WO2021187878A1 - Compound for inhibiting mutagenic trk fusion protein, and pharmaceutical use and manufacturing method thereof - Google Patents

Compound for inhibiting mutagenic trk fusion protein, and pharmaceutical use and manufacturing method thereof Download PDF

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Publication number
WO2021187878A1
WO2021187878A1 PCT/KR2021/003262 KR2021003262W WO2021187878A1 WO 2021187878 A1 WO2021187878 A1 WO 2021187878A1 KR 2021003262 W KR2021003262 W KR 2021003262W WO 2021187878 A1 WO2021187878 A1 WO 2021187878A1
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WIPO (PCT)
Prior art keywords
pyrrolidin
pyrazolo
difluorophenyl
pyrimidin
carbamoyl
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PCT/KR2021/003262
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French (fr)
Korean (ko)
Inventor
유형철
김재선
임지웅
김선주
김형준
김문희
김미선
최지민
이선호
이용협
김성은
전재훈
권영범
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제이투에이치바이오텍 주식회사
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Publication of WO2021187878A1 publication Critical patent/WO2021187878A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • 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
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel compound having a mechanism of inhibiting Neurotrophic Tyrosine Receptor Kinase (NTRK) or a pharmaceutically acceptable salt thereof as a gene-targeted anticancer agent.
  • NTRK Neurotrophic Tyrosine Receptor Kinase
  • the present invention also relates to a pharmaceutical composition for treating solid cancer comprising the compound according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also relates to the pharmaceutical use of the compound according to the present invention or a pharmaceutically acceptable salt thereof for the treatment of solid cancer.
  • the present invention also relates to a process for the preparation of the compounds of the present invention.
  • TRK Tropomyosin Receptor Kinase
  • NTRK1 Neurotrophic Tyrosine Receptor Kinase
  • TrkB Neurotrophic Tyrosine Receptor Kinase
  • Larotrectinib (trade name Vitrakvi) and Entrectinib (trade name Rozlytrek) are inhibitors of TRK activity, and were approved in 2018 for the treatment of adult and pediatric solid cancers with the NTRK fusion gene.
  • Mutant TRK fusion proteins act as oncogenic factors by triggering cell proliferation and survival mechanisms in cancer cell lines. These drugs show efficacy by a mechanism of inhibiting the mutant TRK fusion protein.
  • Larotrectinib (product name: VITRAKVI) is an adenosine triphosphate (ATP) competitive and selective TRK (tropomyosin receptor kinase) inhibitor.
  • the binding affinity of larotrectinib has an IC 50 of 5-11 nM for TrkA, TrkB, and TrkC, and the functional inhibition evaluation result of larotrectinib has an IC 50 of 10-25 nM for TrkA, TrkB, and TrkC.
  • Larotrectinib is formulated as 25 mg and 100 mg hard capsules and 20 mg/mL oral solutions, and is recommended for adult and child solid cancer patients with NTRK fusion.
  • Larottectinib is a sulfate having the structural formula of the following formula (A).
  • Chemical name is (3S)-N- ⁇ 5-[(2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl ⁇ -3-hydroxy-1 -pyrrolidinecarboxamide sulfate, the molecular formula is C 21 H 24 F 2 N 6 O 6 S, and has a molecular weight of 526.51 g/mol (428.44 as a free base).
  • the oral absolute absorption rate of larotrectinib is over 30% in non-clinical animal test species, and the volume of distribution (Vd) is 0.7-2 L/kg, which is moderate in terms of tissue distribution.
  • Vd volume of distribution
  • M14 a compound of the following formula (B), designated as M14, is detected in the blood of humans, rats, and monkeys.
  • Formula B is an in vivo metabolite produced by O-glucuronide after the hydroxypyrrolidine-urea moiety is removed from larotrectinib.
  • Formula B has been identified as a major inactive metabolite in human clinical trials, and has been reported to be detected in both plasma and urine.
  • the figure below shows the results of metabolite analysis after a single oral administration of [ 14 C] Larotrectinib 100 mg ( ⁇ 100 ⁇ Ci) to a healthy male subject.
  • % is the analysis result during excretion, and in the case of Formula B named M14, 9.38% of the dose of larotrectinib administered in urine was confirmed.
  • larotrectinib is mainly metabolized by CYP3A4, and larotrectinib is known as a receptor for CYP3A4, P-gp, and BCRP. Therefore, in clinical administration, special caution is required when co-administering with other CYP3A4 receptors as well as inhibitors or inducers of CYP3A4.
  • larotrectinib is classified as a BCS Class III compound, which means that it has excellent water solubility but relatively low oral absorption.
  • larotrectinib is a very toxic drug, and at the same time is mainly metabolized by CYP3A4, and at the same time as a receptor of CYP3A4, it is a substance with a high risk of co-administration due to drug-drug interaction.
  • the absolute absorption rate in clinical practice is known as 34% (range: 32-37%), and it is recommended to be administered twice a day because it has a short Cmax of 1 hour and a half-life of 3 hours.
  • the problem to be solved by the present disclosure is to provide a compound for inhibiting TRK fusion protein, which has advantages in various aspects as a pharmaceutical ingredient, a pharmaceutical use thereof, and a manufacturing method thereof.
  • Another problem to be solved by the present disclosure is to provide a novel compound in which several disadvantages of larotrectinib are improved, their medicinal use, and a method for preparing such compounds.
  • the present disclosure provides a compound having a structure of any one of Formulas 1 to 3, or a pharmaceutically acceptable salt thereof.
  • the amino acid is a D, L-type amino acid.
  • X is O or S
  • R 1 is H, alkyl, alkyl substituted with one or more halogens, -O-alkyl, -S-alkyl, hydroxy (OH), thiol, amine, ester, carboxylic acid ( COOH), cyano (CN) is branched alkyl, secondary to tertiary amine in which alkyl is introduced as a branched chain, halogen, cyano (CN), cycloalkyl, heterocycle, aryl, or heteroaryl, and n is 0 an integer from to 5.
  • A is , , or ego
  • R 2 is hydrogen, alkyl, alkyl substituted with one or more halogens, -O-alkyl, -S-alkyl, ester, cyano-connected alkyl as a side chain, primary to tertiary amines in which alkyl is introduced as a side chain, car acid (COOH), halogen, cyano (CN), cycloalkyl, heterocycle, aryl, or heteroaryl.
  • esters is -COOR 3 , -CONR 3 R 4 , or -SO 2 OR 3 It means, wherein R 3 and R 4 are each independently hydrogen, alkyl , cycloalkyl, heterocycle, or aryl. Here, preferably, R 3 and R 4 are independently of each other hydrogen or alkyl having 1 to 4 carbon atoms.
  • the present inventors sought to find a novel compound capable of treating various solid cancers having a mutable TRK fusion gene expression protein by supplementing the disadvantages of larotrectinib.
  • the present inventors have identified active prodrug derivatives of larotrectinib that effectively inhibit cell growth in various carcinomas. It was confirmed that it has activity and has the characteristics of a prodrug that is metabolized into larotrectinib in the body, and can exert the effect twice.
  • Larotrectinib has a large effect on absorption of CYP3A4 and P-gp, and metabolism occurs quickly due to the first passage of the liver. There is this.
  • the compounds of the present invention can be an alternative to solve these problems due to the above-mentioned properties.
  • the present inventors intend to provide an active prodrug that maintains the physiological activity of larotrectinib, and such an active prodrug not only serves as a buffer in the metabolism of larotrectinib, but is also an excellent TRK inhibitor. By confirming that the present invention was completed.
  • amino acids are glycine, phenylglycine, leucine, methionine, valine, alanine, isoleucine, proline, tryptophan, tyrosine, phenylalanine, histidine, serine, cysteine, asparagine, threonine, t-leucine , glutamine, glutamic acid, aspartic acid, lysine, arginine, and 3,4-dihydroxyphenylalanine.
  • alkyl refers to a saturated straight or branched chain having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms (when the number of carbon atoms is not particularly limited). means a cyclic hydrocarbon.
  • saturated straight chain alkyls are -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n- contains decyl
  • saturated branched alkyl is -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3- Methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-
  • C 1-4 when described as “C 1-4 ” or “C1 to C6”, this means that the number of carbon atoms is 1 to 6 carbon atoms.
  • C 1-6 alkyl means alkyl having 1 to 6 carbon atoms.
  • halogen and “halo” refer to fluorine, chlorine, bromine or iodine.
  • cycloalkyl refers to a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and no carbon-carbon multiple bonds.
  • cycloalkyl groups include, but are not limited to (C 3 -C 7 )cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl). Cycloalkyl groups may be optionally substituted.
  • the cycloalkyl group is a monocyclic or bicyclic ring (ring).
  • heterocycle means a saturated or unsaturated 5- to 7-membered monocyclic containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 7- to 10-membered bicyclic, heterocyclic ring (ring) wherein nitrogen and sulfur heteroatoms may be optionally oxidized and nitrogen heteroatoms may be optionally quaternized and a bicyclic ring in which some of the heterocycles are fused to a benzene ring.
  • Heterocycles may be attached by heteroatoms or carbon atoms.
  • heterocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, Tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothio contains pyranyl.
  • aryl refers to a carbocyclic aromatic group containing 5 to 10 ring atoms. Representative examples include phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, etc. including, but not limited to. Carbocyclic aromatic groups may be optionally substituted.
  • heteroaryl has at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and includes 5 to 10 carbon atoms including at least one carbon atom, including mono- and bicyclic ring systems. It is an aromatic heterocycle ring of members.
  • heteroaryls include triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl ( benzoxazolyl), imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, tria Zinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanyl, thietanyl and oxazolyl.
  • the compounds represented by Formulas 1 to 3 may be used in the form of salts derived from inorganic acids or organic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, Succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, It may be used in the form of a salt derived from at least one acid selected from the group consisting of benzenesulfonic acid, toluenesulfonic acid, and the like.
  • the term “compound of the present invention” is meant to include compounds of each of the formulas of any one of Formulas 1 to 3, as well as clathrates, hydrates, solvates, or polymorphs thereof. am.
  • the term “compound of the present invention” is meant to include a pharmaceutically acceptable salt of the compound of the present invention unless a pharmaceutically acceptable salt thereof is mentioned.
  • a compound of the invention is a stereoisomerically pure compound (e.g., substantially free of other stereoisomers (e.g., at least 85% ee, at least 90% ee, at least 95% ee, 97% ee or more, or 99% ee or more)). That is, when the compound of Formula 1 or a salt thereof according to the present invention is a tautomeric isomer and/or stereoisomer (eg, geometrical isomer and conformational isomers), their separated isomers and mixtures each are also included within the scope of the compounds of the present invention. When the compound of the present invention or a salt thereof has an asymmetric carbon in its structure, their optically active compounds and racemic mixtures are also included in the scope of the compound of the present invention.
  • stereoisomerically pure compound e.g., substantially free of other stereoisomers (e.g., at least 85% ee, at least 90% ee, at least 95% ee, 97%
  • polymorph refers to a solid crystalline form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical and/or spectral properties. Differences in physical properties include, but are not limited to, stability (eg, thermal or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability).
  • stability eg, thermal or light stability
  • compressibility and density important for formulation and product manufacturing
  • dissolution rate which may affect bioavailability
  • Differences in stability may be due to changes in chemical reactivity (e.g., differential oxidation, such as a faster discoloration when composed of one polymorph than when composed of another polymorph) or mechanical properties (e.g., kinetically Tablet fragments stored as the preferred polymorph are converted to a thermodynamically more stable polymorph) or both (tablets of one polymorph are more susceptible to degradation at high humidity).
  • Other physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form a solvate than another polymorph, for example due to its shape or particle size distribution, or it may be more difficult to filter or wash.
  • solvate refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and can be administered in trace amounts to humans.
  • hydrate refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate refers to a compound of the present invention in the form of a crystal lattice containing spaces (eg, channels) that confine guest molecules (eg, solvent or water). or salts thereof.
  • purified when isolated, means that the isolate is at least 90% pure, in one embodiment at least 95% pure, in another embodiment at least 99% pure, and In another embodiment, it means at least 99.9% pure.
  • Treatment includes eradication, removal, modification, or control of primary, focal or metastatic cancerous tissue; Minimizing or delaying the expansion of cancer.
  • an “effective amount” refers to destroying, modifying, controlling or eliminating primary, local or metastatic cancer cells or cancer tissue; slowing or minimizing the spread of cancer; or an amount of a compound of the invention sufficient to provide a therapeutic benefit in the treatment or management of cancer, neoplastic disease, or tumor.
  • Effective amount also refers to an amount of a compound of the invention sufficient to cause cancer or neoplastic cell death.
  • Effective amount also refers to an amount sufficient to inhibit or reduce a variant TRK fusion protein, either in vitro or in vivo.
  • Non-limiting examples of preferred compounds according to the present invention include the following compounds and pharmaceutically acceptable salts thereof.
  • the present invention provides a (pharmaceutical) composition
  • a (pharmaceutical) composition comprising a therapeutically effective amount of a compound of Formula 1, 2 or 3 or a pharmaceutically acceptable salt thereof according to the present invention, and a pharmaceutically acceptable carrier. do.
  • the present invention provides a therapeutically effective amount of a compound of Formula 1, 2 or 3 according to the present invention, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and other compounds other than the compound of the present invention.
  • an activity selected from the group consisting of anticancer drugs, cytostatic drugs, angiogenesis inhibitors, kinase inhibitors, cytokine blockers and inhibitors of cell adhesion molecules A (pharmaceutical) composition comprising a therapeutically effective amount of an active pharmaceutical ingredient is provided.
  • the present invention relates to a disease or condition comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula 1, 2 or 3 or a pharmaceutically acceptable salt thereof.
  • the disease or condition is a disease or condition that can be ameliorated by inhibition of tropomyosin receptor kinase (TRK).
  • TRK tropomyosin receptor kinase
  • the disease or condition is a disease or condition that can be ameliorated by inhibiting the mutant TRK fusion protein.
  • the disease or condition is a solid cancer.
  • the solid cancer is soft tissue sarcoma, fibrosarcoma, salivary gland cancer, thyroid cancer, lung cancer, melanoma, colon cancer, gastrointestinal stromal tumor, bile duct cancer, cecum cancer, breast cancer or pancreatic cancer.
  • the treatment is a preventative treatment.
  • the treatment is a palliative treatment.
  • the treatment is a restorative treatment.
  • the present invention provides a pharmaceutical use characterized in that the compound of Formula 1, 2 or 3 or a pharmaceutically acceptable salt thereof according to the present invention is used as an active ingredient.
  • the pharmaceutical use of the present invention is the use for the treatment or prophylaxis of a disease or condition described herein.
  • the dosage is as follows.
  • the compounds of the present invention may be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in an effective dosage for the intended treatment.
  • An effective dosage is generally from about 0.001 to about 100 mg/kg body weight/day, preferably from about 0.01 to about 30 mg/kg/day, in single or divided doses. Dosage levels below the lower limit of this range may be suitable depending on the age, species, and disease or condition being treated. In other cases, still larger doses can be used without deleterious side effects. The larger dose may be divided into several smaller doses for administration throughout the day. Methods for determining the appropriate dosage are well known in the art.
