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WO2025129014A1 - Composés indazole pour le traitement du cancer - Google Patents

Composés indazole pour le traitement du cancer Download PDF

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Publication number
WO2025129014A1
WO2025129014A1 PCT/US2024/060055 US2024060055W WO2025129014A1 WO 2025129014 A1 WO2025129014 A1 WO 2025129014A1 US 2024060055 W US2024060055 W US 2024060055W WO 2025129014 A1 WO2025129014 A1 WO 2025129014A1
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WIPO (PCT)
Prior art keywords
cancer
compound
pharmaceutically acceptable
acceptable salt
mmol
Prior art date
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Pending
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PCT/US2024/060055
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English (en)
Inventor
Robert L. Hudkins
Daniel C Bensen
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Tyra Biosciences Inc
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Tyra Biosciences Inc
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Filing date
Publication date
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Publication of WO2025129014A1 publication Critical patent/WO2025129014A1/fr
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Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the disclosure pertains to indazole compounds that are useful in treating cancer, pharmaceutical compositions that include one or more such indazole compounds, and methods of using such indazole compounds in treating cancer.
  • kinase inhibitors have been used to block the activity of kinases and thereby treat cancer (e.g., by inhibiting mitotic processes). These kinase inhibitors are often small molecules that target kinases to block the development, growth or spread of cancer.
  • the compounds disclosed herein provide small molecule kinase inhibitors that are both efficacious and selective.
  • the disclosure provides compounds of formula (I): or pharmaceutically acceptable salts thereof, wherein
  • Q is CH or N
  • R 1 is H, F, or CN
  • R 2 is H or OCH 3 ;
  • Z 1 is absent, CH 2 , NR 3 , or O;
  • Z 2 is absent, CH 2 , NR 3 , or O;
  • Z 3 is absent, CH 2 , NR 3 , or O; wherein at least one of Z 1 , Z 2 , and Z 3 is NR 3 or O; wherein if R 1 is H or CN and Q is CH, then Z 1 is NR 3 , Z 2 is absent or CH 2 , and Z 3 is CH 2 , NR 3 , or O; wherein if R 1 is F or CN and R 2 is OCH 3 , then Z 1 is NR 3 , Z 2 is absent or CH 2 , and Z 3 is CH 2 , NR 3 , or O; each R 3 is independently H or SO 2 CH 3 .
  • Stereoisomers of the compounds of formula (I), and the pharmaceutical salts and solvates thereof, are also described. Methods of using compounds of formula (I) are described, as well as pharmaceutical compositions including the compounds of formula (I).
  • compositions and methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect.
  • salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid.
  • Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic, trifluoroacetic acid, or naphthalene sulfonic acid.
  • an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic, trifluoroacetic acid, or naphthalene sulfonic acid.
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N- methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1 -C 7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N- methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1 -C 7 alkylamine, cyclohe
  • each center may independently be of R-configuration or S -configuration or a mixture thereof
  • the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture.
  • each double bond may independently be E or Z a mixture thereof
  • all possible diastereomers are also envisioned.
  • all tautomers are envisioned.
  • all isotopes of the included atoms are envisioned.
  • any instance of hydrogen may include hydrogen- 1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium) or other isotopes;
  • any instance of carbon may include carbon- 12, carbon- 13, carbon- 14, or other isotopes;
  • any instance of oxygen may include oxygen- 16, oxygen- 17, oxygen- 18, or other isotopes;
  • any instance of fluorine may include one or more of fluorine- 18, fluorine- 19, or other isotopes;
  • any instance of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.
  • kinase inhibitor means any compound, molecule or composition that inhibits or reduces the activity of a kinase.
  • the inhibition can be achieved by, for example, blocking phosphorylation of the kinase (e.g., competing with adenosine triphosphate (ATP), a phosphorylating entity), by binding to a site outside the active site, affecting its activity by a conformational change, or by depriving kinases of access to the molecular chaperoning systems on which they depend for their cellular stability, leading to their ubiquitylation and degradation.
  • ATP adenosine triphosphate
  • subject As used herein, “subject,” “host,” “patient,” and “individual” are used interchangeably and shall be given its ordinary meaning and shall also refer to an organism that has FGFR proteins. This includes mammals, e.g., a human, a non- human primate, ungulates, canines, felines, equines, mice, rats, and the like. The term “mammal” includes both human and non-human mammals.
  • sample or “biological sample” shall be given its ordinary meaning and also encompasses a variety of sample types obtained from an organism and can be used in an imaging, a diagnostic, a prognostic, or a monitoring assay.
  • the term encompasses blood and other liquid samples of biological origin, solid tissue samples, such as a biopsy specimen or tissue cultures or cells derived therefrom and the progeny thereof.
  • the term encompasses samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment for certain components.
  • the term encompasses a clinical sample, and also includes cells in cell culture, cell supernatants, cell lysates, serum, plasma, biological fluids, and tissue samples.
  • treatment shall be given its ordinary meaning and shall also include herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease.
  • Treatment shall be given its ordinary meaning and shall also cover any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, e.g., arresting its development; and/or (c) relieving the disease symptom, e.g., causing regression of the disease or symptom.
  • cancer neoplasm
  • tumor neoplasm
  • tumor cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation.
  • cells of interest for detection or treatment in the present application include precursors, precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells.
  • FGFR related cancer denotes those cancers that involve an increased activity in a mutant FGFR kinase, for example, the continued activation of FGFR.
  • control refers shall be given its ordinary meaning and shall also include a sample or standard used for comparison with a sample which is being examined, processed, characterized, analyzed, etc.
  • the control is a sample obtained from a healthy patient or a non-tumor tissue sample obtained from a patient diagnosed with a tumor.
  • the control is a historical control or standard reference value or range of values.
  • the control is a comparison to a wild-type FGFR arrangement or scenario.
  • Q is CH or N
  • R 1 is H, F, or CN
  • R 2 is H or OCH 3 ;
  • Z 1 is absent, CH 2 , NR 3 , or O;
  • Z 2 is absent, CH 2 , NR 3 , or O;
  • Z 3 is absent, CH 2 , NR 3 , or O; wherein at least one of Z 1 , Z 2 , and Z 3 is NR 3 or O; wherein if R 1 is H or CN and Q is CH, then Z 1 is NR 3 , Z 2 is absent or CH 2 , and Z 3 is CH 2 , NR 3 , or O; wherein if R 1 is F or CN and R 2 is OCH 3 , then Z 1 is NR 3 , Z 2 is absent or CH 2 , and Z 3 is CH 2 , NR 3 , or O; each R 3 is independently H or SO 2 CH 3 .
  • Q is CH.
  • R 1 is H.
  • R 1 is F.
  • R 1 is CN.
  • R 2 is H.
  • R 2 is OCH 3 .
  • Z 1 is absent.
  • Z 1 is CH 2 .
  • Z 1 is NR 3 .
  • Z 1 is O.
  • Z 2 is absent.
  • Z 2 is CH 2 .
  • Z 2 is NR 3 .
  • Z 2 is O.
  • Z 3 is absent.
  • Z 3 is CH 2 .
  • Z 3 is NR 3 .
  • Z 3 is O.
  • Z 1 is NR 3 ;
  • Z 2 is CH 2 ; and
  • Z 3 is CH 2 .
  • Z 1 is NR 3 ; Z 2 is absent; and Z 3 is CH 2 .
  • Z 1 is absent; Z 2 is absent; and Z 3 is NR 3 .
  • Z 1 is NR 3 ; Z 2 is absent; and Z 3 is absent.
  • Z 1 is NR 3 ;
  • Z 2 is CH 2 ; and
  • Z 3 is O.
  • R 3 is H.
  • R 3 is SO 2 CH 3 .
  • At least one of Z 1 , Z 2 , and Z 3 is NR 3 or O.
  • R 1 is H or CN and Q is CH, then Z 1 is NR 3 , Z 2 is absent or CH 2 , and Z 3 is CH 2 , NR 3 , or O.
  • the compound of Formula (I) is:
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof [0060] In some embodiments, the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof
  • the compound of Formula (I) is: , or a pharmaceutically acceptable salt thereof [0069] In some aspects, the disclosure provides a compound of formula: , or a pharmaceutically acceptable salt thereof
  • the disclosure provides a compound of formula: , or a pharmaceutically acceptable salt thereof
  • the disclosure provides a compound of formula: , or a pharmaceutically acceptable salt thereof
  • the disclosure provides a compound of formula: , or a pharmaceutically acceptable salt thereof
  • the disclosure provides a compound of formula: or a pharmaceutically acceptable salt thereof
  • the disclosure provides the following compounds, or pharmaceutically acceptable salts thereof:
  • the disclosure provides a compound of formula: , or a pharmaceutically acceptable salt thereof
  • the disclosure provides a compound of formula: , or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a compound of formula: , or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a compound of formula: or a pharmaceutically acceptable salt thereof.
  • Stereoisomers of compounds of the disclosure are also contemplated by the present disclosure.
  • the disclosure encompasses all stereoisomers and constitutional isomers of any compound disclosed or claimed herein, including all enantiomers and diastereomers, or mixtures thereof
  • compositions and methods of administration are provided.
  • the disclosure provides pharmaceutical compositions comprising a compounds of the disclosure (e.g, formula (I)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • the pharmaceutical compositions contain a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions.
  • the one or more compounds of the invention and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.
  • the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above)
  • the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 5%,
  • the concentration of one or more compounds of the invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately l% to approximately 10% w/w, w/v or v/v.
  • the concentration of one or more compounds of the invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.
  • the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009
  • the amount of one or more compounds of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g,
  • the amount of one or more compounds of the invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.
  • the compounds according to the invention are effective over a wide dosage range.
  • dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used.
  • An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • the amounts of the compounds described herein are set forth on a free base basis. That is, the amounts indicate that amount of the compound administered, exclusive of, for example, solvent (such as in solvates) or counterions (such as in pharmaceutically acceptable salts).
  • compositions for oral administration are provided.
  • the invention provides a pharmaceutical composition for oral administration containing a compound of the invention, and a pharmaceutical excipient suitable for oral administration.
  • the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration.
  • the composition further contains: (iv) an effective amount of a third agent.
  • the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption.
  • Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in- water emulsion, or a water-in-oil liquid emulsion.
  • Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds.
  • water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf- life or the stability of formulations over time.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
  • An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
  • suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, com starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyr
  • suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art.
  • Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof.
  • a lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.
  • the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • the tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • Surfactants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.
  • a suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10.
  • An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value).
  • HLB hydrophilic-lipophilic balance
  • Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
  • Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10.
  • HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
  • Hydrophilic surfactants may be either ionic or non-ionic.
  • Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof
  • ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and diglycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and diglycerides; and mixtures thereof
  • Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, capry
  • Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmalto sides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterol
  • hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyce
  • Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof.
  • preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.
  • the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection.
  • a solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
  • solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG ; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, 8-
  • solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • the amount of solubilizer that can be included is not particularly limited.
  • the amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art.
  • the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200%> by weight, based on the combined weight of the drug, and other excipients.
  • solubilizer may also be used, such as 5%>, 2%>, 1%) or even less.
  • the solubilizer may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25%> by weight.
  • the composition can further include one or more pharmaceutically acceptable additives and excipients.
  • additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof
  • an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons.
  • pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like.
  • bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p -toluene sulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluene sulfonic acid, uric acid, and the like.
  • a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid
  • Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used.
  • the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like.
  • Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.
  • Suitable acids are pharmaceutically acceptable organic or inorganic acids.
  • suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.
  • suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkane sulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methane sulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p- toluene sulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluene sulfonic acid, uric acid and the like.
  • compositions for injection are provided.
  • the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection.
  • a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection.
  • Components and amounts of agents in the compositions are as described herein.
  • Aqueous solutions in saline are also conventionally used for injection.
  • Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • certain desirable methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof
  • compositions for topical e.g. transdermal delivery.
