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WO2025171171A1 - Composés à base de pyridopyrimidinone divalents utilisés en tant qu'inhibiteurs d'egfr - Google Patents

Composés à base de pyridopyrimidinone divalents utilisés en tant qu'inhibiteurs d'egfr

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Publication number
WO2025171171A1
WO2025171171A1 PCT/US2025/014847 US2025014847W WO2025171171A1 WO 2025171171 A1 WO2025171171 A1 WO 2025171171A1 US 2025014847 W US2025014847 W US 2025014847W WO 2025171171 A1 WO2025171171 A1 WO 2025171171A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
compound
group
alkoxy
haloalkyl
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.)
Pending
Application number
PCT/US2025/014847
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English (en)
Inventor
Nathanael S. Gray
Zhengnian LI
Tinghu Zhang
Jianwei Che
Yaning WANG
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.)
Dana Farber Cancer Institute Inc
Leland Stanford Junior University
Original Assignee
Dana Farber Cancer Institute Inc
Leland Stanford Junior University
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 Dana Farber Cancer Institute Inc, Leland Stanford Junior University filed Critical Dana Farber Cancer Institute Inc
Publication of WO2025171171A1 publication Critical patent/WO2025171171A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • EGFR epidermal growth factor receptor
  • NSCLC non-small-cell lung cancer
  • the compound of Formula (I) is a compound of Formula
  • the compound of Formula (I) is a compound of Formula (IA-I):
  • the compound of Formula (I) is a compound of Formula (IB-IA):
  • the compound of Formula (I) is a compound of Formula (IB- IB):
  • divalent pyridopyrimidinone-based compounds that inhibit epidermal growth factor receptor (EGFR), pharmaceutical compositions that comprise these compounds, and methods of treatment. These compounds are useful in the treatment of kinase-mediated disorders including cancer (e.g., non-small cell lung cancer (NSCLC)) and other proliferation diseases.
  • cancer e.g., non-small cell lung cancer (NSCLC)
  • NSCLC non-small cell lung cancer
  • the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.
  • the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ⁇ 20% or ⁇ 10%, including ⁇ 5%, ⁇ 1%, and ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
  • administration refers to the providing a therapeutic agent to a subject.
  • Multiple techniques of administering a therapeutic agent exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
  • treat includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated.
  • the treatment comprises bringing into contact with wild-type or mutant EGFR an effective amount of a compound disclosed herein for conditions related to cancer.
  • prevent means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.
  • the term “patient,” “individual,” or “subject” refers to a human or a non-human mammal.
  • Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and marine mammals.
  • the patient, subject, or individual is human.
  • the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e. , the material may be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present disclosure include the conventional nontoxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • pharmaceutically acceptable salt is not limited to a mono, or 1:1, salt.
  • “pharmaceutically acceptable salt” also includes bis-salts, such as a bis-hydrochloride salt. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
  • composition refers to a mixture of at least one compound useful within the disclosure with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
  • pharmaceutical combination 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.
  • fixed combination means that the active ingredients, e.g., a compound of the disclosure and a co- 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, e.g. a compound of the disclosure and a co-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.
  • the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline
  • EGFR refers to epidermal growth factor receptor (alternately referred to as ErbB-1 or HER1) and may refer to the wild-type receptor or to a receptor containing one or more mutations.
  • alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e. , C 1-6 alkyl means an alkyl having one to six carbon atoms) and includes straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, pentyl, neopentyl, and hexyl. Other examples of C 1-6 alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.
  • alkoxy refers to the group — O-alkyl , wherein alkyl is as defined herein.
  • Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy and the like.
  • halo or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
  • cycloalkyl means a non-aromatic carbocyclic system that is fully saturated having 1 , 2 or 3 rings wherein such rings may be fused.
  • fused means that a second ring is present (i.e., attached or formed) by having two adjacent atoms in common (i.e., shared) with the first ring.
  • Cycloalkyl also includes bicyclic structures that may be bridged or spirocyclic in nature with each individual ring within the bicycle varying from 3-8 atoms.
  • “cycloalkyl” is C3-C10 cycloalkyl.
  • cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1 .1]pentyl.
