WO2023121251A1 - Egfr and hdac dual inhibitor compounds and medical use thereof - Google Patents

Egfr and hdac dual inhibitor compounds and medical use thereof Download PDF

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WO2023121251A1
WO2023121251A1 PCT/KR2022/020882 KR2022020882W WO2023121251A1 WO 2023121251 A1 WO2023121251 A1 WO 2023121251A1 KR 2022020882 W KR2022020882 W KR 2022020882W WO 2023121251 A1 WO2023121251 A1 WO 2023121251A1
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amino
phenyl
methylmethylsulfonamido
oxoheptyl
hydroxyamino
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PCT/KR2022/020882
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French (fr)
Korean (ko)
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유형철
김재선
이윤진
서행란
김지희
송연화
남재경
이해준
임지웅
이주영
최광현
강희근
김선주
백민정
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한국원자력의학원
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Publication of WO2023121251A1 publication Critical patent/WO2023121251A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present disclosure relates to compounds for the treatment or alleviation of fibrosis.
  • the present disclosure also relates to the pharmaceutical use of a compound according to the present disclosure for the treatment or alleviation of fibrosis. That is, the present disclosure relates to methods for the treatment of fibrosis or relief of symptoms of fibrosis.
  • Fibrosis can affect various organs such as the heart, liver, lungs, skeletal muscle, kidneys, blood vessels, and more.
  • fibrosis can be classified into skeletal muscle tissue (dystrophic muscle disease), heart and vascular tissue (myocardial infarction), liver tissue (non-alcoholic fatty liver disease/cirrhosis), lung tissue (idiopathic pulmonary fibrosis), and kidney tissue (chronic kidney disease). /renal fibrosis).
  • HDAC histone deacetylase
  • the problem to be solved by the present disclosure is to provide a compound effective for the treatment or alleviation of fibrosis or a pharmaceutical composition containing such a compound as an active ingredient. That is, the problem to be solved by the present disclosure is to find a component effective for the treatment or alleviation of fibrosis and to provide a medicinal use thereof.
  • the present disclosure provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 independently of each other are hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
  • R 4 is hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl;
  • n 0, 1, 2, 3, or 4;
  • R 5 and R 6 independently represent hydrogen, C 1 -C 6 alkyl substituted with hydroxamic acid, or C 2 -C 6 alkene substituted with hydroxamic acid.
  • R 5 and R 6 are each independently hydrogen, -C 1 ⁇ C 6 alkyl-C(O)N(OH)H, or -C 2 ⁇ C 6 alkene-C(O )N(OH)H.
  • the compounds according to the present invention may be used as pharmaceutically acceptable salts. Indeed, in one aspect of the present invention, salts of compounds according to Formula 1 may be preferred over the respective free bases, since, for example, such salts impart greater stability or solubility to the molecule and thus the dosage form. This is because it promotes the formulation of Rho.
  • compounds according to Formula 1 may function as compounds with basic functional groups.
  • the pharmaceutically acceptable salt of Formula 1 is an acid addition salt.
  • Pharmaceutically acceptable acid addition salts are formed from acids which form non-toxic salts. For example, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulphate, nitrate, phosphate, hydrogen phosphate ( hydrogen phosphate, acetate, maleate, malate, fumarate, malonate, lactate, tartrate, citrate , formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate ), benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate, methanesulphonic, ethanesulphonic ), p-toluenesulphonic, and isethionat
  • pharmaceutically acceptable salt refers to a salt that retains the desired biological activity of a subject compound and exhibits minimal undesirable toxic effects.
  • pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or separately by reacting the purified compound in its free acid or free base form with a suitable base or acid separately.
  • the term “pharmaceutically acceptable” means generally considered safe for such use, officially approved for such use by a national or state regulatory agency, or approved by the U.S. Pharmacopoeia or veterinary , more particularly suitable for use in pharmaceutical preparations listed in other pharmacopeias generally recognized for use in humans.
  • alkyl refers to a saturated straight-chain or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms (unless the number of carbon atoms is specifically limited). "Lower alkyl” means a straight chain or branched alkyl having 1 to 4 carbon atoms.
  • saturated straight-chain alkyls are -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n- decyl, while 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 1-6 when described as “C 1-6 ”, “C1-6”, or “C1-C6”, it means that the number of carbon atoms is 1 to 6.
  • C1-C6 alkyl means an alkyl having 1 to 6 carbon atoms.
  • alkenyl means a saturated straight-chain or branched non-cyclic hydrocarbon containing from 2 to 10 carbon atoms and at least one carbon-carbon double bond.
  • Representative straight-chain and branched (C 2 -C 10 ) alkenyls are -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl , -3-methyl-1-butenyl, -2-methyl-2-butenic, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3 -Hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3octenyl, -1-nonenyl,
  • alkoxy means -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -O(CH 2 ) 3 CH 3 , -O(CH 2 ) 4 CH 3 , -O-(alkyl), including -O(CH 2 ) 5 CH 3 , and the like, wherein alkyl is as defined above.
  • lower alkoxy means -O-(lower alkyl), wherein lower alkyl is as defined above.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
  • haloalkyl As used herein, the terms "haloalkyl”, “haloalkoxy”, “haloalkenyl” or “haloalkynyl” refer to an alkyl, alkoxy, alkenyl or alkynyl group in which one or more hydrogen atoms are replaced by halogen atoms, respectively. .
