WO2017145050A1 - Dérivé de pyridylpyridone utile comme inhibiteur de la kinase ret dans le traitement du sci et du cancer - Google Patents

Dérivé de pyridylpyridone utile comme inhibiteur de la kinase ret dans le traitement du sci et du cancer Download PDF

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Publication number
WO2017145050A1
WO2017145050A1 PCT/IB2017/050981 IB2017050981W WO2017145050A1 WO 2017145050 A1 WO2017145050 A1 WO 2017145050A1 IB 2017050981 W IB2017050981 W IB 2017050981W WO 2017145050 A1 WO2017145050 A1 WO 2017145050A1
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cancer
compound
functional
pharmaceutically acceptable
treatment
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PCT/IB2017/050981
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English (en)
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Michael P. Demartino
Huiping Amy Guan
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Glaxosmithkline Intellectual Property Development Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • RET Transfection
  • IBS irritable bowel syndrome
  • IBS irritable bowel syndrome
  • functional bloating functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity
  • IBS Irritable bowel syndrome
  • IBS does not directly alter life expectancy it has a considerable effect on a patient's quality of life. Moreover there is a significant financial cost for IBS associated healthcare and lost productivity due to worker absenteeism (Nellesen, D., et al., J. Manag. Care Pharm., 2013, 19:755- 764).
  • One of the most important symptoms that greatly affect an IBS patient's quality of life is visceral pain (Spiegel, B., et al., Am. J. Gastroenterol., 2008, 103 :2536-2543).
  • Molecular strategies that inhibit IBS associated visceral pain would greatly influence the IBS patient's quality of life and reduce associated costs.
  • RET Rearranged during transfection
  • GDNF neurotrophic factor
  • neurturin neurotrophic factor
  • artemin neurotrophic factor
  • persephin neurotrophic factor family receptor alpha-1, 2, 3, and 4 respectively
  • RET kinase knock-out mice lack enteric neurons and have other nervous system anomalies suggesting that a functional RET kinase protein product is required during development (Taraviras, S. et al., Development, 1999, 126:2785-2797). Moreover population studies of patients with Hirschsprung's disease characterized by colonic obstruction due to lack of normal colonic enervation have a higher proportion of both familial and sporadic loss of function RET mutations (Butler Tjaden N., et al., Transl. Res., 2013, 162: 1-15).
  • MEN 2A and 2B multiple endocrine neoplasia
  • FMTC familial medullary thyroid carcinoma
  • PTC papillary thyroid carcinoma
  • HSCR Hirschsprung's disease
  • MEN 2B is caused by a Met918Thr mutation in RET which changes the tyrosine kinase specificity.
  • MEN 2B is similar to MEN 2A, but lacks the parathyroid hyperplasia and also leads to development of numerous mucosal ganglia of the lips, tongue, and intestinal tract.
  • RET PTC constitutively activated chimeric forms of the receptor
  • This invention relates to 2-(4'-ethoxy-6-methyl-6'-oxo-r,6'-dihydro-[2,3'-bipyridin]-5-yl)- A i -(4-((4-ethylpiperazin-l-yl)methyl)-2-fluoro-5-(trifluoromethyl)phenyl)acetamide, represented by Formula (I):
  • This invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • This invention also relates to a method of treating irritable bowel syndrome comprising administering to a human in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating cancer comprising administering to a human in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.
  • This invention also relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases mediated by RET.
  • This invention also relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of irritable bowel syndrome.
  • This invention also relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
  • This invention also relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diseases mediated by RET.
  • This invention also relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of irritable bowel syndrome.
  • This invention also relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
  • This invention relates to a compound of Formula (I), or pharmaceutically acceptable salts thereof as defined above.
  • This invention also relates to a compound of Formula (I), or pharmaceutically acceptable salts thereof, for use in therapy, in particular, for use in therapy wherein the subject is a human.
  • diseases mediated by RET irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney
  • IBS irritable
  • this invention relates to a compound of Formula (I), or pharmaceutically acceptable salts thereof, for use in the treatment of irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, cancer of the esophagus and gastro
  • This invention also relates to a compound of Formula (I), or pharmaceutically acceptable salts thereof, for use as a medicament.
  • the invention relates to the use of a compound of Formula (I), or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of diseases mediated by RET.
  • This invention also relates to a compound of Formula (I), or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of irritable bowel syndrome.
  • This invention also relates to a compound of Formula (I), or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of cancer.
  • This invention also relates to the use of a compound of Formula (I), or pharmaceutically acceptable salts thereof, in therapy.
  • the invention further includes the use of a compound of Formula (I), or pharmaceutically acceptable salts thereof, as an active therapeutic substance, in particular in the treatment of diseases mediated by RET.
  • This invention also relates to the use of a compound of Formula (I), or pharmaceutically acceptable salts thereof, for the treatment of irritable bowel syndrome.
