the title compound (0.45 g, 85%). 1 1 H NMR (DMSO- d6) δ: 7.35 (s, 1H), 7.16-7.25 (m, 1H), 7.06-7.14 (m, 1H), 6.97-7.05 (m, 1H), 6.17 (s, 1H), 3.76 (s, 3H), 3.61-3.70 (m, 1H), 3.25-3.27 (m, 1H), 2.77-3.05 (m, 2H); M.S. m / z : 414.1 [M+1] + .

[0378] Step 3. 5-[1H- Benzimidazole -2-day-(5- fluoro -2- Methoxy -phenyl) methyl ]-2- Bromo -6,7-dihydrothieno[3,2-c]pyridin-4-one

[0379]

[0380] DIPEA (0.562 mL, 3.23 mmol) was added to a solution of 2-(2-bromo-4-oxo-6,7-dihydrothieno[3,2-c]pyridine-5-yl)-2-(5-fluoro-2-methoxy-phenyl)acetic acid (0.450 g, 1.08 mmol), 1,2-diaminobenzene (0.174 g, 1.61 mmol), and HATU (0.612 g, 1.61 mmol) in DMF (8 mL). After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate and washed twice with a saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain an amide intermediate, which was used in the following reaction without further purification. MS m / z : 504.0 [M+1] + .

[0381] Acetic acid (10 mL) was added to the above amide intermediate. After addition at 80°C for 1 hour, the solvent was removed under reduced pressure. The unrefined product was purified by C18 column chromatography eluted with 0-100% ACN / water containing 10 mM ammonium acetate to obtain the title compound (0.4 g, 77%). 1 1 H NMR (DMSO- d 6) δ: 12.59 (br s, 1H), 7.40-7.69 (m, 2H), 7.35 (s, 1H), 7.07-7.28 (m, 5H), 6.77-6.89 (m, 1H), 3.64-3.81 (m, 4H), 3.37-3.43 (m, 1H), 2.85-3.12 (m, 2H); M.S. m / z : 486.1 [M+1] + .

[0382] Step 4. 5-[1H- Benzimidazole -2-day-(5- fluoro -2- Methoxy -phenyl) methyl ]-2-[4-(1- methyl -4-piperidyl)phenyl]-6,7-dihydrothieno[3,2-c]pyridin-4-one

[0383]

[0384] A mixture of 5-[1H-benzimidazole-2-yl-(5-fluoro-2-methoxy-phenyl)methyl]-2-bromo-6,7-dihydrothieno[3,2-c]pyridin-4-one (0.200 g, 0.411 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (0.148 g, 0.493 mmol), Pd(dppf)Cl2 (0.030 g, 0.041 mmol) and sodium carbonate (0.130 g, 1.23 mmol) in dioxane / water (9:1, 6 mL) was heated under nitrogen at 100°C for 2 hours. After cooling, the reaction mixture was filtered, the filtrate was concentrated, and purified by silica gel flash chromatography eluted with 0-15% methanol in dichloromethane to obtain the title compound (0.2 g, 84%). 1 ¹H NMR (400 MHz, DMSO- d 6) δ: 12.56 (s, 1H), 7.56-7.64 (m, 4H), 7.41-7.49 (m, 1H), 7.10-7.31 (m, 7H), 6.83-6.90 (m, 1H), 3.66-3.82 (m, 4H), 3.40-3.46 (m, 1H), 2.90-3.17 (m, 4H), 2.52-2.56 (m, 1H), 2.30 (s, 3H), 2.04-2.21 (m, 2H), 1.64-1.81 (m, 4H). M.S. m / z : 581.5 [M+1] + .

[0385] Step 5. 5-[1H-benzimidazole-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-6,7-dihydrothieno[3,2-c]pyridin-4-one;dihydrochloride

[0386]

[0387] Boron tribromide (0.859 g, 3.43 mmol) was added at 0°C to a solution of 5-[1H-benzimidazole-2-yl-(5-fluoro-2-methoxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-6,7-dihydrothieno[3,2-c]pyridin-4-one (0.200 g, 0.344 mmol) in dichloromethane (10 mL). After stirring for 2 hours at room temperature, the reaction mixture was diluted with dichloromethane and poured into ice water. The aqueous phase was extracted three times with dichloromethane. The combined organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The unrefined product was purified by reverse-phase HPLC eluting with 0-100% ACN / water (0.05% HCl modifier) ​​to obtain the title compound (0.107 g, 55%). 1 ¹H NMR (400 MHz, DMSO- d 6) δ: 10.06-10.82 (m, 2H), 7.69-7.78 (m, 2H), 7.60-7.67 (m, 3H), 7.39-7.53 (m, 2H), 7.29 (d, 2H), 6.96-7.20 (m, 4H), 3.76-3.87 (m, 1H), 3.49-3.62 (m, 3H), 2.94-3.20 (m, 4H), 2.68-2.88 (m, 4H), 1.91-2.08 (m, 4H); M.S. m / z : 567.5 [M+1] + .

[0388] The following examples were prepared from methyl 2-bromo-2-(5-fluoro-2-methoxyphenyl)acetate and the corresponding cyclic starting material in a manner similar to Example 4:

[0389]

[0390]

[0391] Examples 5: 6 -[(R)-1H- Benzimidazole -2-day-(5- fluoro -2- Hydroxy -phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]thieno[2,3-c]pyridin-7-one and 6-[(S)-1H-benzimidazole-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]thieno[2,3-c]pyridin-7-one (015 and 016)'s manufacturing

[0392]