  • haloalkyl is -CF 3 , -CHF 2 , -CH 2 F, -CBr 3 , -CHBr 2 , -CH 2 Br, -CC1 3 , -CHC1 2 , -CH 2 CI, -CI 3 , -CHI 2 , -CH 2 I, -CH 2 -CF 3 , -CH 2 -CHF 2 , -CH 2 -CH 2 F, -CH 2 -CBr 3 , -CH 2 -CHBr 2 , -CH 2 -CH 2 Br, -CH 2 -CC1 3 , -CH 2 -CHC1 2 , -CH 2 -CH 2 CI, -CH 2 -CI 3 , -CH 2 -CHI 2 , -CH 2 -CH 2 I, and the like include that wherein alkyl and halogen are as defined above.
  • the term "compound of the present disclosure” or “compound according to an aspect of the present invention” is meant to encompass a compound according to Formula 1 and pharmaceutically acceptable salts thereof, unless otherwise specified. .
  • compound of Formula 1(s) is also meant to include compounds of Formula 1 as well as clathrates, hydrates, solvates, or polymorphs (polymorphs) thereof.
  • polymorph refers to a solid crystal 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 terms of physical properties include, but are not limited to, stability (e.g. heat or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). It doesn't. Differences in stability may be due to chemical reactivity changes (e.g. differential oxidation such as 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 may be thermodynamically converted to a 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 solvates, or may be more difficult to filter or wash, than another polymorph, eg, due to its shape or particle size distribution.
  • solvent compound refers to a compound of the present invention 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 very small amounts to humans.
  • hydrate refers to a compound of the present invention that contains 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) in which guest molecules (eg, solvent or water) are confined.
  • the compound of Formula 1 is isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2 -(N-methylmethylsulfonamido)phenyl)amino)pyrimidine-5-carboxylate or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention provides a pharmaceutical composition for treating, improving or preventing fibrosis, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another aspect of the present invention is also a treatment for fibrosis, comprising administering a therapeutically or prophylactically effective amount of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment, improvement or prevention of fibrosis.
  • Methods of treatment, improvement or prevention are provided. That is, the present disclosure provides a pharmaceutical use of the compound of Formula 1 or a pharmaceutically acceptable salt thereof for treating, improving or preventing fibrosis.
  • prevention includes prevention of recurrence, expansion or development of fibrosis in a patient (subject).
  • treatment includes eradication, elimination, or control of fibrosis, and minimizing or delaying the spread of fibrosis.
  • fibrosis is cardiac, liver, lung, skeletal muscle, kidney, or vascular fibrosis.
  • the fibrosis is liver or pulmonary fibrosis.
  • the fibrosis is pulmonary fibrosis.
  • the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present disclosure is generally administered in a therapeutically or prophylactically effective amount.
  • the compound(s) of the present invention can be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in a dosage effective for the intended treatment.
  • An effective dosage is generally from about 0.01 to about 50 mg/kg of body weight/day, preferably from about 0.05 to about 20 mg/kg/day, in single or divided administration. Dosage levels below the lower end 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 detrimental side effects. Larger doses 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 present disclosure also provides a composition, preferably a pharmaceutical composition, comprising a compound of the present disclosure (a compound of Formula 1 above, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient.
  • the active ingredient described herein can be administered as follows.
  • the active ingredient according to the present invention may be administered intranasally, and nasal administration may be particularly preferable for the pharmaceutical use of the present disclosure.
  • nasal administration is a concept including conventional inhalant administration.
  • intranasal administration is meant delivery of a composition into the nose and nasal cavities through one or both of the nose or nasal passages, and includes delivery by a spray mechanism or droplet mechanism or delivery by aerosolization of an active ingredient.
  • Administration of the composition by inhalation may be through the nose or mouth via delivery by a nebulizer or droplet mechanism.
  • compositions of the present invention may be formulated by methods well known to those skilled in the art, for example, with representative solubilizing, diluting, or dispersing substances such as saline, preservatives such as benzyl alcohol. , absorption enhancers and the like, but is not limited thereto.
  • a liquid pharmaceutical composition may be prepared by the same method as an oral administration composition described later.
  • Such nasal administration may be performed using an intranasal delivery device well known in the art to which the present invention pertains, and propellants such as fluorocarbon and hydrofluoroalkane may be used in such a device.
  • propellants such as fluorocarbon and hydrofluoroalkane may be used in such a device.
  • the compound of the present invention can be administered orally, and oral is a concept including swallowing.
  • Oral administration allows the compounds of the present invention to enter the gastrointestinal tract or be directly absorbed from the mouth into the bloodstream, eg, by buccal or sublingual administration.
  • compositions suitable for oral administration may be in solid, liquid, gel, or powder form, and may have formulations such as tablets, lozenges, capsules, granules, powders, and the like. .
  • compositions for oral administration may optionally be enteric coated and 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 include a pharmaceutically acceptable carrier such as water, ethanol, polyethylene glycol, cellulose, or oil.
  • the formulation may also contain one or more emulsifying and/or suspending agents.
  • the amount of active ingredient drug may be present from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight of the total weight of the tablet.
  • Tablets may also contain a disintegrant comprising from about 0.5% to about 35% by weight, more usually from about 2% to about 25% by weight of the dosage form.
  • disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.
  • Suitable glidants included for making into tablets may be present in amounts 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. It can be used as a lubricant, but the present invention is not limited to these types of additives.
  • Gelatin polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. may be used as a binder for preparing tablets.
  • Mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc. may be used as suitable diluents for preparing tablets, but the present invention is not limited to these types of 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 based on 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 mono/ Diglyceride, sorbitan fatty acid ester, Solutol HS TM and the like can be used in the pharmaceutical composition according to the present invention, but the present invention is not limited to the specific types of these solubilizing agents.
  • Compounds of the present invention may be administered directly into the bloodstream, muscle, or intestine.
  • Suitable methods for parenteral administration include intravenous, intramuscular, 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.
  • parenteral formulations are liquid compositions, and these liquid compositions are aqueous solutions containing the active ingredient, salt, buffer, tonicity agent and the like according to the present invention.
  • 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.
  • Compounds according to the present disclosure are useful for the treatment, amelioration or prevention of fibrosis. That is, the present disclosure provides a pharmaceutical use for treating, ameliorating or preventing fibrosis of a compound according to the present disclosure. Another aspect of the present disclosure provides a method for treating or alleviating fibrosis comprising administering to a subject (preferably a human) in need thereof a therapeutically or prophylactically effective amount of a compound according to the present disclosure.
  • Step 1 Preparation of N-(2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (1-1)
  • step 1 The material from step 1 (3 g, 7.88 mmol), 4-amino-2-methoxybenzoic acid (1.32 g, 7.88 mmol) and para-toluenesulfonic acid (1.50 g, 7.88 mmol) in isopropyl alcohol (240 mL) The mixture was stirred at reflux for 6 hours. The reaction mixture was concentrated and extracted with dichloromethane and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was recrystallized from dichloromethane and cyclohexane to give the title compound (1.26 g, %).
  • O-benzylhydroxylamine hydrochloride salt (1.07 g, 6.73 mmol), 7-((tert-butoxycarbonyl)amino)heptanoic acid (1.50 g, 6.11 mmol), 1-ethyl-3-(3-dimethylamino) Diisopropylethylamine (4.2 mL, 24.40 mmol) in dichloromethane (30 mL) mixture of propyl) carbodiimide (EDC, 1.76 g, 9.17 mmol) and hydroxybenzotriazole (HOBt, 1.24 g, 9.17 mmol) was added and stirred overnight.
  • EDC propyl carbodiimide
  • HOBt hydroxybenzotriazole
  • the reaction mixture was diluted with dichloromethane and washed sequentially with water, 1N HCl aqueous solution, and NaHCO3 aqueous solution.
  • the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated.
  • the residue was purified by column chromatography to give the title compound (1.0 g, 47%).
  • Step 5 N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(tri Preparation of fluoromethyl) pyrimidin-2-yl) amino) benzamide (1-5)
  • Step 6 N-(7-(hydroxyamino)-7-oxoheptyl)-2-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5 Preparation of -(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (1-6)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-2-fluorobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-2-fluoro-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino) Preparation of -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (2-2)
  • Step 3 2-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5 Preparation of -(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (2-3)
  • Step 1 Preparation of 4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid ( 3-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-aminobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(tri Preparation of fluoromethyl) pyrimidin-2-yl) amino) benzamide (3-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoro Preparation of methyl) pyrimidin-2-yl) amino) benzamide (3-3)
  • Step 1 3-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzo
  • ripe acid (4-1) 3-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzo
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-3-methoxy-benzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-3-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino) Preparation of -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (4-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 N-(7-(hydroxyamino)-7-oxoheptyl)-3-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5 Preparation of (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (4-3)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-3-fluoro-benzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-3-fluoro-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino) Preparation of -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (5-2)
  • Step 3 3-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5 Preparation of -(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (5-3)
  • Example 6 Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-3-methoxyphenyl)amino)-4-((2-(N-methyl Preparation of methylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate
  • Step 1 Preparation of isopropyl 2-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidine-5-carboxylate (6-1)
  • Step 2 4-((5-(isopropylcarbonyl)-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-methoxybenzo Preparation of ripe acid (6-2)
  • Step 3 Isopropyl 2-((4-((7-((benzyloxy)amino)-7-oxoheptyl)carbamoyl)-3-methoxyphenyl)amino)-4-((2-(N- Preparation of methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate (6-3)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 2.