  • This invention also relates to the use of a compound of Formula (I), or pharmaceutically acceptable salts thereof, for the treatment of cancer.
  • salts of the compound of Formula (I) are preferably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci. (1977) 66, pp 1-19. Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compound of Formula (I).
  • Salts of the disclosed compound may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-1,6- dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, ⁇ -hydroxybutyrates, glycolates, tartrates mandelates, and
  • Pharmaceutically acceptable salt may also be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, A ⁇ '-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2- hydroxy ethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, ⁇ , ⁇ '- bisdehydroabietylamine, glucamine, -methylglucamine, collidine, choline, quinine, quinoline, and basic amino acid such as lysine and arginine.
  • a base which affords a pharmaceutically acceptable
  • salts which are not pharmaceutically acceptable, may be useful in the preparation of the compound of Formula (I) and these should be considered to form a further aspect of the invention.
  • These salts such as trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compound of Formula (I) and its pharmaceutically acceptable salts.
  • a compound of Formula (I) is isolated as a salt
  • the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pK a than the free base form of the compound.
  • the compound of Formula (I) may exist in a crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically acceptable solvates may be formed for crystalline or non-crystalline compounds.
  • solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve nonaqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
  • polymorphs may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs.”
  • the invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformabihty, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • a compound or salt of Formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
  • the compound of Formula (I) is depicted as containing a pyridin-2-one moiety, the corresponding 2-hydroxypyridine tautomer is also included within the scope of the present invention.
  • pro-drugs for the compound of Formula (I) are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31, pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1. It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in “Design of Prodrugs” may be placed on appropriate functionalities when such functionalities are present within the compound of Formula (I).
  • Preferred "pro-moieties" for the compound of Formula (I) include: ester, carbonate ester, hemi-ester, phosphate ester, nitro ester, sulfate ester, sulfoxide, amide, carbamate, azo-, phosphamide, glycoside, ether, acetal, and ketal derivatives of the compound of Formula (I).
  • a compound of Formula (I) as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound.
  • the subject invention also includes isotopically-labelled compounds, which are identical to the compound of Formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the compound of Formula (I) and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2 H, 3 H, n C, 13 C, 14 C, 15 N, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I.
  • the compound of Formula (I) and pharmaceutically acceptable salts of said compound that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention.
  • Isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H or 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • n C and 18 F isotopes are particularly useful in PET (positron emission tomography), and 125 I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically labelled variants of the compound of Formula (I) can generally be prepared by carrying out the procedures disclosed in the Examples below, by substituting a readily available isotopically labelled reagent for a non- isotopically labelled reagent.
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • the invention further provides a pharmaceutical composition (also referred to as pharmaceutical formulation) comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and one or more excipients (also referred to as carriers and/or diluents in the pharmaceutical arts).
  • a pharmaceutical composition also referred to as pharmaceutical formulation
  • excipients are pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) a compound of Formula (I) or a pharmaceutically acceptable salt thereof, with at least one excipient.
  • compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain a therapeutically effective dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • oral including buccal or sublingual
  • rectal nasal
  • topical including buccal, sublingual, or transdermal
  • vaginal or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • parenteral including subcutaneous, intramuscular, intravenous, or intradermal
  • compositions When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules, powders or granules, solutions or suspensions in aqueous or nonaqueous liquids, edible foams or whips, oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the compound or salt thereof of the invention or the pharmaceutical composition of the invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a "quick-dissolve" medicine.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin or non-gelatinous sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be granulated by wetting a binder such as a syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as a syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through a tablet machine, resulting in imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets.
  • the compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different dosages.
  • Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient.
  • Syrups can be prepared by dissolving the compound or salt thereof of the invention in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound or salt of the invention in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.
  • tablets and capsules are preferred for delivery of the pharmaceutical composition.
  • treatment refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject.
  • the present invention provides a method of treatment in a mammal, especially a human, suffering from irritable bowel syndrome (IBS) including diarrhea-predominant, constipation- predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, caner of the esophagus and gastroe
  • Such treatment comprises the step of administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to said mammal, particularly a human.
  • Treatment can also comprise the step of administering a therapeutically effective amount of a pharmaceutical composition containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to said mammal, particularly a human.
  • the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • therapeutically effective amounts of a compound of Formula (I), as well as salts thereof may be administered as the raw chemical.
  • the active ingredient may be presented as a pharmaceutical composition. While it is possible that, for use in therapy, a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, may be administered as the raw chemical, it is typically presented as the active ingredient of a pharmaceutical composition or formulation.