  • the compound described herein or a pharmaceutically acceptable salt thereof may be administered as follows.
  • the compound of the present invention may be administered orally, and the oral cavity is a concept including swallowing.
  • oral administration the compounds of the present invention may enter the gastrointestinal tract or may be absorbed directly into the bloodstream from the mouth, for example, by buccal or sublingual administration.
  • compositions for oral administration may be in solid, liquid, gel, or powder form, and may have dosage forms such as tablets, lozenges, capsules, granules, and powders. .
  • compositions for oral administration may optionally be enteric coated and may exhibit delayed or sustained release through the enteric coating. That is, the composition for oral administration according to the present invention may be a formulation having an immediate or modified release pattern.
  • Liquid formulations may include solutions, syrups, and suspensions, and such liquid compositions may be contained in soft or hard capsules.
  • Such formulations may contain a pharmaceutically acceptable carrier, for example, water, ethanol, polyethylene glycol, cellulose, or oil.
  • the formulation may also contain one or more emulsifying and/or suspending agents.
  • the amount of drug as the active ingredient may be present in an amount of from about 0.05% to about 95% by weight relative to the total weight of the tablet, more typically from about 2% to about 50% by weight of the dosage form.
  • Tablets may also contain from about 0.5% to about 35% by weight of a disintegrant, more typically from about 2% to about 25% by weight of the dosage form.
  • the disintegrant include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.
  • Suitable glidants included for the preparation of tablets may be present in an amount of from about 0.1% to about 5% by weight and include talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like. This lubricant may be used, but the present invention is not limited to the types of these additives.
  • Gelatin polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc. may be used as a binder for manufacturing tablets.
  • suitable diluents for manufacturing tablets include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc., but the present invention is not limited to the types of these additives. .
  • the solubilizing agent that may be included in the tablet may be used in an amount of about 0.1% to about 3% by weight relative to the total weight of the tablet, for example, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, Diethylene glycol monoethyl ether, dimethylisosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR TM (Nikkol), oleyl ester, Gelucire TM , caprylic/caprylic acid mono/ Diglyceride, sorbitan fatty acid ester, Solutol HS TM, etc. may be used in the pharmaceutical composition according to the present invention, but the present invention is not limited to the specific type of the solubilizer.
  • the compounds of the present invention may be administered directly into the bloodstream, muscle, or intestine.
  • Suitable methods for parenteral administration include intravenous, intra-muscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial injection, and the like.
  • Suitable devices for parenteral administration include injectors (including needle and needleless syringes) and infusion methods.
  • compositions for parenteral administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
  • liquid compositions are liquid compositions, and the liquid composition is an aqueous solution containing the active ingredient according to the present invention, a salt, a buffer, an isotonic agent, and the like.
  • Parenteral formulations may also be prepared in dried form (eg, lyophilized) or as sterile non-aqueous solutions. These formulations may be used with a suitable vehicle such as sterile water. Solubility-enhancing agents may also be used in the preparation of parenteral solutions.
  • compositions of the present invention may be administered topically dermally or transdermally.
  • Formulations for topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like.
  • Pharmaceutically acceptable carriers for topical dosage forms may include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration may also be performed by electroporation, iontophoresis, phonophoresis, and the like.
  • compositions for topical administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
  • the present invention also provides a step of reacting (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine with 4-nitrobenzyl carbonochloridate, And it provides a method for preparing a compound according to the present invention, comprising the step of reacting the compound of the following formula (4).
  • R 1 is the same as the definition of R 1 in Formula 2 above.
  • the preparation method according to the present invention can prepare the compound according to the present invention with high purity with only very simple steps.
  • novel compound of the present disclosure or a pharmaceutically acceptable salt thereof exhibits excellent effects in the treatment of various solid cancers having a mutable NTRK fusion protein.
  • pharmaceutical composition for the treatment of solid cancer of the present invention comprising the compound or a pharmaceutically acceptable salt thereof provides excellent activity for the treatment of various carcinomas.
  • the starting material (315 mg) was dissolved in 10 ml of dichloromethane, dimethyl amino pyridine (DMAP, 0.1 equivalent) was added, and the temperature was lowered to around 0 °C. After that, 4-nitrobenzyl carbonochloridate (1.02 equivalents) was added and stirred until the starting material completely disappeared. After completion of the reaction, the solvent was removed by distillation under reduced pressure. Then, 10 ml of acetonitrile was added, and (S)-pyrrolidin-3-yl acetate (1.05 equivalent) was added at room temperature, followed by stirring for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and extracted using dichloromethane. Then, it was purified by column chromatography to obtain 327 mg of the target compound as a pale yellow solid.
  • DMAP dimethyl amino pyridine
  • IC 50 values were calculated at concentrations in which each compound inhibited the activity of the target enzyme by 50%, and the results are shown as A, B, C, and D in Table 2 below.
  • A means an IC 50 of 100 nM or less
  • B means an IC 50 greater than 100 and 500 nM or less
  • C means an IC 50 greater than 500 and 1000 nM or less
  • D means an IC 50 greater than 1000 nM.
  • Larotrectinib was used as a control drug.
  • test compound in 10% DMSO
  • Enzymes and substrates were used in the following amounts per well: All enzyme assays were 60 mM HEPES-NaOH (pH 7.5), 3 mM MgCl 2 , 3 mM MnCl 2 , 3 ⁇ M Na-orthovanadate, 1.2 mM DTT, 50 ⁇ g/ml PEG20000, 1 ⁇ M [ 33 P]-ATP (approximately 5 x 1005 cpm per well)
  • reaction mixture was incubated at 30° C. for 80 minutes.
  • the reaction was stopped with 50 ⁇ l of 2% (v/v) H 3 PO 4 , the plate was aspirated and washed twice with 200 ⁇ l H20 or 200 ⁇ l 0.9% (w/v) NaCl.
  • the compounds of the present invention show no inhibitory effect on normal kinase enzymes (ACK1(h)), and three types of target kinase enzymes (TrKA(h), TrKB(h), TrKC(h)) showed a very good inhibitory effect.
  • Larotrectinib and the test substance were each prepared in the same manner and administered to rats at a dose of 0.057 mmol/kg. After blood was collected at a predetermined time, plasma was separated. Analysis of the drug was carried out using HPLC (XBridge column C 18 , Waters, mobile phase 0.1% formic acid:acetonitrile (30:70, %/%)) and MS/MS (ESI positive, MRM 429 -> 342). . Rat donor plasma and each commercial standard solution were mixed at a ratio of 9:1 to prepare and calibrate at concentrations of 1, 5, 10, 50, 100 and 500 ng/ml.
  • the QC sample was prepared at 10, 75 and 250 ng/ml concentrations by mixing rat plasma and QC standard solution in a 9:1 ratio.
  • 100 ⁇ l of the plasma sample was transferred to a centrifuge tube, and 10 ⁇ l of the internal standard solution and 300 ⁇ l of methanol were added and mixed for about 30 seconds.
  • the tube was centrifuged at 3,000 xg (4°C) for about 5 minutes, and the supernatant was transferred to an LC vial and then injected into the instrument.
  • concentration of the active ingredient in rat plasma that is, larotrectinib, was quantified by applying a previously verified assay.
  • test substance Bioavailability (F, %) test substance Bioavailability (F, %) Oral Larotrectinib 34 compound 11 40.3 compound 1 146.5 compound 13 89.0 compound 2 104.0 compound 15 134.7 compound 3 121.0 compound 16 170.5 compound 4 170.7 compound 7 32.3
  • the mean AUC t was 1858 hr*ng/ml
  • the mean AUC i was 1858 hr*ng/ml
  • the mean C max was 1424 ng/ml
  • the mean T max was 0.33 hours
  • the mean t 1/ 2 was 2.40 hours
  • the bioavailability was 121.0%.
  • mean AUC t is 4589 hr*ng/ml
  • mean AUC i is 5043 hr*ng/ml
  • mean C max is 1978 ng/ml
  • mean T max is 0.33 hours
  • mean t 1/2 was 6.67 hours
  • the bioavailability was 170.7%.

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Abstract

The present disclosure provides a novel compound having a mechanism of inhibiting Neurotrophic Tyrosine Receptor Kinase (NTRK) as a gene-targeted anticancer agent, or a pharmaceutically acceptable salt thereof. The present disclosure also provides a pharmaceutical composition for treating solid cancer, comprising, as an active ingredient, the compound or a pharmaceutically acceptable salt thereof according to the present invention. The present disclosure also provides a pharmaceutical use of the compound or a pharmaceutically acceptable salt thereof according to the present invention in treating solid cancer. The present disclosure also provides a simple, efficient method for preparing the compounds of the present invention.

Description

변이성 TRK 융합 단백질 억제용 화합물, 이의 의약 용도 및 제조 방법Compound for inhibiting mutagenic TRK fusion protein, pharmaceutical use thereof and manufacturing method
본 발명은 유전자 표적 항암치료제로서 NTRK (Neurotrophic Tyrosine Receptor Kinase)를 억제하는 기전을 갖는 신규 화합물 또는 이의 약학적으로 허용 가능한 염에 관한 것이다. 본 발명은 또한 본 발명에 따른 화합물 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 포함하는 고형암 치료용 약학 조성물에 관한 것이다. 본 발명은 또한, 본 발명에 따른 화합물 또는 이의 약학적으로 허용 가능한 염의 고형암 치료용 의약 용도에 관한 것이다. 본 발명은 또한 본 발명의 화합물들의 제조 방법에 관한 것이다.The present invention relates to a novel compound having a mechanism of inhibiting Neurotrophic Tyrosine Receptor Kinase (NTRK) or a pharmaceutically acceptable salt thereof as a gene-targeted anticancer agent. The present invention also relates to a pharmaceutical composition for treating solid cancer comprising the compound according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention also relates to the pharmaceutical use of the compound according to the present invention or a pharmaceutically acceptable salt thereof for the treatment of solid cancer. The present invention also relates to a process for the preparation of the compounds of the present invention.
TRK (Tropomyosin Receptor Kinase)는 타이로신 카이네이즈 (Tyrosine Kinase)의 일종으로 척추동물의 신경계 조직에서 주로 발현되는 단백질이다. TRK는 신호 전달 과정을 통해 신경계의 발현, 분화 등에 중요한 역할을 하는 것으로 알려져 있다. NTRK (Neurotrophic Tyrosine Receptor Kinase)로 알려진 3개의 유전자인 NTRK1, NTRK2, NTRK3에 의해 발현되는 단백질들은 각각 TrkA, TrkB, TrkC로 분류되고 있다. NTRK 유전자 융합 (Gene Fusion)은 Tumor DNA-RNA sequencing, Plasma Cell-free DNA 프로파일링 등 다양한 방법에 의해 관찰할 수 있다. NTRK 유전자 3’ 부분과 파트너 유전자의 5’ 부분의 재배열 (rearrangement) 융합에 의해 발생한다. TRK (Tropomyosin Receptor Kinase) is a type of tyrosine kinase and is a protein mainly expressed in the nervous system tissues of vertebrates. TRK is known to play an important role in the expression and differentiation of the nervous system through signal transduction. Proteins expressed by NTRK1, NTRK2, and NTRK3, which are three genes known as Neurotrophic Tyrosine Receptor Kinase (NTRK), are classified as TrkA, TrkB, and TrkC, respectively. NTRK gene fusion can be observed by various methods such as tumor DNA-RNA sequencing and plasma cell-free DNA profiling. It is caused by rearrangement fusion of the 3' part of the NTRK gene and the 5' part of the partner gene.
라로트렉티니브 (Larotrectinib, 상표명 Vitrakvi)과 엔트렉티닙 (Entrectinib, 상표명 Rozlytrek)은 TRK 활성 저해제이며, 상기 NTRK 융합 유전자를 가진 성인 및 소아 고형암 (Solid cancer) 치료를 목적으로 2018년 승인된 약물들이다. 변이성 TRK 융합 단백질은 암세포주에서 세포 증식 및 생존 기전을 촉발하여 발암 인자의 역할을 한다. 상기 약물들은 이러한 변이성 TRK 융합 단백질을 억제하는 기전으로 약효를 나타낸다. NTRK 유전자 융합 성인 및 소아 고형암 환자를 대상으로 한 임상시험 (성인을 대상으로 한 1상 시험, NAVIGATE 2상 시험 및 소아를 대상으로 한 SCOUT 1/2상 시험) 결과 라로트렉티니브는 연부조직육종, 영아 섬유육종, 침샘암, 갑상샘암, 폐암, 흑색종, 결장암, 위장관기질종양, 담관암, 맹장암, 유방암, 췌장암 등 다양한 암종에 대해 객관적 반응율(ORR) 75%와 완전반응율(CR) 22%를 달성했다고 보고되었다.Larotrectinib (trade name Vitrakvi) and Entrectinib (trade name Rozlytrek) are inhibitors of TRK activity, and were approved in 2018 for the treatment of adult and pediatric solid cancers with the NTRK fusion gene. . Mutant TRK fusion proteins act as oncogenic factors by triggering cell proliferation and survival mechanisms in cancer cell lines. These drugs show efficacy by a mechanism of inhibiting the mutant TRK fusion protein. Results of clinical trials in adults and children with NTRK gene fusion solid cancer (Phase 1 in adults, Phase 2 in NAVIGATE, and Phase 1/2 in SCOUT in children) Larotrectinib was used in soft tissue sarcoma , Infantile fibrosarcoma, salivary gland cancer, thyroid cancer, lung cancer, melanoma, colon cancer, gastrointestinal stromal tumor, bile duct cancer, appendic cancer, breast cancer, pancreatic cancer, etc. objective response rate (ORR) 75% and complete response rate (CR) 22% reported to have been achieved.
라로트렉티니브(제품명: VITRAKVI)는 adenosine triphosphate (ATP) competitive and selective TRK (tropomyosin receptor kinase) inhibitor이다. 라로트렉티니브의 binding affinity는 TrkA, TrkB, TrkC에 대해 5~11 nM의 IC 50 이며, 라로트렉티니브는 functional inhibition 평가 결과는 TrkA, TrkB, TrkC에 대해 10~25 nM의 IC 50를 갖는다고 알려져 있다. 라로트렉티니브는 25 mg과 100 mg의 경질캡슐 및 20 mg/mL의 경구용 솔루션 제품으로 제형화가 되어 있으며, NTRK 융합을 보이는 성인 및 어린이 고형암 환자에게 투여가 권장된다.Larotrectinib (product name: VITRAKVI) is an adenosine triphosphate (ATP) competitive and selective TRK (tropomyosin receptor kinase) inhibitor. The binding affinity of larotrectinib has an IC 50 of 5-11 nM for TrkA, TrkB, and TrkC, and the functional inhibition evaluation result of larotrectinib has an IC 50 of 10-25 nM for TrkA, TrkB, and TrkC. is known Larotrectinib is formulated as 25 mg and 100 mg hard capsules and 20 mg/mL oral solutions, and is recommended for adult and child solid cancer patients with NTRK fusion.