  • Step 4 Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-3-methoxyphenyl)amino)-4-((2-(N-methylmethyl Preparation of sulfonamido) phenyl) amino) pyrimidine-5-carboxylate (6-4)
  • Example 7 Isopropyl 2-((3-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methyl Preparation of methylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate
  • Step 1 2-Fluoro-4-((5-(isopropylcarbonyl)-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)benzo Preparation of ripe acid (7-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-2-fluorobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 Isopropyl 2-((4-((7-((benzyloxy)amino)-7-oxoheptyl)carbamoyl)-3-fluorophenyl)amino)-4-((2-(N- Preparation of methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate (7-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 Isopropyl 2-((3-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethyl Preparation of sulfonamido) phenyl) amino) pyrimidine-5-carboxylate (7-3)
  • Example 8 Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethylsulfonamido) Preparation of phenyl) amino) pyrimidine-5-carboxylate
  • Step 1 Preparation of 4-((5-(isopropylcarbonyl)-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid ( 8-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-aminobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 Isopropyl 2-((4-((7-((benzyloxy)amino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethylsulfonamido Preparation of )phenyl)amino)pyrimidine-5-carboxylate (8-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethylsulfonamido)phenyl Preparation of )amino)pyrimidine-5-carboxylate (8-3)
  • Example 9 Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-2-methoxyphenyl)amino)-4-((2-(N-methyl Preparation of methylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate
  • Step 1 4-((5-(isopropylcarbonyl)-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxybenzo Manufacture of ripe acid (9-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-3-methoxybenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 Isopropyl 2-((4-((7-((benzyloxy)amino)-7-oxoheptyl)carbamoyl)-2-methoxyphenyl)amino)-4-((2-(N- Preparation of methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate (9-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-2-methoxyphenyl)amino)-4-((2-(N-methyl) Preparation of sulfonamido) phenyl) amino) pyrimidine-5-carboxylate (9-3)
  • Example 10 Isopropyl 2-((2-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methyl Preparation of methylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate
  • Step 1 3-Fluoro-4-((5-(isopropylcarbonyl)-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)benzo Preparation of ripe acid (10-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-3-fluorobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 Isopropyl 2-((4-((7-((benzyloxy)amino)-7-oxoheptyl)carbamoyl)-2-fluorophenyl)amino)-4-((2-(N- Preparation of methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate (10-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 Isopropyl 2-((2-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethyl Preparation of sulfonamido) phenyl) amino) pyrimidine-5-carboxylate (10-3)
  • Step 1 Preparation of 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-fluorobenzoic acid (11 -One)
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)- Preparation of 5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-fluorobenzamide (11-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-fluoro-N-(7- Preparation of (hydroxyamino) -7-oxoheptyl) benzamide (11-3)
  • Example 12 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-(7 Preparation of (hydroxyamino)-7-oxoheptyl)benzamide
  • Step 1 Preparation of 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorobenzoic acid (12 -One)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-2-fluorobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrid Preparation of midin-2-yl) amino) -2-fluorobenzamide (12-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-(7- Preparation of (hydroxyamino) -7-oxoheptyl) benzamide (12-3)
  • Example 13 2-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrid Preparation of midin-2-yl) amino) benzamide
  • Step 1 Preparation of 2-fluoro-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid (13-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-2-fluorobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-2-fluoro-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino) Preparation of pyrimidin-2-yl) amino) benzamide (13-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 2-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidine Preparation of -2-yl) amino) benzamide (13-3)
  • Example 14 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of )-7-oxoheptyl)benzamide
  • Step 1 Preparation of 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid (14-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-aminobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrid Preparation of midin-2-yl) amino) benzamide (14-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of -7-oxoheptyl)benzamide (14-3)
  • Example 15 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of )-7-oxoheptyl)-3-methoxybenzamide
  • Step 1 Preparation of 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxybenzoic acid ( 15-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-3-methoxybenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrid Preparation of midin-2-yl) amino) -3-methoxybenzamide (15-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of -7-oxoheptyl) -3-methoxybenzamide (15-3)
  • Example 16 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of )-7-oxoheptyl)-2-methoxybenzamide
  • Step 1 Preparation of 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-methoxybenzoic acid ( 16-1)
  • the title compound was obtained using a method similar to the step 2 synthesis method of Example 1 above.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrid Preparation of midin-2-yl) amino) -2-methoxybenzamide (16-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of -7-oxoheptyl) -2-methoxybenzamide (16-3)
  • the compound used in the experiment was prepared at the highest concentration of 1 ⁇ M and was sequentially diluted 3-fold. Concentrations of 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, and 0.05 nM were used. Staurosporine was used as a control material to confirm the enzymatic reaction conditions. The concentration of ATP used in the reaction was the concentration corresponding to Km for each protein.
  • Substrates to be used for the reaction were mixed in assay buffer, a reaction buffer solution (composition: 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01%, Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO) was prepared by mixing. Cofactors required for substrate reaction were added. After each enzyme was added to the substrate mixture, the test substance was treated by concentration and the reaction was initiated by treatment with 33 P-ATP. After the reaction for 2 hours, the kinase activity was analyzed by measuring and analyzing the amount of remaining radioactivity after passing through the P81 Filter plate. The kinase activity inhibitory activity results for the compounds of the invention are shown in Table 1.
  • Enzyme activity inhibition was confirmed using purified human-derived HDAC 1, 2, 3, 4, and 6 proteins and substrates for HDAC. Two compounds were prepared at concentrations of 1000, 100, 10, and 1 nM. As a substrate, fluorescently labeled HDAC class 2a was used at a concentration of 20 ⁇ M. Trichostatin A was used as a control material for confirmation of the enzyme reaction conditions. After mixing the enzyme, compound, and substrate, the reaction was carried out at room temperature for 30 minutes, and the degree of inhibition of HDAC activity was relatively analyzed by measuring the final fluorescence value. HDAC activity inhibitory activity results for the compounds of the invention are shown in Figure 1.
  • H&E Hematoxylin and Eosin staining method
  • Mouse tissues were first fixed in 10% neutral formalin for 5 days and then made into paraffin blocks. As a process of removing paraffin penetrating into tissue, xylene was reacted, followed by reaction in 100, 95, 70, and 50% ethanol solutions for 3 minutes, respectively. After the 50% ethanol process was completed, it was washed with running water for 10 minutes. The hematoxylin solution was reacted for 2 minutes to stain the nuclei, and washed with running water for 10 minutes. Then, the cytoplasm was stained by reacting with an eosin solution for 30 seconds, and 50, 70, 95, and 100% ethanol were reacted for 1 minute each. Finally, after reacting with the xylene solution, a drop of the mounting solution was applied, and the cover slide was covered and observed under a microscope.