  • a compound or salt thereof of the invention will depend on a number of factors, including, but not limited to, the age and weight of the subject (patient) being treated, the precise disorder requiring treatment and its severity, the nature of the pharmaceutical formulation/composition, and route of administration, and will ultimately be at the discretion of the attending physician or veterinarian.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be given for the treatment in the range of about 0.1 to 100 mg/kg body weight of recipient (patient, mammal) per day and more usually in the range of 0.1 to 10 mg/kg body weight per day.
  • Acceptable daily dosages may be from about 0.1 to about 1000 mg/day, and preferably from about 1 to about 100 mg/day.
  • This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound of Formula (I) per se. Similar dosages should be appropriate for treatment of the other conditions referred herein for treatment. In general, determination of appropriate dosing can be readily arrived at by one skilled in medicine or the pharmacy art.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof may be used alone or in combination with one or more other therapeutic agents. Accordingly the present invention provides a combination comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents. Such combinations may be presented individually (wherein each active is in separate composition) or the actives are presented in a combined composition.
  • Combination therapies according to the invention comprise the administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the use of at least one other treatment method.
  • combination therapies according to the invention comprise the administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and surgical therapy.
  • combination therapies according to the invention comprise the administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and radiotherapy.
  • combination therapies according to the invention comprise the administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one supportive care agent (e.g., at least one anti-emetic agent).
  • combination therapies according to the present invention comprise the administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one other chemotherapeutic agent.
  • the invention comprises the administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one anti-neoplastic agent.
  • the invention comprises a therapeutic regimen where the RET inhibitors of this disclosure are not in and of themselves active or significantly active, but when combined with another therapy, which may or may not be active as a standalone therapy, the combination provides a useful therapeutic outcome.
  • co-administering refers to either simultaneous administration or any manner of separate sequential administration of a RET inhibiting compound, as described herein, and a further active ingredient or ingredients, particularly those known to be useful in the treatment of cancer, including chemotherapy and radiation treatment.
  • further active ingredient or ingredients includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
  • any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of specified cancers in the present invention.
  • examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti- microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; DNA methyltransferase inhibitors such as azacitidine and decitabine; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.
  • any chemotherapeutic agent that has activity against a susceptible neoplasm being treated may be utilized in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, provided that the particular agent is clinically compatible with therapy employing a compound of Formula (I).
  • Typical anti-neoplastic agents useful in the present invention include, but are not limited to: alkylating agents, anti-metabolites, antitumor antibiotics, antimitotic agents, nucleoside analogues, topoisomerase I and II inhibitors, hormones and hormonal analogues; retinoids, histone deacetylase inhibitors; signal transduction pathway inhibitors including inhibitors of cell growth or growth factor function, angiogenesis inhibitors, and serine/threonine or other kinase inhibitors; cyclin dependent kinase inhibitors; antisense therapies and immunotherapeutic agents, including monoclonals, vaccines or other biological agents.
  • Nucleoside analogues are those compounds which are converted to deoxynucleotide triphosphates and incorporated into replicating DNA in place of cytosine. DNA methyltransf erases become covalently bound to the modified bases resulting in an inactive enzyme and reduced DNA methylation.
  • nucleoside analogues include azacitidine and decitabine which are used for the treatment of myelodysplastic disorder.
  • Histone deacetylase (HDAC) inhibitors include vorinostat, for the treatment of cutaneous T-cell lymphoma. HDACs modify chromatin through the deacetylation of histones. In addition, they have a variety of substrates including numerous transcription factors and signaling molecules. Other HDAC inhibitors are in development.
  • Signal transduction pathway inhibitors are those inhibitors which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation or survival.
  • Signal transduction pathway inhibitors useful in the present invention include, but are not limited to, inhibitors of receptor tyrosine kinases, non- receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphatidyl inositol-3-OH kinases, myoinositol signaling, and Ras oncogenes.
  • Signal transduction pathway inhibitors may be employed in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the compositions and methods described above.
  • Receptor kinase angiogenesis inhibitors may also find use in the present invention.
  • Inhibitors of angiogenesis related to VEGFR and TIE-2 are discussed above in regard to signal transduction inhibitors (both are receptor tyrosine kinases).
  • Other inhibitors may be used in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • anti-VEGF antibodies which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alpha v betas) that inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • VEGFR antibody is bevacizumab (AVASTIN ® ).
  • inhibitors of growth factor receptors include ligand antagonists, antibodies, tyrosine kinase inhibitors, anti-sense oligonucleotides and aptamers. Any of these growth factor receptor inhibitors may be employed in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in any of the compositions and methods/uses described herein.
  • Trastuzumab (Herceptin ® ) is an example of an anti-erbB2 antibody inhibitor of growth factor function.
  • an anti-erbB l antibody inhibitor of growth factor function is cetuximab (ErbituxTM, C225).
  • Bevacizumab (Avastin ® ) is an example of a monoclonal antibody directed against VEGFR.