[0393] 6-[1H-benzimidazole-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]thieno[2,3-c]pyridin-7-one;dihydrochloride ( 009 Enantiomers were separated by purification using prep SFC with a Chiral Technologies Chiralpak IA (5 micron, 250x10 mm) column at 40°C, eluted with 50% (0.3% TEA in MeOH) / 50% CO2 at 10 MPa. The absolute configuration of the chiral centers for each isolated enantiomer is unknown. The first elution peak ( 015 ) (93 mg, 35% yield, 99.6:0.4 er); [α] 20 D +58.2 ( c = 0.91, MeOH); 1 1 H NMR (DMSO- d 6) δ: 12.79 (br s, 1H), 10.01 (br s, 1H), 7.70-7.80 (m, 3H), 7.65 (s, 1H), 7.46-7.61 (m, 2H), 7.32-7.40 (m, 3H), 7.16-7.25 (m, 2H), 7.05-7.14 (m, 1H), 6.85-6.93 (m, 1H), 6.75 (d, 1H), 6.59-6.68 (m, 1H), 2.87 (d, 2H), 2.43-2.48 (m, 1H), 2.20 (s, 3H), 1.90-2.04 (m, 2H), 1.62-1.78 (m, 4H); MS m / z : 565.2 [M+1] + . Second elution peak ( 016 ) (95 mg, 36% yield, 99.4:0.6 er); [α] 20D -52.5 ( c = 0.92, MeOH); 1 H NMR (DMSO- d 6) δ: 12.79 (br s, 1H), 10.02 (br s, 1H), 7.70-7.78 (m, 3H), 7.65 (s, 1H), 7.44-7.60 (m, 2H), 7.33-7.40 (m, 3H), 7.15-7.24 (m, 2H), 7.06-7.13 (m, 1H), 6.86-6.93 (m, 1H), 6.75 (d, 1H), 6.59-6.69 (m, 1H), 2.87 (d, 2H), 2.41-2.47 (m, 1H), 2.20 (s, 3H), 1.92-2.03 (m, 2H), 1.60-1.79 (m, 4H); MS m / z : 565.2 [M+1] + .

[0394] Examples 6: 5-[1H-benzimidazole-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-6H-thieno[2,3-c]pyrrole-4-one;dihydrochloride ( 013 )

[0395] Reaction Equation 5

[0396]

[0397] Step 1. 2-Bromo-4-fluoro-1-(methoxymethoxy)benzene

[0398]

[0399] Sodium hydride (23.0 g, 575 mmol, 60% in mineral oil) was added to a solution of 2-bromo-4-fluorophenol (100 g, 523 mmol) in THF (1 L) for 4 hours at 0°C, followed by the addition of methoxymethyl chloride (44.9 mL, 601 mmol). The mixture was stirred at room temperature for 10 hours, quenched with water, and extracted three times with ethyl acetate. The combined organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The unrefined product was purified by silica gel column chromatography eluting with 1-10% ethyl acetate in petroleum ether to obtain 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).

[0400] Step 2. Ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-oxo-acetate

[0401]

[0402] n-butyllithium (2.5 M in hexane, 142 mL, 357 mmol) was added dropwise at -78°C to a solution of 2-bromo-4-fluoro-1-(methoxymethoxy)benzene (80.0 g, 340 mmol) in THF (1 L). After stirring for 1 hour at -78°C, 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 heated to room temperature. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The unrefined product was purified by silica gel column chromatography eluted with 10% ethyl acetate in petroleum ether to obtain 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).

[0403] Step 3. Ethyl-2-[5- fluoro -2-( Methoxymethoxy )phenyl]-2- Hydroxyimino -acetate

[0404]

[0405] Ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-oxo-acetate (70.0 g, 273 mmol) and sodium acetate (44.7 g, 132 mmol) were added to a solution of hydroxylamine hydrochloride (37.9 g, 546 mmol) in ethanol (500 mL). After stirring at 80°C for 2.5 hours, the solvent was removed under reduced pressure, and the resulting residue was separated between water and dichloromethane. The aqueous phase was extracted with additional dichloromethane. The combined organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (68 g, 92%). 1 H 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).

[0406] Step 4. Ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate

[0407]

[0408] Ethyl-2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-hydroxyimino-acetate (34.0 g, 125 mmol) was added to a solution of Raney Ni (1.46 g, 25.0 mmol) in EtOH / THF (650 mL, 4 / 1). The flask was evacuated, refilled with hydrogen, and the reaction mixture was stirred at 70°C under a hydrogen atmosphere (50 psi) for 24 hours. The reaction mixture was filtered through a Celite pad washed several times with ethanol. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography eluted with 33% ethyl acetate in petroleum ether to obtain the title compound (30.6 g, 48%). 1 ¹H NMR (400 MHz, DMSO- d 6) 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).

[0409] Step 5. methyl 5- Bromo -2-[[[2- Ethoxy -1-[5- fluoro -2-( Methoxymethoxy )phenyl]-2-oxo-ethyl]amino]methyl]thiophene-3-carboxylate

[0410]

[0411] DIPEA (0.789 mL, 4.77 mmol) was added to a solution of ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (0.409 g, 1.59 mmol) and methyl 5-bromo-2-(bromomethyl)thiophene-3-carboxylate (0.500 g, 1.59 mmol) in DMF (15 mL). The reaction mixture was heated at 80°C for 3 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extract was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluted with 0-25% ethyl acetate in petroleum ether to obtain the title compound (0.32 g, 41%); MS m / z : 491.8 [M+1]

[0412] Step 6. Ethyl 2-(2- Bromo -4-oxo-6H- Tieno[2,3-c]pyroll -5-yl)-2-[5-fluoro-2-(methoxymethoxy)-phenyl]acetate

[0413]

[0414] Trimethylaluminum (2 M, 1.86 mL, 3.72 mmol) in toluene was added to a solution of methyl 5-bromo-2-[[[2-ethoxy-1-[5-fluoro-2-(methoxymethoxy)phenyl]-2-oxo-ethyl]amino]methyl]thiophene-3-carboxylate (0.610 g, 1.24 mmol) in toluene (20 mL). The reaction mixture was heated at 110°C for 4 hours. After cooling to room temperature, the reaction mixture was poured into a saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The unrefined product was purified by silica gel column chromatography eluted with 1-10% ethyl acetate in petroleum ether to obtain the title compound (0.13 g, 23%). MS m / z : 458.0 [M+1] + .