  • the invention provides a pharmaceutical composition for transdermal delivery containing a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.
  • compositions of the present invention can be formulated into preparations in solid, semisolid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions.
  • DMSO dimethylsulfoxide
  • carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients.
  • a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.
  • compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum comeum permeability barrier of the skin.
  • suitable solid or gel phase carriers or excipients which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum comeum permeability barrier of the skin.
  • penetrationenhancing molecules known to those trained in the art of topical formulation.
  • humectants e.g., urea
  • glycols e.g., propylene glycol
  • alcohols e.g., ethanol
  • fatty acids e.g., oleic acid
  • surfactants e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.glycerol monolaurate, sulfoxides, terpenes (e.g., menthol)
  • amines amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, either with or without another agent.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • compositions for inhalation are provided.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art.
  • Administration of the compounds or pharmaceutical composition of the present invention can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadipo sally or intrathecally.
  • an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. by dividing such larger doses into several small doses for administration throughout the day.
  • a compound of the invention is administered in a single dose.
  • a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
  • Administration of the compounds of the invention may continue as long as necessary.
  • a compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days.
  • a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day.
  • a compound of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
  • An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
  • a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty.
  • compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis.
  • a compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent.
  • a compound of the invention is admixed with a matrix.
  • Such a matrix may be a polymeric matrix, and may serve to bond the compound to the stent.
  • Polymeric matrices suitable for such use include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g.
  • Compounds of the invention may be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip-coating, and/or brush-coating.
  • the compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent.
  • the compound may be located in the body of the stent or graft, for example in microchannels or micropores.
  • stents When implanted, the compound diffuses out of the body of the stent to contact the arterial wall.
  • stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash.
  • compounds of the invention may be covalently linked to a stent or graft.
  • a covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages.
  • Compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis.
  • the compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure.
  • the subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
  • Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • FGFR receptors (FGFR1, FGFR2, FGFR3, and FGFR4) share several structural features in common, including three extracellular immunoglobulin- like (Ig) domains, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase domain split by a kinase insert domain, followed by a cytoplasmic c-terminal tail (Johnson et al., Adv. Cancer Res. 60:1-40, 1993; and Wilkie et al., Curr. Biol. 5:500-507, 1995).
  • Ig immunoglobulin- like
  • a hydrophobic transmembrane domain an intracellular tyrosine kinase domain split by a kinase insert domain, followed by a cytoplasmic c-terminal tail
  • a kinase insert domain spans positions 582 to 595 of the alpha Al isoform of FGFR1.
  • the kinase insert domain spans positions 585 to 598 of the FGFR2 Ille isoform.
  • the kinase insert domain spans positions 576 to 589 of the FGFR3 Ille isoform.
  • the kinase insert domain spans positions 571 to 584 of FGFR4 isoform 1.
  • the c-terminal tail of FGFRs begins following the end of the tyrosine kinase domain and extends to the c-terminus of the protein.
  • Dysregulation of a FGFR gene, a FGFR protein, or expression or activity, or level of the same has been associated with many types of cancer.
  • dysregulation of FGFRs can occur by multiple mechanisms, such as FGFR gene overexpression, FGFR gene amplification, activating mutations (e.g., point mutations or truncations), and chromosomal rearrangements that lead to FGFR fusion proteins.
  • Dysregulation of a FGFR gene, a FGFR protein, or expression or activity, or level of the same can result in (or cause in part) the development of a variety of different FGFR-associated cancers.
  • FGFR fusion proteins are known in the art. See, e.g., Baroy et al., PloS One; l l(9):e0163859. doi: 10.1371/joumal.pone.0163859, 2016; Ren et al., Int. J. Cancer, 139(4):836-40, 2016; Marchwicka et al., Cell Biosci., 6:7. doi: 10.1186/sl3578-016-0075-9, 2016; PCT Patent Application Publication No. WO 2014/071419A2; U.S. Patent Application Publication No. 2015/0366866 Al; PCT Patent Application Publication No. WO 2016/084883 Al; PCT Patent Application Publication No.
  • FGFR point mutations are known in the art. See, e.g, UniParc entry UPI00000534B8; UniParc entry UPI0000001COF; UniParc entry UPI000002A99A; UniParc entry UPI000012A72A; UniParc entry UPI000059D1C2; UniParc entry UPI000002A9AC; Uniparc entry UPI000012A72C; Uniparc entry UPI000012A72D; Uniparc entry UPI000013EOB8; Uniparc entry UPI0001CE06A3; Gen bank entry BAD92868.1; Ang et al., Diagn. Mo/. Patho/. Feb 24, 2014; U.S. Patent Application Publication No.
  • EP2203449B1 Yoza et al., Genes Cells., (10): 1049-1058, 2016; Bunney et al., EbioMedicine, 2(3): 194-204, 2015; Byron et al., Neop/asia, 15(8):975-88, 2013; European Patent Application Publication No. EP3023101 Al; PCT Application Publication No. WO 2015/099127A1; Thussbas et al., J. Clin. Oneal., 24(23):3747-55, 2006; Chell et al., Oncogene, 32(25):3059-70, 2013; Tanizaki et al, Cancer Res. 75(15):3149-3146 doi: 10.1158/0008-5472.
  • Compounds of the disclosure have been found to inhibit FGFR1, FGFR2, FGFR3, and/or FGFR4 and are therefore believed to be useful for treating diseases and disorders which can be treated with an inhibitor of FGFR1, FGFR2, FGFR3 and/or FGFR4.
  • compounds of the disclosure can be useful in treating FGFR-associated diseases and disorders, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumor, and angiogenesis-related disorders.
  • Compounds of the disclosure may also be useful in treating disorders arising from autosomal dominant mutations in FGFR, e.g., FGFR3, including, for example, developmental disorders.
  • Developmental disorders to be treated with compounds of the disclosure include Achondroplasia (Ach) and related chondrodysplasia syndromes, including Hypochondrop lasia (Hch), Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (S ADD AN), and Thanatophoric dysplasia (TD).
  • Achondroplasia Ach
  • Hch Hypochondrop lasia
  • S ADD AN Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans
  • TD Thanatophoric dysplasia
  • Compounds of the disclosure may also be useful in Double dominant ACH.
  • Compounds of the disclosure may also be useful in Craniosynostosis, e.g., Crouzon syndrome with acanthosis nigricans and Meunke syndrome.
  • Compounds of the disclosure may also be useful in other genetic short stature conditions, e.g., Leri-Weill dyschondrosteosis, Turner syndrome, Osteogenesis imperfecta, Mucopolysaccaridoses IVA, Mucopolysaccaridoses VI, and Laron syndrome (growth hormone insensitivity).
  • Compounds of the disclosure may also be useful in pediatric short stature conditions, e.g., Idiopathic short stature and Severe idiopathic short stature.
  • Non-limiting examples of FGFR-associated diseases and disorders include Acanthosis nigricans, Achondroplasia, Apert syndrome, Beare-Stevenson syndrome (BSS), Camptodactyly, tall stature, and hearing loss syndrome (CATSHL) syndrome, cleft lip and palate, congenital heart disease (e.g., associated with ambiguous genitalia), craniosynostosis, Crouzon syndrome, ectrodactyly, encephalocraniocutaneous lipomatosis, Hartsfield syndrome, hypochondroplasia, hypogonadoropic hypogonadism (e.g., hypogonado tropic hypogonadism 2 with or without anosmia, Kailman syndrome), ichthyosis vulgaris and/or atopic dermatitis, Jackson-Weiss syndrome, lethal pulmonary acinar dysplasia, microphthalmia, Muenke coronal craniosynostosis, osteoglophon
  • Non-limiting examples of FGFR1 associated diseases and disorders include congenital heart disease (e.g., associated with ambiguous genitalia), craniosynostosis, encephalocraniocutaneous lipomatosis, Hartsfield syndrome, hypogonadoropic hypogonadism (e.g., hypogonado tropic hypogonadism 2 with or without anosmia, Kallman syndrome), ichthyosis vulgaris and/or atopic dermatitis, Jackson-Weiss syndrome, osteoglophonic dysplasia, Pfeiffer syndrome, trigonocephaly 1 (also called metopic craniosynostosis), and tumor-induced osteomalacia.
  • congenital heart disease e.g., associated with ambiguous genitalia
  • craniosynostosis e.g., associated with ambiguous genitalia
  • encephalocraniocutaneous lipomatosis e.g., Hartsfield syndrome
  • Non-limiting examples of FGFR2-associated diseases and disorders include Apert syndrome, Beare-Stevenson syndrome (BSS), Crouzon syndrome, ectrodactyly, Jackson-Weiss syndrome, lethal pulmonary acinar dysplasia, Pfeiffer syndrome, and syndactyly.
  • Non-limiting examples of FGFR3 -associated diseases and disorders include acanthosis nigricans, achondroplasia, Camptodactyly, tall stature, and hearing loss syndrome (CATSHL) syndrome, cleft lip and palate, craniosynostosis, hypochondroplasia, microphthalmia, Muenke coronal craniosynostosis, seborrheic keratosis, and thanatophoric dysplasia (e.g., type I or type II).
  • CACSHL hearing loss syndrome
  • angiogenesis-related disorder means a disease characterized in part by an increased number or size of blood vessels in a tissue in a subject or patient, as compared to a similar tissue from a subject not having the disease.
  • Non-limiting examples of angiogenesis-related disorders include: cancer (e.g., any of the exemplary cancers described herein, such as prostate cancer, lung cancer, breast cancer, bladder cancer, renal cancer, colon cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, hepatoma, sarcoma, and lymphoma), exudative macular degeneration, proliferative diabetic retinopathy, ischemic retinopathy, retinopathy of prematurity, neovascular glaucoma, crizis rubeosis, corneal neovascularization, cyclitis, sickle cell retinopathy, and pterygium.
  • cancer e.g., any of the exemplary cancers described herein, such as prostate cancer, lung cancer, breast cancer, bladder cancer, renal cancer, colon cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, hepatoma, sarcoma, and lymphoma
  • Compounds of the disclosure inhibit wild-type FGFR1, FGFR2, FGFR3, and/or FGFR4. In other aspects, compounds of the disclosure inhibit a mutated FGFR1, FGFR2, FGFR3, and/or FGFR4. In other aspects, compounds of the disclosure inhibit FGFR1, FGFR2, FGFR3, and/or FGFR4 that includes an FGFR kinase inhibitor resistance mutation.
  • the cancer e.g., FGFR-associated cancer
  • the cancer is a hematological cancer.
  • the cancer e.g., FGFR- associated cancer
  • the cancer e.g., FGFR-associated cancer
  • a lung cancer e.g., small cell lung carcinoma, non-small cell lung carcinoma, squamous cell carcinoma, lung adenocarcinoma, large cell carcinoma, mesothelioma, lung neuroendocrine carcinoma, smoking-associated lung cancer
  • prostate cancer colorectal cancer (e.g., rectal adenocarcinoma)
  • endometrial cancer e.g., endometrioid endometrial cancer, endometrial adenocarcinoma
  • breast cancer e.g., hormone-receptor-positive breast cancer, triple-negative breast cancer, neuroendodrine carcinoma of the breast
  • skin cancer e.g., melanoma, cutaneous squamous cell carcinoma, basal cell carcinoma, large squamous cell carcinoma
  • gallbladder cancer e.g., dedifferenti
  • the cancer e.g., FGFR-associated cancer
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • the cancer in adolescents, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, unknown primary carcinoma, cardiac tumors, cervical cancer, childhood cancers, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, neoplasms by site, neoplasms, colon cancer
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CML chronic myelogenous leukemia
  • a hematological cancer is selected from the group consisting of leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, for instance, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocyctic leukemia (JMML), adult Tcell ALL, AML with an lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocy
  • hematological cancers include myeloproliferative disorders (MPD) such as polycythemia vera (PV), essential thrombocytopenia (ET) and idiopathic primary myelofibrosis (IMF/IPF/PMF).