  • Mouse tissues were first fixed in 10% neutral formalin for 5 days and then made into paraffin blocks. In order to remove paraffin in the tissue, it was reacted with xylene, reacted with 100, 95, 70, and 50% ethanol solutions for 3 minutes each, and after the last process was finished, washed with running water for 10 minutes. First, Bouin's Solution was reacted in a water bath at 60 ° C for 60 minutes, and after the reaction, it was washed with running water for 10 minutes. After washing, Weigert's hematoxylin A and B solutions were mixed in a 1:1 ratio and reacted for 10 minutes.
  • the Biebrich Scarlet-Acid Fuschin solution was reacted for 3 minutes and rinsed once with tertiary distilled water. Then, the reaction was carried out in Phosphotumstic/Phosphomolydic acid for 20 minutes and aniline blue for 30 minutes without washing. After the last dyeing process was finished, it was rinsed 3 times with tertiary distilled water and reacted in 1% acetic acid solution for 1 minute. After dehydration through 95 and 100% ethanol solutions, xylene solution was finally finished, a drop of mounting solution was dropped, and a cover slide was covered and observed under a microscope.
  • the positive control material (Nintedanib) and the compound of Example 8 were found to significantly inhibit radiation-induced pulmonary fibrosis.

Abstract

The present disclosure pertains to a compound useful for treating or palliating fibrosis, especially pulmonary fibrosis and a medical use thereof.

Description

EGFR 및 HDAC 이중 억제 화합물 및 이의 의약 용도EGFR and HDAC dual inhibitory compounds and their medicinal uses
본 출원은 2021년 12월 21일에 출원된 한국특허출원 제10-2021-0184393호에 기초한 우선권을 주장하며, 해당 출원의 명세서 및 도면에 개시된 모든 내용은 본 출원에 원용된다.This application claims priority based on Korean Patent Application No. 10-2021-0184393 filed on December 21, 2021, and all contents disclosed in the specification and drawings of the application are incorporated into this application.
본 개시는 섬유증의 치료 또는 완화를 위한 화합물에 관한 것이다. 본 개시는 또한 본 개시에 따른 화합물의 섬유증 치료 또는 완화용 의약 용도에 관한 것이다. 즉, 본 개시는 섬유증의 치료 또는 섬유증 증상의 완화를 위한 방법에 관한 것이다.The present disclosure relates to compounds for the treatment or alleviation of fibrosis. The present disclosure also relates to the pharmaceutical use of a compound according to the present disclosure for the treatment or alleviation of fibrosis. That is, the present disclosure relates to methods for the treatment of fibrosis or relief of symptoms of fibrosis.
조직 손상에 대한 세포 외 매트릭스 성분의 축적은 조직 복구에 필수적인 생리학적 과정이다. 불행히도, 손상(injury)을 악화시키는 만성 손상은 섬유아세포(fibroblast) 및 근섬유아세포(myofibroblast)에 의한 세포 외 매트릭스 성분의 과잉 생산을 유발하여, 섬유질 결합 조직의 과도한 축적을 야기하고, 경우에 따라 이는 섬유증으로 알려진 병리학적 상태에 이르게 된다. Accumulation of extracellular matrix components in response to tissue damage is an essential physiological process for tissue repair. Unfortunately, chronic injury exacerbating injury causes overproduction of extracellular matrix components by fibroblasts and myofibroblasts, resulting in excessive accumulation of fibrous connective tissue, in some cases this It leads to a pathological condition known as fibrosis.
섬유증은 심장, 간, 폐, 골격근, 신장, 혈관 등과 같은 다양한 기관에 영향을 줄 수 있다. 예를 들어, 섬유증은 골격근 조직 (이영양성 근육 질환), 심장 및 혈관 조직 (심근 경색), 간 조직 (비알콜성 지방간 질환/간경변), 폐 조직 (특발성 폐 섬유증) 및 신장 조직 (만성 신장 질환/신장 섬유증)에서 나타날 수 있다.Fibrosis can affect various organs such as the heart, liver, lungs, skeletal muscle, kidneys, blood vessels, and more. For example, fibrosis can be classified into skeletal muscle tissue (dystrophic muscle disease), heart and vascular tissue (myocardial infarction), liver tissue (non-alcoholic fatty liver disease/cirrhosis), lung tissue (idiopathic pulmonary fibrosis), and kidney tissue (chronic kidney disease). /renal fibrosis).
한편, EGFR 저해제가 Bleomycin에 의해 유도된 폐섬유화에 대해 현저한 섬유증 개선 효과가 있다는 것이 동물모델에서 입증되었다 (Am. J. Respir. Crit. Care Med. 2006, 174(5), 550). 또한 EGFR 저해제는 Angiotensin-II에 의해 유도된 신장 섬유증 개선에도 효과가 있다는 것이 보고되었다 (Journal of Pharmacology and Experimental Therapeutics 2016, 356 (1), 32-42). On the other hand, it has been demonstrated in animal models that EGFR inhibitors have significant fibrosis improvement effects on pulmonary fibrosis induced by Bleomycin (Am. J. Respir. Crit. Care Med. 2006, 174(5), 550). It has also been reported that EGFR inhibitors are effective in improving renal fibrosis induced by Angiotensin-II (Journal of Pharmacology and Experimental Therapeutics 2016, 356 (1), 32-42).
