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WO2025251058A1 - Inhibiteurs d'egfr dans le traitement du cancer - Google Patents

Inhibiteurs d'egfr dans le traitement du cancer

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Publication number
WO2025251058A1
WO2025251058A1 PCT/US2025/031824 US2025031824W WO2025251058A1 WO 2025251058 A1 WO2025251058 A1 WO 2025251058A1 US 2025031824 W US2025031824 W US 2025031824W WO 2025251058 A1 WO2025251058 A1 WO 2025251058A1
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celyn
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compound
formula
iupac name
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Inventor
Alexander Khvat
Ruben Abagyan
Nikolay Savchuk
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Celyn Therapeutics Inc
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Celyn Therapeutics Inc
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  • EGFR Inhibitors in cancer treatment CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims priority to and benefit of U.S. Provisional Patent Application Serial No. 63/654,848 filed May 31, 2024, entitled “EGFR Inhibitors in cancer treatment” the disclosure of which are incorporated by reference in its entirety for all purposes.
  • FIELD OF INVENTION The present invention is directed to inhibitors of Epidermal Growth Factor Receptor (EGFR or EGF-receptor) – receptor of tyrosine kinase family.
  • the inhibitors described herein can be useful in the treatment of diseases or disorders associated with EGFR, such as cancer.
  • the invention is concerned with compounds and pharmaceutical compositions inhibiting EGFR, methods of treating diseases or disorders associated with EGFR, and methods of synthesizing these compounds.
  • EGFR epidermal growth factor receptor
  • the physiological function of the epidermal growth factor receptor (EGFR) is to regulate epithelial tissue development and homeostasis.
  • the epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor for various growth factors including EGF (epidermal growth factor), TGF- ⁇ (transforming growth factor- ⁇ ) and other EGF-like ligands.
  • the EGFR pathway plays an important role in pulmonary physiology especially the function of epithelial cells via signaling transduction that regulates key cellular processes such as self-renew, wound-healing, proliferation, survival, adhesion, migration, and differentiation.
  • Epidermal growth factor receptor EGFR
  • EGFR gene amplification, overexpression, and mutation are frequently observed in various cancer indications and are associated with a poor prognosis.
  • the epidermal growth factor receptor (EGFR) over-activation is observed in a vast number of cancers.
  • the EGFR is a driver of tumorigenesis. Inappropriate activation of the EGFR in cancer mainly results from amplification and point mutations at the genomic locus, but transcriptional upregulation or ligand overproduction due to autocrine/paracrine mechanisms has also been described. Moreover, the EGFR is increasingly recognized as a biomarker of resistance in tumors, as its amplification or secondary mutations have been found to arise under drug pressure. This evidence, in addition to the prominent function that this receptor plays in normal epithelia, has prompted intense investigations into the role of the EGFR both at physiological and at pathological level. 1. ASB
  • EGFR epidermal growth factor receptor
  • NDDs neurodegenerative diseases
  • AD Alzheimer's disease
  • ALS Amyotrophic Lateral Sclerosis
  • SCI brain and spinal cord injuries
  • EGFR inhibitors have produced impressive therapeutic benefits to responsive types of cancers.
  • patients who initially respond to anti-EGFR drugs almost inevitably develop resistance.
  • Resolving mechanisms of drug resistance translates to higher granularity maps of signaling pathways and it holds the promise of prolonging patient response.
  • a novel targeted therapy that is able to specifically address the EGFR-C797S acquired resistance mutation would be highly beneficial for those patients.
  • a first aspect of the invention relates to compounds of Formula (A): 2.
  • each A is independently selected from N and CH, providing that at least one A is N;
  • Q is selected from O, S, NH, CH2;
  • L 1 is selected from a bond, –(CH2)k-, –(CH2)k-C(O)-, –(CH2)k-O-C(O)-, –(CH2)k-NH- C(O)-, –(CH2)k-O-(CH2)k-;
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with EGFR.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with EGFR an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of inhibiting of EGFR.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of inhibiting of EGFR.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • a compound of Formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the present invention relates to compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting EGFR.
  • Another aspect of the present invention relates to the use of compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with EGFR.
  • Another aspect of the present invention relates to compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a 4.
  • ASB
  • Celyn.24.0001 patient in need of the treatment an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the present invention relates to the use of compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • the present invention further provides methods of treating a disease or disorder associated with EGFR, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • a compound of Formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention provides inhibitors of EGFR that are therapeutic agents in the treatment of diseases and disorders.
  • the present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known inhibitors of EGFR.
  • the present disclosure also provides agents with novel mechanisms of action toward EGFR in the treatment of various types of diseases.
  • the present invention further provides methods of treating a disease or disorder associated with EGFR, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • a compound of Formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention provides inhibitors of EGFR that are therapeutic agents in the treatment of diseases and disorders.