  • heterocyclyl or “heterocycloalkyl” means a non-aromatic carbocyclic system containing 1 , 2, 3 or 4 heteroatoms selected independently from N, O, and S and having 1 , 2 or 3 rings wherein such rings may be fused, wherein fused is defined above.
  • heterocyclyl or “heterocycloalkyl” is 3-10 membered heterocycloalkyl.
  • Heterocyclyl also includes bicyclic structures that may be bridged or spirocyclic in nature with each individual ring within the bicycle varying from 3-8 atoms, and containing 0, 1 , or 2 N, O, or S atoms.
  • heterocyclyl includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams) and also specifically includes, but is not limited to, epoxidyl, oxetanyl, tetrahydro-furanyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1 H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1 ,3-oxazinanyl, 1 ,3-thiazinanyl, 2- azabicyclo[2.1.1]hexanyl, 5-azabicyclo-[2.1.1]hexanyl, 6-azabicyclo[3.1.1
  • aromatic refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. , having (4n + 2) delocalized TT (pi) electrons, where n is an integer.
  • aryl means an aromatic carbocyclic system containing 1, 2 or 3 rings, wherein such rings may be fused, wherein fused is defined above. If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated.
  • “aryl” is C 6 -Cio aryl.
  • the term “aryl” includes, but is not limited to, phenyl, naphthyl, indanyl, and 1 , 2,3,4- tetrahydronaphthalenyl.
  • aryl groups have 6 carbon atoms. In some embodiments, aryl groups have from six to ten carbon atoms. In some embodiments, aryl groups have from six to sixteen carbon atoms.
  • heteroaryl means an aromatic carbocyclic system containing 1, 2, 3, or 4 heteroatoms selected independently from N, O, and S and having 1, 2, or 3 rings wherein such rings may be fused, wherein fused is defined above.
  • heteroaryl is 5-10 membered heteroaryl.
  • cancer includes, but is not limited to, the following cancers: myeloma, lymphoma, or a cancer selected from gastric, renal, head and neck, oropharangeal, non-small cell lung cancer (NSCLC), endometrial, hepatocarcinoma, nonHodgkin’s lymphoma, and pulmonary.
  • NSCLC non-small cell lung cancer
  • cancers include, but are not limited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), renal carcinoma, kidney parenchyma carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gall bladder carcinoma, bronchial carcinoma, multiple myeloma, basalioma, teratoma, retinoblast
  • divalent pyridopyrimidinone-based compounds that inhibit epidermal growth factor receptor (EGFR). These compounds are useful in the treatment of kinase-mediated disorders including cancer (e.g., non-small cell lung cancer (NSCLC)) and other proliferation diseases.
  • cancer e.g., non-small cell lung cancer (NSCLC)
  • NSCLC non-small cell lung cancer
  • X 1 is N or CR X ;
  • X 2 is N, CH, or CR 8 ;
  • R 3 and R 8 are each independently selected from the group consisting of halo, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, NH 2 , N(H)(C 1-6 alkyl), and N(C 1-6 alkyl);
  • R 4 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 6- 10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl, wherein C 6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl are each optionally substituted with one, two, or three substituents independently selected from R 2 and R 4a ; each R 4a is independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, NH 2 , N(H)(C 1-6 alkyl), N(C 1-6 alkyl) 2 , and 3-10 membered heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 alkoxy, N(H)(C 1-6 alkyl), N(C 1-6 alkyl) 2 , and 3-10 membered heterocyclo
  • R x is selected from the group consisting of H, halo, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkyl; each m, n, p, and q is independently 0, 1 , or 2; and each R 2 independently for each occurrence is selected from the group consisting of:
  • each L3 is selected from the group consisting of a bond, N(H), and N(C 1-6 alkyl); each R E1 , R E2 , R E3 , and R E4 is independently selected from the group consisting of H, halo, CN, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with NH 2 , N(H)(C 1-6 alkyl), or N(C 1-6 alkyl) 2 ; and each Y is independently selected from O, S, and CH 2 , wherein the compound of Formula (I) is substituted with at least two R 2 substituents.