  • MPD myeloproliferative disorders
  • PV polycythemia vera
  • ET essential thrombocytopenia
  • IMF/IPF/PMF idiopathic primary myelofibrosis
  • the hematological cancer e.g., the hematological cancer that is a FGFR-associated cancer
  • AML or CMML.
  • the cancer is a solid tumor.
  • solid tumors e.g., solid tumors that are FGFR-associated cancers
  • lung cancer e.g., lung adenocarcinoma, non-small-cell lung carcinoma, squamous cell lung cancer
  • bladder cancer colorectal cancer
  • brain cancer testicular cancer
  • bile duct cancer cervical cancer prostate cancer
  • sparmatocytic seminomas See, for example, Turner and Grose, Nat. Rev. Cancer, 10(2): 116-129, 2010.
  • the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, cholangiocarcinoma, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, uterine cancer. In some embodiments, the cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer.
  • the cancer is hepatocellular carcinoma.
  • a FGFRl-associated cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer.
  • the cancer is selected from the group consisting of breast cancer, uterine cancer, cholangiocarcinoma, and lung cancer.
  • a FGFR2-associated cancer is selected from the group consisting of breast cancer, uterine cancer, cholangiocarcinoma, and lung cancer.
  • the cancer is selected from the group consisting of lung cancer, bladder cancer, urethral cancer, multiple myeloma, and head and neck cancer.
  • a FGFR3 -associated cancer is selected from the group consisting of lung cancer, bladder cancer, urethral cancer, multiple myeloma, and head and neck cancer.
  • the cancer is selected from lung cancer, rhabdomyosarcoma, and breast cancer.
  • a FGFR4-associated cancer is selected from hepatocellular carcinoma, lung cancer, rhabdomyosarcoma, and breast cancer.
  • the compounds of the disclosure are useful in treating cancers associated with amplification or overexpression of FGFR1, for example, Breast cancer or carcinoma (e.g., hormone receptor-positive breast cancer, ductal carcinoma in situ (breast)), pancreatic ductal adenocarcinoma, pancreatic exocrine carcinoma, smoking-associated lung cancer, small cell lung cancer, lung adenocarcinoma, non-small cell lung cancer, squamous cell lung cancer or carcinoma, prostate cancer or carcinoma, ovarian cancer, fallopian tube carcinoma, bladder cancer, rhabdomyosarcoma, head and neck carcinoma (e.g., head and neck squamous cell carcinoma), esophageal cancer (e.g., esophageal squamous cell carcinoma), sar
  • the compounds of the disclosure are useful in treating cancers associated with amplification of FGFR2, for example, Gastric cancer, gastroesophageal junction adenocarcinoma, breast cancer (e.g., triple negative breast cancer), colon cancer, colorectal cancer (e.g., colorectal adenocarcinoma), urothelial cancer, bladder adenocarcinoma, carcinoma of unknown primary, cholangiocarcinoma, endometrial adenocarcinoma, esophageal adenocarcinoma, gallbladder carcinoma, ovarian cancer, fallopian tube carcinoma, pancreatic exocrine carcinoma, sarcoma, squamous cell carcinoma.
  • Gastric cancer gastroesophageal junction adenocarcinoma
  • breast cancer e.g., triple negative breast cancer
  • colon cancer colorectal cancer
  • urothelial cancer e.g., colorectal adenocarcinoma
  • the compounds of the disclosure are useful in treating cancers associated with overexpression of FGFR2, for example, Myxoid lipocarcinoma, rectal cancer, renal cell carcinoma, breast cancer.
  • the compounds of the disclosure are useful in treating cancers associated with upregulation of activity of FGFR3, for example, Colorectal cancer, hepatocellular carcinoma, pancreatic exocrine carcinoma. In some aspects, the compounds of the disclosure are useful in treating cancers associated with overexpression of activity of FGFR3, for example, Multiple myeloma, thyroid carcinoma.
  • the compounds of the disclosure are useful in treating cancers associated with amplification of activity of FGFR3, for example, Bladder cancer and salivary adenoid cystic cancer, urothelial cancer, breast cancer, carcinoid, carcinoma of unknown primary, colorectal cancer (e.g., colorectal adenocarcinoma), gallbladder carcinoma, gastric cancer, gastroesophageal junction adenocarcinoma, glioma, mesothelioma, non-small cell lung carcinoma, small cell lung cancer, ovarian cancer, fallopian tube carcinoma, pancreatic exocrine carcinoma.
  • colorectal cancer e.g., colorectal adenocarcinoma
  • gallbladder carcinoma gastric cancer
  • gastroesophageal junction adenocarcinoma glioma
  • mesothelioma non-small cell lung carcinoma
  • small cell lung cancer small cell lung cancer
  • ovarian cancer fallopian tube carcinoma
  • the compounds of the disclosure are useful in treating cancers associated with amplification of FGFR4, for example, Rhabdomyosarcoma, prostate cancer or carcinoma, breast cancer, urothelial cancer, carcinoid, carcinoma of unknown primary, esophageal adenocarcinoma, head and neck carcinoma, hepatocellular carcinoma, non-small cell lung carcinoma, ovarian cancer, fallopian tube carcinoma, peritoneal carcinoma, renal cell carcinoma.
  • the compounds of the disclosure are useful in treating cancers associated with upregulation of activity of FGFR4, for example, Colorectal cancer, hepatocellular carcinoma, adrenal carcinoma, breast cancer.
  • the compounds of the disclosure are useful in treating cancers associated with overexpression of activity of FGFR4, for example, Pancreatic intraepithelial neoplasia, and pancreatic ductal adenocarcinoma.
  • the compounds of the disclosure are more selective for one FGFR than for another.
  • the "selectivity" of a compound for a first target over a second target means that the compound has more potent activity at the first target than the second target.
  • a fold selectivity can be calculated by any method known in the art. For example, a fold selectivity can be calculated by dividing the IC50 value (or Kd value) of a compound for the second target (e.g., FGFR1) by the IC50 value (or Kd value) of the same compound for the first target (e.g., FGFR2 or FGFR3).
  • An IC50 value (or Kd value) can be determined by any method known in the art.
  • a compound is first determined to have an activity of less than 500 nM for the first target. In some embodiments, a compound is first determined to have an activity of less than 500 nM for the second target.
  • the compounds of the disclosure are more selective for FGFR3 than for FGFR1.
  • the compounds are at least 3-fold more selective for FGFR3 than for FGFR1.
  • the compounds are 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000 fold more selective for FGFR3 than for FGFR1.
  • the compounds of the disclosure are more selective for FGFR4 than for FGFR1.
  • the compounds are at least 3-fold more selective for FGFR4 than for FGFR1.
  • the compounds are 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000 fold more selective for FGFR4 than for FGFR1.
  • the compounds of the disclosure are more selective for FGFR2 than for FGFR1. In some aspects, the compounds are at least 3-fold more selective for FGFR2 than for FGFR1. In some aspects, the compounds are 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000 fold more selective for FGFR2 than for FGFR1.
  • the compounds of the disclosure are more selective for a first FGFR family member (e.g., FGFR2 or FGFR3) over a second FGFR family member (e.g., FGFR1 or FGFR4).
  • the compounds of the disclosure are at least 3 -fold more selective for a first FGFR family member over a second FGFR family member.
  • the compounds are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000 fold more selective for a first FGFR family member over a second FGFR family member.
  • the compounds of the disclosure are more selective for a first FGFR family member (e.g., FGFR4 or FGFR3) over a second FGFR family member (e.g., FGFR1 or FGFR2).
  • the compounds of the disclosure are at least 3 -fold more selective for a first FGFR family member over a second FGFR family member.
  • the compounds are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000 fold more selective for a first FGFR family member over a second FGFR family member.
  • the compounds of the disclosure are more selective for an FGFR kinase over another kinase that is not an FGFR kinase.
  • the compounds of the disclosure are at least 3 -fold more selective for an FGFR kinase over another kinase that is not an FGFR kinase.
  • the compounds of the disclosure are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000 fold more selective for an FGFR kinase over another kinase that is not an FGFR kinase.
  • Kinases that are not FGFR kinases include, for example, KDR kinase and Aurora B kinase.
  • the compounds of the disclosure exhibit brain and/or central nervous system (CNS) penetrance. Such compounds are capable of crossing the blood brain barrier and inhibiting a FGFR kinase in the brain and/or other CNS structures.
  • the compounds provided herein are capable of crossing the blood brain barrier in a therapeutically effective amount.
  • treatment of a subject with cancer e.g., a FGFR-associated cancer such as a FGFR- associated brain or CNS cancer
  • administration e.g., oral administration
  • the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor.
  • a FGFR-associated primary brain tumor or metastatic brain tumor e.g., a FGFR-associated primary brain tumor or metastatic brain tumor.
  • the compounds of the disclosure exhibit one or more of high GI absorption, low clearance, and low potential for drug-drug interactions.
  • compounds of the disclosure can be used for treating a subject diagnosed with (or identified as having) a FGFR-associated disease or disorder (e.g., a FGFR-associated cancer) that include administering to the subject a therapeutically effective amount of a compound of the disclosure.
  • a FGFR-associated disease or disorder e.g., a FGFR-associated cancer
  • methods for treating a subject identified or diagnosed as having a FGFR- associated disease or disorder e.g., a FGFR-associated cancer
  • the subject that has been identified or diagnosed as having a FGFR-associated disease or disorder e.g., a FGFR-associated cancer
  • a regulatory agency-approved e.g., FDA-approved test or assay for identifying dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • the FGFR- associated disease or disorder is a FGFR-associated cancer.
  • the FGFR- associated cancer can be a cancer that includes one or more FGFR inhibitor resistance mutations.
  • Some embodiments of these methods further include administering to the subject an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the disclosure, or an immunotherapy.
  • the subject was previously treated with a first FGFR inhibitor or previously treated with another treatment.
  • the subject is determined to have a FGFR-associated disease or disorder through the use of a regulatory agency-approved, e.g., FDA approved test or assay for identifying dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • a regulatory agency-approved e.g., FDA approved test or assay for identifying dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • an additional therapy or therapeutic agent e.g., a second FGFR inhibitor, a second compound of the disclosure, or an immunotherapy.
  • the subject was previously treated with a first FGFR inhibitor or previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy.
  • the subject is determined to have a FGFR-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • the cancer is a FGFR associated cancer.
  • the FGFR- associated cancer can be a cancer that includes one or more FGFR inhibitor resistance mutations.
  • the cancer is a FGFR associated cancer.
  • the FGFR-associated cancer can be a cancer that includes one or more FGFR activating mutations.
  • Also provided are methods of treating a subject that include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same, and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of the disclosure or pharmaceutically acceptable salt or solvate thereof to the subject determined to have a dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same.
  • Some embodiments of these methods further include administering to the subject an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the disclosure, or immunotherapy).
  • an additional therapy or therapeutic agent e.g., a second FGFR inhibitor, a second compound of the disclosure, or immunotherapy.
  • the subject was previously treated with a first FGFR inhibitor or previously treated with another anticancer treatment, e.g., at least partial resection of a tumor or radiation therapy.
  • the subject is a subject suspected of having a FGFR-associated disease or disorder (e.g., a FGFR-associated cancer), a subject presenting with one or more symptoms of a FGFR-associated disease or disorder (e.g., a FGFR-associated cancer), or a subject having an elevated risk of developing a FGFR-associated disease or disorder (e.g., a FGFR-associated cancer).
  • the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis.
  • the assay is a regulatory agency-approved assay, e.g., FDA-approved kit.
  • the assay is a liquid biopsy.
  • the dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same includes one or more FGFR inhibitor resistance mutations.