  • the present invention further provides methods of treating a disease, disorder, or condition selected from Inflammatory Skin and Bowel Disease, Neonatal, 2 (NISBD2); Lung Cancer; Lung Cancer Susceptibility 3 (LNCR3); Lung Squamous Cell Carcinoma; Gliosarcoma; Brain Stem Glioma; Adenocarcinoma; Colorectal Cancer; Glioblastoma; Breast Cancer; Squamous Cell Carcinoma; Small Cell Cancer of the Lung; Lung Squamous Cell Carcinoma; Inflammatory Skin and Bowel Disease, Neonatal, 2; Gastric Cancer; Prostate Cancer; Squamous Cell Carcinoma, Head and Neck; Pancreatic Cancer; Brain Cancer; Ovarian Cancer; Esophageal Cancer; Giant Cell Glioblastoma; Gliosarcoma; Lung Benign Neoplasm; Glioma; Exanthem; Endometrial Cancer; Adenoid Cystic Carcinoma;
  • the present disclosure provides a compound obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in General Procedure).
  • a method for preparing compounds described herein e.g., a method comprising one or more steps described in General Procedure.
  • the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Preparative part – P1-P16).
  • the present disclosure provides a method of preparing compounds of the present disclosure.
  • the present disclosure provides a method of preparing compounds of the present disclosure, comprising one or more steps described herein.
  • the present disclosure provides methods of preparing compounds of the present disclosure, described in the examples. [0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below.
  • an alkyl group can (but is not required to) be bonded other substituents (e.g., heteroatoms).
  • substituents e.g., heteroatoms
  • an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon).
  • the same optionally substituted alkyl group can have one or more substituents different from hydrogen.
  • any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein.
  • the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups but does not necessarily have any further functional groups.
  • Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, –OH, –CN, –COOH, –CH 2 CN, –O-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C1-C6)haloalkoxy, –O-(C2-C6)alkenyl, –O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, — OP(O)(OH) 2 , –OC(O)(C 1 -C 6 )alkyl, –C(O)(C 1 -C 6 )alkyl, –OC(O)O(C 1 -C 6 )alkyl, —NH 2 , –NH((C 1 -
  • substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.
  • substituted means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions.
  • an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.
  • unsubstituted means that the specified group bears no substituents. 7.
  • aryl refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl).
  • the aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment.
  • substituents include, but are not limited to, –H, -halogen, – O-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, –O-(C 2 -C 6 )alkenyl, –O-(C 2 -C 6 ) alkynyl, (C 2 -C 6 )alkenyl, (C 2 - C6)alkynyl, –OH, –OP(O)(OH)2, –OC(O)(C1-C6)alkyl, –C(O)(C1-C6)alkyl, –OC(O)O(C1- C 6 )alkyl, —NH 2 , –NH((C 1 -C 6 )alkyl), –N((C 1 -C 6 )alkyl) 2 , –S(O) 2 -(C 1 -C 6 )alkyl, –S(O)NH(C 1
  • the substituents can themselves be optionally substituted.
  • the aryl groups herein defined may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring.
  • Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.
  • arylene or “arylenyl” means an organic radical derived from an aromatic divalent radical by removal of at least two hydrogens, from a group such as phenyl, naphthyl, indenyl, indanyl and fluorenyl.
  • An arylene is generally present as a bridging or linking group between two other groups.
  • Non-exclusive examples of such arylene groups include 1,2- disubstituted phenyl, 1,3-disubstituted phenyl, 1,4-disubstituted phenyl, etc.
  • heteroaryl means a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C.
  • a polycyclic aromatic radical includes two or more fused rings and may further include two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, and the like.
  • fused means two rings sharing two ring atoms.
  • spiro-fused means two rings sharing one ring atom.
  • Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein.
  • Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, 8.
  • furyl thienyl
  • pyrrolyl pyridyl
  • pyrazolyl pyrimidinyl
  • imidazolyl isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl,
  • the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with one or more fully unsaturated aromatic ring.
  • a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein.
  • the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring spiro-fused. Any saturated or partially unsaturated ring described herein is optionally substituted with one or more oxo.
  • Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H--isoquinolinyl, 2,3- dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H- pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2- b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-
  • Halogen refers to fluorine, chlorine, bromine, or iodine.
  • Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C1-C6) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • alkanediyl refers to a straight or branched chain saturated hydrocarbon biradicals containing 1-12 carbon atoms. Unless specified otherwise, such alkanediyls include substituted alkanediyls.
  • Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, - CH 2 CH 2 CH 2 CH 2 -, and the like.
  • Alkoxy refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy groups.
  • Alkenyl refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • alkenyl groups examples include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.
  • An alkenyl group can be unsubstituted or substituted.
  • Alkenyl, as herein defined, may be straight or branched.