  • small molecule inhibitors of epidermal growth factor receptors include but are not limited to lapatinib (Tykerb ® ) and erlotinib (TARCEVA ® ).
  • Imatinib mesylate (GLEEVEC ® ) is one example of a PDGFR inhibitor.
  • Examples of VEGFR inhibitors include pazopanib (Votrient ® ), ZD6474, AZD2171, PTK787, sunitinib and sorafenib.
  • Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle.
  • anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
  • Diterpenoids which are derived from natural sources, are phase specific anti -cancer agents that operate at the G2 M phases of the cell cycle. It is believed that the diterpenoids stabilize the ⁇ - tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
  • Paclitaxel 5 ,20-epoxy-l,2a,4,7 ,10 ,13a-hexa-hydroxytax-l l-en-9-one 4, 10-diacetate 2- benzoate 13-ester with (2i?,3S)- -benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL ® . It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am.
  • Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann. Int. Med., 111 :273, 1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst, 83 : 1797, 1991.). It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al., Sem. Oncol., 20:56, 1990).
  • the compound also shows potential for the treatment of polycystic kidney disease (Woo et. al., Nature, 368:750. 1994), lung cancer and malaria.
  • Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages, Ignoff, R.J. et. al, Cancer Chemotherapy Pocket Guide ⁇ 1998) related to the duration of dosing above a threshold concentration (50nM) (Kearns, CM. et. al., Seminars in Oncology, 3(6) p.16-23, 1995).
  • Docetaxel (2R,3S)- jV-carboxy-3-phenylisoserine N-tert-butyl ester, 13-ester with 5 ⁇ -20- epoxy-l,2a,4,7 ,10 , 13a-hexahydroxytax-l l-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE ® .
  • Docetaxel is indicated for the treatment of breast cancer.
  • Docetaxel is a semisynthetic derivative of paclitaxel q.v. , prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is neutropenia.
  • Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
  • Vinblastine vincaleukoblastine sulfate
  • VELBAN ® an injectable solution
  • Myelosuppression is the dose limiting side effect of vinblastine.
  • Vincristine vincaleukoblastine, 22-oxo-, sulfate
  • ONCOVIN ® an injectable solution.
  • Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.
  • Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.
  • Vinorelbine 3 ',4'-didehydro-4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3- dihydroxybutanedioate (l :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE ® ), is a semisynthetic vinca alkaloid.
  • Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.
  • Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA.
  • the platinum complexes enter tumor cells, undergo aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor.
  • Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.
  • Cisplatin cis-diamminedichloroplatinum
  • PLATINOL ® an injectable solution.
  • Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer.
  • the primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.
  • Carboplatin platinum, diammine [l,l-cyclobutane-dicarboxylate(2-)-0,0'], is commercially available as PARAPLATIN ® as an injectable solution.
  • Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.
  • Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death.
  • alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
  • Cyclophosphamide 2-[bis(2-chloroethyl)amino]tetrahydro-2H-l,3,2-oxazaphosphorine 2- oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN ® . Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.
  • Melphalan 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN ® .
  • Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.
  • Chlorambucil 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN ® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.
  • Busulfan 1,4-butanediol dimethanesulfonate, is commercially available as MYLERAN ® TABLETS. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.
  • Carmustine, l,3-[bis(2-chloroethyl)-l-nitrosourea, is commercially available as single vials of lyophilized material as BiCNU ® .
  • Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine.
  • dacarbazine 5-(3,3-dimethyl-l-triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome ® .
  • dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.
  • Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death.
  • antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.
  • Dactinomycin also known as Actinomycin D
  • Actinomycin D is commercially available in injectable form as COSMEGEN ® .
  • Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.
  • Daunorubicin (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)- oxy]-7,8,9,10-tetrahydro-6,8, l l-trihydroxy-l-methoxy-5, 12 naphthacenedione hydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME ® or as an injectable as CERUBIDINE ® . Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.
  • Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas.
  • Bleomycin a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE ® .
  • Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.
  • Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.
  • Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
  • Etoposide 4 ' -demethy 1-epipodophy llotoxin 9 [4,6-0-(R)-ethylidene- -D-glucopyranoside] , is commercially available as an injectable solution or capsules as VePESID ® and is commonly known as VP-16. Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leukopenialeukopenia tends to be more severe than thrombocytopenia.
  • Teniposide, 4 ' -demethyl-epipodophy llotoxin 9 [4,6-0-(R)-thenylidene-P-D- glucopyranoside] is commercially available as an injectable solution as VUMON ® and is commonly known as VM-26.
  • Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. Myelosuppression is the most common dose limiting side effect of teniposide.
  • Teniposide can induce both leukopenialeukopenia and thrombocytopenia.
  • Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows.
  • Examples of antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.
  • 5-fluorouracil 5-fluoro-2,4-(lH,3H)pyrimidinedione
  • fluorouracil is commercially available as fluorouracil.
  • Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death.