또한, 히스톤디아세틸라제 (HDAC) 저해제도 Bleomycin에 의해 유도된 폐섬유화에 효과가 있다는 것이 최근에 보고되었다. (Molecules 2019, 24(15), 2792).In addition, it has recently been reported that histone deacetylase (HDAC) inhibitors are also effective against pulmonary fibrosis induced by Bleomycin. (Molecules 2019, 24(15), 2792).
이러한 연구를 토대로 한 분자 내에 EGFR 저해능과 히스톤디아세틸라제 저해능을 동시에 가진 물질을 개발하여 신규 섬유증 치료제로 개발하고자 한다.Based on these studies, we intend to develop a substance that has both EGFR inhibitory and histone deacetylase inhibitory activities in a molecule and develop it as a new fibrosis treatment.
다만, 아직까지 명확한 기전이 밝혀져 있지 않으므로 섬유증 치료 효과는 섬유증 관련 단백질 1~2개의 발현 조절만으로는 단정하기 어려우며 다양한 측면의 in vitro 및 in vivo 효력 평가가 필요하다. However, since no clear mechanism has been identified yet, it is difficult to determine the fibrosis treatment effect only by regulating the expression of one or two fibrosis-related proteins, and various aspects of in vitro and in vivo efficacy evaluations are required.
따라서 본 개시가 해결하고자 하는 과제는 섬유증의 치료 또는 완화에 효과적인 화합물 또는 이러한 화합물을 유효성분으로 포함하는 약학 조성물을 제공하는 것이다. 즉, 본 개시가 해결하고자 하는 과제는 섬유증의 치료 또는 완화에 효과적인 성분을 찾아내어 이의 의약 용도를 제공하는 것이다.Therefore, the problem to be solved by the present disclosure is to provide a compound effective for the treatment or alleviation of fibrosis or a pharmaceutical composition containing such a compound as an active ingredient. That is, the problem to be solved by the present disclosure is to find a component effective for the treatment or alleviation of fibrosis and to provide a medicinal use thereof.
상기 과제를 해결하기 위하여, 본 개시는 하기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다.In order to solve the above problems, the present disclosure provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
Figure PCTKR2022020882-appb-img-000001
Figure PCTKR2022020882-appb-img-000001
상기 화학식 1에서, In Formula 1,
R1 및 R2는 서로 독립적으로 수소, C1~C6알킬, 또는 C1~C6할로알킬,R 1 and R 2 independently of each other are hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R3는 수소, 할로겐, C1~C6할로알킬, 또는 -C(=O)O-C1~C6알킬,R 3 is hydrogen, halogen, C 1 -C 6 haloalkyl, or -C(=O)OC 1 -C 6 alkyl;
R4는 수소, 할로겐, 시아노, C1~C6알킬, C1~C6알콕시, 또는 C1~C6할로알킬, R 4 is hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl;
n은 0, 1, 2, 3, 또는 4,n is 0, 1, 2, 3, or 4;
R5 및 R6는 서로 독립적으로 수소, 하이드록사믹 애시드(hydroxamic acid)로 치환된 C1~C6알킬, 또는 하이드록사믹 애시드로 치환된 C2~C6알켄임.R 5 and R 6 independently represent hydrogen, C 1 -C 6 alkyl substituted with hydroxamic acid, or C 2 -C 6 alkene substituted with hydroxamic acid.
본 발명의 일 태양에 있어, 상기 R5 및 R6는 서로 독립적으로 수소, -C1~C6알킬-C(O)N(OH)H, 또는 -C2~C6알켄-C(O)N(OH)H일 수 있음.In one aspect of the present invention, R 5 and R 6 are each independently hydrogen, -C 1 ~C 6 alkyl-C(O)N(OH)H, or -C 2 ~C 6 alkene-C(O )N(OH)H.
본 발명의 일 태양에 있어, 본 발명에 따른 화합물들은 약학적으로 허용 가능한 염으로 이용될 수 있다. 실제로, 본 발명의 일 태양에서, 화학식 1에 따른 화합물의 염은 각각의 유리염기보다 바람직할 수 있는데, 이는, 예를 들면, 그러한 염이 분자에 보다 큰 안정성 또는 용해도를 부여하고 그에 따라서 투여 형태로의 제형을 촉진하기 때문이다. In one aspect of the present invention, the compounds according to the present invention may be used as pharmaceutically acceptable salts. Indeed, in one aspect of the present invention, salts of compounds according to Formula 1 may be preferred over the respective free bases, since, for example, such salts impart greater stability or solubility to the molecule and thus the dosage form. This is because it promotes the formulation of Rho.