  • Alkenediyl refers to a straight or branched chain alkene biradicals containing 2-12 carbon atoms. Unless specified otherwise, such alkenediyls include substituted alkenediyls.
  • the “alkendiyl” group contains at least one double bond in the chain.
  • alkendiyl group can be unconjugated or conjugated to another unsaturated group.
  • alkenyl groups include ethendiyl, propendiyl, n-butendiyl, iso-butendiyl, pentendiyl, or hexendiyl.
  • Alkynyl refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain.
  • alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.
  • An alkynyl group can be unsubstituted or substituted.
  • Alkynediyl refers to a straight or branched chain unsaturated hydrocarbon biradicals containing 2-12 carbon atoms. The “alkynediyl” group contains at least one triple bond in the chain.
  • alkendiyl groups include ethyndiyl, propynediyl, n-butynediyl, iso-butynediyl, pentynediyl, or hexynediyl.
  • An alkynediyl group can be unsubstituted or substituted.
  • Cycloalkyl means mono or polycyclic saturated carbon rings containing 3-18 carbon atoms. Polycyclic cycloalkyl may be fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro-fused bicyclic cycloalkyl.
  • a polycyclic cycloalkyl comprises at least one non-aromatic ring. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, 10.
  • Celyn.24.0001 cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3- dihydro-1H-indenyl, spiro[3.5]nonyl, spiro[5.5]undecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.
  • “Cycloalkanediyl” refers to divalent functional groups derived from cycloalkanes by the removal of two hydrogen atoms from ring atoms.
  • Cycloalkanediyl can be mono or polycyclic saturated carbon ring containing 3-18 carbon atoms.
  • Polycyclic cycloalkanediyl may be fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro-fused bicyclic cycloalkanediyl.
  • a polycyclic cycloalkanediyl comprises at least one non-aromatic ring.
  • “Heterocyclyl”, “heterocycle” or “heterocycloalkyl” mono or polycyclic rings containing 3-24 atoms which include carbon and one or more heteroatoms selected from N, O, S, P, or B and wherein the rings are not aromatic.
  • heterocycloalkyl ring structure may be substituted by one or more substituents.
  • the substituents can themselves be optionally substituted.
  • heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.
  • Heterocyclediyl refers to divalent functional groups derived from heterocycle by the removal of two hydrogen atoms from ring atoms.
  • aromatic means a planar ring having 4n + 2 electrons in a conjugated system.
  • conjugated system means a system of connected p-orbitals with delocalized electrons, and the system may include lone electron pairs.
  • haloalkyl refers to an alkyl group, as defined herein, which is substituted one or more halogen.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.
  • haloalkoxy refers to an alkoxy group, as defined herein, which is substituted with one or more halogen.
  • haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.
  • cyano as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C ⁇ N.
  • solvate refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as 11. ASB
  • Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
  • the term "isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (A) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.
  • stereoisomer refers to compounds that have the same molecular formula and sequence of bonded atoms (constitution) but differ in the three-dimensional orientations of their atoms in space.
  • the present disclosure also contemplates isotopically-labelled compounds of Formula I (e.g., those labeled with 2 H and 14 C).
  • Deuterated (i.e., 2 H or D) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • the disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.
  • salts include, e.g., water-soluble and water- insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate
  • a "patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus.
  • An "effective amount" when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.
  • carrier encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
  • treating refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.
  • administer means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.
  • salt refers to pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt also refers to a salt of the compositions of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base.
  • the symbol “ ”, as used in this disclosure, means a double bond in E- or Z- configuration or mi - and Z- configurations.
  • EGFR inhibitor as used herein refer to compounds of Formula (A) and/or compositions comprising a compound of Formula (A) which inhibits EGFR.
  • the amount of compound of composition described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose.
  • therapeutic agents e.g. compounds or compositions of Formula (A) (and/or additional agents) described herein
  • the therapeutic agents are given at a pharmacologically effective dose.
  • a “pharmacologically effective amount,” “pharmacologically effective dose,” “therapeutically effective amount,” or “effective amount” refers to an amount sufficient to produce the desired physiological effect or 13.
  • Celyn.24.0001 amount capable of achieving the desired result, particularly for treating the disorder or disease.
  • An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease.
  • administration of therapeutic agents to a subject suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the subject reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival.
  • Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.
  • the present disclosure provides compounds of Formula (A) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: A), wherein R 1 , R 2 , R 3 , R 4 , A, Q, in.
  • R 1 , R 2 , R 3 , R 4 , A, Q, L 1 , W and L 2 can each be, where applicable, selected from the groups described herein, and any group described herein for any R 1 , R 2 , R 3 , R 4 , A, Q, L 1 , W and L 2 can be combined, where applicable, with any group described herein for one or more of the remainder of R 1 , R 2 , R 3 , R 4 , A, Q, L 1 , W and L 2 .
  • the present disclosure provides compounds of Formula (I) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: 14.
