WO2021231400A1 - Bis-aryl éthers contenant de la n-acyl azétidine en tant qu'inhibiteurs de l'egfr/her2 - Google Patents

Bis-aryl éthers contenant de la n-acyl azétidine en tant qu'inhibiteurs de l'egfr/her2 Download PDF

Info

Publication number
WO2021231400A1
WO2021231400A1 PCT/US2021/031742 US2021031742W WO2021231400A1 WO 2021231400 A1 WO2021231400 A1 WO 2021231400A1 US 2021031742 W US2021031742 W US 2021031742W WO 2021231400 A1 WO2021231400 A1 WO 2021231400A1
Authority
WO
WIPO (PCT)
Prior art keywords
oxy
amino
azetidin
methoxyquinazolin
prop
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2021/031742
Other languages
English (en)
Inventor
Jie Fan
Yimin Qian
Wei He
Ke Liu
Zhinyong LUO
Hui Zhang
Pin HUANG
Jie Su
Xiangyan Sun
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Accutar Biotechnology Inc
Original Assignee
Accutar Biotechnology Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Accutar Biotechnology Inc filed Critical Accutar Biotechnology Inc
Publication of WO2021231400A1 publication Critical patent/WO2021231400A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to certain novel bis-aryl ethers containing N-acyl azetidine compounds, or pharmaceutically acceptable salts thereof, which possess anti-tumor activity and are accordingly useful in methods of treatment of the human or animal body.
  • the present invention relates to compounds that bind irreversibly to Epidermal Growth Factor Receptor (EGFR), pharmaceutical compositions comprising the compounds, and methods of use therefor.
  • EGFR Epidermal Growth Factor Receptor
  • Protein kinases are a group of enzymes that regulate diverse, important biological processes including, for example, cell growth, proliferation, survival, invasion and differentiation, organ formation, tissue repair and regeneration. Protein kinases exert their physiological functions through catalyzing the phosphorylation of protein and thereby modulating cellular activities. Because protein kinases have profound effects on cells, their activities are highly regulated. Kinases are turned on or off by phosphorylation (sometimes by autophosphorylation), by binding of activator proteins or inhibitor proteins, or small molecules, or by controlling their location in the cell relative to their substrates.
  • EGFR is a transmembrane protein tyrosine kinase member of the erbB receptor family.
  • a growth factor ligand such as epidermal growth factor (EGF)
  • the receptor can homo-dimerize with another EGFR molecule or hetero-dimerize with another family member such as erbB2 (HER2), erbB 3 (HER3), or erbB4 (HER4).
  • erbB receptors [5] Homo- and/or hetero-dimerization of erbB receptors results in the phosphorylation of key tyrosine residues in the intracellular domain and leads to the stimulation of numerous intracellular signal transduction pathways involved in cell proliferation and survival. Deregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival and has been described in many human cancers, including those of the lung, head and neck and breast.
  • the erbB family therefore represents a rational target for anticancer drug development and a number of agents targeting EGFR or erbB2 are now clinically available, including gefitinib (IRESSA ® ), erlotinib (TARCEVA ® ) and lapatinib (TYKERB ® ).
  • gefitinib IRESSA ®
  • TARCEVA erlotinib
  • TYKERB lapatinib
  • acquired resistance to therapy with gefitinib or erlotinib arises, for example by mutation of the gatekeeper residue T790M, which is reportedly detected in 50% of clinically resistant patients. This mutation is not believed to hinder the binding of gefitinib or erlotinib to EGFR sterically, merely to alter the affinity to ATP to levels comparable to WT EGFR.
  • Exon20 insertion mutations represents the third most common erbB family activating mutations in NSCLC.
  • EGFR exon 20 insertion mutations are collectively representing approximately 4% to 10% of all EGFR mutations. Most of EGFR exon 20 insertion mutations occur near the end of aC -helix after residue Met766, with EGFR D770_N771insSVD and V769_D770insASV accounting for about 40% of them.
  • erbB 2 exon20 insertion mutations occur in a similar prevalence in NSCLC and also in a similar position after residue Met774, with erbB2 A775_G776insYVMA accounting for about 80% of them. See, Jang, J. et al. Angew. Chem. Int. Ed. (2016) Vol. 57(36), 11629-11633.
  • HER2 mutations are reportedly present in about 2-4% of NSCLC (See, Stephens et al. Nature (2004) Vol. 431, 525-526). The most common mutation is an in-frame insertion within exon 20. In 83% of patients having HER2 associated NSCLC, a four amino acid YVMA insertion mutation occurs at codon 775 in exon 20 of HER2. (See, Arcila et al. Clin Cancer Res (2012) Vol. 18, 4910-
  • the exon 20 insertion results in increased HER2 kinase activity and enhanced signaling through downstream pathways, resulting in increased survival, invasiveness, and tumorigenicity (See, Wang et al. Cancer Cell (2006) Vol. 10, 25-38). Tumors harboring the HER2 YVMA mutation are largely resistant to known EGFR inhibitors. (See, Arcila et al. 2012).
  • Such compounds may be expected to be more suitable as therapeutic agents, particularly for the treatment of cancer, due to reduction of toxicology associated with WT EGFR inhibition.
  • toxicologies are known to manifest themselves in man as skin rashes and/or diarrhea.
  • the inventors have found that bis-aryl ethers containing n-acyl azetidine compounds have high potency against several mutant forms of EGFR and HER2 while at the same showing relatively low inhibition of WT EGFR.
  • the invention provides compounds, compositions and methods for modulating the activity of EGFR.
  • the invention provides compounds which act as inhibitors of EGFR.
  • the present disclosure is directed to a compound of Formula (I), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof: wherein:
  • R 1 is Ci- 6 alkyl, Ci- 6 alkoxyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 alkylene-OH, Ci- 6 alkyleneamine, or Ci - 6 alkylene-CN, each of which is substituted with 0,1, 2, or 3 R a ;
  • R 2 is H, Ci-C5alkyl, deuterated Ci-Csalkyl, Ci-Csalkoxy, Ci-Cshaloalkyl, C3-C7cycloalkyl, or heterocycle, each of which is substituted with 0,1, 2, or 3 R a ;
  • W is O or NH
  • X is C or N, wherein when X is C, Y is cyano; when X is N, Y is absent;
  • R 3 and R 4 are independently H, halogen, hydroxyl, cyano, Ci-Csalkyl, Ci-Csalkoxy, or Ci- Cshaloalkyl;
  • R 5 is 5- to 6-member cycloalkyl, 5- to 6-member aryl, 5- to 6-member heterocycle, or monocyclic or bicyclic 5- to 12-member heteroaryl, each of which is substituted with 0, 1, 2, or 3 R a ;
  • R 6 is absent, or Ci-Csalkyl, Ci-Csalkoxy, or Ci-Cshaloalkyl, or 5- to 6-member cycloalkyl, 5- to 6-member aryl, 5- to 6-member heterocycle, or monocyclic or bicyclic 5- to 12-member heteroaryl, each of which is substituted with 0, 1, 2, or 3 R a ;
  • R a is independently hydrogen, hydroxy, halogen, amino, cyano, Ci-6 alkyl, C3-8 cycloalkyl, Ci-6 alkoxyl, Ci-6haloalkyl, Ci-6 haloalkoxyl, C0(0)-Ci 4 alkyl, C0-3 alkylene-CN, C0-3 alkylene-N-(Ci-6 alkyl)2, C0-3 alkylene-C3-8 heterocycloalkyl, heterocycle, heterocycloalkyl, aryl, or heteroaryl, each of which is substituted with 0, 1, 2, or 3 R b , and may be fully or partially deuterated; and
  • R b is independently H, hydroxy, halogen, cyano, Ci-6 alkyl, C3-6 cycloalkyl, or C3-8 heterocycloalkyl.
  • R b is independently H, hydroxy, halogen, cyano, Ci-6 alkyl, C3-6 cycloalkyl, or C3-8 heterocycloalkyl.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more of a pharmaceutically acceptable carrier, a pharmaceutically acceptable vehicle, a pharmaceutically acceptable excipient, or combinations thereof.
  • a combination therapy comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an additional anti-cancer agent.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for treating cancer associated with EGFR or HER2 exon 20 insertion mutation, wherein the cancer is selected from breast cancer, lung cancer, pancreatic cancer, colon cancer, head and neck cancer, renal cell carcinoma, squamous cell carcinoma, thyroid cancer, gall bladder cancer, thyroid cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, or esophageal cancer.
  • a method for inhibiting EGFR comprising administering to a system or subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Also provided herein is a method for treating a condition associated with EGFR or HER2 exon 20 insertion mutation, comprising administering to a system or subject in need of such treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -CN is attached through the carbon atom.
  • C1-C6 alkyl or “Ci- 6 alkyl” is intended to encompass Ci, C2, C3, C4, C5, , Ci-6, Ci- 5, Ci-4, Ci-3, Ci-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
  • acyl refers to R-C(O)- groups such as, but not limited to, (alkyl)-C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)-C(O)-, and (heterocyclyl)-C(O)-, wherein the group is attached to the parent molecular structure through the carbonyl functionality.
  • acyl radical which refers to the total number of chain or ring atoms of the, for example, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl, portion plus the carbonyl carbon of acyl.
  • a C4-acyl has three other ring or chain atoms plus carbonyl.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2 to 8 carbon atoms, referred to herein as C2-8alkenyl.
  • alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl, 2- butenyl, and 4-(2-methyl-3-butene)-pentenyl.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1 to 8 carbon atoms, referred to herein as Cl-8alkyl.
  • exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl- 1 -propyl, 2-methyl-2- propyl, 2-methyl- 1 -butyl, 3 methyl- 1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl- 1 -propyl, 2-methyl- 1 -pentyl,
  • alkyl is a straight-chain hydrocarbon. In some embodiments, “alkyl” is a branched hydrocarbon.
  • alkoxy means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, e.g., -O(alkyl).
  • alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.
  • alkylene referes to a divalent alkyl radical.
  • Representative examples of Ci-10 alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3- methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene and n-decylene.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2 to 8 carbon atoms, referred to herein as C2-8alkynyl.
  • exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl- 1-butynyl, 4-propyl-2-pentynyl, and 4- butyl-2-hexynyl.
  • aryl refers to a mono-, bi-, or other multi carbocyclic, aromatic ring system with 5 to 14 ring atoms.
  • the aryl group can optionally be fused to one or more rings selected from aryls, cycloalkyls, heteroaryls, and heterocyclyls.
  • aryl groups of this present disclosure can be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
  • Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5, 6,7,8- tetrahydronaphthyl.
  • Exemplary aryl groups also include but are not limited to a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “C 6 -aryl.”
  • cycloalkyl refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-16 carbons, or 3-8 carbons, referred to herein as “C3- 8 cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes.
  • Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
  • Cycloalkyl groups can be fused to other cycloalkyl (saturated or partially unsaturated), aryl, or heterocyclyl groups, to form a bicycle, tetracycle, etc.
  • cycloalkyl also includes bridged and spiro-fused cyclic structures which may or may not contain heteroatoms.
  • halo or halogen as used herein refer to -F, -Cl, -Br, and/or -I.
  • Haloalkyl means an alkyl group substituted with one or more halogens.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.
  • hetero atoms refers to nitrogen (N), oxygen (O), sulfur (S) or phosphorus (P) atoms, wherein the N, S and P can optionally be oxidized to various oxidation states.
  • heteroaryl refers to a mono-, bi-, or multi-cyclic, aromatic ring system containing one or more heteroatoms, for example 1 to 3 heteroatoms, such as nitrogen, oxygen, and sulfur.
  • Heteroaryls can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heteroaryls can also be fused to non-aromatic rings.
  • heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as "C2-5heteroaryl.”
  • Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl.
  • heteroaryl groups also include, but are not limited to, a bicyclic aromatic ring, wherein the ring comprises 5 to 14 carbon atoms and 1 to 3 heteroatoms, referred to herein as "G M i hctcroaryl.”
  • Representative examples of heteroaryl include, but not limited to, indazolyl, indolyl, azaindolyl, indolinyl, benzotriazolyl, benzoxadiazolyl, imidazolyl, cinnolinyl, imidazopyridyl, pyrazolopyridyl, pyrrolopyridyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, indolinonyl, isoindolinonyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • heterocycle refers to a saturated or unsaturated 3- to 18-membered ring containing one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur.
  • Heterocycles can be aromatic (heteroaryls) or non-aromatic.
  • Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfmyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
  • substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl
  • Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryls, cycloalkyls, and heterocycles.
  • Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, o
  • composition refers to a mixture of at least one compound, such as a compound Formula (I), or a pharmaceutically acceptable salt thereof, with at least one and optionally more than one other pharmaceutically acceptable chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • pharmaceutically acceptable chemical components such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound described herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • compositions in which it is contained.
  • pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein. Such materials are administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • carrier refers to chemical compounds or agents that facilitate the incorporation of a compound described herein into cells or tissues.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable vehicle” is used interchangeably and as is known to those skilled in the art, can be any and all solvents, dispersion media, Coatings, surfactants, antioxidants, preservatives (e.g., antimicrobial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricant, including sweeteners, flavors, dyes, and the like, and combinations thereof (e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
  • prodrugs as used herein represents those prodmgs of the compounds of the present disclosure that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present disclosure.
  • a discussion is provided in Higuchi et al., “Prodmgs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14, and in Roche, E.B., ed. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • salts refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
  • Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, / olucncsul fonatc and pamoate (
  • Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • Compounds included in the present compositions, that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • the term “inhibit,” “inhibition,” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “treat,” “treating,” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically (e.g., through stabilization of a discernible symptom), physiologically, (e.g., through stabilization of a physical parameter), or both.
  • “treat,” “treating,” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • cancer refers to diseases, disorders, and conditions that involve abnormal cell growth with the potential to invade or spread to other parts of the body.
  • exemplary cancers include, but are not limited to, breast cancer, lung cancer, pancreatic cancer, colon cancer, head and neck cancer, renal cell carcinoma, squamous cell carcinoma, thyroid cancer, gall bladder cancer, thyroid cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, or esophageal cancer.
  • the term “subject” refers to an animal. Typically, the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human. [55] As used herein, a subject is “in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • exon 20 insertion mutation refers to a mutation in which one or more amino acids (preferably 1 to 7, more preferably 1 to 4) are inserted in the exon 20 region of EGFR, and includes, but is not limited to, a mutation in which amino acid sequence SVD (serine, valine, and aspartic acid in this order from the N-terminus) is inserted between the 770th aspartic acid and 771st asparagine in the exon 20 region (D770_N771insSVD); a mutation in which amino acid sequence ASV (alanine, serine, and valine in this order from the N-terminus) is inserted between the 769th alanine and 770th aspartic acid in the exon region (A769_D770insASV); and a mutation in which amino acid sequence YVMA (tyrosine, valine, methionine, and alanine in this order from the N-terminus) is inserted between the 775th
  • amino acid sequence SVD se
  • administering means providing a compound of the invention, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or solvate thereof to a subject in need of treatment.
  • the term “combination” as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • the term “fixed combination” means that the active ingredients, by way of example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, by way of example, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, n C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 C1 and 125 I respectively.
  • the invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 13 C, and 14 C, are present.
  • isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 ⁇ 4), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Processes using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • the present disclosure is directed to a compound of Formula (I), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof: wherein:
  • R 1 is Ci- 6 alkyl, Ci- 6 alkoxyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 alkylene-OH, Ci- 6 alkyleneamine, or Ci - 6 alkylene-CN, each of which is substituted with 0,1, 2, or 3 R a ;
  • R 2 is H, Ci-C5alkyl, deuterated Ci-Csalkyl, Ci-Csalkoxy, Ci-Cshaloalkyl, C3-C7cycloalkyl, or heterocycle, each of which is substituted with 0,1, 2, or 3 R a ;
  • W is O or NH
  • X is C or N, wherein when X is C, Y is cyano; when X is N, Y is absent;
  • R 3 and R 4 are independently hydrogen, halogen, hydroxyl, cyano, Ci-Csalkyl, Ci-Csalkoxy, or Ci- Cshaloalkyl;
  • R 5 is 5- to 6-member cycloalkyl, 5- to 6-member aryl, 5- to 6-member heterocycle, or monocyclic or bicyclic 5- to 12-member heteroaryl, each of which is substituted with 0, 1, 2, or 3 R a ;
  • R 6 is absent, or Ci-Csalkyl, Ci-Csalkoxy, or Ci-Cshaloalkyl, or 5- to 6-member cycloalkyl, 5- to 6-member aryl, 5- to 6-member heterocycle, or monocyclic or bicyclic 5- to 12-member heteroaryl, each of which is substituted with 0, 1, 2, or 3 R a ;