특정 태양에서, 화학식 1에 따른 화합물은 염기성 작용기를 가진 화합물로 작용할 수 있다. 본 발명의 일 태양에 있어, 화학식 1의 약학적으로 허용 가능한 염은 산 부가 염이다. 약학적으로 허용가능한 산 부가 염은 무독성 염을 형성하는 산으로부터 형성된다. 예를 들어, 하이드로클로라이드(hydrochloride), 하이드로브로마이드(hydrobromide), 하이드로아이오다이드(hydroiodide), 설페이트(sulphate), 바이설페이트(bisulphate), 니트레이트(nitrate), 포스페이트(phosphate), 하이드로겐 포스페이트(hydrogen phosphate), 아세테이트(acetate), 말리에이트(maleate), 말레이트(malate), 퓨마레이트(fumarate), 말로네이트(malonate), 락테이트(lactate), 타르트레이트(tartrate), 시트레이트(citrate), 포르메이트(formate), 글루코네이트(gluconate), 석시네이트(succinate), 피루베이트(pyruvate), 옥살레이트(oxalate), 옥살로아세테이트(oxaloacetate), 트리플루오로아세테이트(trifluoroacetate), 사카레이트(saccharate), 벤조에이트(benzoate), 메탄설포네이트(methanesulphonate), 에탄설포네이트(ethanesulphonate), 벤젠설포네이트(benzenesulphonate), p-톨루엔설포네이트(toluenesulphonate), 메탄설포닉(methanesulphonic), 에탄설포닉(ethanesulphonic), p-톨루엔설포닉(toluenesulphonic), 및 이세티오네이트(isethionate) 염이 사용될 수 있다.In certain embodiments, compounds according to Formula 1 may function as compounds with basic functional groups. In one aspect of the present invention, the pharmaceutically acceptable salt of Formula 1 is an acid addition salt. Pharmaceutically acceptable acid addition salts are formed from acids which form non-toxic salts. For example, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulphate, nitrate, phosphate, hydrogen phosphate ( hydrogen phosphate, acetate, maleate, malate, fumarate, malonate, lactate, tartrate, citrate , formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate ), benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate, methanesulphonic, ethanesulphonic ), p-toluenesulphonic, and isethionate salts may be used.
본 명세서에서 사용된, 용어 "약학적으로 허용 가능한 염"은 대상 화합물의 목적하는 생물학적 활성을 보유하고 원하지 않는 독성 영향을 최소한으로 보이는 염을 지칭한다. 이들 약학적으로 허용 가능한 염은 화합물의 최종 단리 및 정제 중에 in situ에서 제조되거나, 또는 이의 유리 산 또는 유리 염기 형태의 정제된 화합물을 적합한 염기 또는 산과 별개로 반응시켜 제각기 제조될 수 있다. As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of a subject compound and exhibits minimal undesirable toxic effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or separately by reacting the purified compound in its free acid or free base form with a suitable base or acid separately.
본 명세서에서 사용된 용어 "약학적으로 허용 가능한"은 일반적으로 그러한 용도로 안전하다고 간주되거나, 그러한 용도로 국가 또는 주 정부의 규제 기관에 의해 공식적으로 승인되거나, 또는 미국 약전 (U. S. Pharmacopoeia) 또는 동물, 보다 특별히 인간에서의 사용을 위한 것으로 일반적으로 인정되는 기타 약전에 나열된 약학 제제에서의 사용에 적합한 것을 의미한다.As used herein, the term “pharmaceutically acceptable” means generally considered safe for such use, officially approved for such use by a national or state regulatory agency, or approved by the U.S. Pharmacopoeia or veterinary , more particularly suitable for use in pharmaceutical preparations listed in other pharmacopeias generally recognized for use in humans.
본 명세서에서 사용된 용어 "알킬"은 (탄소수가 특별히 한정되지 않은 경우) 탄소수 1 내지 10을 가진 포화된 직쇄상 또는 분지상의 비-고리(cyclic) 탄화수소를 의미한다. "저급 알킬"은 탄소수가 1 내지 4인 직쇄상 또는 분지상 알킬을 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.As used herein, the term "alkyl" refers to a saturated straight-chain or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms (unless the number of carbon atoms is specifically limited). "Lower alkyl" means a straight chain or branched alkyl having 1 to 4 carbon atoms. Representative saturated straight-chain alkyls are -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n- decyl, while 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-decylhexyl, 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 “C1-6”, "C1-6", 또는 "C1-C6"과 같이 기재될 경우 이는 탄소수가 1 내지 6개임을 의미한다. 예를 들어, C1-C6 알킬은 탄소수가 1 내지 6인 알킬을 의미한다.In the present specification, when described as “C 1-6 ”, “C1-6”, or “C1-C6”, it means that the number of carbon atoms is 1 to 6. For example, C1-C6 alkyl means an alkyl having 1 to 6 carbon atoms.
본 명세서에서 사용된 용어 "알케닐"은 2 내지 10개의 탄소 원자 및 적어도 하나의 탄소-탄소 이중 결합을 포함하는 포화된 직쇄상 또는 분지상 비-고리 탄화수소를 의미한다. 대표적인 직쇄상 및 분지상 (C2-C10) 알케닐은 -비닐, -알릴, -1-부테닐, -2-부테닐, -이소부틸레닐, -1-펜테닐, -2-펜테닐, -3-메틸-1-부테닐, -2-메틸-2-부테닉, -2,3-디메틸-2-부테닐, -1-헥세닐(hexenyl), -2-헥세닐, -3-헥세닐, -1-헵텐닐, -2-헵텐닐, -3-헵테닐, -1-옥테닐, -2-옥테닐, -3옥테닐, -1-노네닐(nonenyl), -2-노네닐, -3-노네닐, -1-디세닐, -2-디세닐, 및 -3-디세닐을 포함한다. As used herein, the term "alkenyl" means a saturated straight-chain or branched non-cyclic hydrocarbon containing from 2 to 10 carbon atoms and at least one carbon-carbon double bond. Representative straight-chain and branched (C 2 -C 10 ) alkenyls are -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl , -3-methyl-1-butenyl, -2-methyl-2-butenic, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3 -Hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3octenyl, -1-nonenyl, -2 -nonenyl, -3-nonenyl, -1-disenyl, -2-disenyl, and -3-disenyl.