  • R 1 , R 2 , R 3 , R 4 , A, Q, G, and n can each be, where applicable, selected from the groups described herein, and any group described herein for any R 1 , R 2 , R 3 , R 4 , A, Q, G, and n can be combined, where applicable, with any group described herein for one or more of the remainder of R 1 , R 2 , R 3 , R 4 , A, Q, G, and n.
  • the compound is of Formula (I-A): A), or a pharmaceutically accept ate, or tautomer thereof.
  • the compound is of Formula (I-A-1): 15. ASB
  • the compound is of Formula (I-A-1-a-I): I), or a pharmaceutically acce , , , e, or tautomer thereof. 16.
  • ASB is of Formula (I-A-1-a-I): I), or a pharmaceutically acce , , , e, or tautomer thereof. 16.
  • the compound is of Formula (I-A-1-a-I*): *), or a pharmaceutically acc , or tautomer thereof. [0088] In some embodiments, the compound is of Formula (I-A-1-a-I**): *), or a pharmaceutically ac or tautomer thereof. [0089] In some embodiments, the compound is of Formula (I-A-1-a-I***): *), .
  • the compound is of Formula (I-A-1-a-I****): *), or a pharmaceutically a r tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-a): a), or a pharmaceutically acc or tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-a*): 18.
  • the compound is of Formula (I-A-1-a-I-a**): *), or a pharmaceutically a r tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-a***): *), or a pharmaceutically a p , p g, , , r tautomer thereof. 19.
  • ASB
  • the compound is of Formula (I-A-1-a-I-a****): *), or a pharmaceutically r tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-b): b), or a pharmaceutically acc or tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-b*): *), .
  • the compound is of Formula (I-A-1-a-I-b**): *), or a pharmaceutically a r tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-b***): *), or a pharmaceutically a r tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-b****): 21.
  • the compound is of Formula (I-A-1-a-I-b-1): 1), or a pharmaceutically ac or tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-b-1*): *), or a pharmaceutically ac , , , , or tautomer thereof. 22. ASB
  • the compound is of Formula (I-A-1-a-I-b-1**): *), or a pharmaceutically a r tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-b-1***): *), or a pharmaceutically a r tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-b-1****): *), .
  • the compound is of Formula (I-A-1-a-I-c): c), or a pharmaceutically acc or tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-c*): *), or a pharmaceutically ac or tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-c**): 24.
  • the compound is of Formula (I-A-1-a-I-c***): *), or a pharmaceutically a r tautomer thereof. [0110] In some embodiments, the compound is of Formula (I-A-1-a-I-c****): *), or a pharmaceutically a , , , , r tautomer thereof. 25. ASB
  • the compound is of Formula (I-A-1-a-I-d): d), or a pharmaceutically acc or tautomer thereof. [0112] In some embodiments, the compound is of Formula (I-A-1-a-I-d*): *), or a pharmaceutically ac or tautomer thereof. [0113] In some embodiments, the compound is of Formula (I-A-1-a-I-d**): *), .
  • the compound is of Formula (I-A-1-a-I-d***): *), or a pharmaceutically a r tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-d****): *), or a pharmaceutically tautomer thereof.
  • the compound is of Formula (A1): 1), 27. ASB
  • the compound is of Formula (B): B), or a pharmaceutically acceptab lvate, or tautomer thereof.
  • the compound is of Formula (C): O C), or a pharmaceutically acceptab lvate, or tautomer thereof.
  • the compound is of Formula (D): O F 3 C D), or a pharmaceutically acceptab , , , lvate, or tautomer thereof.
  • the compound is of Formula (E): O E), or a pharmaceutically acceptab lvate, or tautomer thereof.
  • the compound is of Formula (FG): G), or a pharmaceutically accepta vate, or tautomer thereof, wherein W is halogen and all other variables are as defined herein.
  • the compound is of Formula (F): F), 29.
  • the compound is of Formula (G): G), or a pharmaceutically acceptab lvate, or tautomer thereof.
  • the compound is of Formula (H): H), or a pharmaceutically accepta vate, or tautomer thereof.
  • the compound is of Formula (J): J), or a pharmaceutically acceptab , , , olvate, or tautomer thereof. 30. ASB
  • the compound is of Formula (K): K), or a pharmaceutically accept ate, or tautomer thereof.
  • the compound is of Formula (L): L), or a pharmaceutically accept ate, or tautomer thereof.
  • the compound is of Formula (II): I), or a pharmaceutically accepta , , , vate, or tautomer thereof.
  • the compound is of Formula (III): 31.
  • the compound is of Formula (IV): V), or a pharmaceutically accepta vate, or tautomer thereof.
  • the compound is of Formula (V): V), or a pharmaceutically accepta , , , vate, or tautomer thereof.
  • the compound is of Formula (VI): 32.