  • z is 1 , 2, or 3.
  • Ring A is selected from the group consisting of a bond, phenyl, 5-7 membered heterocycloalkyl, and C 5-6 cycloalkyl, provided that when Ring A is a bond, then p is 1 , q is 0, and R 5 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkyl;
  • X 1 is N or R x ;
  • R 4aaa is C 1-6 alkyl; and is the bond to R 4 .
  • R 4aa is selected from the group consisting of OH, C 1-6 alkyl, C 1-6 haloalkyl, NH 2 , N(H)(C 1-6 alkyl), N(C 1-6 alkyl)2, and 5-7 membered heterocycloalkyl, wherein 5-7 membered heterocycloalkyl is optionally substituted with C 1-6 alkyl.
  • R 4aa is C 1-6 alkyl.
  • R 4aa is N(C 1-6 alkyl)2.
  • R 4aa is OH.
  • R 4aa is 5-7 membered heterocycloalkyl optionally substituted with C 1-6 alkyl.
  • the 5-7 membered heterocycloalkyl of R 4aa contains 1 , 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In still another embodiment, the 5-7 membered heterocycloalkyl of R 4aa contains 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen.
  • R 5 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkyl. In another embodiment, R 5 is C 1-6 alkyl.
  • R x is selected from the group consisting of H, halo, CN, OH, and C 1-6 alkyl.
  • at least one R 2 is:
  • one R 2 has the structure of Formula (i-1) and the other R 2 has the structure of Formula (i-14). In an embodiment, one R 2 has the structure of Formula (i-1) and the other R 2 has the structure of Formula (i-3). In another embodiment, both R 2 have the structure of Formula (i-1).
  • L3 is a bond. In another embodiment, L3 is a N(H). In yet another embodiment, when both R 2 have the structure of Formula (i-1), one L3 is a bond and the other L3 is N(H). In an embodiment, when one R 2 has the structure of Formula (i-1) and the other R 2 has the structure of Formula (i-3), each L3 is a bond. In another embodiment, when one R 2 has the structure of Formula (i-1) and the other R 2 has the structure of Formula (i- 13), each L3 is a bond. In yet another embodiment, when one R 2 has the structure of Formula (i-1) and the other R 2 has the structure of Formula (i-14), each L3 is a bond. In still another embodiment, when both R 2 have the structure of Formula (i-1), each L3 is a bond.
  • R E1 , R E2 , and R E3 are each H.
  • R E1 is C 1-6 alkyl.
  • R E1 is C 1-6 alkyl, and R E1 is H.
  • R E2 and R E3 are both H.
  • R E1 is halo.
  • R E1 when both R 2 have the structure of Formula (i- 1), one R E1 is halo and the other R E1 is H. In another embodiment, R E1 is halo, and R E2 and R E3 are both H. In yet another embodiment, when both R 2 have the structure of Formula (i- 1), one R E1 is halo, the other R E1 is H, and each R E2 and R E3 is H.
  • R E1 is CN.
  • one R E1 is CN and the other R E1 is H.
  • R E1 is CN, and R E2 and R E3 are both H.
  • one R E1 is CN, the other R E1 is H, and each R E2 and R E3 is H.
  • R E1 is C 1-6 alkyl optionally substituted with NH 2 , N (H)(C 1-6 alkyl), or N(C 1-6 alkyl)2.
  • R 2 when both R 2 have the structure of Formula (i-1), one R E1 is C 1-6 alkyl and the other R E1 is H, wherein C 1-6 alkyl is optionally substituted with NH 2 , N(H)(C 1-6 alkyl), or N(C 1-6 alkyl)2.
  • R E1 is C 1-6 alkyl
  • R E2 and R E3 are both H, wherein C 1-6 alkyl is optionally substituted with NH 2 , N(H)(C 1-6 alkyl), or N(C 1-6 alkyl)2.
  • one R E1 is C 1-6 alkyl
  • the other R E1 is H
  • each R E2 and R E3 is H, wherein C 1-6 alkyl is optionally substituted with NH 2 , N(H)(C 1-6 alkyl), or N(C 1-6 alkyl)2.
  • R E1 and R E2 are H.