  • Also provided herein are methods of selecting a treatment for a subject wherein the methods include a step of performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same (e.g., one or more FGFR inhibitor resistance mutations), and identifying or diagnosing a subject determined to have a dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same, as having a FGFR-associated cancer. Some embodiments further include administering the selected treatment to the subject identified or diagnosed as having a FGFR-associated cancer.
  • the selected treatment can include administration of a therapeutically effective amount of a compound of the disclosure to the subject identified or diagnosed as having a FGFR-associated cancer.
  • the assay is an in vitro assay.
  • an assay that utilizes the next generation sequencing, immunohistochemistry, or break apart FISH analysis is included in the assay.
  • the assay is a regulatory agency-approved, e.g., FDA-approved, kit.
  • the assay is a liquid biopsy.
  • Also provided herein are methods of treating a FGFR-associated cancer in a subject that include (a) administering one or more (e.g., two or more, three or more, four or more, five or more, or ten or more) doses of a first FGFR kinase inhibitor to a subject identified or diagnosed as having a FGFR associated cancer (e.g., any of the types of FGFR-associated cancers described herein) (e.g., identified or diagnosed as having a FGFR-associated cancer using any of the exemplary methods described herein or known in the art); (b) after step (a), determining a level of circulating tumor DNA in a biological sample (e.g., a biological sample comprising blood, serum, or plasma) obtained from the subject; (c) administering a therapeutically effective amount of a second FGFR inhibitor or a compound of the disclosure as a monotherapy or in conjunction with an additional therapy or therapeutic agent to a subject identified as having about the same or an elevated level of a biological sample (
  • the reference level of circulating tumor DNA is a level of circulating tumor DNA in a biological sample obtained from the subject prior to step (a). Some embodiments of these methods further include determining the level of circulating tumor DNA in the biological sample obtained from the subject prior to step (a).
  • the reference level of circulating tumor DNA is a threshold level of circulating tumor DNA (e.g., an average level of circulating tumor DNA in a population of subjects having a similar FGFR-associated cancer and having a similar stage of the FGFR-associated cancer, but receiving a non-effective treatment or a placebo, or not yet receiving therapeutic treatment, or a level of circulating tumor DNA in a subject having a similar FGFR-associated cancer and having a similar stage of the FGFR-associated cancer, but receiving a non-effective treatment or a placebo, or not yet receiving therapeutic treatment).
  • a threshold level of circulating tumor DNA e.g., an average level of circulating tumor DNA in a population of subjects having a similar FGFR-associated cancer and having a similar stage of the FGFR-associated cancer, but receiving a non-effective treatment or a placebo, or not yet receiving therapeutic treatment.
  • the first FGFR inhibitor is: ARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1 187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, roblitinib, ICP-105, BIO-1262, futibatinib, fisogatinib, LOXO-435, or RLY-4008.
  • the additional therapy or therapeutic agent includes one or more of radiation therapy, a chemotherapeutic agent (e.g., any of the exemplary chemotherapeutic agents described herein or known in the art), a checkpoint inhibitor (e.g., any of the exemplary checkpoint inhibitors described herein or known in the art), surgery (e.g., at least partial resection of the tumor), and one or more other kinase inhibitors (e.g., any of the kinase inhibitors described herein or known in the art).
  • a chemotherapeutic agent e.g., any of the exemplary chemotherapeutic agents described herein or known in the art
  • a checkpoint inhibitor e.g., any of the exemplary checkpoint inhibitors described herein or known in the art
  • surgery e.g., at least partial resection of the tumor
  • one or more other kinase inhibitors e.g., any of the kinase inhibitors described herein or known in the art.
  • Compounds of the disclosure may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example a chemotherapeutic agent that works by the same or by a different mechanism of action.
  • a compound of the disclosure can be used prior to administration of an additional therapeutic agent or additional therapy.
  • a subject in need thereof can be administered one or more doses of a compound of the disclosure for a period of time and then undergo at least partial resection of the tumor.
  • the treatment with one or more doses of a compound of the disclosure reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor.
  • a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a first FGFR inhibitor or a multikinase inhibitor, immunotherapy, radiation, or a platinum-based agent (e.g., cisplatin)).
  • a chemotherapeutic agent such as a first FGFR inhibitor or a multikinase inhibitor
  • immunotherapy e.g., radiation
  • platinum-based agent e.g., cisplatin
  • a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a first FGFR inhibitor or a multikinase inhibitor, immunotherapy, radiation, or a platinum -based agent (e.g., cisplatin)).
  • a chemotherapeutic agent such as a first FGFR inhibitor or a multikinase inhibitor
  • immunotherapy e.g., radiation
  • platinum -based agent e.g., cisplatin
  • the compound of the disclosure is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents.
  • additional therapeutic agents include: other FGFR-targeted therapeutic agents (i.e. a first or second FGFR kinase inhibitor), other kinase inhibitors (e.g., receptor tyrosine kinase targeted therapeutic agents (e.g., Trk inhibitors or EGFR inhibitors)), signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway (e.g. obataclax); cytotoxic chemotherapeutics, angiogenesis- targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy.
  • FGFR-targeted therapeutic agents i.e. a first or second FGFR kinase inhibitor
  • other kinase inhibitors e.g., receptor tyrosine kinase targeted
  • the compound of the disclosure, and the additional therapeutic agent are administered simultaneously as separate dosages.
  • the compound of the disclosure, and the additional therapeutic agent are administered as separate dosages sequentially in any order, in jointly therapeutically effective amounts, e.g. in daily or intermittently dosages.
  • the compound of the disclosure, and the additional therapeutic agent are administered simultaneously as a combined dosage.
  • the disease or disorder is a FGFR- associated disease or disorder.
  • the subject has been administered one or more doses of a compound of the disclosure, prior to administration of the pharmaceutical composition.
  • the treatment period is at least 7 days (e.g., at least or about 8 days, at least or about 9 days, at least or about 10 days, at least or about 11 days, at least or about 12 days, at least or about 13 days, at least or about 14 days, at least or about 15 days, at least or about 16 days, at least or about 17 days, at least or about 18 days, at least or about 19 days, at least or about 20 days, at least or about 21 days, at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, or at least or about 30 days).
  • at least 7 days e.g., at least or about 8 days, at least or about 9 days, at least or about 10 days, at least or about 11 days, at least or about 12 days, at least or about 13 days, at least or about 14 days, at least or about 15 days, at least or about 16 days, at least or
  • the treatment period is at least 21 days (e.g., at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, at least or about 30 days, at least or about 31 days, at least or about 32 days, at least or about 33 days, at least or about 34 days, at least or about 35 days, at least or about 36 days, at least or about 37 days, at least or about 38 days, at least or about 39 days, or at least or about 40 days).
  • at least 21 days e.g., at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, at least or about 30 days, at least or about 31 days, at least or about 32 days, at least or about 33 days, at least or about 34 days, at least or
  • compositions that contain, as the active ingredient, a compound of the disclosure, in combination with one or more pharmaceutically acceptable carriers (excipients).
  • the composition is suitable for topical administration.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the composition is formulated for oral administration.
  • the composition is formulated as a tablet or capsule.
  • compositions comprising a compound of the disclosure can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units for human subjects and other subjects, each unit containing a predetermined quantity of active material (i.e., a compound of the disclosure) to produce the desired therapeutic effect, with a suitable pharmaceutical excipient.
  • the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient, i.e., the compound of the disclosure.
  • the active ingredient i.e., the compound of the disclosure.
  • the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient.
  • compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient.
  • this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient.
  • the active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual subject, the severity of the subject's symptoms, and the like.
  • the compounds provided herein can be administered in an amount ranging from about 1 mg/kg to about 100 mg/kg. In some embodiments, the compound provided herein can be administered in an amount of about 1 mg/kg to about 20 mg/kg, about 5 mg/kg to about 50 mg/kg, about 10 mg/kg to about 40 mg/kg, about 15 mg/kg to about 45 mg/kg, about 20 mg/kg to about 60 mg/kg, or about 40 mg/kg to about 70 mg/kg.
  • such administration can be once-daify or twice-daily (BID) administration.
  • the enantiomers may be separated by conventional means (chiral chromatography, preparing diastereomeric salts, chiral derivatization, crystallization, enzymatic reactions, etc.).
  • a chiral intermediate compound is purified to prepare an enantiomerically pure (or substantially enantiomerically pure, enantiomerically enriched, etc.) intermediate.
  • Step 1 5-[(lR)-l-(3,5-Dichloro-4-pyridyl)ethoxy]-3-(5,6-difluoro-3- pyridyl)-l-tetrahydropyran-2-yl-indazole.
  • Step 2 tert-Butyl 2-(5-(5-((R)-l-(3,5-dichloropyridin-4-yl)ethoxy)- l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)-3-fluoropyridin-2-yl)-2,5- diazaspiro[3.4]octane-5-carboxylate.
  • Step 3 3-[6-(2,5-diazaspiro[3.4]octan-2-yl)-5-fluoro-3-pyridyl]-5- [(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-lH-indazole.
  • Step 1 5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-3-(5,6-difluoro-3- pyridyl)-l-tetrahydropyran-2-yl-indazole.
  • Step 2 2-[5-[5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-l- tetrahydropyran-2-yl-indazol-3-yl]-3-fluoro-2-pyridyl]-8-oxa-2,5- diazaspiro[3.5]nonane.
  • Step 1 [5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-l- tetrahydropyran-2-yl-indazol-3-yl]boronic acid.
  • KOAc 1,3-bis(pinacolato)diboron (19.61 g, 77.2 mmol, 10.0 eq)
  • Pd(dppf)Cl 2 631 mg, 0.77 mmol, 0.1 eq.
  • the reaction mixture was stirred at 100 °C for 10 min under N 2 protection.
  • Step 2 3-(6-Chloropyridazin-3-yl)-5-[(lR)-l-(3,5-dichloro-4- pyridyl)ethoxy]-l-tetrahydropyran-2-yl-indazole.
  • Step 3 2-[6-[5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-l- tetrahydropyran-2-yl-indazol-3-yl]pyridazin-3-yl]-8-oxa-2,5-diazaspiro[3.5]nonane.
  • Step 4. (R)-2-(6-(5-(l-(3,5-dichloropyridin-4-yl)ethoxy)-lH-indazol- 3-yl)pyridazin-3-yl)-8-oxa-2,5-diazaspiro[3.5]nonane.
  • Step 1 tert-Butyl 2-(5-bromo-3-cyanopyridin-2-yl)-2,5- diazaspiro[3.4]octane-5-carboxylate.
  • Step 2 tert-Butyl 2-(3-cyano-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)-2, 5 -diazaspiro [3 ,4]octane-5-carboxylate.
  • Step 3 tert-Butyl 2-(3-cyano-5-(5-((R)-l-(3,5-dichloropyridin-4- yl)ethoxy)-6-methoxy- 1 -(tetrahydro-2H-pyran-2-yl)- 1 H-indazol-3 -yl)pyridin-2-yl)-
  • Step 4 2-(2,5-diazaspiro[3.4]-octan-2-yl)-5-[5-[(lR)-l-(3,5- dichloro-4-pyridyl)ethoxy]-6-methoxy-lH-indazol-3-yl]pyridine-3-carbonitrile.
  • Trifluoro acetic acid (4 mL) was added to a solution of tert-butyl 2-(3-cyano-5-(5-((R)- 1 -(3 , 5 -dichlor opyridin-4-yl)ethoxy)-6-m ethoxy- 1 -(tetrahydro-2H-pyran-2-yl)- 1 H- indazol-3-yl)pyridin-2-yl)-2,5-diazaspiro[3.4]octane-5-carboxylate (300 mg, 0.49 mmol, 1.0 equiv) and 1-dodecanethiol (182 mg, 0.99 mmol, 2.00 equiv) in dichloromethane (4 mL) at room temperature.