  • the compound is of Formula (VII): I), or a pharmaceutically accept ate, or tautomer thereof.
  • the compound is of Formula (VIII): I), or a pharmaceutically accept , , , ate, or tautomer thereof.
  • the compound is of Formula (IX): 33.
  • the compound is of Formula (X): X), or a pharmaceutically accepta vate, or tautomer thereof.
  • the compound is of Formula (XI): I), or a pharmaceutically accepta , , , vate, or tautomer thereof.
  • the compound is of Formula (XII): 34.
  • the compound is of Formula (XIII): I), or a pharmaceutically accept ate, or tautomer thereof.
  • each A is independently selected from N and CH, providing that at least one A is N.
  • the compound of Formula (A) comprises fragme .
  • the compound of Formula (A) comprises fragme . 35. ASB
  • the compound of Formula (A) comprises fragme .
  • the compound of Formula (A) comprises fragme .
  • Q is selected from O, S, NH, CH2.
  • Q is O.
  • Q is S.
  • Q is NH.
  • Q is CH2.
  • G is selected from CH and N.
  • G is CH.
  • G is N.
  • R 1 is selected from H, halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2.
  • R 1 is H.
  • R 1 is halogen.
  • R 1 is F.
  • R 1 is Cl.
  • R 1 is Br. [0159] In some embodiments, R 1 is OH. [0160] In some embodiments, R 1 is CN. [0161] In some embodiments, R 1 is NO2. [0162] In some embodiments, R 1 is C1-C6 alkyl. [0163] In some embodiments, R 1 is methyl. [0164] In some embodiments, R 1 is ethyl. [0165] In some embodiments, R 1 is n-propyl. [0166] In some embodiments, R 1 is iso-propyl. [0167] In some embodiments, R 1 is C 1 -C 6 alkoxy. 36. ASB
  • R 1 is -OCH3.
  • R 1 is -OCH 2 CH 3 .
  • R 1 is -OCH2CH2CH3.
  • R 1 is -OCF 3 .
  • R 1 is C3-C10 cycloalkyl.
  • R 1 is C3-C10 cycloalkoxy.
  • R 2 is selected from H, halogen, OH, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2.
  • R 2 is H.
  • R 2 is halogen.
  • R 2 is F.
  • R 2 is Cl.
  • R 2 is Br. [0180] In some embodiments, R 2 is OH. [0181] In some embodiments, R 2 is CN. [0182] In some embodiments, R 2 is NO 2 . [0183] In some embodiments, R 2 is C1-C6 alkyl. [0184] In some embodiments, R 2 is methyl. [0185] In some embodiments, R 2 is ethyl. [0186] In some embodiments, R 2 is n-propyl. [0187] In some embodiments, R 2 is iso-propyl. [0188] In some embodiments, R 2 is C 1 -C 6 alkoxy. [0189] In some embodiments, R 2 is -OCH3.
  • R 2 is -OCH 2 CH 3 .
  • R 2 is -OCH2CH2CH3.
  • R 2 is -OCF3.
  • R 2 is C 3 -C 10 cycloalkyl.
  • R 2 is C3-C10 cycloalkoxy.
  • R 3 is selected from H, halogen, OH, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2.
  • R 3 is H. 37. ASB
  • R 3 is halogen. [0198] In some embodiments, R 3 is F. [0199] In some embodiments, R 3 is Cl. [0200] In some embodiments, R 3 is Br. [0201] In some embodiments, R 3 is OH. [0202] In some embodiments, R 3 is CN. [0203] In some embodiments, R 3 is NO 2 . [0204] In some embodiments, R 3 is C1-C6 alkyl. [0205] In some embodiments, R 3 is methyl. [0206] In some embodiments, R 3 is ethyl. [0207] In some embodiments, R 3 is n-propyl.
  • R 3 is iso-propyl. [0209] In some embodiments, R 3 is C 1 -C 6 alkoxy. [0210] In some embodiments, R 3 is -OCH3. [0211] In some embodiments, R 3 is -OCH 2 CH 3 . [0212] In some embodiments, R 3 is -OCH2CH2CH3. [0213] In some embodiments, R 3 is -OCF3. [0214] In some embodiments, R 3 is C 3 -C 10 cycloalkyl. [0215] In some embodiments, R 3 is C3-C10 cycloalkoxy.
  • R 4 is selected from H, halogen, OH, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2.
  • R 4 is H.
  • R 4 is halogen.
  • R 4 is F.
  • R 4 is Cl.