  • 5-fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are dose limiting side effects of 5-fluorouracil.
  • Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.
  • Cytarabine 4-amino-l- -D-arabinofuranosyl-2 (l f)-pyrimidinone, is commercially available as CYTOSAR-U ® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2',2'-difluorodeoxycytidine (gemcitabine). Cytarabine induces leukopenialeukopenia, thrombocytopenia, and mucositis.
  • Mercaptopurine l,7-dihydro-6H-purine-6-thione monohydrate
  • PURINETHOL ® is commercially available as PURINETHOL ® .
  • Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses.
  • a useful mercaptopurine analog is azathioprine.
  • Thioguanine 2-amino-l,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID ® .
  • Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
  • Myelosuppression including leukopenialeukopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration.
  • gastrointestinal side effects occur and can be dose limiting.
  • Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.
  • Gemcitabine 2'-deoxy-2', 2'-difluorocytidine monohydrochloride ( ⁇ -isomer), is commercially available as GEMZAR ® .
  • Gemcitabine exhibits cell phase specificity at S-phase and by blocking progression of cells through the Gl/S boundary.
  • Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer.
  • Myelosuppression including leukopenialeukopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.
  • Methotrexate A i -[4[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thy midy late.
  • Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder.
  • Myelosuppression leukopenia, thrombocytopenia, and anemia
  • mucositis are expected side effect of methotrexate administration.
  • Camptothecins including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino- methylene)-10,l l-ethylenedioxy-20-camptothecin described below.
  • Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN- 38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum.
  • the dose limiting side effects of irinotecan HC1 are myelosuppression, including neutropenia, and GI effects, including diarrhea.
  • Topotecan HC1 (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-lH- py rano [3 ' ,4 ' ,6,7]indolizino [ 1 ,2-b]quinoline-3 , 14-(4H, 12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN ® .
  • Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule.
  • Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer.
  • the dose limiting side effect of topotecan HC1 is myelosuppression, primarily neutropenia.
  • the mixture was quenched with saturated aq. NH4CI solution (100 niL).
  • the mixture was combined with another crude reaction mixture (performed at a scale of 5 g, 13.3 mmol of 5-bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine using the same reagent and solvent stoichiometry as above) and worked up together.
  • the crude mixture was extracted with EtOAc (200 mL x 2).
  • Step 1 l-Ethyl-4-(5-fluoro-2-(trifluoromethyl)benzyl)piperazine
  • Step 2 l-Ethyl-4-(5-fluoro-4-nit -2-(trifluoromethyl)benzyl)piperazine
  • Example 1 2-(4'-ethoxy-6-methyl-6'-oxo-r,6'- dihydro-[2,3'-bipyridin]-5-yl)-N-(4-((4- ethylpiperazin-l-yl)methyl)-2-fluoro-5-(trifluoromethyl)phenyl)acetamide
  • Step 1 6-bromo-2-methylnicotinaldehyde
  • the reaction mixture was combined with five additional crade reaction mixtures (performed at scales of 30 g, 120 mmol and 4 x 50 g, 199 mmol of 3,6-dibromo-2-methylpyridine using the same reagent and solvent stoichiometry as above) and worked up together.
  • the reaction mixture was extracted with EtOAc (800 mL x 4).
  • the combined organic layers were washed with H 2 0 (300 mL x 3), dried over Na 2 S04, filtered, and concentrated to give 6-bromo-2-methylnicotinaldehyde (260 g, 492 mmol, 42.5% combined yield) as a red oil.
  • reaction mixture was combined with another crude reaction (performed at a scale of 0.20 g, 0.826 mmol of 2-(6-bromo-2-methylpyridin-3-yl)acetic acid using the same reagent and solvent stoichiometry as above) and worked up together.
  • H 2 0 200 mL was added to the residue which was then extracted with DCM MeOH (10: 1, 150 mL x 4).
  • Step 7 2-(4'-ethoxy-6'-((4-methoxybenzyl)oxy)-6-methyl-[2,3'-bipyridin]-5-yl)-N-(4-((4- ethylpiperazin-l-yl)methyl)-2-fluoro-5-(trifluoromethyl)phenyl)acetamide
  • the reaction mixture was combined with another crude reaction (performed at a scale of 0.50 g, 0.649 mmol of 4-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine using the same reagent and solvent stoichiometry as above) and purified together.
  • the crude product was purified by silica column chromatography (10% MeOH : 90% DCM, 120 g silica column).
  • Step 8 2-(4'-ethoxy-6-methyl-6'-oxo-1 ⁇ 6'-dihydro-[2,3'-bipyridin]-5-yl)-N-(4-((4-ethylpiperazin- l-yl)methyl)-2-fluoro-5-(trifluoromethyl)phenyl)acetamide
  • the compound of the present invention was tested for RET kinase inhibitory activity in a RET kinase enzyme assay, a cell-based mechanistic assay and a cell-based proliferation assay.