  • R a is independently hydrogen, hydroxy, halogen, amino, cyano, Ci- 6 alkyl, C3-8 cycloalkyl, Ci- 6 alkoxyl, Ci-6haloalkyl, Ci-6 haloalkoxyl, C0(0)-Ci 4 alkyl, C0-3 alkylene-CN, C0-3 alkylene-N-(Ci-6 alkyl)2, C0-3 alkylene-C3-8 heterocycloalkyl, heterocycle, heterocycloalkyl, aryl, or heteroaryl, each of which is substituted with 0, 1, 2, or 3 R b , and may be fully or partially deuterated; and
  • R b is independently H, hydroxy, halogen, cyano, Ci- 6 alkyl, C3-6 cycloalkyl, or C3-8 heterocycloalkyl.
  • R 1 is Ci- 6 alkyl, Ci- 6 alkoxyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 alkylene-OH,
  • Ci - 6 alkyleneamine or Ci- 6 alkylene-CN.
  • R 1 is vinyl substituted with 0,1, 2, or 3 R ⁇
  • R 1 is 1-propynyl.
  • R 1 is vinyl.
  • R 2 is H, Ci-Csalkyl, deuterated Ci-Csalkyl, Ci-Csalkoxy, Ci-Cshaloalkyl, C3-C7cycloalkyl, or heterocycle, each of which is substituted with 0,1, 2, or 3 R a .
  • R 2 is Ci-Csalkyl, each of which is substituted with 0,1, 2, or 3 R a .
  • R 2 is methyl.
  • R 2 is ethyl.
  • R 2 is deuterated methyl.
  • R 2 is .
  • R 2 is Cl I Cl I ViCTI , i ,
  • R 3 and R 4 are independently hydrogen or halogen. In a further embodiment, R 3 is Cl and R 4 is H. In another embodiment, R 3 is H and R 4 is F.
  • R 5 is 5- to 6-member cycloalkyl, 5- to 6-member aryl, 5- to 6-member heterocycle, or monocyclic or bicyclic 5- to 12-member heteroaryl. In some embodiments, R 5 is
  • R 5 is ⁇ . In some embodiments, R 5 is . In some embodiments, R 5 some embodiments, R 5 is . In some embodiments, R 5 is . In some embodiments, R 5 is . In some embodiments, R 5 is . In some embodiments, R 5 is, . In some embodiments, R 5 is . In some embodiments, R 5 is, . In some embodiments, R 5 is .
  • R 5 is . In some embodiments, R 5 is . In some H- embodiments, R 5 is N . In some embodiments, R 5 is . In some embodiments, R 5 is . In some embodiments, R 5 is . , . In some embodiments, R 5 is N- N . i some embodiments,
  • R 6 is absent.
  • R 6 is Ci-Csalkyl, Ci-Csalkoxy, or Ci-Cshaloalkyl. In a further embodiment, R 6 is methyl. a .
  • provided herein is a compound, or pharmaceutically acceptable salt thereof, chosen from the compounds listed in Table 1. Table 1. Exemplary Compounds of the Present Disclosure
  • compositions of the present disclosure comprise at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof formulated together with one or more pharmaceutically acceptable carriers.
  • These formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration. The most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the present disclosure as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association at least one compound of the present disclosure as the active compound and a carrier or excipient (which may constitute one or more accessory ingredients).
  • the carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient.
  • the carrier may be a solid or a liquid, or both, and may be formulated with at least one compound described herein as the active compound in a unit-dose formulation, for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound.
  • a unit-dose formulation for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound.
  • Other pharmacologically active substances may also be present including other compounds.
  • the formulations of the present disclosure may be prepared by any of the well-known techniques of pharmacy consisting essentially of admixing the components.
  • liquid compositions conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmacologically administrable compositions can, for example, be prepared by, for example, dissolving or dispersing, at least one active compound of the present disclosure as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • suitable formulations may be prepared by uniformly and intimately admixing the at least one active compound of the present disclosure with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • a tablet may be prepared by compressing or molding a powder or granules of at least one compound of the present disclosure, which may be optionally combined with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, at least one compound of the present disclosure in a free-flowing form, such as a powder or granules, which may be optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s).
  • Molded tablets may be made by molding, in a suitable machine, where the powdered form of at least one compound of the present disclosure is moistened with an inert liquid diluent.
  • Formulations suitable for buccal (sub-lingual) administration include lozenges comprising at least one compound of the present disclosure in a flavored base, usually sucrose and acacia or tragacanth, and pastilles comprising the at least one compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations of the present disclosure suitable for parenteral administration comprise sterile aqueous preparations of at least one compound of Formula (I), or pharmaceutically acceptable salts thereof, which are approximately isotonic with the blood of the intended recipient. These preparations are administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection.
  • compositions according to the present disclosure may contain from about 0.1 to about 5% w/w of the active compound.
  • Formulations suitable for rectal administration are presented as unit-dose suppositories. These may be prepared by admixing at least one compound as described herein with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers and excipients which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof.
  • the active compound i.e., at least one compound of Formula (I), or pharmaceutically acceptable salts thereof
  • the amount of active compound administered may be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician.
  • a dosing schedule may involve the daily or semi-daily administration of the encapsulated compound at a perceived dosage of about 1 pg to about 1000 mg.
  • intermittent administration such as on a monthly or yearly basis, of a dose of the encapsulated compound may be employed.
  • Encapsulation facilitates access to the site of action and allows the administration of the active ingredients simultaneously, in theory producing a synergistic effect.
  • physicians will readily determine optimum dosages and will be able to readily modify administration to achieve such dosages.
  • a therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic effectiveness of the compound.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being used.
  • the therapeutically effective amount of a disclosed compound is sufficient to establish a maximal plasma concentration.
  • Preliminary doses as, for example, determined according to animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices.
  • Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50 ⁇ Compositions that exhibit large therapeutic indices are preferable.
  • Data obtained from the cell culture assays or animal studies can be used in formulating a range of dosage for use in humans.
  • Therapeutically effective dosages achieved in one animal model may be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et ah, Cancer Chemother. Reports 50(4):219-244 (1966) and the following Table for Equivalent Surface Area Dosage Factors).
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • a therapeutically effective amount may vary with the subject's age, condition, and gender, as well as the severity of the medical condition in the subject.
  • the dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
  • the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to be administered to treat cancer in a subject in need thereof.
  • the cancer is associated with an EGER or HER2 exon 20 insertion mutation.
  • the cancer is selected from breast cancer, lung cancer, pancreatic cancer, colon cancer, head and neck cancer, renal cell carcinoma, squamous cell carcinoma, thyroid cancer, gall bladder cancer, thyroid cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, or esophageal cancer.
  • the cancer is lung cancer. In a further embodiment, the cancer is non-small cell lung cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is breast cancer.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition.
  • concentration and route of administration to the patient will vary depending on the cancer to be treated.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with another therapeutic agent, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
  • another therapeutic agent e.g., chemotherapy
  • other treatments such as radiation or surgical intervention
  • Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of a disease or disorder associated with an EGFR or HER2 exon 20 insertion mutation.
  • the invention also provides for a method of inhibiting EGFR kinase activity in a cell comprising contacting the cell with an effective amount of an EGFR antagonist.
  • the administered amount is a therapeutically effective amount and the inhibition of EGFR kinase activity further results in the inhibition of the growth of the cell.
  • the cell is a cancer cell.
  • Inhibition of cell proliferation is measured using methods known to those skilled in the art.