[0415] Step 7. 2-(2- Bromo -4-oxo-6H- Tieno[2,3-c]pyroll -5-day)-2-[5- fluoro -2-( Methoxymethoxy )-phenyl]acetic acid

[0416]

[0417] Lithium hydroxide (0.021 g, 0.849 mmol) was added to a solution of ethyl 2-(2-bromo-4-oxo-6H-thieno[2,3-c]pyrrole-5-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (0.130 g, 0.283 mmol) in THF / water (8 mL, 1 / 1). After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure, and the resulting residue was adjusted to pH 4 with HCl (1 M). The resulting solid was collected by filtration and washed with water to obtain the title compound (0.09 g, 74%). MS m / z : 429.9 [M+1] + .

[0418] Step 8. 5-[1H- Benzimidazole -2-day-[5- fluoro -2-( Methoxymethoxy )phenyl] methyl ]-2- Bromo -6H-thieno[2,3-c]pyrol-4-one

[0419]

[0420] DIPEA (0.103 mL, 0.627 mmol) was added to a solution of 2-(2-bromo-4-oxo-6H-thieno[2,3-c]pyrrole-5-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetic acid (0.090 g, 0.209 mmol), 1,2-diaminobenzene (0.027 g, 0.250 mmol), and HATU (0.103 g, 0.271 mmol) in DMF (3 mL). After stirring at room temperature for 4 hours, the reaction mixture was diluted with ethyl acetate and washed twice with a saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain an amide intermediate, which was used in the following reaction without further purification. MS m / z : 519.9 [M+1] + .

[0421] Acetic acid (8 mL) was added to the above amide intermediate. After addition at 80°C for 1 hour, the solvent was removed under reduced pressure. The crude product was purified by C18 column chromatography eluted with 0-100% ACN / water containing 10 mM ammonium acetate to obtain the title compound (0.07 g, 73%). MS m / z : 502.0 [M+1] + .

[0422] Step 9. 5-[1H-benzimidazole-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-6H-thieno[2,3-c]pyrrole-4-one

[0423]

[0424] A mixture of 5-[1H-benzimidazole-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-2-bromo-6H-thieno[2,3-c]pyrrole-4-one (0.070 g, 0.139 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (0.050 g, 0.166 mmol), Pd(dppf)Cl2 (0.010 g, 0.014 mmol) and sodium carbonate (0.046 g, 0.416 mmol) in dioxane / water (4:1, 3 mL) was heated under nitrogen at 100°C for 4 hours. After cooling, the reaction mixture was filtered, the filtrate was concentrated, and purified by silica gel flash chromatography eluted with 1-10% methanol in dichloromethane to obtain the title compound (0.05 g, 60%). MS m / z : 597.2 [M+1] + .

[0425] Step 10. 5-[1H- Benzimidazole -2-day-(5- fluoro -2- Hydroxy -phenyl) methyl ]-2-[4-(1-methyl-4-piperidyl)phenyl]-6H-thieno[2,3-c]pyrrole-4-one; dihydrochloride

[0426]

[0427] 5-[1H-benzimidazole-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-6H-thieno[2,3-c]pyrrole-4-one (0.050 g, 0.084 mmol) was mixed with HCl (1.25 M, 2 mL, 2.50 mmol) in methanol. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure. The crude product was purified by reverse-phase HPLC eluting with 0-100% ACN / water (0.05% HCl modifier) ​​to obtain the title compound (0.01 g, 22%). 1 1H NMR (400 MHz, methanol- d4) δ: 7.63-7.75 (m, 4H), 7.50-7.59 (m, 3H), 7.37 (d, 2H), 7.12-7.20 (m, 2H), 7.07(s, 1H), 6.95-7.01 (m, 1H), 4.90-4.99 (m, 2H) 4.46 (d, 1H), 3.66-3.78 (m, 2H), 3.12-3.24 (m, 2H), 2.93 (s, 3H), 1.93-2.21 (m, 4H); M.S. m / z : 553.1 [M+1] + .

[0428] The following examples were prepared from ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate and corresponding starting materials in a manner similar to Example 6:

[0429]

[0430] Example 7: Compound 019 and 020 manufacturing

[0431] Reaction Equation 6

[0432]

[0433] Step 1. 2-bromo-4-fluorothieno[2,3-c]pyridin-7(6H)-one

[0434]

[0435] A mixture of 2-bromothieno[2,3-c]pyridin-7(6H)-one (233 mg, 1 mmol), selectfluoride (354 mg, 1 mmol), and dimethylacetamide (3 mL) was heated in a sealed microwave vial at 150°C for 15 minutes while stirring. After cooling to RT, the entire reaction mixture was purified by RP-HPLC eluted with 0-80% ACN / water (0.038% TFA) to obtain the title compound, (47 mg, 19%). NMR MS m / z : 247.8 [M+1] + .

[0436] Step 2. methyl 2-(2- Bromo -4- fluoro -7- Oxothienno[2,3-c]pyridine -6(7H)-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate

[0437]

[0438] A mixture of 2-bromo-4-fluorothieno[2,3-c]pyridine-7(6H)-one (140 mg, 0.59 mmol), methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate (218 mg, 0.71 mmol), cesium carbonate (391 mg, 1.08 mmol), and DMF (2 mL) was heated at 30°C for 6 hours. After cooling, the entire reaction mixture was purified by flash chromatography eluted with 0-50% EtOAc / hexane to obtain the title compound, (107 mg, 38%). 1 H NMR (500 MHz, CDCl3) δ: 7.34 (s, 1H), 7.22 (dd, 1H), 7.14 (dd, 1H), 7.10 (d, 1H), 7.07 (dd, 1H) 6.93 (s, 1H), 5.15 (s, 2H), 3.86 (s, 3H), 3.39 (s, 3H); M.S. m / z : 475.8 [M+1] + .