  • NP 000314.1 was expressed as an N-terminal GST-fusion protein using a baculovirus expression system.
  • GST-RET was purified using glutathione sepharose chromatography.
  • the RET kinase enzymatic assay was performed in a total volume of 10 uL with increasing concentrations of RET kinase inhibitor as a singlet in a 384 well format as follows: RET inhibitor compound plates are prepared by adding 100 nL of RET inhibitor at different concentrations to a 384-well plate.
  • a 2X enzyme mix 50 mM HEPES (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid); 1 mM CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-l-propanesulfonate); 0.1 mg/mL BSA (bovine serum albumin); 1 mM DTT (dithiothreitol); 0.2 nM RET kinase) was added to the 384-well plate and incubated for 30 minutes at 23°C.
  • HEPES 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid
  • CHAPS 3-[(3-cholamidopropyl)dimethylammonio]-l-propanesulfonate
  • BSA bovine serum albumin
  • DTT dithiothreitol
  • a 2X substrate mix 50 mM HEPES; 1 mM CHAPS; 0.1 mg/mL BSA; 20 ⁇ adenosine triphosphate; 20 mM MgCl 2 and 1 ⁇ biotinylated peptide substrate was added and incubated for 1 hour at 23°C.
  • TT cells ATCC CRL-1803
  • a medullary thyroid cancer cell line with constitutively activated RET kinase were maintained in 150 cm 2 dishes in F12 Kaighn's medium, 10% fetal bovine serum, IX Glutamax, IX non-essential amino acids, IX Pen/Strep antibiotics at 37 °C in 5 % carbon dioxide.
  • 1.0E5 TT cells/well were plated in a 96-well cell culture plate and allowed to adhere overnight.
  • TT cells were treated with different concentrations of RET inhibitor compounds for 2 h at 37 °C in 5 % carbon dioxide, washed with ice cold PBS (phosphate buffered saline) and lysed by adding 200 ⁇ . of 25 mM Tris HC1 pH 7.5; 2 mM EDTA; 150 mM NaCl; 1 % sodium deoxycholate; 1 % Triton X-100; 50 mM sodium beta glycerophosphate; 1 mM sodium orthovanadate; IX phosphatase inhibitor cocktail #2 (Sigma #P5726); IX phosphatase inhibitor cocktail #3 (Sigma #P0044) and IX complete mini EDTA free protease inhibitor cocktail (Roche #4693159001), incubation at -80 °C for 10 minutes and thawed on ice.
  • PBS phosphate buffered saline
  • TT cell lysate 100 uL of TT cell lysate was added to a 96-well plate overnight at 4 °C that had been coated overnight at 4 °C with 1: 1,000 dilution of a rabbit anti-RET antibody (Cell Signaling #7032) blocked with IX PBS; 0.05 % Tween-20; 1 % bovine serum albumin. Plates were washed 4X with 200 ⁇ . of IX PBS; 0.05 % Tween-20 and then 100 ⁇ . of a 1: 1,000 dilution of an anti- phosphotyrosine detection antibody (Cell Signaling #7034) was added and incubated for 1 hour at 37 °C. Plates were washed 4X with 200 ⁇ .
  • TT cells ATCC CRL-1803
  • RET kinase a medullary thyroid cancer cell line with constitutively activated RET kinase
  • F12 Kaighn's medium 10% fetal bovine serum
  • IX Glutamax 10% fetal bovine serum
  • IX non-essential amino acids IX Pen/Strep antibiotics at 37 °C in 5 % carbon dioxide.
  • 6.0E3 TT cells/well in 50 ⁇ . of media were added to a 96-well cell culture plate and allowed to adhere overnight.
  • RET inhibitor compounds 50 uL were added to 96-well plate containing cultured TT cells and incubated at at 37 °C in 5 % carbon dioxide for eight days. 50 ⁇ . of CellTiter-Glo (Promega #G-7573) was added, contents mixed for 1 minute on shaker followed by 10 minutes in the dark at 23 °C and the luminescence read by EnVision (PerkinElmer). IC50S were fitted using GraphPad Prism to a sigmoidal dose response.
  • RET kinase inhibitor compounds can be evaluated in an in vivo model of colonic hypersensitivity (Hoffman, J.M., et al., Gastroenterology, 2012, 142:844-854).