  • Step 2 6-Methoxy-l-tosyl-lH-indazol-5-ol. Copper(I) oxide (0.22 g, 1.5 mmol, 0.5 equiv) was added to a solution of (E)-N'-(2-Bromo-5-hydroxy-4- methoxybenzylidene)-4-methylbenzenesulfonohydrazide (1.2 g, 3.0 mmol, 1.0 equiv) in isoamyl alcohol (30 mL) at room temperature. After heating at 132 °C for 2 hours, the mixture was cooled to room temperature and diluted with water (80 mL). The mixture was extract with ethyl acetate (4 x 50 mL).
  • Step 3 (R)-5-(l-(3,5-Dichloropyridin-4-yl)ethoxy)-6-methoxy-l- tosyl-lH-indazole.
  • (lS)-l-(3,5-dichloro-4-pyridyl)ethyl] methane sulfonate (0.57 g, 2.1 mmol, 1.0 equiv) and cesium carbonate (1.03 g, 3.2 mmol, 1.5 equiv) were added to a solution of 6-methoxy-l-tosyl-lH-indazol-5-ol (0.67 g, 2.1 mmol, 1.0 equiv) in acetonitrile (21 mL) at room temperature.
  • Step 4 (R)-5-(l-(3,5-Dichloropyridin-4-yl)ethoxy)-6-methoxy-lH- indazole.
  • IM Tetrabutylammonium fluoride in THF (7.2 mL, 7.2 mmol, 18.0 equiv) was added to a solution of (R)-5-(l-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-l- tosyl- IH-indazole (0.20 g, 0.4 mmol, 1.0 equiv) in tetrahydrofuran (4 mL) at room temperature.
  • Step 5 (R)-5-(l-(3,5-Dichloropyridin-4-yl)ethoxy)-3-iodo-6- methoxy-lH-indazole.
  • Potassium hydroxide 27.9 mg, 0.50 mmol, 2.25 equiv
  • iodine 84.1 mg, 0.33 mmol, 1.5 equiv
  • Step 6 5-((R)-l-(3,5-Dichloropyridin-4-yl)ethoxy)-3-iodo-6- methoxy- l-(tetrahydro-2H-pyran-2-yl)- IH-indazole.
  • Step 7A 2-Fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine-3 -carbonitrile.
  • 5-bromo-2-fluoro-pyridine-3-carbonitrile 10 g, 49.8 mmol, 1.0 eq
  • bis(pinacolato)diboron 25.3 g, 99.5 mmol, 2.0 eq
  • KO Ac 20.6 g, 149.3 mmol, 3.0 eq
  • Pd(dppf)Cl 2 2.0 g, 20wt%).
  • Step 7B 5-[5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-l- tetrahydropyran-2-yl-indazol-3-yl]-2-fluoro-pyridine-3-carbonitrile.
  • Step 8 5-[5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-l- tetrahydropyran-2-yl-indazol-3-yl]-2-(8-oxa-2,5-diazaspiro[3.5]nonan-2-yl)pyridine-
  • Step 1 tert-Butyl 6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane-2- carboxylate.
  • Saturated sodium bicarbonate (10 mL) was added dropwise to a suspension of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemi-oxylate (1 g, 4.1 mmol, 1 equiv) in dichloromethane (70 mL) at 0 °C.
  • a solution of methane sulfonyl chloride (0.94 g, 8.2 mmol, 2 equiv) in dichloromethane (5 mL) was added dropwise.
  • the resulting mixture was stirred at room temperature for 16 hours.
  • the organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid (1.2 g).
  • LCMS m/z 553.2 (M+H
  • Step 2 2-(Methylsulfonyl)-2,6-diazaspiro[3.3]heptane bis(methanesulfonic acid) salt.
  • Methane sulfonic acid (0.85 mL, 1.25 g, 13 mmol, 3 equiv) was added dropwise to a solution of tert-Butyl 6-(methylsulfonyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (1.2 g, 4.3 mmol, 1 equiv) in a mixture of dichloromethane (36 mL) and 1,4-dioxane (4 mL) at 0 °C.
  • Step 3 5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-3-[5-fluoro-6-(2- methylsulfonyl-2, 6-diazaspiro [3.3 ]heptan-6-yl)-3 -pyridyl] - 1 -tetrahydropyran-2-yl- indazole.
  • Step 4 (5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-3-[5-fluoro-6-(2- methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-lH-indazole.
  • the reaction turned white and cloudy, forming a sticky solid. It was then heated at 36 °C for 48 hours. Methyl tert-butyl ether (10 mL) was added, and the reaction was stirred for an additional 10 minutes. The solids were collected by vacuum filtration, washed with isopropanol (20 mL) and dried at 40 °C under vacuum overnight to give a white solid. The solid was dissolved in tetrahydrofuran (20 mL) and 2M sodium hydroxide (7 mL) was added. The biphasic mixture was separated, and the aqueous layer extracted with tetrahydrofuran (2 x 15 mL).
  • Step 1 5-((R)-l-(3,5-Dichloropyridin-4-yl)ethoxy)-3-(6-(6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3-yl)-l-(tetrahydro-2H- pyran-2-yl)-lH-indazole.
  • Step 2 5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2- methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)pyridazin-3-yl]-lH-indazole.
  • Concentrated sulfuric acid 2.0 mL, 35 mmol, 15 equiv was added to water (50 mL), then stirred for 15 minutes.
  • the crude product was dried under vacuum at 40 °C for 15 hours, then was absorbed onto Celite (20 g) with ethyl acetate (40 mL) and purified on a Biotage automated chromatography system (BiotageAmino Duo column, 55 g, 50 pm) eluting with a gradient of 0 to 10% methanol in ethyl acetate to give a white solid (783 mg, 60% yield).
  • Step 1 tert-butyl 6-[6-[5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-l- tetrahydropyran-2-yl-indazol-3-yl]pyridazin-3-yl]-l,6-diazaspiro[3.3]heptane-l- carboxylate.
  • the reaction mixture was then treated with aqueous NaHCCL solution to adjust pH to 7 ⁇ 8, and extracted with DCM (40 mL x 2).
  • the combined organic layers were washed with brine (30 mL x 2), dried over Na 2 SO 4 and concentrated in vacuum.
  • the residue was purified by Prep-HPLC (Prep-C18, 5 pM Triart column, 19 x 150 mm, YMC-Actus; gradient elution of 17% MeCN in water to 42% MeCN in water over a 12 min period, where both solvents contain 0.05% NH 3 .H 2 O) to give a light-yellow solid (16 mg, 25% yield).
  • Step 1 tert-butyl 2-[6-[5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-l- tetrahydropyran-2-yl-indazol-3-yl]pyridazin-3-yl]-2,5-diazaspiro[3.4]octane-5- carboxylate.
  • Step 2 (R)-3-(6-(2,5-diazaspiro[3.4]octan-2-yl)pyridazin-3-yl)-5-(l- (3,5-dichloropyridin-4-yl)ethoxy)-lH-indazole.
  • the product was purified by Prep-HPLC (Prep-C18, 5 pM Triart column, 20 x 150 mm, YMC-Actus; gradient elution of 40% MeCN in water to 60% MeCN in water over a 10 min period, where both solvents contain 0.05% NH3.H2O) to give a white solid (27 mg, 46% yield).
  • Example 10 (R)-3-(6-(2,5-diazaspiro[3.5]nonan-2-yl)pyridazin-3- yl)-5-(l-(3,5-dichloropyridin-4-yl)ethoxy)-lH-indazole was synthesized using the procedure for example 7 and example 8 with 3-(6-chloropyridazin-3-yl)-5-[(lR)-l- (3,5-dichloro-4-pyridyl)ethoxy]-l-tetrahydropyran-2-yl-indazole and tert-butyl 2,5- diazaspiro [3.5 ]nonane-5 -carboxylate.
  • Step 1 tert-Butyl 6-(3-cyano-5-(5-((R)-l-(3,5-dichloropyridin-4- yl)ethoxy)-6-methoxy- 1 -(tetrahydro-2H-pyran-2-yl)- 1 H-indazol-3 -yl)pyridin-2-yl)- 2,6-diazaspiro[3.3]heptane-2-carboxylate.
  • Step 2 (R)-5-(5-(l-(3,5-Dichloropyridin-4-yl)ethoxy)-6-methoxy- lH-indazol-3-yl)-2-(2,6-diazaspiro[3.3]heptan-2-yl)nicotinonitrile.
  • Dodecanethiol (0.30 mL, 1.25 mmol, 2.5 equiv) and 1.8M sulfuric acid (0.85 mL, 1.5 mmol, 3.0 equiv) were sequentially added to a solution of tert-butyl 6-(3-cyano-5-(5-((R)-l-(3,5- dichloropyridin-4-yl)ethoxy)-6-methoxy- 1 -(tetrahydro-2H-pyran-2-yl)- 1 H-indazol-3 - yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (400 mg, 0.5 mmol) in acetonitrile (8 mL).
  • the reaction was heated at 60 °C for 4 hours, then cooled to room temperature and diluted with methyl tert-butyl ether (12 mL) and saturated sodium carbonate (5 mL).
  • the biphasic mixture was concentrated under reduced pressure onto Celite (8 g).
  • the residue was purified on a Biotage automated chromatography system (Redisep Gold 100g C18 column), eluting with a gradient of 0 to 100% acetonitrile in water.
  • Product fractions were concentrated under reduced pressure and reconcentrated from ethanol (10 mL) to give an off-white solid (110 mg, 41% yield over two steps) after drying under vacuum at 40 °C for 8 hours.
  • Step 1 tert-Butyl 6-(5-bromo-3-cyanopyridin-2-yl)-l,6- diazaspiro[3.3]heptane-l-carboxylate.
  • N,N-Diisopropylethylamine (2.22 mL, 12.77 mmol, 5 equiv) was added to a mixture of 5-bromo-2-chloro-pyridine-3-carbonitrile (0.555 g, 2.554 mmol, 1 equiv) and tert-butyl l,6-diazaspiro[3.3]heptane-l- carboxylate (0.81 g, 2.809 mmol, 1.1 equiv) in acetonitrile (40 mL) at room temperature.
  • Step 2 tert-Butyl 6-(3-cyano-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)- l,6-diazaspiro[3 ,3]heptane- 1-carboxylate.
  • Step 3 tert-Butyl 6-(3-cyano-5-(5-((R)-l-(3,5-dichloropyridin-4- yl)ethoxy)-6-methoxy- 1 -(tetrahydro-2H-pyran-2-yl)- 1 H-indazol-3 -yl)pyridin-2-yl)- l,6-diazaspiro-[3.3]heptane-l-carboxylate.
  • Step 4 (R)-5-(5-(l-(3,5-Dichloropyridin-4-yl)ethoxy)-6-methoxy- lH-indazol-3-yl)-2-(l,6-diazaspiro[3.3]heptan-6-yl)nicotinonitrile.
  • Trifluoroacetic acid (6 mL) was added to a solution of tert-butyl 6-(3-cyano-5-(5-((R)-l-(3,5- dichloropyridin-4-yl)ethoxy)-6-methoxy- 1 -(tetr ahydro-2H-pyr an-2-yl)- 1 H-indazol-3 - yl)pyridin-2-yl)-l,6-diazaspiro-[3.3]heptane-l-carboxylate (428 mg, 0.594 mmol, 1.0 equiv) in dichloromethane (6 mL) at room temperature. After stirring at room temperature for 5 hours, the volatiles were removed under reduced pressure.
  • the residue was diluted with dichloromethane (20 mL) and water 10 mL) and adjusted to pH 9 with saturated sodium carbonate. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 20 mL), and the combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • the residue was purified on a Biotage automated chromatography system (Redisep C18 HP reverse phase column, 50 g), eluting with a gradient of 0 to 100% acetonitrile in water to give a white solid (40 mg, 13% yield).