[0439] Step 3. 2-(4- fluoro -2-(4-(1- Methylpiperidine -4-il)phenyl)-7- Oxothienno[2,3-c]pyridine -6(7H)-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetic acid

[0440]

[0441] A mixture of methyl 2-(2-bromo-4-fluoro-7-oxothieno[2,3-c]pyridine-6(7H)-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate (100 mg, 0.21 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (67 mg, 0.63 mmol), Na2CO3 (67 mg, 0.63 mmol), dioxane (3 mL), and water (1 mL) was degassed twice under vacuum and N2 was reintroduced. PdCl2 dppf-dcm (19 mg, 0.023 mmol) was added, and N2 was reintroduced to the reaction mixture. The reaction mixture was heated to 95°C for 6 hours. The entire reaction mixture was purified by RP-HPLC eluting with 0-80% ACN / water (0.038% TFA) to obtain the title compound (40 mg, 52%). 1 ¹H NMR (500 MHz, DMSO- d 6 ) δ: 9.46 (br s, 1H), 7.88 (m, 3H), 7.45 (d, 1H), 7.39 (d, 2H), 7.28 (dd, 1H), 7.26 (dd, 1H), 7.21 (dd, 1H), 6.70 (s, 1H), 5.23 (d, 1H), 5.19 (d, 1H), 3.54 (d, 2H), 3.27 (s, 3H), 3.09 (m, 2H), 2.88 (m, 1H), 2.84 (d, 3H), 2.05 (d, 2H), 1.86 (m, 2H); M.S. m / z : 555.1 [M+1] + .

[0442] Step 4. 2-(4- fluoro -2-(4-(1- Methylpiperidine -4-il)phenyl)-7- Oxothienno[2,3-c]pyridine -6(7H)-yl)-2-(5-fluoro-2-hydroxyphenyl)-N-(thiazole-2-yl)acetamide (019)

[0443]

[0444] A mixture of 2-(4-fluoro-2-(4-(1-methylpiperidin-4-yl)phenyl)-7-oxothieno[2,3-c]pyridine-6(7H)-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetic acid (20 mg, 0.036 mmol), HATU (27 mg, 0.072 mmol), 2-aminothiazole (5.4 mg, 0.072 mmol), DIEA (19 mL, 0.108 mmol), and DMF (2 mL) was stirred overnight at RT. The entire reaction mixture was purified by RP-HPLC eluted with 0-80% ACN / water (0.038% TFA). MS m / z : 637.2 [M+1] + .

[0445] This material was treated with DCM:TFA (1:1, 4 mL) for 30 minutes. The solvent was removed under reduced pressure, and the entire reaction mixture was purified by RP-HPLC eluting with 0-80% ACN / water (0.038% TFA) to obtain the title compound (4.8 mg, 22%, over two steps). 1 ¹H NMR (500 MHz, DMSO- d 6 ) δ: 10.17 (s, 1H), 9.41 (br s, 1H), 7.90 (m, 3H), 7.51 (d, 1H), 7.39 (d, 2H), 7.30 (d, 1H), 7.21 (m, 1H), 7.15 (d, 1H), 6.96 (dd, 1H), 6.95 (s, 1H), 6.88 (dd, 1H), 3.55 (d, 2H), 3.10 (m, 2H), 2.88 (m, 1H), 2.83 (d, 3H), 2.05 (d, 2H), 1.86 (m, 2H); M.S. m / z : 593.1 [M+1] + .

[0446] Step 5. 6-((1H- benzo[d]imidazole -2-day)(5- fluoro -2- hydroxyphenyl ) methyl )-4- fluoro -2-(4-(1-methylpiperidin-4-yl)phenyl)thieno[2,3-c]pyridin-7(6H)-one (020)

[0447]

[0448] A mixture of 2-(4-fluoro-2-(4-(1-methylpiperidin-4-yl)phenyl)-7-oxothieno[2,3-c]pyridine-6(7H)-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetic acid (20 mg, 0.036 mmol), HATU (27 mg, 0.072 mmol), 1,2-phenylenediamine (8 mg, 0.072 mmol), DIEA (19 mL, 0.108 mmol), and DMF (2 mL) was stirred overnight at RT. The entire reaction mixture was purified by RP-HPLC eluting with 0-80% ACN / water (0.038% TFA). MS m / z : 645.4 [M+1] + .

[0449] This substance was dissolved in AcOH (3 mL), and the solution was heated to 100°C for 1 hour. The solvent was removed under reduced pressure. MS m / z : 627.1 [M+1] + .

[0450] This material was treated with DCM:TFA (1:1, 4 mL) for 30 minutes. The solvent was removed under reduced pressure, and the entire reaction mixture was purified by RP-HPLC eluting with 0-80% ACN / water (0.038% TFA) to obtain the title compound (5.7 mg, 27%, over 3 steps). 1 ¹H NMR (500 MHz, DMSO- d 6) δ: 10.12 (br s, 1H), 9.46 (br s, 1H), 7.91 (s, 1H), 7.88 (d, 2H), 7.61 (s, 1H), 7.58 (m, 2H), 7.47 (d, 1H), 7.39 (d, 2H), 7.24 (m, 2H), 7.15 (m, 1H), 6.93 (dd, 1H), 6.74 (dd, 1H), 3.54 (d, 2H), 3.09 (m, 2H), 2.88 (m, 1H), 2.83 (d, 3H), 2.05 (d, 2H), 1.86 (m, 2H); M.S. m / z : 583.2 [M+1] + .