  • R 4 is Br. [0222] In some embodiments, R 4 is OH. [0223] In some embodiments, R 4 is CN. [0224] In some embodiments, R 4 is NO 2 . [0225] In some embodiments, R 4 is C1-C6 alkyl. [0226] In some embodiments, R 4 is methyl. [0227] In some embodiments, R 4 is ethyl. [0228] In some embodiments, R 4 is n-propyl. 38. ASB
  • R 4 is iso-propyl. [0230] In some embodiments, R 4 is C 1 -C 6 alkoxy. [0231] In some embodiments, R 4 is -OCH3. [0232] In some embodiments, R 4 is -OCH 2 CH 3 . [0233] In some embodiments, R 4 is -OCH2CH2CH3. [0234] In some embodiments, R 4 is -OCF3. [0235] In some embodiments, R 4 is C 3 -C 10 cycloalkyl. [0236] In some embodiments, R 4 is C3-C10 cycloalkoxy.
  • L 1 is selected from a bond, –(CH 2 ) k -, –(CH 2 ) k -C(O)-, –(CH 2 ) k -O- C(O)-, –(CH2)k-NH-C(O)-, –(CH2)k-O-(CH2)k-.
  • L 1 is a bond.
  • L 1 is –(CH2)k-.
  • L 1 is -CH 2 -.
  • L 1 is -CH2CH2-.
  • L 1 is -CH 2 CH 2 CH 2 -. [0243] In some embodiments, L 1 is -CH2CH2CH2CH2-. [0244] In some embodiments, L 1 is –(CH2)k-C(O)-. [0245] In some embodiments 1 i )-. [0246] In some embodiments [0247] In some embodiments -. [0248] In some embodiments )-. [0249] In some embodiments )-. [0250] In some embodiments -. [0251] In some embodiments -. [0252] In some embodiments, W is selected from O, NH , . ts, W is O. [0254] In some embodiments, W is NH. [0255] In some embodiments . ASB
  • W is . N [0257] In some embodiments . [0258] In some embodiments . [0259] In some embodiments . [0260] In some embodiments . [0261] In some embodiments . [0262] In some embodiments . [0263] In some embodiments . [0264] In some embodiments . [0265] In some embodiments . [0266] In some embodiments .
  • L 2 is –(CHR)k-.
  • L 2 is –CH2-.
  • L 2 is –(CH 2 ) 2 -. 40.
  • L 2 is –(CH2)3-. [0272] In some embodiments, L 2 is –(CH 2 ) 4 -. 2-. k-. 2 )-. [0298] In some embodiments . [0299] In some embodiments . [0300] In some embodiments . ASB
  • L 1 -W-L 2 is . [0302] In some embodiments . [0303] In some embodiments . L1 [0304] In some embodiments . N L2 [0305] In some embodiments . [0306] In some embodiments . [0307] In some embodiments . L1 [0308] In some embodiments . 2 [0309] In some embodiments . [0310] In some embodiments . [0311] In some embodiments . 42. ASB
  • k is 1. [0318] In some embodiments, k is 2. [0319] In some embodiments, k is 3. [0320] In some embodiments, k is 4. [0321] In some embodiments, k is 5. [0322] In some embodiments, k is 6. [0323] In some embodiments, m is an integer selected from 0, 1, and 2. [0324] In some embodiments, m is 0. [0325] In some embodiments, m is 1.
  • m is 2. [0327] In some embodiments, n is an integer selected from 0, 1, 2, and 3. [0328] In some embodiments, n is 0. [0329] In some embodiments, n is 1. [0330] In some embodiments, n is 2. [0331] In some embodiments, n is 3. [0332] In some embodiments, p is an integer selected from 0, 1, 2, and 3. [0333] In some embodiments, p is 0. [0334] In some embodiments, p is 1. [0335] In some embodiments, p is 2. [0336] In some embodiments, p is 3. 43. ASB
  • the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof. [0338] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof. [0339] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0340] In some embodiments, the compound is selected from the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0341] In some embodiments, the compound is selected from the compounds described in Table 1. [0342] Table 1. Certain examples of the compound of Formula (A). # Structure IUPAC name - '- - - '- - 44. ASB
  • the compound is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds described in Table 1.
  • the compound is a salt of any acid described in the Table 2 and any one of the compounds described in Table 1.
  • Table 2 Pharmaceutical acceptable acid forming salts with the Compound of Formula (A).
  • t e compound s a sa t o acet c ac d and any one o t e compounds described in Table 1.
  • the compound is a salt of adipic acid and any one of the compounds described in Table 1.
  • the compound is a salt of ascorbic acid (L) and any one of the compounds described in Table 1.
  • the compound is a salt of hydrobromic acid and any one of the compounds described in Table 1.
  • the compound is a salt of hydrochloric acid and any one of the compounds described in Table 1.
  • the compound is a salt of citric acid and any one of the compounds described in Table 1.
  • the compound is a salt of glutamic acid and any one of the compounds described in Table 1.
  • the compound is a salt of oxalic acid and any one of the compounds described in Table 1.
  • the compound is a salt of formic acid and any one of the compounds described in Table 1. 76.
  • the compound is a salt of sulfuric acid and any one of the compounds described in Table 1.
  • the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1.