라로트텍티니브는 하기 화학식 A의 구조식을 갖는 황산염이다. 화학식명은 (3S)-N-{5-[(2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxy-1-pyrrolidinecarboxamide sulfate이고, 분자식은 C 21H 24F 2N 6O 6S이며 526.51 g/mol의 분자량(유리염기로서 428.44)을 갖는다. Larottectinib is a sulfate having the structural formula of the following formula (A). Chemical name is (3S)-N-{5-[(2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxy-1 -pyrrolidinecarboxamide sulfate, the molecular formula is C 21 H 24 F 2 N 6 O 6 S, and has a molecular weight of 526.51 g/mol (428.44 as a free base).
[화학식 A][Formula A]
Figure PCTKR2021003262-appb-img-000001
Figure PCTKR2021003262-appb-img-000001
라로트렉티니브의 경구절대흡수율은 비임상 동물시험 종에서 30% 이상이고, volume of distribution(Vd)는 0.7-2 L/kg로 조직분포 측면에서는 중간 정도의 특성을 갖는다. 한편, 비활성대사체로서 M14로 명명된 하기 화학식 B의 화합물이 사람, rat, 및 원숭이의 혈중에서 공히 검출된다.The oral absolute absorption rate of larotrectinib is over 30% in non-clinical animal test species, and the volume of distribution (Vd) is 0.7-2 L/kg, which is moderate in terms of tissue distribution. On the other hand, as an inactive metabolite, a compound of the following formula (B), designated as M14, is detected in the blood of humans, rats, and monkeys.
[화학식 B][Formula B]
Figure PCTKR2021003262-appb-img-000002
Figure PCTKR2021003262-appb-img-000002
상기 화학식 B는 라로트렉티니브에서 hydroxypyrrolidine-urea moiety가 떨어진 후 O-glucuronide 생성된 생체내 대사체이다. 화학식 B는 사람을 대상으로 한 임상에서 주요한 비활성 대사체로서 확인되며, 혈장과 소변에서 모두 검출되는 것으로 보고되고 있다. Formula B is an in vivo metabolite produced by O-glucuronide after the hydroxypyrrolidine-urea moiety is removed from larotrectinib. Formula B has been identified as a major inactive metabolite in human clinical trials, and has been reported to be detected in both plasma and urine.
하기 그림은 건강한 남성 피험자에게 [ 14C] Larotrectinib 100 mg (~100 μCi)을 단회 경구투여한 후에 발생되는 대사체 분석한 결과이다.The figure below shows the results of metabolite analysis after a single oral administration of [ 14 C] Larotrectinib 100 mg (~100 μCi) to a healthy male subject.
Figure PCTKR2021003262-appb-img-000003
Figure PCTKR2021003262-appb-img-000003
상기 그림에서 %는 배설 시의 분석결과이며, M14로 명명된 화학식 B의 경우 urine에서 투여한 라로트렉티니브의 용량 대비 9.38%가 확인되었다. In the above figure, % is the analysis result during excretion, and in the case of Formula B named M14, 9.38% of the dose of larotrectinib administered in urine was confirmed.
한편, 라로트렉티니브는 CYP3A4에 의해 주로 대사가 되는데, 라로트렉티니브는 CYP3A4와 P-gp, BCRP의 수용체로서 알려져 있다. 따라서 임상에서 투여 시 CYP3A4의 저해제(inhibitor)나 활성화제(inducer)뿐만 아니라 다른 CYP3A4 수용체(substrate)와의 병용 시 각별한 주의가 요구된다. 한편 라로트렉티니브는 BCS Class III의 화합물로 분류되며, 이는 수용해도는 우수하나 상대적으로 경구흡수율이 낮음을 의미한다. On the other hand, larotrectinib is mainly metabolized by CYP3A4, and larotrectinib is known as a receptor for CYP3A4, P-gp, and BCRP. Therefore, in clinical administration, special caution is required when co-administering with other CYP3A4 receptors as well as inhibitors or inducers of CYP3A4. On the other hand, larotrectinib is classified as a BCS Class III compound, which means that it has excellent water solubility but relatively low oral absorption.
FDA 리뷰 자료 “RISK ASSESSMENT and RISK MITIGATION REVIEW(S), APPLICATION NUMBER: 210861Orig1s000”에 의하면, 라로트렉티니브에 대해 특히 신경독성 (neurotoxicity), 간독성 (hepatotoxicity), 및 생식발생독성 (embryo-fetal toxicity)의 위험성이 언급되고 있다. 즉, 라로트렉티니브는 독성이 매우 심한 약물인 동시에 CYP3A4에 의해 주로 대사가 되며, 동시에 CYP3A4의 수용체로서 약물상호작용(drug-drug interaction)에 따른 병용투여의 위험요소가 높은 물질이다. 임상에서의 절대흡수율은 34% (범위: 32~37%)로서 알려져 있고, Cmax가 1시간, 반감기(half-life)가 3시간 정도로 짧은 편이라서 1일 2회 투여하도록 권장된다.According to the FDA review document “RISK ASSESSMENT and RISK MITIGATION REVIEW(S), APPLICATION NUMBER: 210861Orig1s000”, neurotoxicity, hepatotoxicity, and embryo-fetal toxicity were particularly associated with larotrectinib. danger is mentioned. That is, larotrectinib is a very toxic drug, and at the same time is mainly metabolized by CYP3A4, and at the same time as a receptor of CYP3A4, it is a substance with a high risk of co-administration due to drug-drug interaction. The absolute absorption rate in clinical practice is known as 34% (range: 32-37%), and it is recommended to be administered twice a day because it has a short Cmax of 1 hour and a half-life of 3 hours.
따라서 본 개시가 해결하고자 하는 과제는 의약품 성분으로 다양한 측면에서 장점을 가진 TRK 융합 단백질 억제용 화합물, 이의 의약 용도 및 제조 방법을 제공하는 것이다. Therefore, the problem to be solved by the present disclosure is to provide a compound for inhibiting TRK fusion protein, which has advantages in various aspects as a pharmaceutical ingredient, a pharmaceutical use thereof, and a manufacturing method thereof.
본 개시가 해결하고자 하는 다른 과제는 라로트렉티니브의 여러 단점이 개선된 신규 화합물, 이들의 의약 용도 및 이러한 화합물들의 제조 방법을 제공하는 것이다. Another problem to be solved by the present disclosure is to provide a novel compound in which several disadvantages of larotrectinib are improved, their medicinal use, and a method for preparing such compounds.
상기 과제를 해결하기 위하여, 본 개시는 화학식 1 내지 3 중 어느 하나의 구조를 갖는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다.In order to solve the above problems, the present disclosure provides a compound having a structure of any one of Formulas 1 to 3, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2021003262-appb-img-000004
Figure PCTKR2021003262-appb-img-000004
상기 화학식 1에서, 상기 amino acid는 D,L-type의 아미노산임.In Formula 1, the amino acid is a D, L-type amino acid.
[화학식 2][Formula 2]
Figure PCTKR2021003262-appb-img-000005
Figure PCTKR2021003262-appb-img-000005
상기 화학식 2에서, In Formula 2,
X는 O 또는 S이고, X is O or S;
R 1는 H, 알킬, 할로겐이 하나 이상 치환된 알킬, -O-알킬, -S-알킬, 히드록시 (OH), 티올 (thiol), 아민 (amine), 에스터(ester), 카르복실산(COOH), 시아노(CN)가 측쇄로 연결된 알킬, 알킬이 측쇄로 도입된 2~3차 아민, 할로겐, 시아노(CN), 사이클로알킬, 헤테로사이클, 아릴, 또는 헤테로아릴이며, n은 0 내지 5의 정수임. R 1 is H, alkyl, alkyl substituted with one or more halogens, -O-alkyl, -S-alkyl, hydroxy (OH), thiol, amine, ester, carboxylic acid ( COOH), cyano (CN) is branched alkyl, secondary to tertiary amine in which alkyl is introduced as a branched chain, halogen, cyano (CN), cycloalkyl, heterocycle, aryl, or heteroaryl, and n is 0 an integer from to 5.
[화학식 3][Formula 3]
Figure PCTKR2021003262-appb-img-000006
Figure PCTKR2021003262-appb-img-000006
상기 화학식 3에서, In Formula 3,
A는
Figure PCTKR2021003262-appb-img-000007
,
Figure PCTKR2021003262-appb-img-000008
, 또는
Figure PCTKR2021003262-appb-img-000009
이고,A is
Figure PCTKR2021003262-appb-img-000007
,
Figure PCTKR2021003262-appb-img-000008
, or
Figure PCTKR2021003262-appb-img-000009
ego,
R 2는 수소, 알킬, 할로겐이 하나 이상 치환된 알킬, -O-알킬, -S-알킬, 에스터(ester), 시아노가 측쇄로 연결된 알킬, 알킬이 측쇄로 도입된 1~3차 아민, 카르복실산(COOH), 할로겐, 시아노(CN), 사이클로알킬, 헤테로사이클, 아릴, 또는 헤테로아릴임.R 2 is hydrogen, alkyl, alkyl substituted with one or more halogens, -O-alkyl, -S-alkyl, ester, cyano-connected alkyl as a side chain, primary to tertiary amines in which alkyl is introduced as a side chain, car acid (COOH), halogen, cyano (CN), cycloalkyl, heterocycle, aryl, or heteroaryl.
상기 화학식 1 내지 3에 있어, 용어 "에스터(ester)"는 -COOR 3, -CONR 3R 4, 또는 -SO 2OR 3을 의미하며, 여기에서 R 3 및 R 4는 서로 독립적으로 수소, 알킬, 사이클로알킬, 헤테로사이클, 또는 아릴임. 여기에서, 바람직하게, R 3 및 R 4는 서로 독립적으로 수소 또는 탄소수 1 내지 4의 알킬임. In Formulas 1 to 3, the term "ester" is -COOR 3 , -CONR 3 R 4 , or -SO 2 OR 3 It means, wherein R 3 and R 4 are each independently hydrogen, alkyl , cycloalkyl, heterocycle, or aryl. Here, preferably, R 3 and R 4 are independently of each other hydrogen or alkyl having 1 to 4 carbon atoms.
본 발명자들은 라로트렉티니브가 갖는 단점을 보완하여 변이성 TRK 융합 유전자 발현 단백질을 가진 다양한 고형암을 치료할 수 있는 신규한 화합물을 찾고자 하였다. 그 결과, 본 발명자들은 다양한 암종에서 세포성장을 효과적으로 억제하는 라로트렉티니브의 활성 전구약물(active prodrug) 유도체들을 확인하였고, 이들 화합물들은 그 물질 자체로서 라로트렉티니브에 상응하는 정도의 TRK 저해활성을 가지며, 체내에서 라로트렉티니브로 대사되는 전구약물(Prodrug)로서의 특징을 가져 2번에 걸쳐 효과를 발휘할 수 있는 것을 확인하였다. The present inventors sought to find a novel compound capable of treating various solid cancers having a mutable TRK fusion gene expression protein by supplementing the disadvantages of larotrectinib. As a result, the present inventors have identified active prodrug derivatives of larotrectinib that effectively inhibit cell growth in various carcinomas. It was confirmed that it has activity and has the characteristics of a prodrug that is metabolized into larotrectinib in the body, and can exert the effect twice.
이와 같은 활성전구약물이 갖는 장점은 1) BCS Class III의 라로트렉티니브 대비 높은 경구흡수율을 가지며, 2) 그 자체적으로 더 활성이 있으며, 동시에 체내에서 라로트렉티니브로 대사되어 활성을 계속 유지함으로써 약제학적으로 서방출형의 특성을 부여하기 용이하며, 3) 라로트렉티니브가 간의 초회통과로 인해 혈중에서 빠르게 소실되는 것 대비 간 대사에만 의존하지 않고 혈장과 조직에 널리 분포되어 있는 에스터라아제(esterase)에 의해 약물의 대사작용을 양분하기 때문에 약물의 혈중농도와 조직농도를 일정하게(consistent) 조절하기 용이하다. The advantages of such an active prodrug are: 1) it has a higher oral absorption compared to larotrectinib of BCS Class III; Pharmaceutically, it is easy to give the characteristics of a sustained-release type, and 3) Larotrectinib is widely distributed in plasma and tissues without relying solely on liver metabolism compared to that larotrectinib is rapidly lost from the blood due to the first passage of the liver. Because the metabolism of the drug is divided by esterase, it is easy to control the blood concentration and tissue concentration of the drug consistently (consistent).
특히, 라로트렉티니브와 같이 독성이 심한 약물의 경우 체내 약물농도의 조절은 매우 중요하다. 라로트렉티니브는 CYP3A4와 P-gp가 흡수에 미치는 영향이 크고, 간의 초회통과로 대사가 신속하게 일어나면서 병용하는 약물의 특성에 따라 약물상호작용이 높게 나타나 체내 약물농도의 조절이 쉽지 않다는 문제점이 있다. 본 발명의 화합물들은 앞서 언급한 특성으로 인해 이러한 문제점을 해결할 수 있는 대안이 될 수 있다. In particular, in the case of highly toxic drugs such as larotrectinib, it is very important to control the drug concentration in the body. Larotrectinib has a large effect on absorption of CYP3A4 and P-gp, and metabolism occurs quickly due to the first passage of the liver. There is this. The compounds of the present invention can be an alternative to solve these problems due to the above-mentioned properties.
즉, 본 발명자들은 라로트렉티니브가 갖는 생리활성을 유지하는 활성전구약물을 제공하고자 하며, 이와 같은 활성전구약물이 라로트렉티니브의 대사작용에 완충역할을 할 뿐만 아니라 그 자체로서도 우수한 TRK 저해제임을 확인함으로써 본 발명을 완성하게 되었다.That is, the present inventors intend to provide an active prodrug that maintains the physiological activity of larotrectinib, and such an active prodrug not only serves as a buffer in the metabolism of larotrectinib, but is also an excellent TRK inhibitor. By confirming that the present invention was completed.
본 개시에 따른 상기 화학식 1의 화합물에 있어, 아미노산은 글리신, 페닐글리신, 류신, 메티오닌, 발린, 알라닌, 이소류신, 프롤린, 트립토판, 티로신, 페닐알라닌, 히스티딘, 세린, 시스테인, 아스파라긴, 트레오닌, t-류신, 글루타민, 글루탐산, 아스파르트산, 리신, 아르기닌, 및 3,4-디히드록시페닐알라닌으로 이루어진 군에서 선택된다. In the compound of Formula 1 according to the present disclosure, amino acids are glycine, phenylglycine, leucine, methionine, valine, alanine, isoleucine, proline, tryptophan, tyrosine, phenylalanine, histidine, serine, cysteine, asparagine, threonine, t-leucine , glutamine, glutamic acid, aspartic acid, lysine, arginine, and 3,4-dihydroxyphenylalanine.