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  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau composé qui est un inhibiteur de la kinase réarrangée au cours de la transfection (RET), des compositions pharmaceutiques le contenant, des procédés pour sa préparation, et son utilisation en thérapie, seul ou en combinaison, pour la normalisation de la sensibilité, motilité et/ou sécrétion gastro-intestinale, et/ou pour les maladies ou troubles abdominaux et/ou pour le traitement de maladies associées à un dysfonctionnement de la kinase RET ou de maladies dans lesquelles une modulation de l'activité de la kinase RET peut avoir un avantage thérapeutique tel que, entre autres, sur l'ensemble des classifications du syndrome du côlon irritable (SCI), y compris le SCI à diarrhée prédominante, à constipation prédominante ou à alternance de diarrhée et de constipation, à ballonnements fonctionnels, à constipation fonctionnelle, à diarrhée fonctionnelle, un trouble fonctionnel intestinal non spécifié, un syndrome de douleur abdominale fonctionnelle, une constipation idiopathique chronique, des troubles œsophagiques fonctionnels, des troubles gastroduodénaux fonctionnels, une douleur anorectale fonctionnelle, une maladie intestinale inflammatoire, des maladies prolifératives telles qu'un cancer bronchopulmonaire non à petites cellules, un carcinome hépatocellulaire, un cancer colorectal, un cancer médullaire de la thyroïde, un cancer folliculaire de la thyroïde, un cancer anaplasique de la thyroïde, un cancer papillaire de la thyroïde, des tumeurs cérébrales, un cancer de la cavité péritonéale, des tumeurs solides, d'autres cancers pulmonaires, un cancer de la tête et du cou, des gliomes, des neuroblastomes, le syndrome de Von Hippel-Lindau et des tumeurs du rein, un cancer du sein, un cancer de la trompe de Fallope, un cancer de l'ovaire, un cancer à cellules transitionnelles, un cancer de la prostate, un cancer de l'œsophage et de la jonction gastro-œsophagienne, un cancer des voies biliaires, un adénocarcinome, et toute malignité présentant une activité accrue de la kinase RET. Formule (I)
PCT/IB2017/050981 2016-02-23 2017-02-21 Dérivé de pyridylpyridone utile comme inhibiteur de la kinase ret dans le traitement du sci et du cancer WO2017145050A1 (fr)

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WO2018136663A1 (fr) 2017-01-18 2018-07-26 Array Biopharma, Inc. Inhibiteurs de ret
WO2018136661A1 (fr) 2017-01-18 2018-07-26 Andrews Steven W Composés de pyrazolo[1,5-a]pyrazine substitués utilisés en tant qu'inhibiteurs de la kinase ret
US10112942B2 (en) 2016-10-10 2018-10-30 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10144734B2 (en) 2016-10-10 2018-12-04 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
CN109096264A (zh) * 2018-08-28 2018-12-28 山东理工职业学院 Ret抑制剂及其制备方法、组合物和用途
WO2019075108A1 (fr) 2017-10-10 2019-04-18 Metcalf Andrew T Formes cristallines
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US10966985B2 (en) 2017-03-16 2021-04-06 Array Biopharma Inc. Macrocyclic compounds as ROS1 kinase inhibitors
WO2021135938A1 (fr) 2019-12-31 2021-07-08 南京创济生物医药有限公司 Composé de sulfoximine hétérocyclique et intermédiaire de celui-ci, son procédé de préparation et son application
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US10647730B2 (en) 2010-05-20 2020-05-12 Array Biopharma Inc. Macrocyclic compounds as TRK kinase inhibitors
US10174028B2 (en) 2015-07-16 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10023570B2 (en) 2015-07-16 2018-07-17 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10138243B2 (en) 2015-07-16 2018-11-27 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10174027B2 (en) 2015-07-16 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US11279688B2 (en) 2015-11-02 2022-03-22 Blueprint Medicines Corporation Inhibitors of RET
US10555944B2 (en) 2016-10-10 2020-02-11 Eli Lilly And Company Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US11998545B2 (en) 2016-10-10 2024-06-04 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10172851B2 (en) 2016-10-10 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10144734B2 (en) 2016-10-10 2018-12-04 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10137124B2 (en) 2016-10-10 2018-11-27 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10172845B2 (en) 2016-10-10 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