  • a convenient assay for measuring cell proliferation is the CellTiter-GloTM Luminescent Cell Viability Assay, which is commercially available from Promega (Madison, Wis.). That assay determines the number of viable cells in culture based on quantitation of ATP present, which is an indication of metabolically active cells. See Crouch et al (1993) J. Immunol. Meth. 160:81-88, U.S. Pat. No. 6,602,677. The assay may be conducted in 96- or 384-well format, making it amenable to automated high-throughput screening (HTS).
  • HTS high-throughput screening
  • the assay procedure involves adding a single reagent (CellTiter-Glo® Reagent) directly to cultured cells. This results in cell lysis and generation of a luminescent signal produced by a luciferase reaction.
  • the luminescent signal is proportional to the amount of ATP present, which is directly proportional to the number of viable cells present in culture. Data can be recorded by luminometer or CCD camera imaging device.
  • the luminescence output is expressed as relative light units (RLU). Inhibition of cell proliferation may also be measured using colony formation assays known in the art.
  • the invention provides for methods of treating a condition associated with an EGFR or HER2 exon 20 insertion mutation in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of an EGFR antagonist.
  • the condition is a cell proliferative disease.
  • Treatment of the cell proliferative disorder by administration of an EGFR antagonist results in an observable and/or measurable reduction in or absence of one or more of the following: reduction in the number of cancer cells or absence of the cancer cells; reduction in the tumor size; inhibition of cancer cell infiltration into peripheral organs including the spread of cancer into soft tissue and bone; inhibition of tumor metastasis; inhibition, to some extent, of tumor growth; and/or relief to some extent, one or more of the symptoms associated with the specific cancer; reduced morbidity and mortality, and improvement in quality of life issues.
  • the EGFR antagonist may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. Reduction of these signs or symptoms may also be felt by the patient.
  • the chemical entities described herein can be synthesized according to one or more illustrative schemes herein and/or techniques well known in the art. Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from about -10° C to about 200° C. Further, except as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10° C to about 200° C over a period that can be, for example, about 1 to about 24 hours; reactions left to run overnight in some embodiments can average a period of about 16 hours.
  • Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. See, e.g., Carey et al. Advanced Organic Chemistry, 3 rd Ed., 1990 New York: Plenum Press; Mundy et al., Name Reaction and Reagents in Organic Synthesis, 2 nd Ed., 2005 Hoboken, NJ: J. Wiley & Sons.
  • protecting groups for sensitive or reactive groups may be employed where necessary, in accordance with general principles of chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons). These groups may be removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
  • the compounds described herein can be optionally contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salts. Also, the compounds described herein can be optionally contacted with a pharmaceutically acceptable base to form the corresponding basic addition salts.
  • disclosed compounds can generally be synthesized by an appropriate combination of generally well-known synthetic methods. Techniques useful in synthesizing these chemical entities are both readily apparent and accessible to those of skill in the relevant art, based on the instant disclosure. Many of the optionally substituted starting compounds and other reactants are commercially available, e.g., from Millipore Sigma or can be readily prepared by those skilled in the art using commonly employed synthetic methodology.
  • the claimed compounds can be prepared according to the following schemes.
  • the following schemes represent the general methods used in preparing these compounds. However, the synthesis of these compounds is not limited to these representative methods, as they can also be prepared through various other methods by those skilled in the art of synthetic chemistry.
  • Chlorination of intermediate 2F can be accomplished with POCI3 or SOCI2. After removal of phenol protecting group, Mitsunobu reaction of intermediate 2H with N-protected 3-hydroxylazetidine can provide intermediate 21. The chloro substituent of 21 can be displaced with aniline represented as structure 1A’ to provide intermediate 2J. After removal of nitrogen protecting group and reaction with acryloyl chloride can provide the desired final compounds.
  • Example 1 Preparation of l-(3-((4-((3-chloro-4-(quinolin-3-yloxy)phenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 1)
  • Stepl Preparation of tert-butyl 3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)azetidine-l-carboxylate
  • Step 4 Preparation of tert-butyl 3-((4-((3-chloro-4-(quinolin-3-yloxy)phenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate
  • Step 5 Preparation of 6-(azetidin-3-yloxy)-N-(3-chloro-4-(quinolin-3-yloxy)phenyl)-7- methoxyquinazolin-4-amine
  • Step 6 Preparation of l-(3-((4-((3-chloro-4-(quinolin-3-yloxy)phenyl)amino)-7-methoxyquinazolin-6- yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • Example 2 Preparation of l-(3-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 2)
  • Step 1 Preparation of 7-(2-chloro-4-nitrophenoxy)-[l,2,4]triazolo[l,5-a]pyridine
  • Step 3 Preparation of tert-butyl 3-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)- 7 -methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate
  • Step 5 Preparation of l-(3-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • Example 3 Preparation of l-(3-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)amino)-7-ethoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 3)
  • Step 1 Preparation of ethyl 3-(benzyloxy)-4-ethoxybenzoate [131] To a solution of ethyl 4-ethoxy-3-hydroxybenzoate (4.3 g, 20.4 mmol) in 13 mL DML was added
  • Step 5 Preparation of 7-ethoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate
  • Step 8 Preparation of tert-butyl 3-((4-chloro-7-ethoxyquinazolin-6-yl)oxy)azetidine-l-carboxylate
  • Step 9 Preparation of tert-butyl 3-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)- 7 -ethoxy quinazolin-6-yl)oxy)azetidine- 1 -carboxylate
  • Step 10 Preparation of N-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-6-(azetidin-3- yloxy)-7 -ethoxyquinazolin-4-amine
  • Step 11 Preparation of l-(3-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-7- ethoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • Step 3 Preparation of tert-butyl 3-((4-((3-chloro-4-(pyrazolo[l,5-a]pyridin-5-yloxy)phenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate [144] The mixture of 3-chloro-4-(pyrazolo[l,5-a]pyridin-5-yloxy)aniline (57 mg, 0.22 mmol), tert-butyl
  • Step 4 Preparation of 6-(azetidin-3-yloxy)-N-(3-chloro-4-(pyrazolo[l,5-a]pyridin-5-yloxy)phenyl)-7- methoxyquinazolin-4-amine
  • Step 5 Preparation of l-(3-((4-((3-chloro-4-(pyrazolo[l,5-a]pyridin-5-yloxy)phenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • Step 3 Preparation of tert-butyl 3-((4-((3-chloro-4-((2-methylbenzo[d]oxazol-5- yl)methoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidine-l-carboxylate
  • Step 4 Preparation of 6-(azetidin-3-yloxy)-N-(3-chloro-4-((2-methylbenzo[d]oxazol-5- yl)methoxy)phenyl)-7-methoxyquinazolin-4-amine
  • Step 5 Preparation of l-(3-((4-((3-chloro-4-((2-methylbenzo[d]oxazol-5-yl)methoxy)phenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • Step 2 Preparation of tert-butyl 6-(2-chloro-4-nitrophenoxy)-2-methyl-lH-benzo[d]imidazole-l- carboxylate
  • Step 3 Preparation of tert-butyl 6-(4-amino-2-chlorophenoxy)-2-methyl-lH-benzo[d]imidazole-l- carboxylate
  • Step 4 Preparation of tert-butyl 6-(4-((6-((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)-7- methoxyquinazolin-4-yl)amino)-2-chlorophenoxy)-2-methyl-lH-benzo[d]imidazole-l-carboxylate [155] To a solution of tert-butyl 6-(4-amino-2-chlorophenoxy)-2-methyl-lH-benzo[d]imidazole-l- carboxylate (150 mg, 0.4 mmol) in 5 mL i-PrOH was added tert-butyl 3-((4-chloro-7-methoxyquinazolin- 6-yl)oxy)azetidine-l-carboxylate (161 mg, 0.44 mmol) and 0.1 mL HC1 (12 M in H2O).
  • Step 5 Preparation of 6-(azetidin-3-yloxy)-N-(3-chloro-4-((2-methyl-lH-benzo[d]imidazol-6- yl)oxy)phenyl)-7-methoxyquinazolin-4-amine
  • Step 6 Preparation of l-(3-((4-((3-chloro-4-((2-methyl-lH-benzo[d]imidazol-6-yl)oxy)phenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • Step 3 Preparation of tert-butyl 3-((4-((4-(benzo[d]thiazol-5-yloxy)-3-chlorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate
  • Step 4 Preparation of 6-(azetidin-3-yloxy)-N-(4-(benzo[d]thiazol-5-yloxy)-3-chlorophenyl)-7- methoxyquinazolin-4-amine
  • Step 5 Preparation of l-(3-((4-((4-(benzo[d]thiazol-5-yloxy)-3-chlorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one [162] To a solution of 6-(azetidin-3-yloxy)-N-(4-(benzo[d]thiazol-5-yloxy)-3-chlorophenyl)-7- methoxyquinazolin-4-amine triflate (crude) in anhydrous DCM (5 mL) stirred at -78 °C was added DIEA (55 mg, 0.43 mmol).
  • Example 8 Preparation of l-(3-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)amino)-7-ethoxyquinazolin-6-yl)amino)azetidin-l-yl)prop-2-en-l-one (Compound 8)
  • Step 3 Preparation of N-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-7-ethoxy-6- nitroquinazolin-4-amine
  • Step 4 Preparation of N-4-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-7- ethoxyquinazoline-4, 6-diamine