본 개시에 있어, 용어 "알킬"은 (탄소수가 특별히 한정되지 않은 경우) 탄소수 1 내지 10, 바람직하게는 탄소수 1 내지 6, 더욱 바람직하게는 탄소수 1 내지 4를 가진 포화된 직쇄상 또는 분지상의 비-고리 (cyclic) 탄화수소를 의미한다. 대표적인 포화 직쇄상 알킬은 -메틸, -에틸, -n-프로필, -n-부틸, -n-펜틸, -n-헥실, -n-헵틸, -n-옥틸, -n-노닐 과 -n-데실을 포함하고, 반면에 포화 분지상 알킬은 -이소프로필, -sec-부틸, -이소부틸, -tert-부틸, 이소펜틸, 2-메틸헥실, 3-메틸부틸, 2-메틸펜틸, 3-메틸펜틸, 4-메틸펜틸, 2-메틸헥실, 3-메틸헥실, 2-메틸펜틸, 3-메틸펜틸, 4-메틸펜틸, 2-메틸헥실, 3-메틸헥실, 4-메틸헥실, 5- 메틸헥실, 2,3-디메틸부틸, 2,3-디메틸펜틸, 2,4-디메틸펜틸, 2,3-디메틸헥실, 2,4-디메틸헥실, 2,5-디메틸헥실, 2,2-디메틸펜틸, 2,2-디메틸헥실, 3,3-디메틸펜틸, 3,3-디메틸헥실, 4,4-디메틸헥실, 2-에틸펜틸, 3-에틸펜틸, 2-데틸헥실, 3-에틸헥실, 4-에틸헥실, 2-메틸-2-에틸펜틸, 2-메틸-3-에틸펜틸, 2-메틸-4-에틸펜틸, 2-메틸-2-에틸헥실, 2-메틸-3-에틸헥실, 2-메틸-4-에틸헥실, 2,2-디에틸펜틸, 3,3-디에틸헥실, 2,2-디에틸헥실, 및 3,3-디에틸헥실을 포함한다. In the present disclosure, the term "alkyl" refers to a saturated straight or branched chain having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms (when the number of carbon atoms is not particularly limited). means a cyclic hydrocarbon. Representative saturated straight chain alkyls are -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n- contains decyl, whereas saturated branched alkyl is -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3- Methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- Methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethyl pentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and 3,3-diethylhexyl.
본 명세서에서 “C 1-4” 또는 “C1 내지 C6”와 같이 기재될 경우 이는 탄소수가 1 내지 6개임을 의미한다. 예를 들어, C 1-6 알킬은 탄소수가 1 내지 6인 알킬을 의미한다.In the present specification, when described as “C 1-4 ” or “C1 to C6”, this means that the number of carbon atoms is 1 to 6 carbon atoms. For example, C 1-6 alkyl means alkyl having 1 to 6 carbon atoms.
본 명세서에서 사용된 용어 "할로겐" 및 "할로"는 플루오린, 클로린, 브로민 또는 아이오딘을 의미한다.As used herein, the terms “halogen” and “halo” refer to fluorine, chlorine, bromine or iodine.
본 명세서에서 사용된 용어 "사이클로알킬(cycloalkyl)"은 탄소 및 수소 원자를 가지며 탄소-탄소 다중 결합을 가지지 않는 모노사이클릭 또는 폴리사이클릭 포화 고리(ring)를 의미한다. 사이클로알킬 그룹의 예는 (C 3-C 7)사이클로알킬 (예를 들어, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실 및 사이클로헵틸)을 포함하나 이에 한정되는 것은 아니다. 사이클로알킬 그룹은 선택적으로 치환될 수 있다. 일 실시예에서, 사이클로알킬 그룹은 모노사이클릭 또는 바이사이클릭 링(고리)이다. As used herein, the term “cycloalkyl” refers to a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and no carbon-carbon multiple bonds. Examples of cycloalkyl groups include, but are not limited to (C 3 -C 7 )cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl). Cycloalkyl groups may be optionally substituted. In one embodiment, the cycloalkyl group is a monocyclic or bicyclic ring (ring).
본 명세서에서 사용된 "헤테로사이클(헤테로고리)"은 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4의 헤테로원자를 함유하는 포화되거나, 포화되지 않은 5- 내지 7-멤버의 모노사이클릭, 또는 7- 내지 10-멤버의 바이사이클릭, 헤테로사이클릭 링(고리)를 의미하며, 여기에서 질소 및 황 헤테로원자는 선택적으로 산화될 수 있고, 질소 헤테로원자는 선택적으로 사가화(quaternized)될 수 있으며, 상기 헤테로고리 중 일부가 벤젠 고리에 융합한 바이사이클릭 링을 포함한다. 헤테로고리는 헤테로원자 또는 탄소 원자에 의하여 부착될 수 있다. 대표적인 헤테로고리는 모포리닐(morpholinyl), 피롤리디노닐(pyrrolidinonyl), 피롤리디닐(pyrrolidinyl), 피페리디닐, 히단토이닐(hydantoinyl), 발레롤락타밀(valerolactamyl), 옥시라닐, 옥세타닐, 테트라하이드로퓨라닐, 테트라하이드로피라닐(tetrahydropyranyl), 테트라하이드로피리디닐, 테트라하이드로피리미디닐, 테트라하이드로티오페닐, 테트라하이드로티오피라닐, 테트라하이드로피리미디닐, 테트라하이드로티오페닐, 및 테트라하이드로티오피라닐을 포함한다.As used herein, "heterocycle (heterocycle)" means a saturated or unsaturated 5- to 7-membered monocyclic containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 7- to 10-membered bicyclic, heterocyclic ring (ring) wherein nitrogen and sulfur heteroatoms may be optionally oxidized and nitrogen heteroatoms may be optionally quaternized and a bicyclic ring in which some of the heterocycles are fused to a benzene ring. Heterocycles may be attached by heteroatoms or carbon atoms. Representative heterocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, Tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothio contains pyranyl.
본 명세서에서 사용된 용어 "아릴"은 5 내지 10의 고리 원자를 함유하는 탄소고리 방향족 그룹을 의미한다. 대표적인 예는 페닐, 톨일 (tolyl), 자이릴 (xylyl), 나프틸, 테트라하이드로나프틸, 안트라세닐 (anthracenyl), 플루오레닐 (fluorenyl), 인데닐 (indenyl), 아주레닐 (azulenyl) 등을 포함하나 이에 한정되는 것은 아니다. 탄소고리 방향족 그룹은 선택적으로 치환될 수 있다.As used herein, the term "aryl" refers to a carbocyclic aromatic group containing 5 to 10 ring atoms. Representative examples include phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, etc. including, but not limited to. Carbocyclic aromatic groups may be optionally substituted.
본 명세서에서 사용된 "헤테로아릴"은 질소, 산소 및 황으로 구성된 군으로부터 선택된 적어도 하나의 헤테로원자를 가지고, 모노- 및 바이사이클릭 링 시스템을 포함하는 적어도 하나의 탄소 원자를 포함하는 5 내지 10 멤버의 방향족 헤테로고리 (heterocycle) 링이다. 대표적인 헤테로아릴은 트리아졸일, 테트라졸일, 옥사디아졸일, 피리딜, 퓨릴, 벤조퓨라닐, 티오페닐, 벤조티오페닐, 퀴노리닐, 피롤일 (pyrrolyl), 인돌일, 옥사졸일, 벤족사졸일 (benzoxazolyl), 이미다졸일, 벤즈이미다졸일, 티아졸일 (thiazolyl), 벤조티아졸일, 이속사졸일, 파이라졸일 (pyrazolyl), 이소티아졸일, 피리다지닐, 피리미디닐, 파이라지닐, 트리아지닐, 신놀리닐 (cinnolinyl), 프탈라지닐, 퀴나졸리닐, 피리미딜, 옥세타닐, 아제피닐, 피페라지닐, 모포리닐 (morpholinyl), 디옥사닐, 티에타닐 및 옥사졸일이다.As used herein, "heteroaryl" has at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and includes 5 to 10 carbon atoms including at least one carbon atom, including mono- and bicyclic ring systems. It is an aromatic heterocycle ring of members. Representative heteroaryls include triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl ( benzoxazolyl), imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, tria Zinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanyl, thietanyl and oxazolyl.
본 개시에서 상기 화학식 1 내지 3으로 표시되는 화합물은 무기산 또는 유기산으로 유도된 염 형태로 사용될 수 있으며, 예컨대 염산, 브롬화수소산, 황산, 인산, 질산, 아세트산, 글리콜산, 락트산, 피루브산, 말론산, 석신산, 글루타르산, 푸마르산, 말산, 만델산, 타르타르산, 시트르산, 아스코르브산, 팔미트산, 말레산, 벤조산, 하이드록시벤조산, 페닐아세트산, 신남산, 살리실산, 메탄설폰산, 에탄설폰산, 벤젠설폰산, 톨루엔설폰산 등으로 이루어진 군으로부터 선택되는 1종 이상의 산에 의해 유도된 염 형태로 사용될 수 있다.In the present disclosure, the compounds represented by Formulas 1 to 3 may be used in the form of salts derived from inorganic acids or organic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, Succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, It may be used in the form of a salt derived from at least one acid selected from the group consisting of benzenesulfonic acid, toluenesulfonic acid, and the like.
본 명세서에서 사용된 용어인 "본 발명의 화합물"은 화학식 1 내지 3 중 어느 하나의 화학식 각각의 화합물들뿐만 아니라, 이들의 클라드레이트 (clathrates), 수화물, 용매화물, 또는 다형체를 포함하는 의미이다. 또한 용어 “본 발명의 화합물”은 이의 약학적으로 허용 가능한 염이 언급되지 않을 경우 본 발명 화합물의 약학적으로 허용 가능한 염도 포함하는 의미이다. As used herein, the term "compound of the present invention" is meant to include compounds of each of the formulas of any one of Formulas 1 to 3, as well as clathrates, hydrates, solvates, or polymorphs thereof. am. In addition, the term “compound of the present invention” is meant to include a pharmaceutically acceptable salt of the compound of the present invention unless a pharmaceutically acceptable salt thereof is mentioned.
일 실시예에 본 발명의 화합물은 입체이성질체적으로 순수한 화합물들(예를 들어, 다른 입체이성질체가 실질적으로 없는(예를 들어, 85% ee 이상, 90% ee 이상, 95% ee 이상, 97% ee 이상, 또는 99% ee 이상))로 존재할 수 있다. 즉, 본 발명에 따른 화학식 1의 화합물 또는 그의 염이 호변이성적 (tautomeric) 이성질체 및/또는 입체이성질체 (예를 들어, 기하이성질체 (geometrical isomer) 및 배좌 이성질체 (conformational isomers))일 경우 그들의 분리된 이성질체 및 혼합물 각각 또한 본 발명의 화합물의 범주에 포함된다. 본 발명의 화합물 또는 그의 염이 구조 내에 비대칭 탄소 (asymmetric carbon)를 가지고 있는 경우에, 그들의 광학 활성 화합물 및 라세믹 혼합물들 또한 본 발명의 화합물의 범위에 포함된다. In one embodiment, a compound of the invention is a stereoisomerically pure compound (e.g., substantially free of other stereoisomers (e.g., at least 85% ee, at least 90% ee, at least 95% ee, 97% ee or more, or 99% ee or more)). That is, when the compound of Formula 1 or a salt thereof according to the present invention is a tautomeric isomer and/or stereoisomer (eg, geometrical isomer and conformational isomers), their separated isomers and mixtures each are also included within the scope of the compounds of the present invention. When the compound of the present invention or a salt thereof has an asymmetric carbon in its structure, their optically active compounds and racemic mixtures are also included in the scope of the compound of the present invention.
본 명세서에서 사용될 경우, 용어 "결정다형(polymorph)"은 본 발명의 화합물의 고체 결정 형태 또는 그것의 복합체를 의미한다. 같은 화합물의 다른 결정다형은 다른 물리적, 화학적 그리고/또는 스펙트럼적 특성을 보인다. 물리적 특성 측면의 차이점으로는 안정성(예를 들어, 열 또는 빛 안정성), 압축성과 밀도(제제화 및 생산물 제조에 중요함), 그리고 용해율(생물학적 이용률에 영향을 줄 수 있음)을 포함하나, 이에 한정되지 아니한다. 안정성에서 차이는 화학반응성 변화들(예를 들어, 또 다른 다형으로 구성되었을 때보다 하나의 다형으로 구성되었을 때 더 빠르게 변색이 되는 것 같은 차별적 산화) 또는 기계적인 특징들(예를 들어 동역학적으로 선호된 다형체로서 저장된 정제 파편들이 열역학 적으로 더 안정된 다형으로 변환) 또는 둘 다(하나의 다형의 정제는 높은 습도에서 더 분해에 예민)를 야기한다. 결정다형의 다른 물리적 성질들은 그들의 가공에 영향을 줄 수 있다. 예를 들어, 한 결정다형은 또 다른 결정다형에 비하여, 예를 들어, 그것의 형태 또는 입자의 크기 분포에 기인하여 용매화합물을 형성할 가능성이 많을 수 있거나, 여과 또는 세척이 더 어려울 수 있다.As used herein, the term "polymorph" refers to a solid crystalline form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical and/or spectral properties. Differences in physical properties include, but are not limited to, stability (eg, thermal or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). doesn't happen Differences in stability may be due to changes in chemical reactivity (e.g., differential oxidation, such as a faster discoloration when composed of one polymorph than when composed of another polymorph) or mechanical properties (e.g., kinetically Tablet fragments stored as the preferred polymorph are converted to a thermodynamically more stable polymorph) or both (tablets of one polymorph are more susceptible to degradation at high humidity). Other physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form a solvate than another polymorph, for example due to its shape or particle size distribution, or it may be more difficult to filter or wash.
본 명세서에서 사용된 용어 "용매화물"은 비공유 분자간의 힘에 의해 결합된 화학량론적 또는 비-화학량론적인 양의 용매를 포함하는 본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염을 의미한다. 바람직한 용매들은 휘발성이고, 비독성이며, 인간에게 극소량 투여될 수 있다.As used herein, the term “solvate” refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and can be administered in trace amounts to humans.
본 명세서에서 사용된 용어 "수화물 (hydrate)"은 비공유 분자간의 힘에 의해 결합된 화학량론적 또는 비-화학량론적인 양의 물을 포함하는 본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염을 의미한다. As used herein, the term "hydrate" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. .
본 명세서에서 사용된 용어 "클라드레이트 (clathrate)"은 게스트 분자(예를 들어, 용매 또는 물)를 가두어 놓은 공간 (예를 들어, 채널(channel))을 포함한 결정 격자의 형태의 본 발명의 화합물 또는 그것의 염을 의미한다.As used herein, the term "clathrate" refers to a compound of the present invention in the form of a crystal lattice containing spaces (eg, channels) that confine guest molecules (eg, solvent or water). or salts thereof.
본 명세서에서 사용된 용어 "정제된 (purified)"은 분리될 때, 분리체는 90% 이상 순수한 것을 의미하며, 일 실시예에서는 95% 이상 순수하고, 다른 실시 예에서는 99% 이상 순수하고, 또 다른 실시예에서는 99.9% 이상 순수한 것을 의미한다.The term "purified" as used herein, when isolated, means that the isolate is at least 90% pure, in one embodiment at least 95% pure, in another embodiment at least 99% pure, and In another embodiment, it means at least 99.9% pure.