  • each R E1 and R E2 is H, and R E3 is H.
  • R E1 is C 1-6 alkyl and R E2 is H.
  • the R E1 of Formula (i-1) is H
  • the R E1 of Formula (i-14) is C 1-6 alkyl
  • each R E2 is H
  • R E3 is H.
  • R E1 is halo and R E2 is H.
  • the composition further comprises a second active agent.
  • the second active agent is selected from the group consisting of a MEK inhibitor, a PI3K inhibitor, and an mTor inhibitor.
  • the second active agent prevents EGFR dimer formation in a subject.
  • the second active agent is selected from the group consisting of cetuximab, trastuzumab, and panitumumab.
  • the second active agent is an ATP competitive EGFR inhibitor.
  • the ATP competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib.
  • the ATP competitive EGFR inhibitor is osimertinib.
  • compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a method of inhibiting the activity of EGFR comprising administering to a subject in need thereof an effective amount of a compound of disclosed herein or a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier.
  • the compound targets Cys775 on EGFR.
  • a method of inhibiting a kinase in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound provided herein.
  • the kinase is EGFR. In another embodiment, the kinase is HER.
  • a method of treating or preventing a kinase- mediated disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.
  • the kinase-mediated disorder is resistant to an EGFR-targeted therapy.
  • the EGFR-treated therapy is selected from the group consisting of gefitinib, erlotinib, osimertinib, CO-1686, and WZ4002.
  • provided herein is a method of inhibiting the activity of EGFR in a subject in need thereof comprising targeting both Cys775 and Cys797 on EGFR.
  • a method of inhibiting the activity of EGFR in a subject in need thereof comprising administering a compound that targets both Cys775 and Cys797 on EGFR.
  • the compound can simultaneously form two covalent bonds to cysteine 797 and cysteine 775.
  • the compound is a compound of Formula I, described herein.
  • the compounds of the present disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of EGFR containing one or more mutations, but do not affect the activity of a wild-type EGFR.
  • Modulation of EGFR containing one or more mutations, such as those described herein, but not a wild-type EGFR provides an approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis, inflammation, arthritis, systemic lupus erythematosus, skin-related disorders, pulmonary disorders, cardiovascular disease, ischemia, neurodegenerative disorders, liver disease, gastrointestinal disorders, viral and bacterial infections, central nervous system disorders, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and peripheral neuropathy.
  • diseases including, but not limited to, cancer and metastasis, inflammation, arthritis, systemic lupus erythematosus, skin-related disorders, pulmonary disorders, cardiovascular disease, ischemia, neurodegenerative disorders, liver disease, gastrointestinal disorders, viral and bacterial infections, central nervous system disorders, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal
  • the inhibition of EGFR by a compound of the disclosure can be measured via a biochemical assay.
  • a homogenous time-resolved fluorescence (HTRF) assay may be used to determine inhibition of EGFR activity using conditions and experimental parameters disclosed herein.
  • the HTRF assay may, for example, employ concentrations of substrate (e.g., biotin-Lck-peptide substrate) of about 1 ⁇ M; concentrations of EGFR (mutant or WT) from about 0.2 nM to about 40 nM; and concentrations of inhibitor from about 0.000282 ⁇ M to about 50 ⁇ M.
  • a compound of the disclosure screened under these conditions may, for example, exhibit an IC 50 value from about 1 nM to >1 ⁇ M; from about 1 nM to about 400 nM; from about 1 nM to about 150 nM; from about 1 nM to about 75 nM; from about 1 nM to about 40 nM; from about 1 nM to about 25 nM; from about 1 nM to about 15 nM; or from about 1 nM to about 10 nM.
  • a compound of the disclosure screened under the above conditions for inhibition of EGFR having a mutation or combination of mutations selected from L858R/T790M, L858R, and T790M may, for example, exhibit an IC 50 value from about 1 nM to >1 ⁇ M; from about 1 nM to about 400 nM; from about 1 nM to about 150 nM; from about 1 nM to about 75 nM; from about 1 nM to about 40 nM; from about 1 nM to about 25 nM; from about 1 nM to about 15 nM; or from about 1 nM to about 10 nM.