  • Step 5 Preparation of benzyl 3-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-7- ethoxyquinazolin-6-yl)amino)azetidine- 1 -carboxylate
  • Step 6 Preparation of N-4-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-N-6-(azetidin-3- y l)-7 -ethoxy quinazoline-4, 6-diamine
  • Step 7 Preparation of l-(3-((4-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-7- ethoxyquinazolin-6-yl)amino)azetidin- 1 -yl)prop-2-en- 1 -one
  • Step 3 Preparation of tert-butyl 3-((4-((4-(benzo[d]thiazol-6-yloxy)-3-chlorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate
  • Step 4 Preparation of 6-(azetidin-3-yloxy)-N-[4-(l,3-benzothiazol-6-yloxy)-3-chlorophenyl]-7- methoxyquinazolin-4-amine
  • Step 5 Preparation of l-[3-[(4-[[4-(l,3-benzothiazol-6-yloxy)-3-chlorophenyl]amino ⁇ -7-metho- xyquinazolin-6-yl)oxy]azetidin- 1 -yl ⁇ prop-2-en- 1 -one
  • Step 4 Preparation of 4-(benzo[d]oxazol-5-yloxy)-3-chloroaniline [178] To a solution of 5-(2-chloro-4-nitrophenoxy)benzo[d]oxazole (580 mg, 2.0 mmol) in THE (20 mL) was added Pd/C (200 mg) portion-wise. The reaction mixture was stirred under hydrogen at room temperature for 1 hour. The reaction mixture was filtered and evaporated in vacuo to give the desired product as a yellow solid (290 mg, 55.8 %). LC/MS: 260.9 [M+H] + .
  • Step 5 Preparation of tert-butyl 3-((4-((4-(benzo[d]oxazol-5-yloxy)-3-chlorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate
  • Step 6 Preparation of 6-(azetidin-3-yloxy)-N-(4-(benzo[d]oxazol-5-yloxy)-3-chlorophenyl)-7- methoxyquinazolin-4-amine
  • Step 7 Preparation of l-(3-((4-((4-(benzo[d]oxazol-5-yloxy)-3-chlorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • Example 11 Preparation of l-(3-((4-((4-(benzo[d]oxazol-6-yloxy)-3-chlorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one. (Compound 11)
  • Example 12 Preparation of l-(3-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)amino)-7-(methoxy-d3)quinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 12)
  • Step 7 Preparation of 4-chloro-7-fluoroquinazolin-6-yl acetate
  • Step 8 Preparation of 4-chloro-7-fluoroquinazolin-6-ol
  • Nth-MeOH (7N, 30 mL) was added to half of the ethyl acetate solution of 4-chloro-7- fluoroquinazolin-6-yl acetate and the mixture was stirred at room temperature for 20 hours.
  • the mixture was concentrated under vacuum and was purified by column chromatography eluted with DCM to DCM/EA (2/1) to afford 4-chloro-7-fluoroquinazolin-6-ol as white solid (610 mg, -60% for 2 steps).
  • LC/MS 199.0[M+H] + .
  • Step 9 Preparation of tert-butyl 3-((4-chloro-7-fluoroquinazolin-6-yl)oxy)azetidine-l-carboxylate
  • Step 10 Preparation of tert-butyl 3-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)amino)-7 -fluoroquinazolin-6-yl)oxy)azetidine- 1 -carboxylate
  • Step 11 Preparation of tert-butyl 3-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)amino)-7-(methoxy-d3)quinazolin-6-yl)oxy)azetidine-l -carboxylate
  • Step 12 Preparation of N-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-6-(azetidin-3- yloxy)-7-(methoxy-d3)quinazolin-4-amine
  • Step 13 Preparation of l-(3-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-7- (methoxy-d3)quinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one [195] To a solution of N-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-6-(azetidin-3- yloxy)-7-(methoxy-d3)quinazolin-4-amine triflate (90 mg, 95% purity, 0.17 mmol) in anhydrous DCM (2 mL) stirred at -78°C was added DIEA (116 mg, 0.9 mmol).
  • Example 13 Preparation of l-(3-((4-((3-chloro-4-(imidazo[l,2-a]pyridin-7-yloxy)phenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 13)
  • Example 14 Preparation of l-(3-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)amino)-7-(methoxy-d3)quinazolin-6-yl)amino)azetidin-l-yl)prop-2-en-l-one (Compound 14)
  • Step 3 Preparation of tert-butyl 3-((4-chloro-7-(methoxy-d3)quinazolin-6-yl)amino)azetidine-l- carboxylate
  • Step 4 Preparation of tert-butyl 3-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)- 7-(methoxy-d3)quinazolin-6-yl)amino)azetidine- 1 -carboxylate
  • Step 5 Preparation of N4-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-N6-(azetidin-3-yl)- 7-(methoxy-d3)quinazoline-4, 6-diamine
  • Step 6 Preparation of l-(3-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-7- (methoxy-d3)quinazolin-6-yl)amino)azetidin- 1 -yl)prop-2-en- 1 -one
  • reaction mixture was extracted with water (3x15 mL), dried with Na2SC>4 and concentrated under vacuum.
  • Example 15 Preparation of l-(3-((4-((2-fluoro-4-((l-(6-methylpyridin-3-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 15)
  • Step 1 Preparation of tert-butyl 3-hydroxy- lH-pyrazole-l-carboxylate
  • Step 2 Preparation of tert-butyl 3-(3-fluoro-4-nitrophenoxy)-lH-pyrazole-l-carboxylate and tert-butyl 3- (5 -fluoro-2-nitrophenoxy)- lH-pyrazole- 1 -carboxylate
  • Step 4 Preparation of tert-butyl 3-(4-(((benzyloxy)carbonyl)amino)-3-fluorophenoxy)-lH-pyrazole-l- carboxylate
  • Step 5 Preparation of benzyl (4-((lH-pyrazol-3-yl)oxy)-2-fluorophenyl)carbamate
  • Step 6 Preparation of benzyl (2-fluoro-4-((l-(6-methylpyridin-3-yl)-lH-pyrazol-3- yl)oxy)phenyl)carbamate
  • Step 7 Preparation of 2-fluoro-4-((l-(6-methylpyridin-3-yl)-lH-pyrazol-3-yl)oxy)aniline
  • benzyl (2-fluoro-4-((l-(6-methylpyridin-3-yl)-lH-pyrazol-3-yl)oxy)phenyl)carbamate 90 mg, 0.22 mmol
  • Pd/C 23 mg, 0.22 mmol
  • Step 8 Preparation of tert-butyl 3-((4-((2-fluoro-4-((l-(6-methylpyridin-3-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)-7 -methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate
  • Step 9 Preparation of 6-(azetidin-3-yloxy)-N-(2-fluoro-4-((l-(6-methylpyridin-3-yl)-lH-pyrazol-3- yl)oxy)phenyl)-7-methoxyquinazolin-4-amine
  • Step 10 Preparation of l-(3-((4-((2-fluoro-4-((l-(6-methylpyridin-3-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)-7 -methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • Example 16 Preparation of l-(3-((4-((2-fluoro-4-((l-(5-fluoro-6-methylpyridin-3-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 16)
  • Compound 16 was prepared according to the procedures described for compound 15 by replacing 5-iodo-2-methylpyridine with 5-bromo-3-fluoro-2-methylpyridine in step 6.
  • Example 17 Preparation of l-(3-((4-((2-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 17)
  • Compound 17 was prepared according to the procedures described for compound 15 by replacing 5-iodo-2-methylpyridine with 5-bromo-2-methoxypyrimidine in step 6.
  • Example 18 l-(3-((4-((2-fluoro-4-((4-(5-isopropyl-l,3,4-oxadiazol-2-yl)thiazol-2- yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one. (Compound 18)
  • Step 1 Preparation of ethyl 2-(4-amino-3-fluorophenoxy)thiazole-4-carboxylate
  • Step 4 Preparation of 2-fluoro-4-((4-(5-isopropyl-l,3,4-oxadiazol-2-yl)thiazol-2-yl)oxy)aniline.
  • Step 5 Preparation of tert-butyl 3-((4-((2-fluoro-4-((4-(5-isopropyl-l,3,4-oxadiazol-2-yl)thiazol-2- yl)oxy)phenyl)amino)-7 -methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate.
  • Step 7 Preparation of l-(3-((4-((2-fluoro-4-((4-(5-isopropyl-l,3,4-oxadiazol-2-yl)thiazol-2- yl)oxy)phenyl)amino)-7 -methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one.
  • Example 19 Preparation of l-(3-((4-((2-fluoro-4-((4-(2-methoxypyrimidin-5-yl)thiazol-2- yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 19)
  • Step 3 Preparation of tert-butyl 3-((4-((2-fluoro-4-((4-(2-methoxypyrimidin-5-yl)thiazol-2- yl)oxy)phenyl)amino)-7 -methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate
  • Step 4 6-(azetidin-3-yloxy)-N-(2-fluoro-4-((4-(2-methoxypyrimidin-5-yl)thiazol-2-yl)oxy) phenyl)-7- methoxyquinazolin-4-amine
  • Step 5 Preparation of l-(3-((4-((2-fluoro-4-((4-(2-methoxypyrimidin-5-yl)thiazol-2- yl)oxy)phenyl)amino)-7 -methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one [224] To a solution of 6-(azetidin-3-yloxy)-N-(2-fluoro-4-((4-(2-methoxypyrimidin-5-yl)thiazol-2- yl)oxy)phenyl)-7-methoxyquinazolin-4-amine (110 mg crude) and DIEA (77 mg, 0.6 mmol) in DCM (10 mL) was added acryloyl chloride (18 mg, 0.1 mmol) dropwise at -40 °C.
  • Example 20 l-(3-((4-((2-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)amino)azetidin-l-yl)prop-2-en-l-one (Compound 20)
  • Step 1 Preparation of 2-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3-yl)oxy)aniline
  • 4-((lH-pyrazol-3-yl)oxy)-2-fluoroaniline 800 mg, 4.14 mmol
  • 5-iodo-2- methoxypyrimidine 1.17 g, 4.967 mmol
  • K2CO3 1.14 g, 8.28 mmol
  • Step 2 Preparation of tert-butyl 3-((4-((2-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)amino)azetidine-l-carboxylate
  • Step 3 Preparation of N6-(azetidin-3-yl)-N4-(2-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3- yl)oxy)phenyl)-7-methoxyquinazoline-4, 6-diamine
  • Step 4 Preparation of l-(3-((4-((2-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3-yl)oxy) phenyl)amino)-7 -methoxyquinazolin-6-yl)amino)azetidin- 1 -yl)prop-2-en- 1 -one
  • Example 21 l-(3-((4-((2-fluoro-4-((4-(2-methoxypyrimidin-5-yl)thiazol-2-yl)oxy)phenyl)amino)-7- methoxyquinazolin-6-yl)amino)azetidin- 1 -yl)prop-2-en- 1 -one (Compound 22)
  • Step 3 Preparation of 6-bromo-N-(2-fluoro-4-((4-(2-methoxypyrimidin-5-yl)thiazol-2-yl)oxy) phenyl)-7- methoxyquinazolin-4-amine
  • Step 4 Preparation of tert-butyl 3-((4-((2-fluoro-4-((4-(2-methoxypyrimidin-5-yl)thiazol-2-yl)oxy) phenyl)amino)-7 -methoxyquinazolin-6-yl)amino)azetidine- 1 -carboxylate
  • Step 5 Preparation of N 6 -(azetidin-3-yl)-N 4 -(2-fluoro-4-((4-(2-methoxypyrimidin-5-yl)thiazol-2- yl)oxy)phenyl)-7-methoxyquinazoline-4, 6-diamine