[0451] The following examples are derived from methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and corresponding starting materials Compound 019 Manufactured in a similar manner to:

[0452]

[0453] The following examples are derived from methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and corresponding starting materials Compound 020 Manufactured using a method similar to:

[0454]

[0455]

[0456] 2-Bromo- N -(Pivaloyloxy)thiazole-5-carboxamide

[0457]

[0458] Oxalyl chloride (15 mL, 30 mmol, 2 M solution in DCM) was added dropwise over 20 minutes to a suspension of 2-bromothiazole-5-carboxylic acid (4.2 g, 20 mmol) and anhydrous DMF (4 drops) in DCM (20 mL). The reaction was stirred at room temperature for 3 days, and the solvent was removed under reduced pressure to obtain the acid chloride. Hydroxylamine hydrochloride (1.39 g, 20 mmol) was added to a two-phase mixture of K2CO3 (5.52 g, 20 mmol) in a 2:1 mixture of EtOAc (40 mL) and water (20 mL). The resulting solution was cooled to 0°C, and then the unpurified acid chloride in EtOAc (12 mL) was added dropwise over 20 minutes. The reaction was allowed to warm to room temperature, and a thick white suspension was formed. After 4 hours, pivaloyl chloride (2.46 mL, 20 mmol) was added dropwise over approximately 10 minutes. After 2 hours, additional pivaloyl chloride (0.5 mL) was added, and the reaction was stirred for 16 hours. The mixture was diluted with water (125 mL) and extracted with EtOAc (2 x 125 mL). The combined organic extract was washed with water and saturated brine, dried (Na2SO4), filtered, and the residue was purified by flash chromatography with 0-35% EtOAc / hexane to obtain 2.44 g (40%) of white solid. 1 ¹H NMR (500 MHz, DMSO- d 6 ) δ: 8.22 (s, 1H), 1.28 (s, 9H); M.S. m / z : 308.8 [M+1] + .

[0459] 2-bromothiazolo[5,4-c]pyridin-4(5H)-one

[0460]

[0461] 2-bromo- in MeOH (8 mL) NA mixture of (pivaloyloxy)thiazole-5-carboxamide (233 mg, 1 mmol), CsCO3 (58 mg, 0.3 mmol), and [Cp*RhCl2]2 (12 mg, 0.02 mmol) was degassed, and N2 was injected twice. Vinyl acetate (131 mL, 1.5 mmol) was added, and the mixture was heated at 45°C for 60 hours. The entire reaction mixture was purified by RP-HPLC eluting with 0-80% ACN / water (0.038% TFA) to obtain the title compound (16 mg, 7%). MS m / z : 232.8 [M+1] + .

[0462]

[0463] Methyl 2-(5-fluoro-2-methoxyphenyl)acetate

[0464]

[0465] Thionyl chloride (5.8 mL, 81.3 mmol) was added dropwise over 15 minutes at 0°C to a solution of 2-(5-fluoro-2-methoxyphenyl)acetic acid (5.0 g, 27.1 mmol) in MeOH (3 mL). The mixture was heated at 60°C for 16 hours, and the solvent was removed under reduced pressure. EtOAc (100 mL) and saturated brine (100 mL) were added, and the pH was adjusted to 9 with a saturated NaHCO3 solution. The organic layer was washed with brine, dried (Na2SO4), and concentrated to obtain the title compound (5.13 g, 95%), which was used without further purification. 1 H NMR (500 MHz, CDCl3) δ: 6.96 (m, 2H), 6.81 (m, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 3.63 (s, 2H).

[0466] Methyl 2-(5-fluoro-2-hydroxyphenyl)acetate

[0467]

[0468] BBr3 (77 mL, 1 M in DCM) was added dropwise over 45 minutes to a solution of methyl 2-(5-fluoro-2-methoxyphenyl)acetate in DCM (100 mL) at -78°C, and the mixture was stirred for 1 hour. The reaction was quenched with water (50 mL). DCM (100 mL) and water (50 mL) were added, and the pH was adjusted to 8 with a saturated NaHCO3 solution. The organic layer was washed with brine, dried (Na2SO4), and concentrated to obtain the title compound (4.38 g, 92%), which was used without further purification. 1 H NMR (500 MHz, CDCl3) δ: 7.16 (s, 1H), 6.90 (dd, 1H), 6.85 (dd, 1H), 3.79 (s, 3H), 3.66 (s, 2H), 3.67 (s, 2H).

[0469] Methyl 2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate

[0470]

[0471] Diisopropylethylamine (12.4 mL, 71.4 mmol) and chloromethyl methyl ether (4.52 mL, 59.5 mmol) were added to a solution of methyl 2-(5-fluoro-2-hydroxyphenyl)acetate (4.38 g, 23.8 mmol) in DCM (150 mL). The reaction mixture was stirred for 20 hours. DCM (100 mL) and brine (100 mL) were added, the organic layer was washed with brine, dried (Na2SO4), and the residue was purified by silica chromatography (0-20% EtOAc in Hex) to obtain the title compound (4.78 g, 88%). 1 H NMR (500 MHz, CDCl3) δ: 7.07 (dd, 1H), 6.96 (dd, 1H), 6.94 (m, 1H), 5.16 (s, 2H), 3.72 (s, 3H), 3.66 (s, 2H), 3.48 (s, 3H).

[0472] Methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate

[0473]

[0474] NBS (3.05 g, 17.1 mmol) and benzoyl peroxide (396 mg, 1.63 mmol) were added to a solution of methyl 2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate (3.72 g, 16.3 mmol) in CCl4 (80 mL). The reaction mixture was stirred at 80°C for 20 hours. EtOAc (150 mL) and brine (100 mL) were added, the organic layer was washed with brine, dried (Na2SO4), and the residue was purified by silica chromatography (0-10% EtOAc in Hex) to obtain the title compound (3.59 g, 72%). 1 H NMR (500 MHz, CDCl3) δ: 7.41 (dd, 1H), 7.09 (dd, 1H), 7.02 (m, 1H), 5.85 (s, 1H), 5.22 (d, 1H), 5.21 (d, 1H), 3.82 (s, 3H), 3.51 (s, 3H).