  • the compounds of the disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Lys745, Leu788, and Ala 743; at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Cys755, Leu777, Phe856, and Asp855; and at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Met766, Ile759, Glu762, and Ala763.
  • the compounds of the disclosure do not interact with any of the amino acid residues of epidermal growth factor receptor (EGFR) selected from Met793, Gly796, and Cys797.
  • An EGFR sensitizing mutation comprises without limitation L858R, G719S, G719C, G719A, L861Q, a deletion in exon 19 and/or an insertion in exon 20.
  • a drug- resists nt EGFR mutant can have without limitation a drug resistance mutation comprising T790M, T854A, L718Q, C797S, or D761Y.
  • the selectivity between wild-type EGFR and EGFR containing one or more mutations as described herein can also be measured using cellular proliferation assays where cell proliferation is dependent on kinase activity.
  • murine Ba/F3 cells transfected with a suitable version of wild-type EGFR such as VIII; containing a WT EGFR kinase domain
  • Ba/F3 cells transfected with L858R/T790M, Del/T790M/L718Q, L858R/T790M/L718Q, L858R/T790M/C797S, Del/T790M/C797S, L858R/T790M/I941R, or Exon 19 deletion/T790M can be used.
  • Proliferation assays are performed at a range of inhibitor concentrations (10 ⁇ M, 3 ⁇ M, 1.1 ⁇ M, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and an ECso is calculated.
  • the disclosure provides a method of inhibiting epidermal growth factor receptor (EGFR), the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • the method further comprises administering a second active agent, wherein said second active agent prevents EGFR dimer formation.
  • the second active agent that prevents EGFR dimer formation is an antibody.
  • the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab.
  • the second active agent that prevents EGFR dimer formation is cetuximab.
  • the second active agent is an ATP competitive EGFR inhibitor.
  • the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib.
  • the ATP competitive EGFR inhibitor is osimertinib.
  • a method of treating or preventing a disease comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • the disease is mediated by a kinase.
  • the kinase comprises a mutated cysteine residue.
  • the mutated cysteine residue is located in or near the position equivalent to Cys 797 in EGFR, including such positions in Jak3, Blk, Bmx, Btk, HER2 (ErbB2), HER4 (ErbB4), Itk, Tec, and Txk.
  • the disease is mediated by EGFR (e.g., EGFR plays a role in the initiation or development of the disease).
  • the disease is mediated by a Her-kinase.
  • the Her-kinase is HER1 , HER2, or HER4.
  • the disease is resistant to a known EGFR inhibitor, including but not limited to, gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002.
  • a diagnostic test is performed to determine if the disease is associated with an activating mutation in EGFR.
  • a diagnostic test is performed to determine if the disease is associated with an EGFR harboring an activating mutation and/or a drug resistance mutation.
  • Activating mutations comprise without limitation L858R, G719S, G719C, G719A, L718Q, L861Q, a deletion in exon 19 and/or an insertion in exon 20.
  • the disease is cancer or a proliferation disease.
  • the disease is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas, myelomas, or solid tumors.
  • the disease is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer.
  • the disease is non-small cell lung cancer.
  • Drug resistant EGFR mutants can have without limitation a drug resistance mutation comprising T790M, T854A, L718Q, C797S, or D761Y.
  • the diagnostic test can comprise sequencing, pyrosequencing, PCR, RT-PCR, or similar analysis techniques known to those of skill in the art that can detect nucleotide sequences.
  • the disclosure provides a method of treating a kinase mediated disorder, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a second active agent, wherein said second active agent prevents EGFR dimer formation.
  • the compound is an inhibitor of HER1, HER2, or HER4.
  • the subject is administered an additional therapeutic agent.
  • the compound, the second active agent that prevents EGFR dimer formation, and the additional therapeutic agent are administered simultaneously or sequentially.
  • the second active agent that prevents EGFR dimer formation is an antibody.
  • the disease is cancer.
  • the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas, myelomas, or solid tumors.
  • the disease is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer.
  • the disease is non-small cell lung cancer.