본 명세서에서 사용된 "치료"는 원발, 국소성 또는 전이성 암조직의 근절, 제거, 변형, 또는 통제를 포함하고; 암의 확장을 최소화하거나 지연시키는 것이다."Treatment" as used herein includes eradication, removal, modification, or control of primary, focal or metastatic cancerous tissue; Minimizing or delaying the expansion of cancer.
본 명세서에서 사용된 "유효량"은 원발, 국소성 또는 전이성(metastatic) 암세포 또는 암조직을 파괴, 변형, 통제 또는 제거하거나; 암의 확장을 늦추거나 또는 최소화하거나; 또는 암, 신생물 질환, 또는 종양의 치료 또는 관리에서 치료상 이점을 제공하기에 충분한 본 발명의 화합물의 양을 말한다. "유효량" 은 또한 암 또는 신생물 세포 사멸을 야기하기에 충분한 본 발명의 화합물의 양을 말한다. "유효량"은 또한 생체외(in vitro) 또는 생체내(in vivo) 어떤 쪽이든 변이성 TRK 융합 단백질을 억제 또는 줄이기에 충분한 양을 말한다.As used herein, an “effective amount” refers to destroying, modifying, controlling or eliminating primary, local or metastatic cancer cells or cancer tissue; slowing or minimizing the spread of cancer; or an amount of a compound of the invention sufficient to provide a therapeutic benefit in the treatment or management of cancer, neoplastic disease, or tumor. "Effective amount" also refers to an amount of a compound of the invention sufficient to cause cancer or neoplastic cell death. "Effective amount" also refers to an amount sufficient to inhibit or reduce a variant TRK fusion protein, either in vitro or in vivo.
비-한정적인, 본 발명에 따른 바람직한 화합물의 예로는 하기 화합물들 및 이의 약학적으로 허용 가능한 염을 포함한다. Non-limiting examples of preferred compounds according to the present invention include the following compounds and pharmaceutically acceptable salts thereof.
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 아세테이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl acetate,
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)-3-카르바모일)-피롤리딘-3-일 아실레이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )-3-carbamoyl)-pyrrolidin-3-yl acylate,
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 이소부티레이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl isobutyrate,
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 프로피오네이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl propionate,
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 글리시네이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl glycinate,
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 피페리딘-1-카르복실레이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl piperidine-1-carboxylate,
4-(((S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일)옥시)-4-옥소부타노익에시드,4-(((S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine -3-yl) carbamoyl) pyrrolidin-3-yl) oxy) -4-oxobutanoic acid,
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일-2-부티노에이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl-2-butinoate,
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 카르바메이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl carbamate,
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 디메틸카르바메이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl dimethylcarbamate,
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 시클로헥세인카르복실레이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl cyclohexanecarboxylate,
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 벤조에이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl benzoate,
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 L-세리네이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl L-serinate,
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 L-알라니네이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl L-alaninate,
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 아세틸-L-알라니네이트, 또는 (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl acetyl-L-alaninate, or
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 메틸 푸마레이트.(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )carbamoyl)pyrrolidin-3-yl methyl fumarate.
본 개시에 따른 상기 화합물들 중에서 특히Among the compounds according to the present disclosure in particular
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 아세테이트 (화합물 1), (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl acetate (Compound 1),
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)-3-카르바모일)-피롤리딘-3-일 아실레이트 (화합물 2), (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )-3-carbamoyl)-pyrrolidin-3-yl acylate (Compound 2),
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 이소부티레이트(화합물 3), (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl isobutyrate (compound 3),
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 프로피오네이트(화합물 4), (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl propionate (compound 4),
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 L-세리네이트(화합물 13), (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )carbamoyl)pyrrolidin-3-yl L-serinate (compound 13),
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 아세틸-L-알라니네이트(화합물 15), (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )carbamoyl)pyrrolidin-3-yl acetyl-L-alaninate (Compound 15),
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 메틸 푸마레이트(화합물 16), 및 이들의 약학적으로 허용 가능한 염이 경구 투여 생체이용률 등 다양한 측면에서 바람직하다. (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )carbamoyl)pyrrolidin-3-yl methyl fumarate (Compound 16), and pharmaceutically acceptable salts thereof, are preferred in various aspects such as oral administration bioavailability.
또 다른 양태에서, 본 발명은 본 발명에 따른 화학식 1, 2 또는 3의 화합물 또는 이의 약학적으로 허용 가능한 염의 치료적으로 유효한 양, 및 약학적으로 허용 가능한 담체를 포함하는 (약학) 조성물을 제공한다.In another aspect, the present invention provides a (pharmaceutical) composition comprising a therapeutically effective amount of a compound of Formula 1, 2 or 3 or a pharmaceutically acceptable salt thereof according to the present invention, and a pharmaceutically acceptable carrier. do.
또 다른 양태에서, 본 발명은 본 발명에 따른 화학식 1, 2 또는 3의 화합물의 치료적으로 유효한 양 또는 이의 약학적으로 허용 가능한 염, 약학적으로 허용 가능한 담체, 및 본 발명의 화합물이 아닌 다른 항암제, 세포 증식 억제제(cytostatic drug), 혈관 신생 억제제(angiogenesis inhibitor), 키나아제 억제제(kinase inhibitor), 사이토카인 차단제(cytokine blocker) 및 세포 접착 분자(cell adhesion molecule)의 억제제로 이루어진 군으로부터 선택되는 활성 약학 성분(active pharmaceutical ingredient)의 치료적으로 유효한 양을 포함하는 (약학) 조성물을 제공한다.In another embodiment, the present invention provides a therapeutically effective amount of a compound of Formula 1, 2 or 3 according to the present invention, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and other compounds other than the compound of the present invention. an activity selected from the group consisting of anticancer drugs, cytostatic drugs, angiogenesis inhibitors, kinase inhibitors, cytokine blockers and inhibitors of cell adhesion molecules A (pharmaceutical) composition comprising a therapeutically effective amount of an active pharmaceutical ingredient is provided.
또 다른 양태에서, 본 발명은 화학식 1, 2 또는 3의 화합물 또는 이의 약학적으로 허용 가능한 염의 치료적으로 유효한 양을 이를 필요로 하는 개체에게 투여하는 단계를 포함하는 질병(disease) 또는 상태(condition)를 치료하는 방법이 제공되며, 상기 질병 또는 상태(condition)는 TRK (tropomyosin receptor kinase) 저해로 개선될 수 있는 질병 또는 상태이다. 다른 양태에서, 상기 질병 또는 상태는 변이성 TRK 융합 단백질 억제로 개선될 수 있는 질병 또는 상태이다. 다른 양태에서, 상기 질병 또는 상태는 고형암이다. 또 다른 양태에서, 상기 고형암은 연부조직육종, 섬유육종, 침샘암, 갑상샘암, 폐암, 흑색종, 결장암, 위장관기질종양, 담관암, 맹장암, 유방암 또는 췌장암이다. 일 양태에서, 상기 치료는 예방 치료(preventative treatment)이다. 또 다른 양태에서, 상기 치료는 완화 치료(palliative treatment)이다. 또 다른 양태에서, 상기 치료는 회복 치료(restorative treatment)이다.In another embodiment, the present invention relates to a disease or condition comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula 1, 2 or 3 or a pharmaceutically acceptable salt thereof. ) is provided, wherein the disease or condition is a disease or condition that can be ameliorated by inhibition of tropomyosin receptor kinase (TRK). In another embodiment, the disease or condition is a disease or condition that can be ameliorated by inhibiting the mutant TRK fusion protein. In another embodiment, the disease or condition is a solid cancer. In another embodiment, the solid cancer is soft tissue sarcoma, fibrosarcoma, salivary gland cancer, thyroid cancer, lung cancer, melanoma, colon cancer, gastrointestinal stromal tumor, bile duct cancer, cecum cancer, breast cancer or pancreatic cancer. In one aspect, the treatment is a preventative treatment. In another embodiment, the treatment is a palliative treatment. In another embodiment, the treatment is a restorative treatment.
즉, 본 발명은 본 발명에 따른 화학식 1, 2 또는 3의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 이용하는 것을 특징으로 하는 의약 용도를 제공한다. 일 양태에서, 본 발명의 의약 용도는 본 명세서에서 설명된 질병 또는 상태의 치료 또는 예방 용도이다. That is, the present invention provides a pharmaceutical use characterized in that the compound of Formula 1, 2 or 3 or a pharmaceutically acceptable salt thereof according to the present invention is used as an active ingredient. In one aspect, the pharmaceutical use of the present invention is the use for the treatment or prophylaxis of a disease or condition described herein.
본 발명에 따른 신규 화합물들이 항암제로 사용될 경우의 투여량은 다음과 같다. 본 발명의 화합물은 임의의 적합한 경로에 의하여 이러한 경로에 적당한 약학 조성물의 형태, 그리고 의도된 치료를 위하여 효과적인 투여량으로 투여될 수 있다. 효과적인 투여량은 단일 또는 분할 투여로 일반적으로 약 0.001 내지 약 100 mg/체중kg/일이고, 바람직하게는 약 0.01 내지 약 30 mg/kg/일이다. 나이, 종, 및 치료될 질병 또는 상태(condition)에 따라 이 범위의 하한 미만의 투여량 수준이 적합할 수 있다. 다른 경우에는, 여전히 더 큰 투여량이 해로운 부작용없이 사용될 수 있다. 더 큰 투여량은 하루 동안 투여를 위하여, 여러 작은 투여량으로 분할될 수 있다. 적절한 투여량을 결정하기 위한 방법들이 본 발명이 속한 분야에 잘 알려져 있다.When the novel compounds according to the present invention are used as anticancer agents, the dosage is as follows. The compounds of the present invention may be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in an effective dosage for the intended treatment. An effective dosage is generally from about 0.001 to about 100 mg/kg body weight/day, preferably from about 0.01 to about 30 mg/kg/day, in single or divided doses. Dosage levels below the lower limit of this range may be suitable depending on the age, species, and disease or condition being treated. In other cases, still larger doses can be used without deleterious side effects. The larger dose may be divided into several smaller doses for administration throughout the day. Methods for determining the appropriate dosage are well known in the art.
상기 설명된 질병 또는 상태(condition)의 치료를 위하여, 본 명세서에서 설명된 상기 화합물 또는 이의 약학적으로 허용 가능한 염은 다음과 같이 투여될 수 있다.For the treatment of the above-described disease or condition, the compound described herein or a pharmaceutically acceptable salt thereof may be administered as follows.
구강 투여(Oral administration)Oral administration
본 발명의 화합물은 구강으로 투여될 수 있으며, 구강은 연하(swallowing)를 포함하는 개념이다. 구강 투여에 의하여 본 발명의 화합물이 위장관(gastrointestinal tract)에 들어가거나, 예를 들어, 구강(buccal) 또는 설하(sublingual) 투여와 같이, 입으로부터 혈류로 직접적으로 흡수될 수 있다. The compound of the present invention may be administered orally, and the oral cavity is a concept including swallowing. By oral administration, the compounds of the present invention may enter the gastrointestinal tract or may be absorbed directly into the bloodstream from the mouth, for example, by buccal or sublingual administration.
구강 투여를 위한 적합한 조성물은 고형상, 액상, 겔(gel), 또는 파우더 형상일 수 있으며, 정제(tablet), 로젠지(lozenge), 캡슐(capsule), 과립제, 산제 등의 제형을 가질 수 있다. Suitable compositions for oral administration may be in solid, liquid, gel, or powder form, and may have dosage forms such as tablets, lozenges, capsules, granules, and powders. .
구강 투여를 위한 조성물은 선택적으로 장용 코팅(enteric coating)될 수 있으며, 장용 코팅을 통하여 지연된(delayed) 또는 지속된(sustained) 방출을 나타낼 수 있다. 즉, 본 발명에 따른 구강 투여를 위한 조성물은 즉시 또는 변형된(modified) 방출 패턴을 가진 제형일 수 있다. Compositions for oral administration may optionally be enteric coated and may exhibit delayed or sustained release through the enteric coating. That is, the composition for oral administration according to the present invention may be a formulation having an immediate or modified release pattern.
액체 제형은 용액, 시럽 및 현탁액을 포함할 수 있으며, 이러한 액상 조성물은 연질 또는 경질 캡슐 내에 함유된 형태일 수 있다. 이러한 제형은 약학적으로 허용 가능한 담체, 예를 들어, 물, 에탄올, 폴리에틸렌글리콜, 셀룰로오스, 또는 오일(oil)을 포함할 수 있다. 상기 제형은 또한 하나 이상의 유화제 및/또는 현탁제를 포함할 수 있다.Liquid formulations may include solutions, syrups, and suspensions, and such liquid compositions may be contained in soft or hard capsules. Such formulations may contain a pharmaceutically acceptable carrier, for example, water, ethanol, polyethylene glycol, cellulose, or oil. The formulation may also contain one or more emulsifying and/or suspending agents.
정제(tablet) 제형에서, 활성 성분인 약물의 양은 정제 총 중량 대비 약 0.05 중량% 내지 약 95 중량%, 더욱 일반적으로 제형의 약 2 중량% 내지 약 50 중량%로 존재할 수 있다. 또한, 정제는 약 0.5 중량% 내지 약 35 중량%, 더욱 일반적으로 제형의 약 2 중량% 내지 약 25 중량%를 포함하는 붕해제를 함유할 수 있다. 붕해제의 예로는 유당, 전분, 소디움스타치글리콜레이트, 크로스포비돈, 크로스카멜로스소디움(croscarmellose sodium), 말토덱스트린 또는 이들의 혼합물이 사용될 수 있으나 이에 한정되는 것은 아니다.In tablet formulations, the amount of drug as the active ingredient may be present in an amount of from about 0.05% to about 95% by weight relative to the total weight of the tablet, more typically from about 2% to about 50% by weight of the dosage form. Tablets may also contain from about 0.5% to about 35% by weight of a disintegrant, more typically from about 2% to about 25% by weight of the dosage form. Examples of the disintegrant include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.
정제로 제조하기 위해 포함되는 적합한 활택제는 약 0.1 중량% 내지 약 5 중량% 양으로 존재할 수 있고, 탈크(talc), 이산화규소, 스테아린산, 칼슘, 아연 또는 마그네슘 스테아레이트, 소듐 스테아릴 푸마레이트 등이 활택제로 사용될 수 있으나, 본 발명은 이러한 첨가제들의 종류에 한정되는 것은 아니다. Suitable glidants included for the preparation of tablets may be present in an amount of from about 0.1% to about 5% by weight and include talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like. This lubricant may be used, but the present invention is not limited to the types of these additives.