  • Example 15 (R)-5-(l-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5- fluoro-6-(2,5-diazaspiro[3.5]-nonan-2-yl)pyridin-3-yl)-lH-indazole was synthesized using 5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-3-(5,6-difluoro-3- pyridyl)-l-tetrahydropyran-2-yl-indazole and tert-butyl 2,5-diazaspiro[3.5]nonane-5- carboxylate.
  • Example 16 3-[6-(2,5-diazaspiro[3.4]octan-2-yl)-3-pyridyl]-5- [(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-lH-indazole was synthesized using the procedure for example 1 with 5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-3-(5,6- difluoro-3 -pyridyl)- l-tetrahydropyran-2-yl-indazole and tert-butyl 2,5- diazaspiro[3.4]octane-5-carboxylate.
  • Example 18 (R)-2-(5-(5-(l-(3,5-dichloropyridin-4-yl)ethoxy)-lH- indazol-3-yl)pyridin-2-yl)-8-oxa-2,5-diazaspiro[3.5]nonane was synthesized using 5-[(lR)-l-(3, 5 -dichloro-4-pyridyl)ethoxy ] -3 -(6-fluoro-3 -pyridyl)- 1 -tetrahy dropyran- 2-yl-indazole and tert-butyl 8-oxa-2,5-diazaspiro[3.5]nonane-5-carboxylate.
  • Example 19 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-5-fluoro-3- pyridyl]-5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-lH-indazole was synthesized using 5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-3-(5,6-difluoro-3-pyridyl)-l- tetrahydropyran-2-yl-indazole and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemi-oxylate.
  • Example 20 5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-3-[5- fluoro-6-(l-methylsulfonyl-l,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-lH- indazole.
  • Example 21 (R)-5-(l-(3,5-Dichloropyridin-4-yl)ethoxy)-3-(5-(6-(methylsulfonyl)- 2,6-diazaspiro[3.3]heptan-2-yl)pyrazin-2-yl)-lH-indazole.
  • Step 1 2-(5-Chloropyrazin-2-yl)-6-(methylsulfonyl)-2,6- diazaspiro[3.3]heptane.
  • 2-Methylsulfonyl-2,6-diazaspiro[3.3]heptane dimesylate salt (1.11 g, 3.0 mmol) in acetonitrile (12 mL) was treated with N,N- diisopropylethylamine (4 mL, 23 mmol, 7.6 equiv) and 2,5-dichloropyrazine (0.91 g, 6.1 mmol, 2 equiv) at room temperature. The mixture was then heated at 60 °C for 24 hours.
  • Step 3 5-((R)-l-(3,5-Dichloropyridin-4-yl)ethoxy)-3-(5-(6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrazin-2-yl)-l-(tetrahydro-2H- pyran-2-yl)-lH-indazole.
  • Step 4 (R)-5-(l-(3,5-Dichloropyridin-4-yl)ethoxy)-3-(5-(6- (methylsulfonyl)-2,6-diazaspiro[3 ,3]heptan-2-yl)pyrazin-2-yl)- IH-indazole.
  • Step 1 5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-3-(6-fluoro-3- pyridyl)-l-tetrahydropyran-2-yl-indazole.
  • Step 2 5-((R)-l-(3,5-Dichloropyridin-4-yl)ethoxy)-3-(6-(4- methylpiperazin- 1 -yl)pyridin-3 -yl)- 1 -(tetrahy dro-2H-pyran-2-yl)- 1 H-indazole .
  • Step 3 (R)-5-(l-(3,5-Dichloropyridin-4-yl)ethoxy)-3-(6-(4- methylpiperazin- l-yl)pyridin-3-yl)- IH-indazole.
  • the mixture was purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient of 0 to 100% acetonitrile in water to give a white solid (78 mg, 46% yield).
  • Example 23 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-3-pyridyl]-5-[(lR)-l-(3,5- dichloro-4-pyridyl)ethoxy]-lH-indazole.
  • Step 1 (R)-5-(l-(3,5-Dichloropyridin-4-yl)ethoxy)-3-(6- fluoropyridin-3-yl)-lH-indazole.
  • Step 2 tert-Butyl (R)-6-(5-(5-(l-(3,5-dichloropyridin-4-yl)ethoxy)- lH-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.
  • the reaction mixture was filtered through a syringe filter and the filtrate was pre-absorbed on Celite (5 g).
  • the material was purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge), eluting with a gradient of 0 to 100% acetonitrile in water.
  • the fractions containing product were collected and lyophilized to give a yellowish solid (0.3 g, 71% yield).
  • LCMS m/z 581 (M+H).
  • Step 3 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-3-pyridyl]-5-[(lR)-l- (3,5-dichloro-4-pyridyl)ethoxy]-lH-indazole.
  • the reaction mixture was concentrated under reduced pressure to dryness.
  • the residue was dissolved in methanol (10 mL), treated with MP-carbonate resin (3.2 mmol/g, 1 g), stirred for 30 minutes, filtered, and concentrated under reduced pressure.
  • the residue was absorbed onto Celite (1 g) and purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge), eluting with a gradient of 0 to 100% acetonitrile in water.
  • the fractions containing product were collected and lyophilized to give a white solid (30 mg, 73% yield).
  • Step 4. (R)-5-(l-(3,5-Dichloropyridin-4-yl)ethoxy)-3-(6-(6-methyl- 2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-lH-indazole.
  • Example 24 5-[(lS)-l-(3,5-dichloropyridazin-4-yl)ethoxy]-3-[6-(2- methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-lH-indazole.
  • Step 1 5-[(lS)-l-(3,5-dichloropyridazin-4-yl)ethoxy]-3-iodo-l- tetrahydropyran-2-yl-indazole.
  • Step 2 tert-butyl 6-[5-[5-[(lS)-l-(3,5-dichloropyridazin-4- yl)ethoxy]-l-tetrahydropyran-2-yl-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptane-2-carboxylate.
  • Step 4 5-[(lS)-l-(3,5-dichloropyridazin-4-yl)ethoxy]-3-[6-(2- methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-lH-indazole.
  • Kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove cell debris. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays.
  • Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in lx binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT).
  • Test compounds were prepared as 11 IX stocks in 100% DMSO. Kds were determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions performed in polypropylene 384-well plate. Each was a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20).
  • the beads were then re-suspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 pM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes.
  • elution buffer lx PBS, 0.05% Tween 20, 0.5 pM non-biotinylated affinity ligand
  • Binding constants were calculated with a standard dose-response curve using the Hill equation: [00274] The Hill Slope was set to -1. Curves were fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm.
  • Cell Viability Assay Procedure Cell Titer-Gio® 2.0 Luminescent cell viability assay reagent was purchased from Promega (Madison, WI). Ba/F3 cell lines were cultured in RP MI 1640 media supplemented with 10% fetal bovine serum. Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2 and 95% air.
  • the cells in cell culture plates were incubated with the compounds at 37 °C and 5% CO 2 for 48 hours. Then 50 pl of Cell Titer Gio 2.0 reagent was added to each well of the cell culture plates. The contents were covered from light and mixed on an orbital shaker at room temperature for 10 min. Luminescence was recorded by a Synergy Hl Microplate Reader (Biotek, Winooski, VT ). Cells were assessed as a percentage of DMSO only treated control cells. Curves were plotted and IC 50 values were calculated using the GraphPad Prism 8 program based on a sigmoidal dose-response equation (4 parameter).
  • Luminescent cell viability assay reagent was purchased from Promega (Madison, WI). KG-1, KATO-III, and MDA-MB-453 cell lines were purchased from American Type Culture Collection (Manassas, VA). RT 112/84 cell line was purchased from Millipore-Sigma (St. Louis, MO). HuH7 cells were purchased from Seikisui Xenotech (Kansas City, KS). RT112/84 and MDA-MB- 453 cells were cultured in RPMI1640 media supplemented with 10% fetal bovine serum. KG-1 and KATO-III cell lines were cultured in IMDM media supplemented with 20% FBS. HuH7 cells were cultured in IMDM media supplemented with 10% FBS. Cultures were maintained at 37°C in a humidified atmosphere of 5% CO 2 and 95% air.
  • Cell Viability Assay Procedure Cells were plated in 96-well clear bottom/white plates (Coming #3903) at a range of densities depending on the optimal assay window (5,000-20,000 cells/well in lOOpl of media), incubated overnight. The next day, test compound DMSO stock solutions were made at 10 mM and 2 pM final concentration. Compounds were then added to cells in a 9-dose, 4-fold dilution series starting at 3 pM with an HP 300e Digital Dispenser (each dose was applied in triplicate).
  • DMSO was backfilled to each well up to 301 nL total volume of test compound + DMSO, and a total of 301 nL DMSO was added to a control/no test compound well in triplicate.
  • the cells in cell culture plates were incubated with the compounds at 37 °C and 5% CO 2 for 72 hours- 120 hours depending on the cell line. Then 50 ⁇ l of Cell Titer Gio 2.0 reagent was added to each well of the cell culture plates. The contents were covered from light and mixed on an orbital shaker at room temperature for minimum of 10 min. Luminescence was recorded by a Clariostar Plus Microplate Reader (BMG Labtech, Cary, NC ). Cells were assessed as a percentage of DMSO only treated control cells. Curves were plotted and IC 50 values were calculated using the GraphPad Prism 9 program based on a sigmoidal dose-response equation (log (inhibitor) vs. response - Variable slope, 4-parameter).

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Abstract

L'invention concerne des composés et des méthodes de traitement de maladies et/ou d'états associés à l'inhibition de FGFR.