  • Step 6 Preparation of l-(3-((4-((2-fluoro-4-((4-(2-methoxypyrimidin-5-yl)thiazol-2-yl)oxy) phenyl)amino)-7 -methoxyquinazolin-6-yl)amino)azetidin- 1 -yl)prop-2-en- 1 -one [234] To a solution of N 6 -(azetidin-3-yl)-N 4 -(2-fluoro-4-((4-(2-methoxypyrimidin-5-yl)thiazol-2- yl)oxy)phenyl)-7-methoxyquinazoline-4, 6-diamine (60 mg, TFA salt, 0.09 mmol) and DIEA (24 mg, 0.19 mmol) in dry DCM (5 mL) was added acryloyl chloride (9 mg, 0.099 mmol) at -70 °C.
  • Example 22 l-(3-((4-((2-fluoro-4-((4-(6-methylpyridin-3-yl)thiazol-2-yl)oxy)phenyl)amino)-7- methoxy quinazolin-6-yl)amino)azetidin-l-yl)prop-2-en-l-one (Compound 23)
  • Step 1 Preparation of 2-fluoro-4- ⁇ [4-(6-methylpyridin-3-yl)-l,3-thiazol-2-yl]oxy janiline
  • Step 2 Preparation of 6-bromo-N-(2-fluoro-4- ⁇ [4-(6-methylpyridin-3-yl)-l,3-thiazol-2-yl]oxy ⁇ phenyl)- 7-methoxyquinazolin-4-amine
  • Step 3 Preparation of tert-butyl 3-((4-((2-fluoro-4-((4-(6-methylpyridin-3-yl)thiazol-2- yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)amino)azetidine-l-carboxylate
  • Step 5 Preparation of l-(3-((4-((2-fluoro-4-((4-(6-methylpyridin-3-yl)thiazol-2-yl)oxy)phenyl) amino)-7- methoxyquinazolin-6-yl)amino)azetidin- 1 -yl)prop-2-en- 1 -one.
  • Example 23 Preparation of 6-((l-acryloylazetidin-3-yl)amino)-7-ethoxy-4-((2-fluoro-4-((l-(6- methylpyridin-3-yl)-lH-pyrazol-3-yl)oxy)phenyl)amino)quinoline-3-carbonitrile (Compound 27) Step 1: Preparation of benzyl (2-fluoro-4-((l-(6-methylpyridin-3-yl)-lH-pyrazol-3-yl)oxy)phenyl) carbamate
  • Step 2 Preparation of benzyl 2-fluoro-4-((l-(6-methylpyridin-3-yl)-lH-pyrazol-3-yl)oxy)aniline
  • Step 3 Preparation of N-(3-cyano-7-ethoxy-4-((2-fluoro-4-((l-(6-methylpyridin-3-yl)-lH-pyra zol-3- yl)oxy)phenyl)amino)quinolin-6-yl)acetamide
  • Step 4 Preparation of 6-amino-7-ethoxy-4-((2-fluoro-4-((l-(6-methylpyridin-3-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)quinoline-3-carbonitrile
  • Step 5 Preparation of 6-((l-acryloylazetidin-3-yl)amino)-7-ethoxy-4-((2-fluoro-4-((l-(6-methyl pyridin- 3-yl)-lH-pyrazol-3-yl)oxy)phenyl)amino)quinoline-3-carbonitrile
  • Example 24 Preparation of l-(3-((4-((2-fluoro-4-((6-(l-methyl-lH-pyrazol-4-yl)pyridin-2- yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)amino)azetidin-l-yl)prop-2-en-l-one (Compound 66) Step 1: Preparation of tert-butyl (4-((6-bromopyridin-2-yl)oxy)-2-fluorophenyl)carbamate
  • Step 2 Preparation of tert-butyl(2-fluoro-4-((6-(l -methyl- lH-pyrazol-4-yl)pyridin-2-yl)oxy) phenyl) carbamate
  • Step 4 Preparation of 6-bromo-N-(2-fluoro-4-((6-(l-methyl-lH-pyrazol-4-yl)pyridin-2-yl)oxy) phenyl)- 7 -methoxyquinazolin-4- amine
  • Step 5 Preparation of tert-butyl 3-((4-((2-fluoro-4-((6-(l-methyl-lH-pyrazol-4-yl)pyridin-2-yl) oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)amino)azetidine-l-carboxylate
  • Step 6 Preparation of N6-(azetidin-3-yl)-N4-(2-fluoro-4-((6-(l -methyl- lH-pyrazol-4-yl)pyridin-2- yl)oxy)phenyl)-7-methoxyquinazoline-4, 6-diamine
  • Step 7 Preparation of l-(3-((4-((2-fluoro-4-((6-(l-methyl-lH-pyrazol-4-yl)pyridin-2-yl)oxy) phenyl)amino)-7 -methoxyquinazolin-6-yl)amino)azetidin- 1 -yl)prop-2-en- 1 -one
  • Example 25 Preparation of l-(3-((4-((4-((4-((4-((4-((4-(l-cyclopropyl-lH-pyrazol-4-yl)thiazol-2-yl)oxy)-2- fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 71)
  • Step 1 Preparation of 4-((4-(l -cyclopropyl- lH-pyrazol-4-yl)thiazol-2-yl)oxy)-2-fluoroaniline
  • Step 2 Preparation of 6-(azetidin-3-yloxy)-N-(4-((4-(l-cyclopropyl-lH-pyrazol-4-yl)thiazol-2-yl)oxy)-2- fluorophenyl)-7-methoxyquinazolin-4-amine
  • Step 3 Preparation of l-(3-((4-((4-((4-((4-((4-((4-(l-cyclopropyl-lH-pyrazol-4-yl)thiazol-2-yl)oxy)-2- fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one [254] To a solution of 6-(azetidin-3-yloxy)-N-(4-[[4-(l-cyclopropylpyrazol-4-yl)-l,3-thiazol-2- yl]oxy ⁇ -2-fluorophenyl)-7-methoxyquinazolin-4-amine (70 mg, 90 % purity, 0.12mmol) and TEA (20 mg, 0.19mmol) in DCM (15 mL) was added prop-2-enoyl chloride (9.4 mg,
  • Example 26 Preparation of l-(3-((4-((2-fluoro-4-(3-(5-methyl-l,3,4-oxadiazol-2- yl)phenoxy)phenyl)amino)-7-methoxy quinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 80)
  • Step 1 Preparation of tert-butyl 3-((4-((2-fluoro-4-(3-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy) phenyl)amino)-7 -methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate [255] To a solution of 2-fluoro-4-[3-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy]aniline (190 mg, 0.66 mmol) and tert-butyl 3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)azetidine-l-carboxylate (244 mg, 0.66 mmol) in dioxane (20 mL) stirred under nitrogen at 25 °C was added HCl/dioxane (0.3 mL).
  • Step 3 Preparation of l-(3-((4-((2-fluoro-4-(3-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy)phenyl) amino)- 7 -methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • Example 27 Preparation of l-(3-((4-((2-fluoro-4-(3-(5-methyl-l,3,4-oxadiazol-2- yl)phenoxy)phenyl)amino)-7-methoxy quinazolin-6-yl)amino)azetidin-l-yl)prop-2-en-l-one (Compound 81)
  • Step 1 Preparation of ethyl 3-(4-amino-3-fluorophenoxy /benzoate
  • Step 3 Preparation of 3-(4-((tert-butoxycarbonyl)amino)-3-fluorophenoxy /benzoic acid
  • Step 4 Preparation of tert-butyl (4-(3-(2-acetylhydrazine-l-carbonyl)phenoxy)-2-fluorophenyl) carbamate
  • Step 5 Preparation of tert-butyl (2-fluoro-4-(3-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy)phenyl) carbamate
  • Step 7 Preparation of 6-bromo-N-(2-fluoro-4-(3-(5 -methyl- 1, 3, 4-oxadiazol-2-yl)phenoxy)phenyl) -7- methoxyquinazolin-4-amine
  • Step 8 Preparation of tert-butyl 3-((4-((2-fluoro-4-(3-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy) phenyl)amino)-7-methoxyquinazolin-6-yl)amino)azetidine-l-carboxylate [265] To a suspension of 6-bromo-N-[2-fluoro-4-[3-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy]phenyl ⁇ - 7-methoxyquinazolin-4-amine (200 mg, 0.38 mmol), (3-aminoazetidin-l-yl) tert-butylformate (332 mg, 1.91 mmol) and CS CO (374 mg, 1.15 mmol) in dioxane (20 mL) stirred under nitrogen at 25 °C was added Brettphos-Pd-G3 (35 mg, 0.04 m
  • Step 9 Preparation of N6-(azetidin-3-yl)-N4-(2-fluoro-4-(3-(5-methyl-l,3,4-oxadiazol-2-yl) phenoxy)phenyl)-7-methoxyquinazoline-4, 6-diamine
  • Step 10 Preparation of l-(3-((4-((2-fluoro-4-(3-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy)phenyl) amino)- 7 -methoxyquinazolin-6-yl)amino)azetidin- 1 -yl)prop-2-en- 1 -one
  • Example 28 Preparation of l-(3-((4-((3-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)amino)azetidin-l-yl)prop-2-en-l-one (Compound 93)
  • Step 1 Preparation of 6-bromo-N-(3-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3- yl)oxy)phenyl)-7-methoxyquinazolin-4-amine
  • Step 2 Preparation of tert-butyl 3-((4-((3-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)amino)azetidine-l-carboxylate
  • Step 3 Preparation of N6-(azetidin-3-yl)-N4-(3-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3- yl)oxy)phenyl)-7-methoxyquinazoline-4, 6-diamine
  • Step 4 Preparation of l-(3-((4-((3-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)-7 -methoxyquinazolin-6-yl)amino)azetidin- 1 -yl)prop-2-en- 1 -one [271] To a solution of N6-(azetidin-3-yl)-N4-(3-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3- yl)oxy)phenyl)-7-methoxyquinazoline-4, 6-diamine (90 mg, TFA salt, 0.14 mmol) and DIPEA ( 73 mg, 0.57 mmol) in DCM (10 mL) was added acryloyl chloride (13 mg, 0.15 mmol) slowly at -78
  • Example 29 Preparation of l-(3-((4-((3-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 96)
  • Step 1 Preparation of tert-butyl 3-((4-((3-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)-7 -methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate
  • Step 3 Preparation of l-(3-((4-((3-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3-yl)oxy) phenyl)amino)-7 -methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • Example 30 Preparation of l-(3-((4-((2-fluoro-4-((6-methyl-[3,4'-bipyridin]-2'- yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 106)
  • Step 2 Preparation of tert-butyl (2-fluoro-4-((6-methyl-[3,4'-bipyridin]-2'-yl)oxy)phenyl)carbamate
  • Step 3 Preparation of 2-fluoro-4-((6-methyl-[3,4 , -bipyridin]-2 , -yl)oxy)aniline
  • Step 4 Preparation of tert-butyl 3-((4-((2-fluoro-4-((6-methyl-[3,4'-bipyridin]-2 , -yl)oxy)phenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate
  • Step 5 Preparation of 6-(azetidin-3-yloxy)-N-(2-fluoro-4-((6-methyl-[3,4'-bipyridin]-2 , -yl)oxy)phenyl)-7- methoxyquinazolin-4-amine
  • Step 6 Preparation of l-(3-((4-((2-fluoro-4-((6-methyl-[3,4'-bipyridin]-2 , -yl)oxy)phenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • Example 31 Preparation of l-(3-((4-((2-fluoro-4-((6'-methyl-[3,3'-bipyridin]-5- yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 107)
  • Step 2 Preparation of 2-fluoro-4-((6'-methyl-[3,3'-bipyridin]-5-yl)oxy) [282] To a solution of 4-((5-bromopyridin-3-yl)oxy)-2-fluoroaniline (386 mg, 1.36 mmol) in dioxane/fhO (8 mL/2 mL) was added (6-methylpyridin-3-yl)boronic acid (186 mg, 1.36 mmol),
  • Step 3 Preparation of tert-butyl 3-((4-((2-fluoro-4-((6'-methyl-[3,3'-bipyridin]-5-yl)oxy)phenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate
  • Step 4 Preparation of 6-(azetidin-3-yloxy)-N-(2-fluoro-4-((6'-methyl-[3,3'-bipyridin]-5-yl)oxy)phenyl)-7- methoxyquinazolin-4-amine
  • Step 5 Preparation of l-(3-((4-((2-fluoro-4-((6'-methyl-[3,3'-bipyridin]-5-yl)oxy)phenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • Example 32 Preparation of l-(3-((4-((3-chloro-2-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH- pyrazol-3-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 111)