정제로 제조하기 위한 결합제(binder)로는 젤라틴, 폴리에틸렌글리콜, 당(sugar), 검(gum), 녹말(starch), 폴리비닐피롤리돈, 하이드록시프로필셀룰로오스, 하이드록시프로필메틸셀룰로오스 등이 사용될 수 있으며, 정제로 제조하기 위한 적합한 희석제로는 만니톨, 자일리톨, 락토오스, 덱스트로오스, 수크로오스, 솔비톨, 녹말(starch), 미결정셀룰로오스 등이 사용될 수 있으나, 본 발명은 이러한 첨가제들의 종류에 한정되는 것은 아니다. Gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc. may be used as a binder for manufacturing tablets. In addition, suitable diluents for manufacturing tablets include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc., but the present invention is not limited to the types of these additives. .
선택적으로 정제에 포함될 수 있는 가용화제는 정제 총 중량 대비 약 0.1 중량% 내지 약 3 중량% 양이 사용될 수 있고, 예를 들어, 폴리소르베이트, 소디움 라우릴설페이트, 소디움 도데실설페이트, 프로필렌 카보네이트, 디에틸렌글리콜모노에틸에테르, 디메틸이소소르비드, 폴리옥시에틸렌글리콜화된 천연 또는 수소화 피마자유, HCOR TM(Nikkol), 올레일에스테르, 젤루시어(Gelucire TM), 카프릴릭/카프릴산 모노/디글리세리드, 소르비탄지방산에스테르, 솔루톨HS TM 등이 본 발명에 따른 약학 조성물에 사용될 수 있으나, 본 발명은 이러한 가용화제의 구체적 종류에 한정되는 것은 아니다.Optionally, the solubilizing agent that may be included in the tablet may be used in an amount of about 0.1% to about 3% by weight relative to the total weight of the tablet, for example, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, Diethylene glycol monoethyl ether, dimethylisosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR ™ (Nikkol), oleyl ester, Gelucire ™ , caprylic/caprylic acid mono/ Diglyceride, sorbitan fatty acid ester, Solutol HS TM, etc. may be used in the pharmaceutical composition according to the present invention, but the present invention is not limited to the specific type of the solubilizer.
비경구 투여(Parenteral Administration)Parenteral Administration
본 발명의 화합물은 혈류, 근육, 또는 내장 내로 직접 투여될 수 있다. 비경구 투여를 위한 적합한 방법은 정맥내(intravenous), 근육내(intra-muscular), 피하 동맥내(subcutaneous intraarterial), 복강내(intraperitoneal), 척추강내(intrathecal), 두개내(intracranial) 주사 등을 포함한다. 비경구 투여를 위한 적합한 장치는 (바늘 및 바늘 없는 주사기를 포함하는) 주사기(injector) 및 주입 방법(infusion method)을 포함한다.The compounds of the present invention may be administered directly into the bloodstream, muscle, or intestine. Suitable methods for parenteral administration include intravenous, intra-muscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial injection, and the like. include Suitable devices for parenteral administration include injectors (including needle and needleless syringes) and infusion methods.
비경구 투여를 위한 조성물은 즉시 또는 변형된 방출 패턴을 가진 제형일 수 있으며, 변형된 방출 패턴은 지연된(delayed) 또는 지속된(sustained) 방출 패턴일 수 있다. Compositions for parenteral administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
대부분의 비경구 제형은 액상 조성물이며, 이러한 액상 조성물은 본 발명에 따른 약효 성분, 염, 완충제, 등장화제 등을 포함하는 수용액이다.Most parenteral formulations are liquid compositions, and the liquid composition is an aqueous solution containing the active ingredient according to the present invention, a salt, a buffer, an isotonic agent, and the like.
비경구 제형은 또한 건조된 형태(예를 들어, 동결 건조) 또는 멸균 비-수용액으로서 제조될 수 있다. 이들 제형은 멸균수(sterile water)와 같은 적합한 비히클(vehicle)과 함께 사용될 수 있다. 용해도 증강제(solubility-enhancing agents) 또한 비경구 용액의 제조에 사용될 수 있다.Parenteral formulations may also be prepared in dried form (eg, lyophilized) or as sterile non-aqueous solutions. These formulations may be used with a suitable vehicle such as sterile water. Solubility-enhancing agents may also be used in the preparation of parenteral solutions.
국소 투여(Topical Administration)Topical Administration
본 발명의 화합물은 피부 또는 경피로 국소적으로 투여될 수 있다. 이 국소 투여를 위한 제형은 로션, 용액, 크림, 젤, 하이드로젤, 연고, 폼(foam), 임플란트(implant), 패치 등을 포함한다. 국소 투여 제형을 위한 약학적으로 허용 가능한 담체는 물, 알코올, 미네랄 오일, 글리세린, 폴리에틸렌글리콜 등을 포함할 수 있다. 국소 투여는 또한 전기천공법(electroporation), 이온도입법(iontophoresis), 음파영동(phonophoresis) 등에 의하여 수행될 수 있다.The compounds of the present invention may be administered topically dermally or transdermally. Formulations for topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like. Pharmaceutically acceptable carriers for topical dosage forms may include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration may also be performed by electroporation, iontophoresis, phonophoresis, and the like.
국소 투여를 위한 조성물은 즉시 또는 변형된 방출 패턴을 가진 제형일 수 있으며, 변형된 방출 패턴은 지연된(delayed) 또는 지속된(sustained) 방출 패턴일 수 있다. Compositions for topical administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
본 발명은 또한, (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine과 4-nitrobenzyl carbonochloridate를 반응시키는 단계, 및 여기에 하기 화학식 4의 화합물을 반응시키는 단계를 포함하는, 본 발명에 따른 화합물의 제조 방법을 제공한다. The present invention also provides a step of reacting (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine with 4-nitrobenzyl carbonochloridate, And it provides a method for preparing a compound according to the present invention, comprising the step of reacting the compound of the following formula (4).
[화학식 4][Formula 4]
Figure PCTKR2021003262-appb-img-000010
Figure PCTKR2021003262-appb-img-000010
상기 화학식 4에서, R 1은 상기 화학식 2의 R 1의 정의와 같음. In Formula 4, R 1 is the same as the definition of R 1 in Formula 2 above.
본 발명에 따른 제조 방법은, 매우 간단한 단계들만으로 본 발명에 따른 화합물을 고순도로 제조할 수 있다.The preparation method according to the present invention can prepare the compound according to the present invention with high purity with only very simple steps.
본 개시의 신규한 화합물 또는 이의 약학적으로 허용 가능한 염은 변이성 NTRK 융합 단백질을 가진 다양한 고형암 치료에 우수한 효과를 나타낸다. 또한 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 본 발명의 고형암 치료용 약제학적 조성물은 다양한 암종 치료에 우수한 활성을 제공한다. The novel compound of the present disclosure or a pharmaceutically acceptable salt thereof exhibits excellent effects in the treatment of various solid cancers having a mutable NTRK fusion protein. In addition, the pharmaceutical composition for the treatment of solid cancer of the present invention comprising the compound or a pharmaceutically acceptable salt thereof provides excellent activity for the treatment of various carcinomas.
이하, 본 발명의 이해를 돕기 위하여 실시예 등을 들어 상세하게 설명하기로 한다. 그러나, 본 발명에 따른 실시예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 하기 실시예들에 한정되는 것으로 해석되어서는 안 된다. 본 발명의 실시예들은 본 발명이 속한 분야에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, examples and the like will be described in detail to help the understanding of the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art to which the present invention pertains.
본 발명에 따른 상기 화학식 1 내지 3으로 표시되는 화합물들은, 반응식 1과 2에 나타낸 단계별 방법을 참고하여 용이하게 제조될 수 있다. 반응식 2에서 사용된 아실화 (Acylation)는 통상의 기술자가 공지 기술로부터 용이하게 실시할 수 있는 아실화 반응을 나타낸다.The compounds represented by Formulas 1 to 3 according to the present invention can be easily prepared with reference to the step-by-step methods shown in Schemes 1 and 2. Acylation used in Scheme 2 refers to an acylation reaction that a person skilled in the art can easily carry out from a known technique.
[반응식 1][Scheme 1]
Figure PCTKR2021003262-appb-img-000011
Figure PCTKR2021003262-appb-img-000011
[반응식 2][Scheme 2]
Figure PCTKR2021003262-appb-img-000012
Figure PCTKR2021003262-appb-img-000012
실시예: 본 발명 화합물들의 제조EXAMPLES: Preparation of Compounds of the Invention
실시예에서 사용한 반응식 1의 출발물질과 라로트렉티니브(larotrectinib)는 중국의 Reliable Chem 사로부터 구입하여 사용하였고, 나머지 시약은 알드리치 (Aldrich)를 통하여 구입하여 사용하였다.The starting material of Scheme 1 and larotrectinib used in Examples were purchased from Reliable Chem of China and used, and the remaining reagents were purchased from Aldrich and used.
화합물 1compound 1
Figure PCTKR2021003262-appb-img-000013
Figure PCTKR2021003262-appb-img-000013
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 아세테이트 (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )carbamoyl)pyrrolidin-3-yl acetate
반응식 1의 방법Method of Scheme 1
상온에서 출발물질 (315mg)을 디클로로메탄 (Dichloromethan) 10ml에 녹인 후 디메틸아미노피리딘(dimethyl amino pyridine, DMAP, 0.1당량)을 넣고 온도를 0 ℃도 부근으로 낮추었다. 그 후 4-nitrobenzyl carbonochloridate (1.02당량)을 넣고 출발 물질이 완전히 사라질 때까지 교반하였다. 반응 종료 후 용매를 감압증류하여 제거하였다. 그 후, 아세토니트릴 (Acetonitrile) 10ml를 넣고 상온에서 (S)-pyrrolidin-3-yl acetate (1.05당량)을 넣은 다음 5시간 동안 교반하였다. 반응 종료 후 용매를 감압증류하여 제거하고, 디클로로메탄을 이용하여 추출하였다. 다음, 컬럼 크로마토그래피로 정제하여 목적 화합물을 연노랑색 고체로 327mg 수득하였다.At room temperature, the starting material (315 mg) was dissolved in 10 ml of dichloromethane, dimethyl amino pyridine (DMAP, 0.1 equivalent) was added, and the temperature was lowered to around 0 °C. After that, 4-nitrobenzyl carbonochloridate (1.02 equivalents) was added and stirred until the starting material completely disappeared. After completion of the reaction, the solvent was removed by distillation under reduced pressure. Then, 10 ml of acetonitrile was added, and (S)-pyrrolidin-3-yl acetate (1.05 equivalent) was added at room temperature, followed by stirring for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and extracted using dichloromethane. Then, it was purified by column chromatography to obtain 327 mg of the target compound as a pale yellow solid.
반응식 2의 방법Method of Scheme 2
라로트렉티니브(larotrectinib) 424mg을 디클로로메탄에 녹인 후 아세틱안하이드라이드(acetic anhydride, 1.1당량)과 디메틸아미노피리딘 (dimethyl amino pyridine, DMAP, 0.1당량)을 넣고 상온에서 3시간 동안 교반하였다. 반응 종료 후 디클로로메탄을 이용하여 추출하고 컬럼 크로마토그래피로 정제하여 목적 화합물을 연노랑색 고체로 350mg 수득하였다. After dissolving 424 mg of larotrectinib in dichloromethane, acetic anhydride (1.1 equivalents) and dimethyl aminopyridine (dimethyl amino pyridine, DMAP, 0.1 equivalents) were added and stirred at room temperature for 3 hours. After completion of the reaction, the mixture was extracted with dichloromethane and purified by column chromatography to obtain 350 mg of the target compound as a pale yellow solid.
화합물 2compound 2
Figure PCTKR2021003262-appb-img-000014
Figure PCTKR2021003262-appb-img-000014
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)-3-카르바모일)-피롤리딘-3-일 아실레이트(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )-3-carbamoyl)-pyrrolidin-3-yl acylate
화합물 1의 제조에서 이용된 반응식 2의 방법 중 아세틱 안하이드라이드 (acetic anhydride, 1.1당량) 대신 아크릴로일 클로라이드 (acryloyl chloride, 1.05당량)를 사용하는 것 외에 동일한 방법을 사용하였다. 목적화합물 385mg을 연노란색 고체로 수득하였다.In the method of Scheme 2 used in the preparation of compound 1 The same method was used except for using acryloyl chloride (1.05 equivalent) instead of acetic anhydride (1.1 equivalent). 385 mg of the target compound was obtained as a pale yellow solid.
화합물 3compound 3
Figure PCTKR2021003262-appb-img-000015
Figure PCTKR2021003262-appb-img-000015
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 이소부티레이트(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )carbamoyl)pyrrolidin-3-yl isobutyrate
화합물 1의 제조에서 이용된 반응식 2의 방법 중 아세틱안 하이드라이드(acetic anhydride, 1.1당량) 대신 이소부티릴 클로라이드(isobutyryl chloride, 1.05당량)를 사용하는 것 외에 동일한 방법을 사용하였다. 목적화합물 316mg을 노란색 고체로 수득하였다.In the method of Scheme 2 used in the preparation of compound 1 The same method was used except for using isobutyryl chloride (1.05 equivalent) instead of acetic anhydride (1.1 equivalent). 316 mg of the target compound was obtained as a yellow solid.
화합물 4compound 4
Figure PCTKR2021003262-appb-img-000016
Figure PCTKR2021003262-appb-img-000016
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 프로피오네이트(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl propionate
화합물 1의 제조에서 이용된 반응식 2의 방법 중 아세틱 안하이드라이드(acetic anhydride, 1.1당량) 대신 프로피오닐 클로라이드(propionyl chloride, 1.05당량)를 사용하는 것 외에 동일한 방법을 사용하여 목적화합물 323mg을 노란색 고체로 수득하였다.In the method of Scheme 2 used in the preparation of compound 1 323 mg of the target compound was obtained as a yellow solid by using the same method except for using propionyl chloride (1.05 equivalent) instead of acetic anhydride (1.1 equivalents).
화합물 5compound 5
Figure PCTKR2021003262-appb-img-000017
Figure PCTKR2021003262-appb-img-000017
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 글리시네이트(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )carbamoyl)pyrrolidin-3-yl glycinate
화합물 1의 제조에서 이용된 반응식 2의 방법 중 아세틱안 하이드라이드(acetic anhydride, 1.1당량) 대신 질소에 Boc (tert-butoxy carbonyl)이 치환된 Glycine (1.05당량)과 EDC.HCl (1.1당량)를 사용하는 것 외에 동일한 방법을 사용하여 목적 화합물 323mg을 노란색 고체로 수득하였다.In the method of Scheme 2 used in the preparation of compound 1 323 mg of the target compound using the same method except using Glycine (1.05 equiv.) and EDC.HCl (1.1 equiv.) in which Boc (tert-butoxy carbonyl) is substituted for nitrogen instead of acetic anhydride (1.1 equiv.) was obtained as a yellow solid.