  • the isotopic derivative can be prepared using any of a variety of art- recognized techniques.
  • the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the isotopic derivative is a deuterium labeled compound.
  • the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.
  • the term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled.
  • an isotopic derivative of a compound of Formula (I) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I).
  • the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from 2 H, 13 C, 14 C, 15 N, 18 O, 29 Si, 31 P, and 34 S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with 2 H with regard to one or more atoms thereof). [0366] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof. [0367] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0368] In some embodiments, the compound is a deuterium labeled compound of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof. 77. ASB
  • the compound is a deuterium labeled compound of any one of the compounds described in Table 1.
  • the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.
  • the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium.
  • the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques.
  • the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a deuterium labeled reagent for a non-deuterium labeled reagent.
  • a compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the disclosure.
  • the compound is a 18 F labeled compound.
  • the compound is a 123 I labeled compound, a 124 I labeled compound, a 125 I labeled compound, a 129 I labeled compound, a 131 I labeled compound, a 135 I labeled compound, or any combination thereof.
  • the compound is a 33 S labeled compound, a 34 S labeled compound, a 35 S labeled compound, a 36 S labeled compound, or any combination thereof.
  • the 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 33 S, 34 S, 35 S, and/or 36 S labeled compound can be prepared using any of a variety of art-recognized techniques.
  • the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 33 S, 34 S, 35 S, and/or 36 S labeled reagent for a non-isotope labeled reagent.
  • a compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 33 S, 34 S, 35 S, and 36 S atom(s) is within the scope of the disclosure.
  • substitution with isotope e.g, 18 F, 123 I, 124 I, 78.
  • ASB substitution with isotope
  • Celyn.24.0001 125 I, 129 I, 131 I, 135 I, 33 S, 34 S, 35 S, and/or 36 S may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.
  • a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.
  • the various functional groups and substituents making up the compounds of the Formula (A) are typically chosen such that the molecular weight of the compound does not exceed 900 Daltons.
  • a suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure, which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers.
  • racemic mixture A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”
  • chiral center refers to a carbon atom bonded to four nonidentical substituents.
  • chiral isomer means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, 79. ASB
  • Celyn.24.0001 a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center.
  • Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • the substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew. Chem.1966, 78, 413; Cahn and Ingold, J. Chem.
  • the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.
  • atropic isomers are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.
  • tautomer is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another.
  • Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • the concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting 80.
  • ASB aldehyde group
  • stereoisomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • the compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.
  • the present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.
  • compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable.
  • a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted 81.
  • Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).
  • pharmaceutically acceptable anion refers to an anion suitable for forming a pharmaceutically acceptable salt.
  • a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion.
  • the substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.
  • Nonlimiting examples of hydrates include monohydrates, dihydrates, etc.
  • Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
  • the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O.
  • analog refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • derivative refers to compounds that have a common core structure and are substituted with various groups as described herein.
  • bioisostere refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms.
  • the objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound.
  • the bioisosteric replacement may be physicochemically or topologically based.
  • Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996. 82.
  • ASB See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996. 82.
  • crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy.
  • DRIFT Diffuse Reflectance Infrared Fourier Transform
  • NIR Near Infrared
  • solution and/or solid state nuclear magnetic resonance spectroscopy The water content of such crystalline materials may be determined by Karl Fischer analysis.
  • Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compound of Formula (A) include all such forms.
  • tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • keto/enol illustrated below
  • imine/enamine imine/enamine
  • amide/imino alcohol amidine/amidine
  • nitroso/oxime thioketone/enethiol
  • nitro/aci-nitro H O OH H+ O- C C C C C e
  • a reference herein to a compound of Formula (A) that contains an amine function also includes the N-oxide.
  • N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N- oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W.
  • the compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure.
  • a prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure.
  • a prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein.
  • the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically produced compound or a metabolically- produced compound.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.
  • Bundgaard Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable 84. ASB
  • Celyn.24.0001 pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C 1 - C10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups.
  • C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups
  • C 1 - C10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl
  • 2- dialkylaminoacetyl and 2-carboxyacetyl groups
  • Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include ⁇ -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C 1 -C 4 alkoxy-C 2 -C 4 alkylamine such as 2-methoxyethylamine, a phenyl-C 1 -C 4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a C1-4alkylamine such as methylamine
  • a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl,morpholinomethyl,piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1- ylmethyl.
  • the in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).
  • the compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.
  • the compounds of Formula (A) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective 85. ASB
  • Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes. Preparation of Compounds [0416]
  • the compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Suitable methods include but are not limited to those methods described below.
  • Compounds of the present invention can be synthesized by following the steps outlined in General Procedure which comprise different sequences of assembling intermediates or compounds. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below.
  • GENERAL PROCEDURE [0417]
  • the compound of the Formula (A) can be prepared using reactions presented at the Scheme 1. [0418] Scheme 1 86.