  • Drug resistant EGFR mutants can have without limitation a drug resistance mutation comprising T790M, T854A, L718Q, C797S, or D761Y.
  • the diagnostic test can comprise sequencing, pyrosequencing, PCR, RT-PCR, or similar analysis techniques known to those of skill in the art that can detect nucleotide sequences.
  • a method of preventing resistance to a known EGFR inhibitor comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a second active agent, wherein said second active agent prevents EGFR dimer formation.
  • the second active agent that prevents EGFR dimer formation is an antibody.
  • the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab.
  • the second active agent that prevents EGFR dimer formation is cetuximab.
  • said condition is selected from a proliferative disorder and a neurodegenerative disorder.
  • the compounds of this disclosure are useful for treating cancer, such as colorectal, thyroid, breast, and lung cancer; and myeloproliferative disorders, such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mast cell disease.
  • cancer such as colorectal, thyroid, breast, and lung cancer
  • myeloproliferative disorders such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mast cell disease.
  • the compounds of this disclosure are useful for treating hematopoietic disorders, in particular, acute-myelogenous leukemia (AML), chronic- myelogenous leukemia (CML), acute-promyelocytic leukemia, and acute lymphocytic leukemia (ALL).
  • AML acute-myelogenous leukemia
  • CML chronic- myelogenous leukemia
  • ALL acute lymphocytic leukemia
  • the second active agent that prevents EGFR dimer formation is cetuximab.
  • the second active agent is an ATP competitive EGFR inhibitor.
  • the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib.
  • the ATP competitive EGFR inhibitor is osimertinib.
  • the activity of the compounds and compositions of the present disclosure as EGFR kinase inhibitors may be assayed in vitro, in vivo, or in a cell line.
  • In vitro assays include assays that determine inhibition of either the kinase activity or ATPase activity of the activated kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and may be measured either by radio labelling the inhibitor prior to binding, isolating the inhibitor/kinase complex and determining the amount of radio label bound, or by running a competition experiment where new inhibitors are incubated with the kinase bound to known radioligands.
  • Detailed conditions for assaying a compound utilized in this disclosure as an inhibitor of various kinases are set forth in the Examples below.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents,
  • Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Powders and sprays can contain, in addition to the compounds of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • disorders are treated or prevented in a subject, such as a human or other animal, by administering to the subject a therapeutically effective amount of a compound of the disclosure, in such amounts and for such time as is necessary to achieve the desired result.
  • a therapeutically effective amount of a compound of the disclosure means a sufficient amount of the compound so as to decrease the symptoms of a disorder in a subject.
  • a therapeutically effective amount of a compound of this disclosure will be at a reasonable benefit/risk ratio applicable to any medical treatment.
  • compounds of the disclosure will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents.
  • a therapeutic amount or dose of the compounds of the present disclosure may range from about 0.1 mg/Kg to about 500 mg/Kg, alternatively from about 1 to about 50 mg/Kg.
  • treatment regimens according to the present disclosure comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this disclosure per day in single or multiple doses.
  • Therapeutic amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.
  • a maintenance dose of a compound, composition or combination of this disclosure may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained; when the symptoms have been alleviated to the desired level, treatment should cease.
  • the subject may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.
  • the specific inhibitory dose for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • kits comprising a) a first agent which is a compound of the disclosure as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • the kit can comprise instructions for its administration.
  • these compositions optionally further comprise one or more additional therapeutic agents.
  • an agent that prevents EGFR dimer formation, chemotherapeutic agents or other antiproliferative agents may be combined with the compounds of this disclosure to treat proliferative diseases and cancer.
  • non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • the protein kinase inhibitors or pharmaceutical salts thereof may be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions, which comprise an amount of the protein inhibitor effective to treat or prevent a protein kinase-mediated condition and a pharmaceutically acceptable carrier, are other embodiments of the present disclosure.
  • kits comprising a compound capable of inhibiting kinase activity selected from one or more compounds of disclosed herein, or pharmaceutically acceptable salts thereof, and instructions for use in treating cancer.
  • the kit further comprises components for performing a test to determine whether a subject has activating and/or drug resistance mutations in EGFR.