화합물 6compound 6
Figure PCTKR2021003262-appb-img-000018
Figure PCTKR2021003262-appb-img-000018
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 피페리딘-1-카르복실레이트(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )carbamoyl)pyrrolidin-3-yl piperidine-1-carboxylate
화합물 1의 제조에서 이용된 반응식 2의 방법 중 아세틱 안하이드라이드 (acetic anhydride, 1.1당량) 대신 피페리딘-1-카보닐 클로라이드 (piperidine-1-carbonyl chloride, 1.05당량)를 사용하는 것 외에 동일한 방법을 사용하여 목적 화합물 325mg을 노란색 고체로 수득하였다.In the method of Scheme 2 used in the preparation of compound 1 325 mg of the target compound as a yellow solid using the same method except for using piperidine-1-carbonyl chloride (1.05 equivalent) instead of acetic anhydride (1.1 equivalents) obtained.
화합물 7compound 7
Figure PCTKR2021003262-appb-img-000019
Figure PCTKR2021003262-appb-img-000019
4-(((S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일)옥시)-4-옥소부타노익에시드4-(((S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine -3-yl)carbamoyl)pyrrolidin-3-yl)oxy)-4-oxobutanoic acid
화합물 1의 제조에서 이용된 반응식 2의 방법 중 아세틱 안하이드라이드(acetic anhydride, 1.1당량) 대신 숙시닉 안하이드라이드 (succinic anhydride, 1.2당량)를 사용하는 것 외에 동일한 방법을 사용하여 목적 화합물 220mg을 노란색 고체로 수득하였다.In the method of Scheme 2 used in the preparation of compound 1 220 mg of the target compound was obtained as a yellow solid by using the same method except for using succinic anhydride (1.2 equivalents) instead of acetic anhydride (1.1 equivalents).
화합물 8compound 8
Figure PCTKR2021003262-appb-img-000020
Figure PCTKR2021003262-appb-img-000020
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일-2-부티노에이트(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl-2-butinoate
화합물 1의 제조에서 이용된 반응식 2의 방법 중 아세틱 안하이드라이드(acetic anhydride, 1.1당량) 대신 부트-2-이노일 클로라이드(but-2-ynoyl chloride, 1.05당량)를 사용하는 것 외에 동일한 방법을 사용하여 목적 화합물 354mg을 노란색 고체로 수득하였다.In the method of Scheme 2 used in the preparation of compound 1 354 mg of the target compound was obtained as a yellow solid by using the same method except for using but-2-ynoyl chloride (1.05 equivalent) instead of acetic anhydride (1.1 equivalents) .
화합물 9compound 9
Figure PCTKR2021003262-appb-img-000021
Figure PCTKR2021003262-appb-img-000021
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 카르바메이트(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )carbamoyl)pyrrolidin-3-yl carbamate
화합물 1의 제조에서 이용된 반응식 2의 방법 중 아세틱안 하이드라이드(acetic anhydride, 1.1당량) 대신 술포닐클로로이소시아네이트 (sulfonyl chloro isocyante, 1.5당량)를 사용하는 것 외에 동일한 방법을 사용하여 목적 화합물 167mg을 노란색 고체로 수득하였다.In the method of Scheme 2 used in the preparation of compound 1 167 mg of the target compound was obtained as a yellow solid by using the same method except for using sulfonyl chloro isocyante (1.5 equivalents) instead of acetic anhydride (1.1 equivalents).
화합물 10compound 10
Figure PCTKR2021003262-appb-img-000022
Figure PCTKR2021003262-appb-img-000022
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 디메틸카르바메이트(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )carbamoyl)pyrrolidin-3-yl dimethylcarbamate
화합물 1의 제조에서 이용된 반응식 2의 방법 중 아세틱 안하이드라이드(acetic anhydride, 1.1당량) 대신 디메틸 카바믹 클로라이드 (dimethylcarbamic chloride, 1.05당량)를 사용하는 것 외에 동일한 방법을 사용하여 목적 화합물 268mg을 노란색 고체로 수득하였다.In the method of Scheme 2 used in the preparation of Compound 1, 268 mg of the target compound was prepared using the same method except for using dimethylcarbamic chloride (1.05 equivalent) instead of acetic anhydride (1.1 equivalent). It was obtained as a yellow solid.
화합물 11compound 11
Figure PCTKR2021003262-appb-img-000023
Figure PCTKR2021003262-appb-img-000023
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 시클로헥세인카르복실레이트(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )carbamoyl)pyrrolidin-3-yl cyclohexanecarboxylate
화합물 1의 제조에서 이용된 반응식 2의 방법 중 아세틱 안하이드라이드(acetic anhydride, 1.1당량) 대신 씨클로헥산카보닐 클로라이드 (cyclohexanecarbonyl chloride, 1.05당량)를 사용하는 것 외에 동일한 방법을 사용하여 목적화합물 316mg을 노란색 고체로 수득하였다.Among the methods of Scheme 2 used in the preparation of Compound 1, 316 mg of the target compound was used except for using cyclohexanecarbonyl chloride (1.05 equivalents) instead of acetic anhydride (1.1 equivalents). was obtained as a yellow solid.
화합물 12compound 12
Figure PCTKR2021003262-appb-img-000024
Figure PCTKR2021003262-appb-img-000024
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 벤조에이트(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )carbamoyl)pyrrolidin-3-yl benzoate
화합물 1의 제조에서 이용된 반응식 2의 방법 중 아세틱 안하이드라이드 (acetic anhydride, 1.1당량) 대신 벤조일 클로라이드 (benzoyl chloride, 1.05당량)를 사용하는 것 외에 동일한 방법을 사용하여 목적 화합물 377mg을 노란색 고체로 수득하였다.In the method of Scheme 2 used in the preparation of compound 1, 377 mg of the target compound was prepared as a yellow solid by using the same method except for using benzoyl chloride (1.05 equivalent) instead of acetic anhydride (1.1 equivalent) was obtained with
화합물 13compound 13
Figure PCTKR2021003262-appb-img-000025
Figure PCTKR2021003262-appb-img-000025
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 L-세리네이트(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )carbamoyl)pyrrolidin-3-yl L-serinate
화합물 1의 제조에서 이용된 반응식 2의 방법 중 아세틱 안하이드라이드(acetic anhydride, 1.1당량) 대신 N-복세린 (N-Boc Serine, 1.05당량)를 사용하는 것 외에 동일한 방법을 사용하여 목적 화합물 226mg을 노란색 고체로 수득하였다.Among the methods of Scheme 2 used in the preparation of Compound 1, the target compound was used in the same manner except for using N-boxerine (N-Boc Serine, 1.05 equivalents) instead of acetic anhydride (1.1 equivalents). 226 mg was obtained as a yellow solid.
화합물 14compound 14
Figure PCTKR2021003262-appb-img-000026
Figure PCTKR2021003262-appb-img-000026
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 L-알라니네이트(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl L-alaninate
화합물 1의 제조에서 이용된 반응식 2의 방법 중 아세틱 안하이드라이드(acetic anhydride, 1.1당량) 대신 N-Boc Alanine (1.05당량)를 사용하는 것 외에 동일한 방법을 사용하여 목적 화합물 234 mg을 노란색 고체로 수득하였다.In the method of Scheme 2 used in the preparation of Compound 1, 234 mg of the target compound was prepared using the same method except for using N-Boc Alanine (1.05 equivalent) instead of acetic anhydride (1.1 equivalent) as a yellow solid. was obtained with
화합물 15compound 15
Figure PCTKR2021003262-appb-img-000027
Figure PCTKR2021003262-appb-img-000027
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 아세틸-L-알라니네이트(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )carbamoyl)pyrrolidin-3-yl acetyl-L-alaninate
화합물 1의 제조에서 이용된 반응식 2의 방법 중 아세틱 안하이드라이드(acetic anhydride, 1.1당량) 대신 acetyl-L-alanine (1.05당량)를 사용하는 것 외에 동일한 방법을 사용하여 목적 화합물 316mg을 노란색 고체로 수득하였다.Among the methods of Scheme 2 used in the preparation of Compound 1, 316 mg of the target compound was prepared as a yellow solid by using the same method except for using acetyl-L-alanine (1.05 equivalents) instead of acetic anhydride (1.1 equivalents). was obtained with
화합물 16compound 16
Figure PCTKR2021003262-appb-img-000028
Figure PCTKR2021003262-appb-img-000028
(S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 메틸 푸마레이트(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )carbamoyl)pyrrolidin-3-yl methyl fumarate
화합물 1의 제조에서 이용된 반응식 2의 방법 중 아세틱 안하이드라이드(acetic anhydride, 1.1당량) 대신 monomethyl fumaric acid (1.05당량)를 사용하는 것 외에 동일한 방법을 사용하여 목적 화합물 325mg을 노란색 고체로 수득하였다.325 mg of the target compound was obtained as a yellow solid by using the same method except for using monomethyl fumaric acid (1.05 equivalents) instead of acetic anhydride (1.1 equivalents) in the method of Scheme 2 used in the preparation of compound 1 did.
상기 실시예 화합물들의 분석 결과는 표 1에 나타내었다.The results of analysis of the compounds of the Examples are shown in Table 1.
Figure PCTKR2021003262-appb-img-000029
Figure PCTKR2021003262-appb-img-000029
Figure PCTKR2021003262-appb-img-000030
Figure PCTKR2021003262-appb-img-000030
Figure PCTKR2021003262-appb-img-000031
Figure PCTKR2021003262-appb-img-000031
실험예 1: 표적 카이네이즈 효소 IC50 효과 측정Experimental Example 1: Measurement of the effect of target kinase enzyme IC50
상기 합성예에서 얻어진 화합물들에 대하여 정상 카이네이즈 효소 1종인 ACK1(h) 및 표적 카이네이즈 효소 3종인 TrKA(h), TrKB(h), 및 TrKC(h)에 대한 저해 효과를 각각 측정하였다. 각 화합물이 표적 효소의 활성을 50 % 억제한 농도로 IC 50 값을 산출하여, 그 결과를 하기 표 2에 A, B, C, 및 D로 나타냈다. 여기에서 A는 IC 50가 100 nM 이하, B는 IC 50가 100 초과 500 nM 이하, C는 IC 50가 500 초과 1000 nM 이하, 및 D는 IC 50가 1000 nM 초과임을 의미한다. 대조약물로는 라로트렉티닙 (Larotrectinib)을 사용하였다.For the compounds obtained in the above synthesis example, the inhibitory effect on ACK1(h), which is one normal kinase enzyme, and TrKA(h), TrKB(h), and TrKC(h), which are three types of target kinase enzymes, were measured, respectively. IC 50 values were calculated at concentrations in which each compound inhibited the activity of the target enzyme by 50%, and the results are shown as A, B, C, and D in Table 2 below. where A means an IC 50 of 100 nM or less, B means an IC 50 greater than 100 and 500 nM or less, C means an IC 50 greater than 500 and 1000 nM or less, and D means an IC 50 greater than 1000 nM. As a control drug, Larotrectinib was used.
모든 키나아제 분석은 50㎕ 반응 용적으로 Perkin Elmer/NEN (Boston, MA, 미국)으로부터 96-웰 플래시플레이트TM에서 수행하였다. 반응 혼합물은 다음 순서로 피펫팅 하였다:All kinase assays were performed in 96-well flashplates™ from Perkin Elmer/NEN (Boston, MA, USA) in 50 μl reaction volumes. The reaction mixture was pipetted in the following order:
- 20㎕의 분석 완충제 (표준 완충제)- 20 μl assay buffer (standard buffer)
- 5㎕의 ATP 용액(H20중)- 5 μl of ATP solution (in H20)
- 5㎕의 시험 화합물(10% DMSO 중)- 5 μl of test compound (in 10% DMSO)
- 10㎕의 기질/10㎕의 효소 용액 (예비 혼합)- 10 μl substrate/10 μl enzyme solution (premix)
효소 및 기질은 웰 마다 다음과 같은 량으로 사용하였다: 모든 효소에 대한 분석은 60 mM HEPES-NaOH (pH 7.5), 3 mM MgCl2, 3 mM MnCl2, 3μM Na-오르토바나데이트, 1.2mM DTT, 50 ㎍/ml PEG20000, 1μM [ 33P]-ATP (웰당 약 5 x 1005 cpm) Enzymes and substrates were used in the following amounts per well: All enzyme assays were 60 mM HEPES-NaOH (pH 7.5), 3 mM MgCl 2 , 3 mM MnCl 2 , 3 μM Na-orthovanadate, 1.2 mM DTT, 50 μg/ml PEG20000, 1 μM [ 33 P]-ATP (approximately 5 x 1005 cpm per well)
반응 혼합물은 30℃에서 80 분 동안 배양하였다. 반응은 50㎕의 2% (v/v) H 3PO 4로 정지시키고, 플레이트는 흡인하고 200㎕ H20 또는 200㎕ 0.9% (w/v) NaCl로 두 번 세척하였다.The reaction mixture was incubated at 30° C. for 80 minutes. The reaction was stopped with 50 μl of 2% (v/v) H 3 PO 4 , the plate was aspirated and washed twice with 200 μl H20 or 200 μl 0.9% (w/v) NaCl.
33P의 편입은 마이크로플레이트 신틸레이션 계수기(Microbeta, Wallac)로 측정하였다. 모든 분석은 베크만 카운터/사기안 로보트 시스템으로 수행하였다. Incorporation of 33 P was measured with a microplate scintillation counter (Microbeta, Wallac). All analyzes were performed with a Beckman Counter/Sagian robotic system.
하기 표 2에 각 화합물들에 대한 암세포 성장억제 효과 측정 값, 즉, 표적 카이네이즈 효소에 대한 IC 50을 종합하여 나타내었다. In Table 2 below, the measured values of the cancer cell growth inhibitory effect for each compound, ie, the IC 50 for the target kinase enzyme, are summarized.
화합물 번호compound number ACK1(h)ACK1(h) TrkA(h)TrkA(h) TrkB(h)TrkB(h) TrkC(h)TrkC(h)
1One DD AA AA AA
22 DD AA AA AA
33 DD AA AA AA
44 DD AA AA BB
55 DD AA AA AA
66 DD AA AA AA
77 DD AA AA AA
88 DD AA BB BB
99 DD AA AA AA
1010 DD AA AA AA
1111 DD AA AA AA
1212 DD AA AA AA
1313 DD BB AA BB
1414 DD BB BB BB
1515 DD BB BB CC
1616 DD AA AA AA
라로트렉티닙Larotrectinib >1,000 (D)>1,000 (D) 8 (A)8 (A) 18 (A)18 (A) 20 (A)20 (A)
상기 표 2에 나타나는 바와 같이, 본 발명의 화합물들은 정상 카이네이즈 효소 (ACK1(h)) 에서는 저해 효과를 보이지 않고, 표적 카이네이즈 효소 3종(TrKA(h), TrKB(h), TrKC(h))에 대해서는 매우 우수한 저해 효과를 나타내었다.As shown in Table 2, the compounds of the present invention show no inhibitory effect on normal kinase enzymes (ACK1(h)), and three types of target kinase enzymes (TrKA(h), TrKB(h), TrKC(h)) showed a very good inhibitory effect.