[0475] Examples 8: 6-((1H-benzo[d]imidazole-2-yl)(5-fluoro-2-hydroxyphenyl)methyl-d)-2-(4-(1-methylpiperidin-4-yl)phenyl)thieno[2,3-c]pyridin-7(6H)-one,( 024 Manufacturing of )

[0476]

[0477] 6-((1H-benzo[d]imidazole-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-2-(4-(1-methylpiperidin-4-yl)phenyl)thieno[2,3-c]pyridin-7(6H)-one ( 009 A solution of (20 mg, 0.035 mmol), deuterium oxide (350 mL, 19.3 mmol), DIEA (38 mL, 6.3 mmol), and anhydrous THF (1 mL) was stirred at 70°C for 60 hours. The entire reaction mixture was purified by RP-HPLC eluted with 0-80% ACN / H2O (0.038% TFA modifier) ​​to obtain the title compound (12 mg, 62%). NMR (500 MHz, DMSO-d 6 ) δ: 1 H 10.06 (br s, 1H), 9.39 (br s, 1H), 7.80 (d, 2H), 7.77 (s, 1H), 7.57 (m, 2H), 7.38 (m, 3H), 7.24 (m, 2H), 7.13 (m, 1H), 6.92 (dd, 1H), 6.78 (d, 1H), 6.69 (dd, 1H), 3.54 (m, 2H), 3.09 (m, 2H), 2.87 (m, 1H), 2.84 (d, 3H), 2.06 (d, 2H), 1.85 (m, 2H). MS, m / z 566.15, [M + 1] + .

[0478] Examples 9: 6 -((1H-indole-2-yl)(phenyl) methyl )-2- (4-(1-methylpiperidine-4-yl)phenyl) Thieno[2,3-c]pyridin-7(6H)-one ( 025 Manufacturing of )

[0479] Reaction Equation 7

[0480]

[0481] Step 1. tert -Butyl 2-formyl-1H-indole-1-carboxylate

[0482]

[0483] A solution of triethylamine (0.6 mL, 4.0 mmol), DMAP (41 mg, 0.34 mmol), ¹H-indole-2-carbaldehyde (0.5 g, 3.4 mmol), and THF (15 mL) was cooled to 0°C. Di-tert-butyl dicarbonate (0.87 g, 4.0 mmol) was added dropwise, and the reaction mixture was stirred at RT for 16 hours. The solvent was removed under reduced pressure, and the residue was divided between water (30 mL) and EtOAc (30 mL). The aqueous phase was later extracted with EtOAc, the combined organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by silica chromatography (0-30% EtOAc / hexane) to obtain the title compound (570 mg, 68%). 1 H NMR (500 MHz, CDCl3) δ: 10.46 (s, 1H), 8.19 (d, 1H), 7.70 (d, 1H), 7.51 (t, 1H), 7.46 (s, 1H), 7.33 (t, 1H), 1.74 (s, 9H).

[0484] Step 2. tert -Butyl 2-(hydroxy(phenyl)methyl)-1H-indole-1-carboxylate

[0485]

[0486] Phenylmagnesium bromide (1 M in THF, 2.79 mL, 2.79 mmol) in anhydrous THF tert 2-butyl 2-formyl-1H-indole-1-carboxylate (0.57 g, 2.32 mmol) was added dropwise to a solution at 0°C under N2. The reaction was stirred at 0°C for 30 minutes and quenched with saturated aq. NH4Cl (10 mL). The mixture was extracted with EtOAc (2 x 20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica chromatography (0-30% EtOAc / hexane) to obtain the title compound (500 mg, 67%). 1H NMR (500 MHz, CDCl3) δ: 7.99 (d, 1H), 7.45 (d, 3H), 7.39 (m, 2H), 7.34 (m, 1H), 7.31 (m, 1H), 7.23 (t, 1H), 6.23 (s, 1H), 6.21 (d, 1H), 4.71 (br d, 1H), 1.67 (s, 9H).

[0487] Step 3. tert -Butyl 2-(((methylsulfonyl)oxy)(phenyl)methyl)-1H-indole-1-carboxylate

[0488]

[0489] Mesil chloride (143 mL, 1.86 mmol) tert 2-butyl 2-(hydroxy(phenyl)methyl)-1H-indole-1-carboxylate (300 mg, 0.93 mmol), DIEA (647 mL, 3.72 mmol), and anhydrous DCM (10 mL) were added dropwise at 0°C. The reaction was stirred at 0°C for 15 minutes and at RT for 1 hour, then diluted with DCM (10 mL) and quenched with ice water (20 mL). The organic layer was collected, dried (Na2SO4), filtered, and concentrated under reduced pressure to obtain unpurified mesylate, which was used in the next step without further purification.

[0490] Step 4. 6-((1H-indole-2-yl)(phenyl)methyl)-2-bromothieno[2,3-c]pyridine-7(6H)-one

[0491]

[0492] The material from Step 3 was dissolved in DMF (3 mL) and added to a suspension of 2-bromothieno[2,3-c]pyridin-7(6H)-one (193 mg, 0.81 mmol) and Cs2CO3 (673 mg, 1.86 mmol) in DMF (8 mL). The reaction mixture was heated at 36°C for 6 hours. After cooling, the reaction mixture was poured into ice water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extract was washed with saturated brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica chromatography (0-30% EtOAc / hexane) to obtain the title compound (120 mg, 30%, over two steps). 1 H NMR (500 MHz, CDCl3) δ: 9.81 (s, 1H), 7.62 (s, 1H), 7.58 (d, 1H), 7.39 (m, 4H), 7.33 (m, 2H), 7.23 (m, 2H), 7.13 (t, 1H), 7.09 (s, 1H), 6.50 (d, 1H), 6.31 (s, 1H),

[0493] Step 4. 6-((1H-indole-2-yl)(phenyl) methyl )-2- (4-(1-methylpiperidine-4-yl)phenyl)thieno [2,3-c]pyridin-7(6H)-one