PCT/US2024/060055 2023-12-15 2024-12-13 Composés indazole pour le traitement du cancer Pending WO2025129014A1 (fr)

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Citations (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3657744A (en) 1970-05-08 1972-04-25 Univ Minnesota Method for fixing prosthetic implants in a living body
US4739762A (en) 1985-11-07 1988-04-26 Expandable Grafts Partnership Expandable intraluminal graft, and method and apparatus for implanting an expandable intraluminal graft
US4992445A (en) 1987-06-12 1991-02-12 American Cyanamid Co. Transdermal delivery of pharmaceuticals
US5001139A (en) 1987-06-12 1991-03-19 American Cyanamid Company Enchancers for the transdermal flux of nivadipine
US5023252A (en) 1985-12-04 1991-06-11 Conrex Pharmaceutical Corporation Transdermal and trans-membrane delivery of drugs
US5040548A (en) 1989-06-01 1991-08-20 Yock Paul G Angioplasty mehtod
US5061273A (en) 1989-06-01 1991-10-29 Yock Paul G Angioplasty apparatus facilitating rapid exchanges
US5195984A (en) 1988-10-04 1993-03-23 Expandable Grafts Partnership Expandable intraluminal graft
US5292331A (en) 1989-08-24 1994-03-08 Applied Vascular Engineering, Inc. Endovascular support device
US5451233A (en) 1986-04-15 1995-09-19 Yock; Paul G. Angioplasty apparatus facilitating rapid exchanges
US5496346A (en) 1987-01-06 1996-03-05 Advanced Cardiovascular Systems, Inc. Reinforced balloon dilatation catheter with slitted exchange sleeve and method
US5674278A (en) 1989-08-24 1997-10-07 Arterial Vascular Engineering, Inc. Endovascular support device
US6344053B1 (en) 1993-12-22 2002-02-05 Medtronic Ave, Inc. Endovascular support device and method
US20110008347A1 (en) 2006-12-01 2011-01-13 Agency For Science ,Technology And Research Cancer-related protein kinases
US20130009621A1 (en) 2011-07-07 2013-01-10 Silergy Semiconductor Technology (Hangzhou) Ltd Low offset, fast response voltage controlled current source and controlling method thereof
WO2014071419A2 (fr) 2012-11-05 2014-05-08 Foundation Medicine, Inc. Nouvelles molécules de fusion et leurs utilisations
WO2015099127A1 (fr) 2013-12-27 2015-07-02 中外製薬株式会社 Gène mutant de fgfr gardien et médicament ciblant celui-ci
WO2015120094A2 (fr) 2014-02-04 2015-08-13 Mayo Foundation For Medical Education And Research Procédé d'identification de réarrangements des récepteurs à activité tyrosine kinase chez des patients
WO2015150900A2 (fr) 2014-03-31 2015-10-08 Debiopharm International Sa Fusions de fgfr
CN102741256B (zh) 2010-01-29 2015-12-02 韩美药品株式会社 对于蛋白激酶具有抑制活性的双环杂芳基衍生物
US20150366866A1 (en) 2013-01-18 2015-12-24 Foundation Medicine, Inc. Methods of treating cholangiocarcinoma
US9254288B2 (en) 2012-05-07 2016-02-09 The Translational Genomics Research Institute Susceptibility of tumors to tyrosine kinase inhibitors and treatment thereof
US9267176B2 (en) 2011-08-05 2016-02-23 Astellas Pharma Inc. Method for detecting novel FGFR4 mutant
JP5868992B2 (ja) 2010-11-29 2016-02-24 アステックス、セラピューティックス、リミテッドＡｓｔｅｘ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｉｍｉｔｅｄ 癌疾患の治療のためのｆｇｆｒキナーゼ阻害剤としての置換ベンゾピラジン誘導体
WO2016030509A1 (fr) 2014-08-28 2016-03-03 Oncoethix Gmbh Méthodes de traitement de la leucémie myéloïde aiguë, ou de la leucémie lymphoïde aiguë à l'aide de compositions pharmaceutiques contenant des composés de thiénotriazolodiazépine
EP2203449B1 (fr) 2007-10-12 2016-04-27 Astex Therapeutics Limited Composés hétérocycliques bicycliques utilisés comme inhibiteurs de la protéine tyrosine kinase
EP3023101A1 (fr) 2013-07-18 2016-05-25 Taiho Pharmaceutical Co., Ltd. Agent thérapeutique pour un cancer résistant à un inhibiteur de fgfr
WO2016084883A1 (fr) 2014-11-26 2016-06-02 国立研究開発法人国立がん研究センター Nouveau gène de fusion cible thérapeutique dans le cancer des voies biliaires
AU2014362227A1 (en) 2013-12-11 2016-06-23 Accuragen Holdings Limited Compositions and methods for detecting rare sequence variants
WO2016105503A1 (fr) 2014-12-24 2016-06-30 Genentech, Inc. Méthodes de traitement, de diagnostic et de pronostic du cancer de la vessie
US20160215350A1 (en) 2013-09-09 2016-07-28 Nantomics, Llc Proteomics Analysis and Discovery through DNA and RNA Sequencing, Systems and Methods
US20160235744A1 (en) 2011-10-28 2016-08-18 Astex Therapeutics Limited SUBSTITUTED PYRIDO[2,3-b]PYRAZINES AS FGFR KINASE INHIBITORS
WO2016139227A1 (fr) 2015-03-03 2016-09-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonistes de fgfr3
US9447098B2 (en) 2012-05-30 2016-09-20 Astex Therapeutics Ltd Pteridines as FGFR inhibitors
WO2022147246A1 (fr) * 2020-12-30 2022-07-07 Tyra Biosciences, Inc. Composés d'indazole utilisés en tant qu'inhibiteurs de kinase
WO2024006897A1 (fr) * 2022-06-29 2024-01-04 Tyra Biosciences, Inc. Composés d'indazole
WO2024050396A1 (fr) * 2022-08-30 2024-03-07 Tyra Biosciences, Inc. Méthodes de traitement de tumeurs solides présentant des altérations activatrices du gène fgfr3

Patent Citations (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3657744A (en) 1970-05-08 1972-04-25 Univ Minnesota Method for fixing prosthetic implants in a living body
US4739762A (en) 1985-11-07 1988-04-26 Expandable Grafts Partnership Expandable intraluminal graft, and method and apparatus for implanting an expandable intraluminal graft
US4739762B1 (en) 1985-11-07 1998-10-27 Expandable Grafts Partnership Expandable intraluminal graft and method and apparatus for implanting an expandable intraluminal graft
US5023252A (en) 1985-12-04 1991-06-11 Conrex Pharmaceutical Corporation Transdermal and trans-membrane delivery of drugs
US5451233A (en) 1986-04-15 1995-09-19 Yock; Paul G. Angioplasty apparatus facilitating rapid exchanges
US5496346A (en) 1987-01-06 1996-03-05 Advanced Cardiovascular Systems, Inc. Reinforced balloon dilatation catheter with slitted exchange sleeve and method
US5001139A (en) 1987-06-12 1991-03-19 American Cyanamid Company Enchancers for the transdermal flux of nivadipine
US4992445A (en) 1987-06-12 1991-02-12 American Cyanamid Co. Transdermal delivery of pharmaceuticals
US5195984A (en) 1988-10-04 1993-03-23 Expandable Grafts Partnership Expandable intraluminal graft
US5040548A (en) 1989-06-01 1991-08-20 Yock Paul G Angioplasty mehtod
US5061273A (en) 1989-06-01 1991-10-29 Yock Paul G Angioplasty apparatus facilitating rapid exchanges
US5292331A (en) 1989-08-24 1994-03-08 Applied Vascular Engineering, Inc. Endovascular support device
US5674278A (en) 1989-08-24 1997-10-07 Arterial Vascular Engineering, Inc. Endovascular support device
US5879382A (en) 1989-08-24 1999-03-09 Boneau; Michael D. Endovascular support device and method
US6344053B1 (en) 1993-12-22 2002-02-05 Medtronic Ave, Inc. Endovascular support device and method
US20110008347A1 (en) 2006-12-01 2011-01-13 Agency For Science ,Technology And Research Cancer-related protein kinases
EP2203449B1 (fr) 2007-10-12 2016-04-27 Astex Therapeutics Limited Composés hétérocycliques bicycliques utilisés comme inhibiteurs de la protéine tyrosine kinase
CN102741256B (zh) 2010-01-29 2015-12-02 韩美药品株式会社 对于蛋白激酶具有抑制活性的双环杂芳基衍生物
JP5868992B2 (ja) 2010-11-29 2016-02-24 アステックス、セラピューティックス、リミテッドＡｓｔｅｘ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｉｍｉｔｅｄ 癌疾患の治療のためのｆｇｆｒキナーゼ阻害剤としての置換ベンゾピラジン誘導体
US20130009621A1 (en) 2011-07-07 2013-01-10 Silergy Semiconductor Technology (Hangzhou) Ltd Low offset, fast response voltage controlled current source and controlling method thereof
US9267176B2 (en) 2011-08-05 2016-02-23 Astellas Pharma Inc. Method for detecting novel FGFR4 mutant
US20160235744A1 (en) 2011-10-28 2016-08-18 Astex Therapeutics Limited SUBSTITUTED PYRIDO[2,3-b]PYRAZINES AS FGFR KINASE INHIBITORS
US9254288B2 (en) 2012-05-07 2016-02-09 The Translational Genomics Research Institute Susceptibility of tumors to tyrosine kinase inhibitors and treatment thereof
US9447098B2 (en) 2012-05-30 2016-09-20 Astex Therapeutics Ltd Pteridines as FGFR inhibitors
WO2014071419A2 (fr) 2012-11-05 2014-05-08 Foundation Medicine, Inc. Nouvelles molécules de fusion et leurs utilisations
US20150366866A1 (en) 2013-01-18 2015-12-24 Foundation Medicine, Inc. Methods of treating cholangiocarcinoma
EP3023101A1 (fr) 2013-07-18 2016-05-25 Taiho Pharmaceutical Co., Ltd. Agent thérapeutique pour un cancer résistant à un inhibiteur de fgfr
US20160215350A1 (en) 2013-09-09 2016-07-28 Nantomics, Llc Proteomics Analysis and Discovery through DNA and RNA Sequencing, Systems and Methods
AU2014362227A1 (en) 2013-12-11 2016-06-23 Accuragen Holdings Limited Compositions and methods for detecting rare sequence variants
WO2015099127A1 (fr) 2013-12-27 2015-07-02 中外製薬株式会社 Gène mutant de fgfr gardien et médicament ciblant celui-ci
WO2015120094A2 (fr) 2014-02-04 2015-08-13 Mayo Foundation For Medical Education And Research Procédé d'identification de réarrangements des récepteurs à activité tyrosine kinase chez des patients
WO2015150900A2 (fr) 2014-03-31 2015-10-08 Debiopharm International Sa Fusions de fgfr
WO2016030509A1 (fr) 2014-08-28 2016-03-03 Oncoethix Gmbh Méthodes de traitement de la leucémie myéloïde aiguë, ou de la leucémie lymphoïde aiguë à l'aide de compositions pharmaceutiques contenant des composés de thiénotriazolodiazépine
WO2016084883A1 (fr) 2014-11-26 2016-06-02 国立研究開発法人国立がん研究センター Nouveau gène de fusion cible thérapeutique dans le cancer des voies biliaires
WO2016105503A1 (fr) 2014-12-24 2016-06-30 Genentech, Inc. Méthodes de traitement, de diagnostic et de pronostic du cancer de la vessie
WO2016139227A1 (fr) 2015-03-03 2016-09-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonistes de fgfr3