실험예 2: 약동학적 평가Experimental Example 2: Pharmacokinetic evaluation
상기 실시예 화합물들 및 라로트렉티닙에 대한 약물동태 시험을 다음과 같이 실시하였다. 즉, 시험물질을 SD (Sprague-Dawley) 랫트 (rat)에 단회 경구투여한 후 대사과정에 의해 혈중 방출되는 라로트렉티니브 약물의 동태를 표준물질과 비교함으로써 본 발명의 화합물의 효능을 입증하였다. 구체적으로, 라로트렉티니브은 정맥 및 경구 투여를 각각 실시하였으며, 시험물질은 경구투여하여 혈중 라로트렉티니브 물질의 농도를 분석하였다. Pharmacokinetic studies of the compounds of Examples above and larotrectinib were performed as follows. That is, the efficacy of the compound of the present invention was demonstrated by comparing the kinetics of the larotrectinib drug released into the blood by the metabolic process with a standard substance after a single oral administration of the test substance to SD (Sprague-Dawley) rats. . Specifically, larotrectinib was administered intravenously and orally, respectively, and the test substance was orally administered to analyze the concentration of larotrectinib in the blood.
라로트렉티닙 및 시험물질은 각각 동일한 방법으로 조제한 후 랫트에 0.057 mmol/kg 용량으로 투여하였다. 정해진 시간에 채혈한 후 혈장을 분리하였다. 약물의 분석은 HPLC (XBridge column C 18, Waters, mobile phase 0.1% formic acid:acetonitrile (30:70, %/%)) 및 MS/MS (ESI positive, MRM 429 -> 342)를 이용하여 실시하였다. 랫트 공혈장과 각각의 상용 표준용액을 9:1 비율로 혼합하여 1, 5, 10, 50, 100 및 500 ng/ml의 농도로 조제, 검량을 하였다. 또한 QC 시료의 조제는 랫트 공혈장과 QC용 표준용액을 9:1 비율로 혼합하여, 10, 75 및 250 ng/ml 농도로 조제하였다. 전처리 방법은 혈장시료 100 μl를 원심분리용 튜브로 옮기고, 내부표준용액 10 μl와 메탄올 300 μl를 첨가한 후 약 30초간 혼합하였다. 튜브를 3,000 x g (4℃)에서 약 5분간 원심분리하고, 상층액을 취하여 LC 바이알로 옮긴 후 기기에 주입하였다. 그리고 미리 검증된 분석법을 적용하여 랫트 혈장 중 유효성분, 즉 라로트렉티니브의 농도를 정량하였다. Larotrectinib and the test substance were each prepared in the same manner and administered to rats at a dose of 0.057 mmol/kg. After blood was collected at a predetermined time, plasma was separated. Analysis of the drug was carried out using HPLC (XBridge column C 18 , Waters, mobile phase 0.1% formic acid:acetonitrile (30:70, %/%)) and MS/MS (ESI positive, MRM 429 -> 342). . Rat donor plasma and each commercial standard solution were mixed at a ratio of 9:1 to prepare and calibrate at concentrations of 1, 5, 10, 50, 100 and 500 ng/ml. In addition, the QC sample was prepared at 10, 75 and 250 ng/ml concentrations by mixing rat plasma and QC standard solution in a 9:1 ratio. As for the pretreatment method, 100 μl of the plasma sample was transferred to a centrifuge tube, and 10 μl of the internal standard solution and 300 μl of methanol were added and mixed for about 30 seconds. The tube was centrifuged at 3,000 xg (4°C) for about 5 minutes, and the supernatant was transferred to an LC vial and then injected into the instrument. And the concentration of the active ingredient in rat plasma, that is, larotrectinib, was quantified by applying a previously verified assay.
약물 동태 파라미터는 WinNonlin 5.2 (Pharsight, USA) 프로그램을 사용하였고, Noncompartment modeling (best fit)으로 AUC 0-t, AUC 0-∞, C max, T max, t 1/2를 계산하였다. 약물동태 파라미터 결과는 평균 (Mean)과 표준편차 (SD)로 표기하였고, SPSS 프로그램 (Statistical Package for the Social Sciences, 10.0K, USA)을 사용하여 통계 처리하였다.For pharmacokinetic parameters, WinNonlin 5.2 (Pharsight, USA) program was used, and AUC 0-t , AUC 0-∞ , C max , T max , t 1/2 were calculated by noncompartment modeling (best fit). Pharmacokinetic parameter results were expressed as mean (Mean) and standard deviation (SD), and statistically processed using the SPSS program (Statistical Package for the Social Sciences, 10.0K, USA).
시험 결과, 정맥 투여된 라로트렉티니브 대비 경구 투여된 라라트렉티니브와 본 개시의 시험물질들의 생체이용률을 정리하면 다음의 표 3과 같다.As a result of the test, the bioavailability of the orally administered larotrectinib and the test substances of the present disclosure compared to the intravenously administered larotrectinib is summarized in Table 3 below.
시험물질test substance 생체이용률 (F, %)Bioavailability (F, %) 시험물질test substance 생체이용률 (F, %)Bioavailability (F, %)
경구 투여 라로트렉티니브Oral Larotrectinib 34 34 화합물 11compound 11 40.340.3
화합물 1compound 1 146.5146.5 화합물 13compound 13 89.089.0
화합물 2compound 2 104.0104.0 화합물 15compound 15 134.7134.7
화합물 3compound 3 121.0121.0 화합물 16compound 16 170.5170.5
화합물 4compound 4 170.7170.7
화합물 7compound 7 32.332.3
대표적인 실시예 3 화합물의 경우, 평균 AUC t는 1858 hr*ng/ml, 평균 AUC i는 1858 hr*ng/ml, 평균 C max는 1424 ng/ml, 평균 T max는 0.33시간, 평균 t 1/2은 2.40시간, 생체이용률은 121.0%이었다. 실시예 4 화합물의 경우, 평균 AUC t는 4589 hr*ng/ml, 평균 AUC i는 5043 hr*ng/ml, 평균 C max는 1978 ng/ml, 평균 T max는 0.33시간, 평균 t 1/2은 6.67시간, 생체이용률은 170.7%이었다.For the Representative Example 3 compound, the mean AUC t was 1858 hr*ng/ml, the mean AUC i was 1858 hr*ng/ml, the mean C max was 1424 ng/ml, the mean T max was 0.33 hours, the mean t 1/ 2 was 2.40 hours, and the bioavailability was 121.0%. For Example 4 compound, mean AUC t is 4589 hr*ng/ml, mean AUC i is 5043 hr*ng/ml, mean C max is 1978 ng/ml, mean T max is 0.33 hours, mean t 1/2 was 6.67 hours, and the bioavailability was 170.7%.
상기 표 3의 결과에 나타나는 바와 같이, 본 개시에 따른 몇몇 화합물들의 경우 경구 투여 생체이용률이 탁월하였다.As shown in the results of Table 3, some of the compounds according to the present disclosure exhibited excellent orally administered bioavailability.

Claims (7)

  1. 화학식 1 내지 3 중 어느 하나의 구조를 갖는 화합물 또는 이의 약학적으로 허용 가능한 염.A compound having the structure of any one of Formulas 1 to 3, or a pharmaceutically acceptable salt thereof.
    [화학식 1][Formula 1]
    Figure PCTKR2021003262-appb-img-000032
    Figure PCTKR2021003262-appb-img-000032
    상기 화학식 1에서, 상기 amino acid는 D,L-type의 아미노산임,In Formula 1, the amino acid is an amino acid of D, L-type,
    [화학식 2][Formula 2]
    Figure PCTKR2021003262-appb-img-000033
    Figure PCTKR2021003262-appb-img-000033
    상기 화학식 2에서, In Formula 2,
    X는 O 또는 S이고, X is O or S;
    R 1는 H, 알킬, 할로겐이 하나 이상 치환된 알킬, -O-알킬, -S-알킬, 히드록시 (OH), 티올 (thiol), 아민 (amine), 에스터(ester), 카르복실산(COOH), 시아노(CN)가 측쇄로 연결된 알킬, 알킬이 측쇄로 도입된 2~3차 아민, 할로겐, 시아노(CN), 사이클로알킬, 헤테로사이클, 아릴, 또는 헤테로아릴이며, n은 0 내지 5의 정수임, R 1 is H, alkyl, alkyl substituted with one or more halogens, -O-alkyl, -S-alkyl, hydroxy (OH), thiol, amine, ester, carboxylic acid ( COOH), cyano (CN) is branched alkyl, secondary to tertiary amine in which alkyl is introduced as a branched chain, halogen, cyano (CN), cycloalkyl, heterocycle, aryl, or heteroaryl, and n is 0 an integer from to 5;
    [화학식 3][Formula 3]
    Figure PCTKR2021003262-appb-img-000034
    Figure PCTKR2021003262-appb-img-000034
    상기 화학식 3에서, In Formula 3,
    A는
    Figure PCTKR2021003262-appb-img-000035
    ,
    Figure PCTKR2021003262-appb-img-000036
    , 또는
    Figure PCTKR2021003262-appb-img-000037
    이고,     A is
    Figure PCTKR2021003262-appb-img-000035
    ,
    Figure PCTKR2021003262-appb-img-000036
    , or
    Figure PCTKR2021003262-appb-img-000037
    ego,
    R 2는 수소, 알킬, 할로겐이 하나 이상 치환된 알킬, -O-알킬, -S-알킬, 에스터(ester), 시아노가 측쇄로 연결된 알킬, 알킬이 측쇄로 도입된 1~3차 아민, 카르복실산(COOH), 할로겐, 시아노(CN), 사이클로알킬, 헤테로사이클, 아릴, 또는 헤테로아릴임.R 2 is hydrogen, alkyl, alkyl substituted with one or more halogens, -O-alkyl, -S-alkyl, ester, cyano-connected alkyl as a side chain, primary to tertiary amines in which alkyl is introduced as a side chain, car acid (COOH), halogen, cyano (CN), cycloalkyl, heterocycle, aryl, or heteroaryl.
  2. 제1항에 있어서, 상기 화합물은 The method of claim 1, wherein the compound is
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 아세테이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl acetate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)-3-카르바모일)-피롤리딘-3-일 아실레이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )-3-carbamoyl)-pyrrolidin-3-yl acylate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 이소부티레이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl isobutyrate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 프로피오네이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl propionate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 글리시네이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl glycinate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 피페리딘-1-카르복실레이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl piperidine-1-carboxylate,
    4-(((S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일)옥시)-4-옥소부타노익에시드,4-(((S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine -3-yl) carbamoyl) pyrrolidin-3-yl) oxy) -4-oxobutanoic acid,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일-2-부티노에이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl-2-butinoate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 카르바메이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl carbamate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 디메틸카르바메이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl dimethylcarbamate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 시클로헥세인카르복실레이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl cyclohexanecarboxylate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 벤조에이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl benzoate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 L-세리네이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl L-serinate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 L-알라니네이트,(S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl L-alaninate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 아세틸-L-알라니네이트, 또는 (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl acetyl-L-alaninate, or
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 메틸 푸마레이트인, (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl methyl fumarate,
    화합물 또는 이의 약학적으로 허용 가능한 염.A compound or a pharmaceutically acceptable salt thereof.
  3. 제2항에 있어서, 상기 화합물은 3. The method of claim 2, wherein the compound is
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 아세테이트, (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl acetate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)-3-카르바모일)-피롤리딘-3-일 아실레이트, (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )-3-carbamoyl)-pyrrolidin-3-yl acylate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 이소부티레이트, (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl isobutyrate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 프로피오네이트, (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl propionate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 L-세리네이트, (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl L-serinate,
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 아세틸-L-알라니네이트, 또는 (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl acetyl-L-alaninate, or
    (S)-1-((5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)카르바모일)피롤리딘-3-일 메틸 푸마레이트인, (S)-1-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) carbamoyl) pyrrolidin-3-yl methyl fumarate,
    화합물 또는 이의 약학적으로 허용 가능한 염.A compound or a pharmaceutically acceptable salt thereof.
  4. 제1항 내지 제3항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 변이성 TRK 융합 단백질 억제용 약학 조성물.A pharmaceutical composition for inhibiting a mutable TRK fusion protein comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  5. 제1항 내지 제3항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 고형암 치료용 약학 조성물.A pharmaceutical composition for treating solid cancer comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  6. 제5항에 있어서, 상기 고형암은 연부조직육종, 섬유육종, 침샘암, 갑상샘암, 폐암, 흑색종, 결장암, 위장관기질종양, 담관암, 맹장암, 유방암 또는 췌장암인, 약학 조성물. The pharmaceutical composition according to claim 5, wherein the solid cancer is soft tissue sarcoma, fibrosarcoma, salivary gland cancer, thyroid cancer, lung cancer, melanoma, colon cancer, gastrointestinal stromal tumor, bile duct cancer, appendix cancer, breast cancer or pancreatic cancer.
  7. (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine과 4-nitrobenzyl carbonochloridate를 반응시키는 단계, 및reacting (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine with 4-nitrobenzyl carbonochloridate, and
    여기에 하기 화학식 4의 화합물을 반응시키는 단계를 포함하는,Including the step of reacting the compound of Formula 4 here,
    제1항 내지 제3항 중 어느 한 항에 따른 화합물의 제조 방법.A process for the preparation of a compound according to any one of claims 1 to 3.
    [화학식 4][Formula 4]
    Figure PCTKR2021003262-appb-img-000038
    Figure PCTKR2021003262-appb-img-000038
    상기 화학식 4에서, R 1은 상기 화학식 2의 R 1의 정의와 같음.In Formula 4, R 1 is the same as the definition of R 1 in Formula 2 above.
PCT/KR2021/003262 2020-03-17 2021-03-16 Compound for inhibiting mutagenic trk fusion protein, and pharmaceutical use and manufacturing method thereof WO2021187878A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20180043851A (en) * 2008-10-22 2018-04-30 어레이 바이오파마 인크. SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS
CN107987082A (en) * 2017-11-14 2018-05-04 苏州东南药业股份有限公司 A kind of Preparation Method And Their Intermediate of Larotrectinib
CN108003161A (en) * 2016-10-28 2018-05-08 正大天晴药业集团股份有限公司 Neurotrophic factor tyrosine kinase receptor inhibitor
CN109705124A (en) * 2018-12-14 2019-05-03 上海健康医学院 A kind of labeled with radioactive fluorine Larotrectinib compound and preparation method thereof
CN109942582A (en) * 2019-03-15 2019-06-28 上海健康医学院 It is a kind of target tropomyosin kinases TRK fusion protein PET probe and its synthesis and application

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20180043851A (en) * 2008-10-22 2018-04-30 어레이 바이오파마 인크. SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS
CN108003161A (en) * 2016-10-28 2018-05-08 正大天晴药业集团股份有限公司 Neurotrophic factor tyrosine kinase receptor inhibitor
CN107987082A (en) * 2017-11-14 2018-05-04 苏州东南药业股份有限公司 A kind of Preparation Method And Their Intermediate of Larotrectinib
CN109705124A (en) * 2018-12-14 2019-05-03 上海健康医学院 A kind of labeled with radioactive fluorine Larotrectinib compound and preparation method thereof
CN109942582A (en) * 2019-03-15 2019-06-28 上海健康医学院 It is a kind of target tropomyosin kinases TRK fusion protein PET probe and its synthesis and application

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