[0494]

[0495] A mixture of 6-((1H-indole-2-yl)(phenyl)methyl)-2-bromothieno[2,3-c]pyridine-7(6H)-one (120 mg, 0.27 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (90 mg, 0.3 mmol), Na2CO3 (86 mg, 0.81 mmol), dioxane (3 mL), and water (1 mL) was degassed and N2 was added twice. PdCl2dppf-dcm (44 mg, 0.054 mmol) was added, the mixture was degassed, and N2 was added. The reaction mixture was heated to 95°C for 20 minutes. After cooling, the entire reaction mixture was purified by RP-HPLC eluted with 0-80% ACN / H2O (0.038% TFA) to obtain the title compound (54 mg, 38%). NMR (500 MHz, DMSO- d 6 ) δ: 1 H 11.42 (s, 1H), 9.43 (br s, 1H), 7.80 (d, 2H), 7.77 (s, 1H), 7.50 (d, 2H), 7.44 (m, 2H), 7.38 (m, 3H), 7.31 (m, 4H), 7.11 (t, 1H), 7.00 (t, 1H), 6.78 (d, 1H), 6.09 (s, 1H), 3.54 (d, 2H), 3.10 (m, 2H), 2.87 (m, 1H), 2.84 (d, 3H), 2.06 (d, 2H), 1.86 (m, 2H). M.S. m / z: 530.25 [M + 1] + .

[0496] Example 10: HTRF-based EGFR biochemical assay

[0497] EGFR biochemical activity measurements were performed using a homogeneous time-resolution fluorescence (HTRF) assay (Cisbio). Inhibitors and DMSO normalization were first dispensed to empty black, low-volume 384-well plates (Corning) using a D300 digital liquid dispenser (HP). All reactions were performed at room temperature, and solutions were added to the plates using a Multidrop Combi Reagent Dispenser (ThermoFisher). The reaction mixture (final volume 10 μL) contained 1 μM tyrosine kinase peptide-biotin substrate and mutant EGFR in reaction buffer (50 mM HEPES pH 7.0, 5 mM MgCl2, 1 mM MnCl2, 0.01% BSA, 2 mM TCEP, 0.1 mM NaVO4). Enzyme concentrations were adjusted to accommodate varying kinase activities (L858R 0.1 nM, L858R / T790M 0.02 nM). Enzyme reaction solution (2x concentration, 5 μL) was added to a 384-well plate containing the compounds and incubated for 30 minutes. The enzyme reaction was initiated by adding 5 μL of ATP until a final concentration of 100 μM was reached, and the reaction was carried out for 20 minutes. The reaction was quenched by adding 10 μL of phospho-tyrosine antibody-europium(III) cryptate (1 to 180 volume ratio) and streptavidin-XL665 (46.7 nM) to EDTA-containing detection buffer, followed by incubation at room temperature for 1 hour and reading with a PHERAstar plate reader (excitation = 337 nm, emission = 620 nm and 665 nm). IC5 50 The values ​​were determined by triple suppression curves (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 fitted to GraphPad Prism 7.0d. The obtained data are shown in Table 4 below.

[0498]

[0499] Examples 11: Ba / F3 cell proliferation model

[0500] EGFR mutant L858R and L858R / T790M Ba / F3 cells have been previously described (Zhou, W., et al. Nature 462, 2009, 1070-1074). All cell lines were maintained in RPMI 1640 (Cellgro; Mediatech Inc., Herndon, CA) supplemented with 10% FBS, 100 units / mL penicillin, and 100 units / mL streptomycin. The EGFR I941R mutation was introduced via site-directed mutagenesis using the Quick Change Site-Directed Mutagenesis Kit (Stratagene; La Jolla, CA) according to the manufacturer's instructions. All constructs were verified by DNA sequencing. Constructs were shuttled to the retroviral vector JP1540 using the Cre-recombinant system (Agilent Technologies, Santa Clara, CA). Ba / F3 cells were then infected with retroviruses according to standard protocols as previously described (Zhou, et al, Nature 2009). Stable clones were obtained by screening in puromycin (2 μg / ml).

[0501] Growth and growth inhibition were evaluated by the Cell Titer Glo assay (Promega, Madison, WI) and performed according to the manufacturer's instructions. The Cell Titer Glo assay is a luminescence-based method used to determine the number of viable cells based on the quantification of present ATP, which is directly proportional to the amount of metabolically active cells present. Different EGFR Genotyped Ba / F3 cells were exposed to the compound for 72 hours as a single agent or in combination with 1 μg / mL cetuximab, and the number of cells used per experiment was determined empirically as previously established (Zhou, et al. Nature 2009). All experimental points were set up in triples on 384-well plates, and all experiments were repeated at least three times. Luminescence signals were detected using a spectrometer, and the data were graphically displayed using GraphPad Prism version 5.0 for Windows (GraphPad Software, www.graphpad.com). Curves were fitted using a nonlinear regression model with an S-shaped dose response. The results of this test for the compounds disclosed herein are presented in Table 5 below.

[0502]

[0503] The scope of the disclosed content is not limited by the specific embodiments and examples described herein. In fact, various modifications of the disclosure other than those described will be apparent to those skilled in the art from the foregoing description and the accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

[0504] All references cited herein (e.g., publications or patents or patent applications) are incorporated by reference in their entirety for all purposes to the same extent that each individual reference (e.g., publications, patents or patent applications) is specifically and individually indicated as being incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