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US10881652B2 (en) 2016-10-10 2021-01-05 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10112942B2 (en) 2016-10-10 2018-10-30 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US11648243B2 (en) 2016-10-10 2023-05-16 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10441581B2 (en) 2016-10-10 2019-10-15 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US11168090B2 (en) 2017-01-18 2021-11-09 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyrazines as RET kinase inhibitors
WO2018136663A1 (fr) 2017-01-18 2018-07-26 Array Biopharma, Inc. Inhibiteurs de ret
US11851434B2 (en) 2017-01-18 2023-12-26 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyrazine compounds as ret kinase inhibitors
WO2018136661A1 (fr) 2017-01-18 2018-07-26 Andrews Steven W Composés de pyrazolo[1,5-a]pyrazine substitués utilisés en tant qu'inhibiteurs de la kinase ret
US10966985B2 (en) 2017-03-16 2021-04-06 Array Biopharma Inc. Macrocyclic compounds as ROS1 kinase inhibitors
WO2019075114A1 (fr) 2017-10-10 2019-04-18 Mark Reynolds Formulations comprenant du 6-(2-hydroxy-2-méthylpropoxy)-4-(6-(6-((6-méthoxypyridin-3-yl)méthyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
WO2019075108A1 (fr) 2017-10-10 2019-04-18 Metcalf Andrew T Formes cristallines
WO2019143977A1 (fr) 2018-01-18 2019-07-25 Array Biopharma Inc. Composés de pyrrolo[2,3-d]pyrimidines substitués utilisés en tant qu'inhibiteurs de la kinase ret
WO2019143994A1 (fr) 2018-01-18 2019-07-25 Array Biopharma Inc. Composés de pyrazolyl[4,3-c]pyridine substitués utilisés en tant qu'inhibiteurs de la kinase ret
US11472802B2 (en) 2018-01-18 2022-10-18 Array Biopharma Inc. Substituted pyrazolyl[4,3-c]pyridine compounds as RET kinase inhibitors
US11524963B2 (en) 2018-01-18 2022-12-13 Array Biopharma Inc. Substituted pyrazolo[3,4-d]pyrimidines as RET kinase inhibitors
US11603374B2 (en) 2018-01-18 2023-03-14 Array Biopharma Inc. Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors
CN110218182B (zh) * 2018-03-01 2021-01-26 南京亘泰医药技术有限公司 Ido抑制剂
CN110218182A (zh) * 2018-03-01 2019-09-10 南京亘泰医药技术有限公司 Ido抑制剂
US11273160B2 (en) 2018-04-03 2022-03-15 Blueprint Medicines Corporation RET inhibitor for use in treating cancer having a RET alteration
US11963958B2 (en) 2018-04-03 2024-04-23 Rigel Pharmaceuticals, Inc. RET inhibitor for use in treating cancer having a RET alteration
US11872192B2 (en) 2018-04-03 2024-01-16 Blueprint Medicines Corporation RET inhibitor for use in treating cancer having a RET alteration
CN109096264A (zh) * 2018-08-28 2018-12-28 山东理工职业学院 Ret抑制剂及其制备方法、组合物和用途
WO2020055672A1 (fr) 2018-09-10 2020-03-19 Array Biopharma Inc. Composés hétérocycliques condensés comme inhibiteurs de kinases ret
US11964988B2 (en) 2018-09-10 2024-04-23 Array Biopharma Inc. Fused heterocyclic compounds as RET kinase inhibitors
WO2021135938A1 (fr) 2019-12-31 2021-07-08 南京创济生物医药有限公司 Composé de sulfoximine hétérocyclique et intermédiaire de celui-ci, son procédé de préparation et son application
JP7461605B2 (ja) 2020-02-20 2024-04-04 広州白雲山医薬集団股▲フン▼有限公司白雲山制薬総廠 キノリン系化合物
EP4089082A4 (fr) * 2020-02-20 2023-07-19 Guangzhou Baiyunshan Pharmaceutical Holdings Co., Ltd. Baiyunshan Pharmaceutical General Factory Composés de quinoléine
JP2023512546A (ja) * 2020-02-20 2023-03-27 広州白雲山医薬集団股▲フン▼有限公司白雲山制薬総廠 キノリン系化合物
CN115667253A (zh) * 2020-04-27 2023-01-31 伊莱利利公司 可用于抑制ret激酶的化合物
JP2023523315A (ja) * 2020-04-27 2023-06-02 イーライ リリー アンド カンパニー Ｒｅｔキナーゼを阻害するのに有用な化合物
AU2021263541B2 (en) * 2020-04-27 2024-03-07 Eli Lilly And Company Compounds useful for inhibiting RET kinase
US11613533B2 (en) 2020-04-27 2023-03-28 Eli Lilly And Company Compounds useful for inhibiting RET kinase
JP7441972B2 (ja) 2020-04-27 2024-03-01 イーライ リリー アンド カンパニー Ｒｅｔキナーゼを阻害するのに有用な化合物
US11964968B2 (en) 2020-04-27 2024-04-23 Eli Lilly And Company Compounds useful for inhibiting RET kinase
TWI777509B (zh) * 2020-04-27 2022-09-11 美商美國禮來大藥廠 用於抑制ret激酶之化合物
WO2021222017A1 (fr) * 2020-04-27 2021-11-04 Eli Lilly And Company Composés utiles pour inhiber la kinase ret
JP7338072B2 (ja) 2020-11-06 2023-09-04 イーライ リリー アンド カンパニー Ｒｅｔキナーゼ阻害剤としてのピラゾール誘導体
US11697647B2 (en) 2020-11-06 2023-07-11 Eli Lilly And Company RET kinase inhibitors
JP2023504303A (ja) * 2020-11-06 2023-02-02 イーライ リリー アンド カンパニー Ｒｅｔキナーゼ阻害剤としてのピラゾール誘導体
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