WO2022147246A1 (fr) * 2020-12-30 2022-07-07 Tyra Biosciences, Inc. Composés d'indazole utilisés en tant qu'inhibiteurs de kinase
WO2024006897A1 (fr) * 2022-06-29 2024-01-04 Tyra Biosciences, Inc. Composés d'indazole
WO2024050396A1 (fr) * 2022-08-30 2024-03-07 Tyra Biosciences, Inc. Méthodes de traitement de tumeurs solides présentant des altérations activatrices du gène fgfr3

Non-Patent Citations (128)

* Cited by examiner, † Cited by third party
Title
"Handbook of Clinical Drug Data", 2002, MCGRAW-HILL
"Principles of Drug Action", 1990, CHURCHILL LIVINGSTON
ANG ET AL., DIAGN. MOL. PATHOL., 24 February 2014 (2014-02-24)
ASTSATUROV ET AL.: "Annual Meeting of the American Society of Clinical Oncology, Chicago, IL", JOURNAL OF CLINICAL ONCOLOGY, vol. 34, no. 11012, 2016
BABINATURNER, NAT REV CANCER, vol. 17, no. 5, 2017, pages 318 - 332
BARNETT ET AL., HUM. MUTAT., vol. 37, no. 9, 2016, pages 955 - 63
BAROY2016 ET AL., PLOS ONE, vol. 11, no. 9, pages e0163859
BASTURK ET AL., MOD PATHOL, vol. 30, no. 12, 2017, pages 1760 - 1772
BELLUS ET AL., AM. J. MED. GENET., vol. 85, no. 1, 1999, pages 53 - 65
BENNETT ET AL., AM. J. HUM. GENET., vol. 98, no. 3, 2016, pages 579 - 87
BUNNEY ET AL., EBIOMEDICINE, vol. 2, no. 3, 2015, pages 194 - 204
BUSSE ET AL., GENES CHROMOSOMES CANCER, vol. 56, no. 10, 2017, pages 730 - 749
BYRON ET AL., NEOPLASIA, vol. 15, no. 8, 2013, pages 975 - 88
CAZIER ET AL., NAT. COMMUN., vol. 5, 2014, pages 3756
CHA ET AL., MOLONEAL, vol. 12, no. 7, 2018, pages 993 - 1003
CHAKRABARTY ET AL., BR J CANCE, vol. 117, no. 1, 2017, pages 136 - 143
CHANDRANI ET AL., ANN ONEAL, vol. 28, no. 3, 2017, pages 597 - 603
CHELL ET AL., ONCOGENE, vol. 32, no. 25, 2013, pages 3059 - 70
CHELLAIAH ET AL., J. BIOL. CHEM., vol. 269, 1994, pages 11620 - 11627
CHEON ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 91, 1994, pages 989 - 993
CHESI ET AL.: "Note that the deletion of FGFR3 isoform Ille residues 795-808 also deletes the stop codon, elongating the protein by 99 amino acids", BLOOD, vol. 97, no. 3, 2001, pages 729 - 736
DALIN ET AL., NAT COMMUN, vol. 8, no. 1, 2017, pages 1197
DAVIES ET AL., J. CANCER RES., vol. 65, 2005, pages 7591
DE MATTOS-ARRUDA ET AL., ONCOTARGET, vol. 9, no. 29, 2018, pages 20617 - 20630
DIAS ET AL., EXP. MOL. PATHOL., vol. 101, no. 1, 2016, pages 116 - 23
DODE ET AL., NAT GENET, vol. 33, no. 4, 2003, pages 463 - 465
EEVA-MARIA LAITINEN ET AL., PLOS ONE, vol. 7, no. 6, 2012, pages e39450
FERGUSON ET AL., J NEUROPATHO/ EXP NEURAL, vol. 77, no. 6, 2018, pages 437 - 442
FERNANDES ET AL., AM. J. MED. GENET. A., vol. 170, no. 6, 2016, pages 1532 - 7
GALLO ET AL., CYTOKINE GROWTH FACTOR REV., vol. 26, 2015, pages 425
GALLO ET AL., CYTOKINE GROWTH FACTOR, vol. 26, 2015, pages 425 - 449
GE ET AL., AM J CANCER RES., vol. 7, no. 7, 2017, pages 1540 - 1553
GEELVINK ET AL., INTJ MOLSCI., vol. 19*, no. 9, 2018, pages 2548
GONCALVES, FERTIL. STERIL., vol. 104, no. 5, 2015, pages 1261 - 7
GONZALEZ-DEL ANGEL ET AL., AM J MED GENET A, vol. 176, no. 1, 2018, pages 161 - 166
GOYAL ET AL., CANCER DISCOV, vol. 7, no. 3, 2017, pages 252 - 263
GRAND ET AL., GENES CHROMOSOMES CANCER, vol. 40, no. 1, 2004, pages 78 - 83
GREENMAN ET AL., NATURE, vol. 446, no. 7132, 2007, pages 153 - 158
GUYARD ET AL., RESPIR RES, vol. 18, no. 1, 2018, pages 120
HALL ET AL., MOLECULAR CANCER THERAPEUTICS,, vol. 14, no. 12, 2015
HALL ET AL., PLOS ONE, vol. 11, no. 9, 2016, pages e1062594
HART ET AL., ONCOGENE, vol. 19, no. 29, 2000, pages 3309 - 3320
HASEGAWA ET AL., AM. J. MED. GENET. A, vol. 170A, no. 7, 2016, pages 1908 - 11
HAUGH ET AL., J INVEST DERMATOL, vol. 138, no. 2, 2018, pages 384 - 393
HELSTEN ET AL., CLIN CANCER RES, vol. 22, no. 1, 2016, pages 259 - 267
HOANG ET AL., SCI TRANSLMED.,, vol. 5, no. 197, pages 197ra10
IKEDA ET AL., ONCOLOGIST, vol. 23, no. 5, 2018, pages 586 - 593
JIAO ET AL., NAT GENET, vol. 45, no. 12, 2013, pages 1470 - 1473
JOHNSON ET AL., ADV. CANCER RES., vol. 60, 1993, pages 1 - 40
JOHNSON ET AL., MOL. CELL. BIOL., vol. 11, 1995, pages 4627 - 4634
JOHNSON ET AL., ONCOLOGIST, vol. 22, no. 12, 2017, pages 1478 - 1490
JUSAKUL ET AL., CANCER DISCOV., vol. 7, no. 10, 2017, pages 1116 - 1135
KANT ET AL., EUROJOURN ENDOCRINOL, vol. 172, no. 6, 2015, pages 763 - 770
KARADIMAS ET AL., PRENAT DIAGN, vol. 26, no. 3, 2006, pages 258 - 261
KAS ET AL., CANCER RES, vol. 78, no. 19, 2018, pages 5668 - 5679
KASAIAN ET AL., BMC CANCER.,, vol. 15, 2015, pages 984
KELLEHER ET AL., CARCINOGENESIS, vol. 34, 2013, pages 2198
KIM ET AL., ANN ONEAL., vol. 28, no. 6, pages 1250 - 1259
KIM ET AL., BMC UROL, vol. 18, 2018, pages 68
KRSTEVSKA-KONSTANTINOVA ET AL., MED. ARCH., vol. 70, no. 2, 2016, pages 148 - 50
KUENTZ ET AL., BR. J. DERMATOL, 2016
KUMAR ET AL., AM J CLIN PATHOL., vol. 143, no. 5, 2015, pages 738 - 748
LAJEUNIE ET AL., EURJ HUM GENET, vol. 14, no. 3, 2006, pages 289 - 298
LBRAHIMI ET AL., HUM MOLGENET, vol. 13, no. 19, 2004, pages 2313 - 2324
LCHIYAMA ET AL., J. EUR. ACAD. DERMATOL. VENEREAL., vol. 30, no. 3, 2016, pages 442 - 5
LEE ET AL., EXP THER MED., vol. 16, no. 2, 2018, pages 1343 - 1349
LEGEAI-MALLET, ENDOCR. DEV, vol. 30, 2016, pages 98 - 105
LEIDENG, INT J BIOL SCI, vol. 13, no. 9, 2017, pages 1163 - 1171
LI ET AL., HUM. PATHOL., vol. 55, 2016, pages 143 - 50
LIAO ET AL., CANCER RES., vol. 73, 2013, pages 5195 - 5205
LIN ET AL., MOL. MED. REP., vol. 14, no. 3, 2016, pages 1941 - 6
LIU ET AL., GENET. MOL. RES., vol. 13, 2014, pages 1109
LO IACONO ET AL., ONCOTARGET., vol. 7, no. 12, 2016, pages 14394 - 404
MARCHWICKA ET AL., CELL BIOSCI, vol. 6, 2016, pages 7
MARTINCORENA ET AL., SCIENCE, vol. 348, 2015, pages 880
MAZEN ET AL., SEX DEV., vol. 10, no. 1, 2016, pages 16 - 22
MIKI ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 89, 1992, pages 246 - 250
MILLER ET AL., JOURNAL OF CLINICAL ONCOLOGY, vol. 34, 2016
MOEINI ET AL., CLIN. CANCER. RES., vol. 22, no. 2, 2016, pages 291 - 300
NAGAHARA ET AL., CLIN. PEDIATR. ENDOCRINOL., vol. 25, no. 3, 2016, pages 103 - 106
NGUYEN ET AL., MOLECULAR CANCER THERAPEUTICS, vol. 14, no. 12, 2015
OLIVEIRA ET AL., J EXP CLIN CANCER RES, vol. 37, no. 1, 2018, pages 84
PAIK ET AL., CLIN CANCER RES., vol. 23, no. 18, 2017, pages 5366 - 5373
PAPDOPOULOS ET AL., BR J CANCER,, vol. 1117, no. 11, 2017, pages 1592 - 1599
PEKMEZCI ET AL., ACTA NUROTAPHOL. COMMUN, vol. 6, no. 1, pages 47
PEKMEZCI ET AL., CTA NUROTAPHOL. COMMUN., vol. 6, no. 1, pages 47
PELAEZ-GARDA ET AL., PLOS ONE, vol. 8, no. 5, 2013, pages e63695
PREMOV ET AL., ONCOGENE, vol. 36, no. 22, 2017, pages 3168 - 3177
REARDON ET AL., NATURE GENET., vol. 8, 1994, pages 275 - 279
REESER ET AL., J MOL DIAGN, vol. 19, no. 5, 2017, pages 682 - 696
REN ET AL., INT. J. CANCER, vol. 139, no. 4, 2016, pages 836 - 40
REUTHER ET AL.: "bstract Number: ST02, 2015 Annual Meeting of the Association for Molecular Pathology, Austin, TX", JOURNAL OF MOLECULAR DIAGNOSTICS, vol. 17, no. 6, pages 813
RIVERA ET AL., ACTA. NEUROPATHOL., vol. 131, no. 6, 2016, pages 847 - 63
RON ET AL., AM. J. CASE REP, vol. 15, no. 17, 2016, pages 254 - 8
ROSSEAU ET AL., NATURE, vol. 371, 1994, pages 252 - 254
ROY ET AL., MOD PATHOL., vol. 30, no. 8, 2017, pages 1133 - 1143
RYLAND ET AL., J CLIN PATHOL., 14 May 2018 (2018-05-14)
RYLAND ET AL., J CLIN PATHOLPI
SARABIPOUR ET AL., J. MOL. BIOL., vol. 428, no. 20, 2016, pages 3903 - 3910
SCHROCK ET AL., J THORAC. ONEAL, vol. 1556-0864, no. 18, 2018, pages 30674 - 9
SHI ET AL., J TRANSLMED, vol. 14, no. 1, 2016, pages 339
SHIANG ET AL., CELL, vol. 76, 1994, pages 335 - 342
SHIBATA ET AL., CANCER SCI, vol. 109, no. 5, 2018, pages 1282 - 1291
SHIMADA ET AL., ONCOTARGET, vol. 8, no. 55, 2017, pages 93567 - 93579
STONE ET AL., ACTA NEUROPATHOL, vol. 135, no. 1, 2017, pages 115 - 129
SULLIVAN ET AL., JOURNAL OF CLINICAL ONCOLOGY,, vol. 34
TAKAGI, AM, J. MED. GENET. A, vol. 167A, no. ll, 2015, pages 2851 - 4
TANIZAKI ET AL., CANCER RES., vol. 75, no. 15, pages 3149 - 3146
TAURIN ET AL., INTL GYNECOL CANCER, vol. 28, no. 1, 2018, pages 152 - 160
TAVORMINA ET AL., NATURE GENET., vol. 10, 1995, pages 165 - 172
TAYLAN ET AL., J ALLERGY CLIN IMMUNOL, vol. 136, no. 2, 2015, pages 507 - 9
THUSSBAS ET AL., J. CLIN. ONEAL., vol. 24, no. 23, 2006, pages 3747 - 55
TRARBACH ET AL., J CLIN ENDOCRINOL METAB, vol. 91, no. 10, 2006, pages 4006 - 4012
TRUDEL ET AL., BLOOD, vol. 107, 2006, pages 4039
TURNERGROSE, NAT. REV. CANCER, vol. 10, no. 2, 2010, pages 116 - 129
VAKIL ET AL.: "Abstract Number: LG-64, 17th International Symposium on Pediatric Neuro-Oncology, Liverpool, United Kingdom", NEURO-ONCOLOGY, vol. 18, 2016, pages 93
WANG, CANCER, vol. 123, no. 20, 2017, pages 3916 - 3924
WELANDER ET AL., WORLD J SURG, vol. 42, no. 2, 2018, pages 482 - 489
WILKIE ET AL., CURR. BIOL., vol. 5, 1995, pages 500 - 507
WU ET AL., BMC CANCER, vol. 18, no. 1, 2018, pages 343
YANG ET AL., AM J HUM GENET, vol. 98, no. 5, 2016, pages 843 - 856
YANG ET AL., EBIOMEDICINE, no. 18, pages 2352 - 3964
YE ET AL., PLAST. RECONSTR. SURG., vol. 137, no. 3, 2016, pages 952 - 61
YONG-XING ET AL., HUM. MOL. GENET., vol. 9, no. 13, 2000, pages 2001 - 2008
YOZA ET AL., GENES CELLS., vol. 10, 2016, pages 1049 - 1058
YOZA ET AL., GENES CELLS.,, no. 10, 2016, pages 1049 - 1058
ZHAO ET AL., INT. J. CLIN. EXP. MED., vol. 8, no. 10, 2015, pages 19241 - 9
ZIMMER ET AL., J. BIOL. CHEM., vol. 268, 1993, pages 7899 - 7903

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