  • the disclosure provides a kit comprising a compound capable of inhibiting EGFR activity selected from a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • the EGFR mutant L858R Ba/F3 cells have been previously described (Zhou, W, et al. Nature 462, 2009, 1070-1074).
  • the EGFR C797S and C775S mutations were introduced via site directed mutagenesis using the Quick Change Site-Directed Mutagenesis kit into a vector containing EGFR L858R mutation (Stratagene; La Jolla, CA) according to the manufacturer's instructions. All constructs were confirmed by DNA sequencing.
  • the constructs were then shuttled into the retroviral vector JP1540 by either using the Cre- recombination system (Agilent Technologies, Santa Clara, CA) or the In-fusion HD Cloning kit (Takara Bio USA, Inc.; Mountain view, CA).
  • Ba/F3 cells were then infected with retrovirus per standard protocols, as described previously (Zhou, et al, Nature 2009). Stable clones were obtained by selection in puromycin (2 pg/ml). All BaF/3 mutant cells were maintained in RPMI 1640 (Cellgro; Mediatech Inc., Herndon, CA) supplemented with 10% FBS, 100 units/mL penicillin, 100 units/mL streptomycin.
  • the Cell Titer Gio assay is a luminescence-based method used to determine the number of viable cells based on quantitation of the ATP present, which is directly proportional to the amount of metabolically active cells present.
  • Ba/F3 cells of different EGFR genotypes were exposed to compounds for 72 hours and the number of cells used per experiment was determined empirically as has been previously established (Zhou, et al., Nature 2009). All experimental points were set up in triplicates in 384-well plates.
  • the luminescent signal was detected using a spectrometer and the data was graphically displayed using GraphPad Prism version 5.0 for Windows, (GraphPad Software; www.graphpad.com). The curves were fitted using a non-linear regression model with a sigmoidal dose response.
  • EGFR L858R protein (10 pg) was treated with DMSO or a 10-fold molar excess of compound for 2 h at 37 °C and analyzed by LC-MS using an HPLC (Shimadzu, Marlborough, MA) interfaced to an LTQ ion trap mass spectrometer (ThermoFisher Scientific, San Jose, CA).
  • the mass spectrometer was programmed to acquire profile mass spectra (m/z 300-2000). Raw data was deconvoluted using MagTran version 1.03b2. (Rao, S. et al. Cell chemical biology 2019, 26, 818- 829.
  • labeled protein was first reduced (10 mM dithiothreitol for 30 min at 56 °C), alkylated (22.5 mM iodoacetamide for 30 min at room temperature and protected from light), and digested with trypsin. Peptides were then desalted by C18, dried by vacuum centrifugation, reconstituted in 50% MeCN, 1% formic acid, and 100 mM ammonium acetate, and analyzed by CE-MS using a ZipChip autosampler and CE system (908 Devices, Boston, MA) interfaced to a QE- HF mass spectrometer (Thermofisher Scientific).
  • Raw data were converted to .mgf using the multiplierz toolset (Zhu, K. et al. J. Chem. Inf. Model. 2014, 54, 1932- 1940) and searched using Mascot 2.6.1 against a forward reversed human refseq database (NCBI).

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Abstract

L'invention concerne des composés qui agissent en tant qu'inhibiteurs du récepteur du facteur de croissance épidermique (EGFR) ; des compositions pharmaceutiques qui contiennent les composés ; et des méthodes de traitement ou de prévention de troubles médiés par la kinase, dont le cancer et d'autres maladies de prolifération.
PCT/US2025/014847 2024-02-06 2025-02-06 Composés à base de pyridopyrimidinone divalents utilisés en tant qu'inhibiteurs d'egfr Pending WO2025171171A1 (fr)

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WO2023196409A1 (fr) * 2022-04-05 2023-10-12 Dana-Farber Cancer Institute, Inc. Découverte d'un inhibiteur covalent de l'egfr par le biais de la cystéine 775

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WO2023196409A1 (fr) * 2022-04-05 2023-10-12 Dana-Farber Cancer Institute, Inc. Découverte d'un inhibiteur covalent de l'egfr par le biais de la cystéine 775

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