  • Step 2 Preparation of tert-butyl 3-(4-amino-2-chloro-3-fluorophenoxy)-lH-pyrazole-l-carboxylate
  • Step 3 Preparation of 4-((lH-pyrazol-3-yl)oxy)-3-chloro-2-fluoroaniline [288] To a solution of tert-butyl 3-(4-amino-2-chloro-3-fluorophenoxy)-lH-pyrazole-l-carboxylate (1.1 g, 3.4 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at 20 °C for 1 h. The mixture was quenched with sat. NaHCCL solution and extracted with DCM (30 mL*2).
  • Step 4 Preparation of 3-chloro-2-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3-yl)oxy)aniline
  • Step 5 Preparation of tert-butyl 3-((4-((3-chloro-2-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-
  • Step 6 Preparation of 6-(azetidin-3-yloxy)-N-(3-chloro-2-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH- pyrazol-3-yl)oxy)phenyl)-7-methoxyquinazolin-4-amine
  • Step 7 Preparation of l-(3-((4-((3-chloro-2-fluoro-4-((l-(2-methoxypyrimidin-5-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)-7 -methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • Example 33 l-(3-((4-((2-fluoro-4-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 123)
  • Step 1 Preparation of tert-butyl (2-fluoro-4-((2-(l-methyl-lH-pyrazol-4-yl) pyridin-4-yl) oxy) phenyl) carbamate
  • Step 2 Preparation of 2-fluoro-4-((2-(l-methyl-lH-pyrazol-4-yl) pyridin-4-yl) oxy) aniline
  • Step 3 Preparation of tert-butyl 3-((4-((2-fluoro-4-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)phenyl)amino)-7 -methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate [295] To a solution of 2-fluoro-4-((2-(l -methyl- lH-pyrazol-4-yl) pyridin-4-yl) oxy) aniline (180 mg, 0.63 mmol) in ACN (10 mL) was added tert-butyl 3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)azetidine- 1-carboxylate (230 mg, 0.63 mmol) and TsOH (108 mg, 0.63 mmol).
  • Step 4 Preparation of 6-(azetidin-3-yloxy)-N-(2-fluoro-4-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)phenyl)-7-methoxyquinazolin-4-amine
  • Step 5 Preparation of l-(3-((4-((2-fluoro-4-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)phenyl)amino)-7 -methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • Step 1 Preparation of tert-butyl (2-fluoro-4-((2-morpholinopyridin-4-yl)oxy)phenyl)carbamate
  • Step 3 Preparation of tert-butyl 3-((4-((2-fluoro-4-((2-morpholinopyridin-4-yl)oxy)phenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate
  • Step 5 Preparation of l-(3-((4-((2-fluoro-4-((2-morpholinopyridin-4-yl)oxy)phenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • reaction was quenched with FLO, concentrated and purified by prep-HPLC (ACN-FLO (0.1 % TFA), 30%-55%) to afford l-(3-((4-((2-fluoro-4-((2-morpholinopyridin-4-yl)oxy)phenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (14 mg, 12%) as a yellow solid.
  • Example 35 Preparation of l-(3-((4-((4-((l-(6-(dimethylamino)pyridazin-3-yl)-lH-pyrazol-3- yl)oxy)-2-fluorophenyl) amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one ( Step 1: Preparation of benzyl (4-((l-(6-(dimethylamino)pyridazin-3-yl)-lH-pyrazol-3-yl)oxy)-2- fluorophenyl)carbamate
  • Step 2 Preparation of 6-(3-(4-amino-3-fluorophenoxy)-lH-pyrazol-l-yl)-N,N-dimethylpyridazin-3-amine
  • Step 3 Preparation of tert-butyl 3-((4-((4-((l-(6-(dimethylamino)pyridazin-3-yl)-lH-pyrazol-3-yl)oxy)-2- fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidine-l-carboxylate
  • Step 4 Preparation of 6-(azetidin-3-yloxy)-N-(4-((l-(6-(dimethylamino)pyridazin-3-yl)-lH-pyrazol-3- yl)oxy)-2-fluorophenyl)-7-methoxyquinazolin-4-amine
  • Step 5 Preparation of l-(3-((4-((4-((l-(6-(dimethylamino)pyridazin-3-yl)-lH-pyrazol-3-yl)oxy)-2- fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • Example 36 Preparation of l-(3-((4-((2-fluoro-4-((l-(5-methoxypyridazin-3-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)prop-2-en-l-one (Compound 133)
  • Step 1 Preparation of benzyl (2-fluoro-4-((l-(5-methoxypyridazin-3-yl)-lH-pyrazol-3-yl)oxy) phenyl)carbamate
  • Step 3 Preparation of tert-butyl-3-((4-((2-fluoro-4-((l-(5-methoxypyridazin-3-yl)-lH-pyrazol-3- yl)oxy)phenyl)amino)-7 -methoxyquinazolin-6-yl)oxy)azetidine- 1 -carboxylate
  • Step 4 Preparation of 6-(azetidin-3-yloxy)-N-(2-fluoro-4-((l-(5-methoxypyridazin-3-yl)-lH-pyrazol-3- yl)oxy)phenyl)-7-methoxyquinazolin-4-amine
  • Step 5 Preparation of l-(3-((4-((4-((l-(6-(dimethylamino)pyridazin-3-yl)-lH-pyrazol-3-yl)oxy)-2- fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin- 1 -yl)prop-2-en- 1 -one
  • HCC827-SVD cell line were generated by first transducing HCC827 cells (ATCC) with lentiviral particles expressing codon-optimized human EGFR exon 20 insertion mutant D770_N771insSVD, and then selecting under 5 pg/mL purimycin treatment for a week. The resulting cells were further transduced with lentiviral particles carrying EGFR sgRNA and CAS9 to knockout the endogenous alleles of EGFR, and then selected under 500 pg/mF hygromycin B treatment for two weeks. Single clone was subsequently generated by limiting dilution approach. Endogenous EGFR knockout was confirmed by Sanger sequencing of cell genomic DNA and expression of exogenous mutant EGFR was verified by Western blot analysis.
  • HCC827-ASV and HCC827-YVMA cell lines were generated in the similar approach as HCC827-SVD except that HCC827 cells (ATCC) were first transduced with lentiviral particles expressing codon-optimized human EGFR exon 20 insertion mutant A769_D770insASV and human ERBB2 exon20 insertion mutant A775_G776ins YVMA, respectively.
  • HCC827 (ATCC), HCC827-SVD, HCC827-ASV, HCC827-YVMA were seeded in 96-well plates at 5000 cell/well in 90 pL of RPMI growth medium containing 10% FBS and 1% Penicillin Streptomycin.
  • A431 (ATCC) cells were seed in 96-well plates at 5000 cell/well in 90 pL of DMEM growth medium containing 10% FBS and 1% Penicillin Streptomycin. Cells were incubated at 37°C overnight. The following day, the test compound was administered to the cells by using lOx compound stock solution prepared in growth medium at various concentrations. After administration of the compound, cells were then incubated at 37°C for 3 days.
  • NCI-H2073 (ATCC) were plated in 24-well plate and were grown overnight in RPMI growth medium containing 10% FBS and 1% Penicillin Streptomycin. Next day, NCI-H2073 cells were washed and incubated in serum free RPMI medium for 3 hours, followed by 2 hours compound treatment. EGF 100 ng/mL were added to the well and incubated for 15 minutes before harvesting the cells for protein analysis. 1.5xl0 5 /well of HCC827-SVD, HCC827-ASV, HCC827-YVMA were plated in 24-well plate and were grown overnight in RPMI growth medium containing 10% FBS and 1% Penicillin Streptomycin. Next day, cells were treated with compounds for 2 hours. To collect protein from cells, cells were washed with PBS and protein were collected in Laemmli sample buffer (lx)
  • the membranes were then incubated overnight at 4 °C with primary antibodies mouse anti-EGFR (1:500, Santa Cruz Biotechnology, sc-377073), rabbit anti-p-EGFR (Tyrl068) (1:500, Cell Signaling, 3777), mouse anti-Her2 (1:500, Santa Cruz Biotechnology, sc-33684), rabbit anti-p-Her2 (Tyrl221/1222) (1:500, Cell Signaling, 2249), and mouse anti- GAPDH (1:5,000, Santa Cruz Biotechnology, sc-47724) diluted in Intercept Blocking Buffer containing 0.1% Tween 20.
  • NCI-H2073, HCC827-S VD, HCC827-ASV cells were seeded in 96-well plates at 4xl0 4 cell/well in 90 pL of RPMI growth medium containing 10% LBS and 1% Penicillin Streptomycin. The following day, the test compound was administered to HCC827-SVD, HCC827-ASV in 96 wells by using lOx compound stock solution prepared in growth medium at various concentrations. After administration of the compound, cells were then incubated at 37°C for 2 hours. Lor NCI-H2073 treatment, cells were washed and incubated with serum free RPMI for 3 hours and followed by 2 hours compound treatment.
  • EGL 100 ng/mL was applied to H2073 for 15 minutes before harvesting the cells.
  • the AlphaLISA ® SureLire ® UltraTM HV p-EGLR (Tyrl068) assay kit (PerkinElmer) was used to measure p-EGLR level in cell lysate.
  • To prepare lysate cells were washed with PBS, freshly prepared IX Lysis Buffer from the kit (50 pL per well) was added to the well and the plate was agitated on a plate shaker (600 rpm) for 20 minutes at room temperature. 8 pL of lysate from wells were transferred to AlphaLisa reading plate (384 well plate) in triplicate. 4 pL of Acceptor beads Mix (from kit) were added to wells.
  • Table 4 illustrates growth inhibition (GI50) by exemplary compounds of the present disclosure in multiple cell lines 3 days after administration.
  • Table 5 illustrates p-EGFR(Tyrl068) or p-Her2 (Tyrl221/1222) inhibition (EC50) by exemplary compounds of the present disclosure in multiple cell lines carrying wild type (NCI-H2073) or mutant EGER (HCC827-SVD, HCC827-ASV and HCC827-YVME).
  • P-EGFR and p-Her2 were either measured by Western blot analysis or alphaLISA. Those numbers measured by alphaLISA were shown inside the parenthesis.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des composés et des compositions pharmaceutiques de ceux-ci, qui sont utiles pour inhiber l'activité EGFR et erbB2, ainsi que des procédés d'utilisation de tels composés pour traiter un cancer associé à une activité EGFR et erbB2 mutante.
PCT/US2021/031742 2020-05-12 2021-05-11 Bis-aryl éthers contenant de la n-acyl azétidine en tant qu'inhibiteurs de l'egfr/her2 Ceased WO2021231400A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063023690P 2020-05-12 2020-05-12
US63/023,690 2020-05-12