  • ASB Scheme 1 86.
  • the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.
  • high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.
  • in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure.
  • These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.
  • the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.
  • the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
  • the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions.
  • Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia.
  • Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents.
  • Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • the compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers 88.
  • parenteral administration e.g., by injection, for example bolus injection or continuous infusion
  • ASB single-filled syringes, small volume infusion or in multi-dose containers 88.
  • compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
  • a suitable vehicle e.g., sterile, pyrogen-free water.
  • the compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
  • the compounds of present disclosure can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle.
  • the aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof.
  • any suitable solubility enhancing agent can be used.
  • a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl- ⁇ - cyclodextrin, methyl- ⁇ -cyclodextrin, randomly methylated- ⁇ -cyclodextrin, ethylated- ⁇ - cyclodextrin, triacetyl- ⁇ -cyclodextrin, peracetylated- ⁇ -cyclodextrin, carboxymethyl- ⁇ - cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl- ⁇ - cyclodextrin, glucosyl- ⁇ -cyclodextrin, sulfated ⁇ -cyclodextrin (S- ⁇ -CD), maltosyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin sulfobut
  • Any suitable chelating agent can be used.
  • a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.
  • Any suitable preservative can be used.
  • Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium 89.
  • quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury n
  • examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.
  • quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenyl
  • the aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure).
  • the tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.
  • the tonicity agent is selected from the group consisting of a glycol (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.
  • the aqueous vehicle may also contain a viscosity/suspending agent.
  • Suitable viscosity/suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.
  • the formulation may contain a pH modifying agent.
  • the pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid.
  • the aqueous vehicle may also contain a buffering agent to stabilize the pH.
  • the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and ⁇ -aminocaproic acid, and mixtures thereof.
  • the formulation may further comprise a wetting agent.
  • Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules.
  • Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition described herein may further comprise one or more additional pharmaceutically active agents.
  • compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely 91.
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs
  • topical use for example as creams, ointments, gels, or aqueous or oily solutions or suspensions
  • inhalation for example as a finely divided powder or a liquid aerosol
  • compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • a therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a EGFR related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • a therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat an EGFR related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of Formula (A) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or subject and the route of administration, according to well-known principles of medicine. Methods of Use [0448]
  • the present disclosure provides a method of inhibiting of EGFR (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the disease or disorder is associated with EGFR.
  • the disease or disorder is a disease or disorder in which EGFR is implicated.
  • the compounds of the invention are also useful in treating diseases associated with EGFR.
  • diseases and conditions treatable according to the methods of the invention include Lung Cancer; Lung Cancer Susceptibility 3 (LNCR3); Lung Squamous Cell Carcinoma; 92. ASB
  • the disease or disorder is a Lung Cancer.
  • the present disclosure provides a method of treating or preventing a Lung Cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a Lung Cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting of EGFR (e.g., in vitro or in vivo).
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a Lung Cancer in a subject in need thereof.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating Lung Cancer in a subject in need thereof. 93. ASB
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting of EGFR (e.g., in vitro or in vivo).
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Lung Cancer in a subject in need thereof.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Lung Cancer in a subject in need thereof.
  • the present disclosure provides compounds that function as inhibitors of EGFR (e.g., in vitro or in vivo).
  • the present disclosure therefore provides a method of inhibiting of EGFR in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.
  • the inhibitor of EGFR is a compound of the present disclosure.
  • Effectiveness of compounds of the disclosure can be determined by industry-accepted assays/ disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.
  • the present disclosure also provides a method of treating a disease or disorder in which EGFR is implicated in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.
  • the subject is a mammal.
  • the subject is a human.
  • Routes of Administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by 94.
  • oral e.g. by ingestion
  • buccal sublingual
  • transdermal including, e.g., by a patch, plaster, etc.
  • transmucosal including, e.g., by 94.
  • Ba/F3 (EGFRev), Ba/F3 (H773_V774 ins NPH), Ba/F3 (EGFR A767_dup ASV), Ba/F3 (D770_N771insSVD), Ba/F3 (EGFRwt + 10 ng/ml EGF) were seeded at a density of 4000 cells 137.

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Abstract

La présente invention concerne les composés de formule (A) inhibiteurs de l'EGFR. Les inhibiteurs décrits ici peuvent être utiles dans le traitement de maladies ou de troubles associés à EGFR, tels que le cancer du poumon. En particulier, l'invention concerne des composés et des compositions pharmaceutiques inhibant l'activité de la kinase EGFR dans une cellule, des méthdoes de traitement de maladies ou de troubles associés à EGFR, et des méthodes de synthèse de ces composés.
PCT/US2025/031824 2024-05-31 2025-05-30 Inhibiteurs d'egfr dans le traitement du cancer Pending WO2025251058A1 (fr)

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