Claims

Claim 1 Compound of Formula I or its pharmaceutically acceptable salt: During the meal: represents a single or double bond; A is CH; and A' is CH, CR 8 or selected from the group consisting of N; W is N or C; Z is selected from the group consisting of S, N, and CH; X is S or CH; Y is CR 3 And; provided that only one of X and Z is S, and when Z is N, X is S and; R 1 is C(O)NHR 9 , selected from the group consisting of 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, wherein the heteroaryls, cycloalkyls, and heterocycloalkyls have 1, 2, or 3 Rs 8 Optionally substituted as;R 2 is 1, 2, or 3 R 6 It is a phenyl selectively substituted with;R 3 silver Igo;R 6 are independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 Selected from the group consisting of NH2 or CN; alternatively, 2 R 6 They can form 5-10 member heteroaryls, 6-10 member aryls, 3-10 member heterocycloalkyls, or 3-10 member cycloalkyls together with the atoms to which they are attached; R 7 is a C1-C6 alkyl; R 8 is a halogen; R 9 is selected from the group consisting of 6-10-membered aryls, 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, all of which have 1, 2, or 3 Rs 8 Optionally replaced with. Claim 2 Compound of chemical formula X or its pharmaceutically acceptable salt: During the meal: represents a single or double bond; A and A' are each CH2; alternatively, A is absent; W is C; Z is selected from the group consisting of S, N, and CH; X is S or CH; and Y is CR 3 And; provided that only one of X and Z is S, and when Z is N, X is S and; R 1 is C(O)NHR 9 , selected from the group consisting of 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, wherein the heteroaryls, cycloalkyls, and heterocycloalkyls have 1, 2, or 3 Rs 8 Optionally substituted as;R 2 is 1, 2, or 3 R 6 It is a phenyl selectively substituted with;R 3 silver Igo;R 6 are independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 Selected from the group consisting of NH2 or CN; alternatively, 2 R 6 They can form 5-10 member heteroaryls, 6-10 member aryls, 3-10 member heterocycloalkyls, or 3-10 member cycloalkyls together with the atoms to which they are attached; R 7 It is a C1-C6 alkyl; R 8 Independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 Selected from the group consisting of NH2 or CN; R 9 is selected from the group consisting of 6-10-membered aryls, 5-10-membered heteroaryls, 3-10-membered heterocycloalkyls, and 3-10-membered cycloalkyls, all of which have 1, 2, or 3 Rs 8 Optionally replaced with. Claim 3 In claim 1, the compound of formula I is a compound of formula IV or a pharmaceutically acceptable salt thereof, the compound: . Claim 4 In paragraph 2, the compound of formula X is a compound of formula Xb or a pharmaceutically acceptable salt thereof, wherein: . Claim 5 Compound of chemical formula XX or its pharmaceutically acceptable salt: In the formula: A is CH2 and A' is CH2 or NR 8 And;Y is CR 3 and; X and Z are CH and R respectively. 1 is 1, 2, or 3 R 8 It is a 5-10-membered heteroaryl that is selectively substituted with R 2 is 1, 2, or 3 R 6 It is a phenyl selectively substituted with;R 3 silver Igo;R 6 are independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 Selected from the group consisting of NH2 or CN; alternatively, 2 R 6 They can form 5-10 member heteroaryls, 6-10 member aryls, 3-10 member heterocycloalkyls, or 3-10 member cycloalkyls together with the atoms to which they are attached; R 7 is a C1-C6 alkyl; R 8 Independently, in each case, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 Selected from the group consisting of NH2 or CN. Claim 6 In paragraph 5, the compound of formula XX is a compound of formula XXa or a pharmaceutically acceptable salt thereof, a compound: . Claim 7 In claim 1, the compound of formula I is a compound of formula II or a pharmaceutically acceptable salt thereof, the compound: . Claim 8 In claim 1, the compound of formula I is a compound of formula III or a pharmaceutically acceptable salt thereof, the compound: . Claim 9 In paragraph 2, the compound of formula X is a compound of formula Xa or a pharmaceutically acceptable salt thereof, compound: . Claim 10 In claim 1, the compound of formula I is a compound of formula IVb or a pharmaceutically acceptable salt thereof, compound: . Claim 11 In any one of paragraphs 1 through 10, R 6 Independently, in each case, a hydroxy or haloin, compound. Claim 12 In any one of paragraphs 1 through 10, R 1 is selected from the group consisting of benzimidazole, imidazopyridine, indole, triazole, pyrazole, imidazole, pyridinylamide, and thiazolylamide, all of which have 1, 2, or 3 R 8 A compound that is selectively substituted with Claim 13 In any one of paragraphs 1 through 10, R 1 silver and Selected from a group consisting of; all of these are 1, 2, or 3 R 8 A compound that is selectively substituted with Claim 14 In any one of paragraphs 1 through 10, R 7 A compound that is a C1-C3 alkyl. Claim 15 In claim 1, the compound of formula I is selected from the group consisting of the following or its pharmaceutically acceptable salts: Claim 16 In paragraph 2, the compound is selected from the group consisting of the following or its pharmaceutically acceptable salts: . Claim 17 In claim 5, the compound of formula XX is a compound selected from the group consisting of the following or their pharmaceutically acceptable salts: . Claim 18 In claim 1, the compound of formula I is a compound that is the following compound or a pharmaceutically acceptable salt thereof. Claim 19 In paragraph 18, the compound of formula I is a compound that is the following compound or a pharmaceutically acceptable salt thereof. or Claim 20 A pharmaceutical composition for treating cancer comprising a compound of any one of claims 1 to 10 and claims 15 to 19, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. Claim 21 A pharmaceutical composition for treating cancer in a subject requiring treatment for cancer, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10 and claims 15 to 19. Claim 22 A pharmaceutical composition according to claim 21, 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. Claim 23 A pharmaceutical composition according to claim 21, wherein the cancer is non-small cell lung cancer (NSCLC). Claim 24 A pharmaceutical composition according to claim 21, wherein the cancer is resistant to EGFR targeted therapy. Claim 25 In claim 24, the above EGFR targeted therapy is a pharmaceutical composition selected from the group consisting of gefitinib, erlotinib, and osimertinib. Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete Claim 35 delete Claim 36 delete Claim 37 delete Claim 38 delete Claim 39 delete Claim 40 delete Claim 41 delete Claim 42 delete

Images