Publications (1)

Publication Number Publication Date
WO2021231400A1 true WO2021231400A1 (fr) 2021-11-18

Family

ID=76250457

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/031742 Ceased WO2021231400A1 (fr) 2020-05-12 2021-05-11 Bis-aryl éthers contenant de la n-acyl azétidine en tant qu'inhibiteurs de l'egfr/her2

Country Status (1)

Country Link
WO (1) WO2021231400A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022105908A1 (fr) * 2020-11-23 2022-05-27 上海和誉生物医药科技有限公司 Inhibiteur d'egfr, son procédé de préparation et son utilisation pharmaceutique
JP2023512343A (ja) * 2020-04-24 2023-03-24 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ＨＥＲ２阻害薬としての［１，３］ジアジノ［５，４－ｄ］ピリミジン
KR20230127880A (ko) * 2022-02-25 2023-09-01 중앙대학교 산학협력단 헤테로아릴 유도체를 유효성분으로 함유하는 her2 억제용 조성물
WO2023185793A1 (fr) 2022-03-28 2023-10-05 江苏恒瑞医药股份有限公司 Composé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation pharmaceutique
WO2024027695A1 (fr) * 2022-08-04 2024-02-08 微境生物医药科技(上海)有限公司 Composés utiles comme inhibiteurs de her2
WO2024026056A3 (fr) * 2022-07-29 2024-03-14 Accutar Biotechnology, Inc. Composés hétéroaryle en tant qu'inhibiteurs de l'egfr et leurs utilisations
WO2024119028A1 (fr) * 2022-12-02 2024-06-06 Accutar Biotechnology, Inc. Dérivés de quinoléine substitués ayant des activités d'inhibition de sos1 et leurs utilisations
US12037346B2 (en) 2021-04-13 2024-07-16 Nuvalent, Inc. Amino-substituted heteroaryls for treating cancers with EGFR mutations
WO2025021182A1 (fr) * 2023-07-27 2025-01-30 Acerand Therapeutics (Hong Kong) Limited Inhibiteurs de cyp11a1
WO2025067398A1 (fr) * 2023-09-27 2025-04-03 江苏恒瑞医药股份有限公司 Forme cristalline d'un dérivé de la quinazoline et son procédé de préparation
EP4506343A4 (fr) * 2022-04-05 2026-03-04 Voronoi Inc Dérivé hétéroaryle et son utilisation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6602677B1 (en) 1997-09-19 2003-08-05 Promega Corporation Thermostable luciferases and methods of production
WO2005026151A1 (fr) * 2003-09-16 2005-03-24 Astrazeneca Ab Dérivés de quinozaline en tant qu'inhibiteurs de la tyrosine kinase
WO2008150118A2 (fr) * 2007-06-05 2008-12-11 Hanmi Pharm. Co., Ltd. Nouveau dérivé d'amide pouvant inhiber la croissance de cellules cancéreuses
WO2020262998A1 (fr) * 2019-06-26 2020-12-30 한미약품 주식회사 Nouveau dérivé de quinazoline ayant une activité antitumorale et composition pharmaceutique le comprenant

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6602677B1 (en) 1997-09-19 2003-08-05 Promega Corporation Thermostable luciferases and methods of production
WO2005026151A1 (fr) * 2003-09-16 2005-03-24 Astrazeneca Ab Dérivés de quinozaline en tant qu'inhibiteurs de la tyrosine kinase
WO2008150118A2 (fr) * 2007-06-05 2008-12-11 Hanmi Pharm. Co., Ltd. Nouveau dérivé d'amide pouvant inhiber la croissance de cellules cancéreuses
WO2020262998A1 (fr) * 2019-06-26 2020-12-30 한미약품 주식회사 Nouveau dérivé de quinazoline ayant une activité antitumorale et composition pharmaceutique le comprenant

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS
"Remington: The Science and Practice of Pharmacy", 2011, PHARMACEUTICAL PRESS
ARCILA ET AL., CLIN CANCER RES, vol. 18, 2012, pages 4910
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 319, 2004, pages 1 - 11
CAREY ET AL.: "Remington's Pharmaceutical Sciences", 1990, MACK PRINTING COMPANY, pages: 1289 - 1329
CREE ET AL., ANTICANCER DRUGS, vol. 6, 1995, pages 398 - 404
CROUCH ET AL., J. IMMUNOL. METH., vol. 160, 1993, pages 81 - 88
FREIREICH ET AL., CANCER CHEMOTHER. REPORTS, vol. 50, no. 4, 1966, pages 219 - 244
HIGUCHI ET AL.: "Prodrugs as Novel Delivery Systems", ACS SYMPOSIUM SERIES, vol. 14
JANG, J. ET AL., ANGEW. CHEM. INT. ED., vol. 57, no. 36, 2018, pages 11629 - 11633
MUNDY ET AL.: "Name Reaction and Reagents in Organic Synthesis", 2005, J. WILEY & SONS
NEW ENGLAND JOURNAL OF MEDICINE, vol. 350, 2004, pages 2129 - 39
NEW ENGLAND JOURNAL OF MEDICINE, vol. 358, 2008, pages 1160 - 74
SCIENCE, vol. 304, 2004, pages 1497 - 500
STEPHENS ET AL., NATURE, vol. 431, 2004, pages 525 - 526
T.W. GREENEP.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS
UDAGER, A. M. ET AL., CANCER RES., vol. 75, 2015, pages 2600 - 2606
WANG ET AL., CANCER CELL, vol. 10, 2006, pages 25 - 38

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2023512343A (ja) * 2020-04-24 2023-03-24 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ＨＥＲ２阻害薬としての［１，３］ジアジノ［５，４－ｄ］ピリミジン
JP7260723B2 (ja) 2020-04-24 2023-04-18 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ＨＥＲ２阻害薬としての［１，３］ジアジノ［５，４－ｄ］ピリミジン
WO2022105908A1 (fr) * 2020-11-23 2022-05-27 上海和誉生物医药科技有限公司 Inhibiteur d'egfr, son procédé de préparation et son utilisation pharmaceutique
US12037346B2 (en) 2021-04-13 2024-07-16 Nuvalent, Inc. Amino-substituted heteroaryls for treating cancers with EGFR mutations
KR20230127880A (ko) * 2022-02-25 2023-09-01 중앙대학교 산학협력단 헤테로아릴 유도체를 유효성분으로 함유하는 her2 억제용 조성물
KR102884401B1 (ko) * 2022-02-25 2025-11-11 중앙대학교 산학협력단 헤테로아릴 유도체를 유효성분으로 함유하는 her2 억제용 조성물
WO2023185793A1 (fr) 2022-03-28 2023-10-05 江苏恒瑞医药股份有限公司 Composé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation pharmaceutique
EP4506343A4 (fr) * 2022-04-05 2026-03-04 Voronoi Inc Dérivé hétéroaryle et son utilisation
WO2024026056A3 (fr) * 2022-07-29 2024-03-14 Accutar Biotechnology, Inc. Composés hétéroaryle en tant qu'inhibiteurs de l'egfr et leurs utilisations
WO2024027695A1 (fr) * 2022-08-04 2024-02-08 微境生物医药科技(上海)有限公司 Composés utiles comme inhibiteurs de her2
WO2024119028A1 (fr) * 2022-12-02 2024-06-06 Accutar Biotechnology, Inc. Dérivés de quinoléine substitués ayant des activités d'inhibition de sos1 et leurs utilisations
WO2025021182A1 (fr) * 2023-07-27 2025-01-30 Acerand Therapeutics (Hong Kong) Limited Inhibiteurs de cyp11a1
WO2025067398A1 (fr) * 2023-09-27 2025-04-03 江苏恒瑞医药股份有限公司 Forme cristalline d'un dérivé de la quinazoline et son procédé de préparation

Similar Documents

Publication Publication Date Title
WO2021231400A1 (fr) Bis-aryl éthers contenant de la n-acyl azétidine en tant qu'inhibiteurs de l'egfr/her2
US11414401B2 (en) Substituted 2-anilinopyrimidine derivatives as EGFR modulators
JP6418622B2 (ja) ２−（２，４，５−置換アニリン）ピリミジン誘導体、その薬物組成物及びその用途
KR101917972B1 (ko) ERK 억제제로서 티에노[2,3-c]피롤-4-온 유도체
WO2022170043A1 (fr) Composés dérivés de quinazoline en tant qu'inhibiteurs d'egfr et leurs utilisations
CN105377835B (zh) 酪氨酸蛋白激酶调节剂及其应用方法
US20200331918A1 (en) Triazolo-pyrimidine compounds and uses thereof
CN105237515A (zh) 氘代嘧啶类化合物、其制备方法、药物组合物和用途
CN115141202A (zh) 嘧啶并吡嗪酮化合物及其用途
TWI710554B (zh) 新穎苯并咪唑化合物及其醫藥用途
CN106279160A (zh) N‑苯基‑2‑氨基嘧啶类化合物制备方法和用途
WO2022170164A1 (fr) Sulfonamides ayant des activités d'inhibition de l'egfr et leur utilisation
TW202204351A (zh) 具有大環結構的化合物及其用途
WO2024026056A2 (fr) Composés hétéroaryle en tant qu'inhibiteurs de l'egfr et leurs utilisations
CN106916112B (zh) 嘧啶衍生物及其制备方法和在医药上的应用
CN113840823B (zh) 显示癌细胞生长抑制效果的新型杂环取代的嘧啶衍生物，以及包含其的药物组合物
US11479559B2 (en) Urea-substituted aromatic ring-linked dioxinoquinoline compounds, preparation method and uses thereof
CN104557955B (zh) 作为PI3K/mTOR抑制剂的三环类化合物，其制备方法和用途
JP2025534514A (ja) ブルトンチロシンキナーゼ阻害活性を有する新規なピリミジン誘導体
OA18657A (en) Substituted 2-anilinopyrimidine derivatives as EGFR modulators.
HK1221953A1 (zh) 酪氨酸蛋白激酶调节剂及其应用方法
HK1221953B (en) Protein tyrosine kinase modulators and methods of use
OA18720A (en) 2-H-indazole derivatives as cyclin-dependent kinase (CDK) inhibitors and therapeutic uses thereof.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21729718

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21729718

Country of ref document: EP

Kind code of ref document: A1