본 명세서에서 사용된 용어 "알콕시"는 -OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, 및 이와 유사한 것을 포함하는 -O-(알킬)을 의미하며, 여기에서 알킬은 위에서 정의된 것과 같다. 본 명세서에서 사용된 용어 "저급알콕시"는 -O-(저급알킬)을 의미하며, 여기에서 저급 알킬은 위에서 정의된 것과 같다. As used herein, the term "alkoxy" means -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -O(CH 2 ) 3 CH 3 , -O(CH 2 ) 4 CH 3 , -O-(alkyl), including -O(CH 2 ) 5 CH 3 , and the like, wherein alkyl is as defined above. As used herein, the term "lower alkoxy" means -O-(lower alkyl), wherein lower alkyl is as defined above.
본 명세서에서 사용된, 용어 "할로겐"은 플루오린 (F), 염소 (Cl), 브로민 (Br), 또는 요오드 (I)를 지칭한다.As used herein, the term “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
본 명세서에서 사용된 용어 "할로알킬", “할로알콕시”, “할로알케닐” 또는 “할로알키닐”은 각각 하나 이상의 수소 원자가 할로겐 원자로 치환된 알킬, 알콕시, 알케닐 또는 알키닐 그룹을 의미한다. 예를 들어, 할로알킬은 -CF3, -CHF2, -CH2F, -CBr3, -CHBr2, -CH2Br, -CC13, -CHC12, -CH2CI, -CI3, -CHI2, -CH2I, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CH2-CBr3, -CH2-CHBr2, -CH2-CH2Br, -CH2-CC13, -CH2-CHC12, -CH2-CH2CI, -CH2-CI3, -CH2-CHI2, -CH2-CH2I, 및 이와 유사한 것을 포함한다. 여기에서 알킬 및 할로겐은 위에서 정의된 것과 같다.As used herein, the terms "haloalkyl", "haloalkoxy", "haloalkenyl" or "haloalkynyl" refer to an alkyl, alkoxy, alkenyl or alkynyl group in which one or more hydrogen atoms are replaced by halogen atoms, respectively. . For example, haloalkyl is -CF 3 , -CHF 2 , -CH 2 F, -CBr 3 , -CHBr 2 , -CH 2 Br, -CC1 3 , -CHC1 2 , -CH 2 CI, -CI 3 , -CHI 2 , -CH 2 I, -CH 2 -CF 3 , -CH 2 -CHF 2 , -CH 2 -CH 2 F, -CH 2 -CBr 3 , -CH 2 -CHBr 2 , -CH 2 -CH 2 Br, -CH 2 -CC1 3 , -CH 2 -CHC1 2 , -CH 2 -CH 2 CI, -CH 2 -CI 3 , -CH 2 -CHI 2 , -CH 2 -CH 2 I, and the like include that wherein alkyl and halogen are as defined above.
본 명세서에서 사용된, 용어 "본 개시의 화합물" 또는 "본 발명의 태양(양태)에 따른 화합물"은 특별히 언급되지 않는 한 화학식 1에 따른 화합물 및 이의 약학적으로 허용 가능한 염을 포괄하는 의미이다.As used herein, the term "compound of the present disclosure" or "compound according to an aspect of the present invention" is meant to encompass a compound according to Formula 1 and pharmaceutically acceptable salts thereof, unless otherwise specified. .
본 명세서에서 사용된 용어인 "화학식 1(의) 화합물"은 또한 화학식 1의 화합물뿐만 아니라, 이들의 클라드레이트(clathrates), 수화물, 용매화물, 또는 다형체(결정다형)를 포함하는 의미이다. As used herein, the term “compound of Formula 1(s)” is also meant to include compounds of Formula 1 as well as clathrates, hydrates, solvates, or polymorphs (polymorphs) thereof.
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 crystal 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 terms of physical properties include, but are not limited to, stability (e.g. heat or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). It doesn't. Differences in stability may be due to chemical reactivity changes (e.g. differential oxidation such as 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 may be thermodynamically converted to a 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 solvates, or may be more difficult to filter or wash, than another polymorph, eg, due to its shape or particle size distribution.
본 명세서에서 사용된 용어 "용매 화합물"은 비공유 분자간의 힘에 의해 결합된 화학량론적 또는 비-화학량론적인 양의 용매를 포함하는 본 발명의 화합물을 의미한다. 바람직한 용매들은 휘발성이고, 비독성이며, 인간에게 극소량 투여될 수 있다.As used herein, the term “solvent compound” refers to a compound of the present invention 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 very small amounts to humans.
본 명세서에서 사용된 용어 "수화물(hydrate)"은 비공유 분자간의 힘에 의해 결합된 화학량론적 또는 비-화학량론적인 양의 물을 포함하는 본 발명의 화합물을 의미한다. As used herein, the term “hydrate” refers to a compound of the present invention that contains 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 화합물을 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) in which guest molecules (eg, solvent or water) are confined. means
바람직하게, 본 개시에 있어 화학식 1의 화합물은 Preferably, in the present disclosure, the compound of Formula 1 is
N-(7-(히드록시아미노)-7-옥소헵틸)-2-메톡시-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드, N-(7-(hydroxyamino)-7-oxoheptyl)-2-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(tri fluoromethyl)pyrimidin-2-yl)amino)benzamide;
2-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드,2-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(tri fluoromethyl)pyrimidin-2-yl)amino)benzamide;
N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드,N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoromethyl)pyridine midin-2-yl) amino) benzamide;
N-(7-(히드록시아미노)-7-옥소헵틸)-3-메톡시-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드,N-(7-(hydroxyamino)-7-oxoheptyl)-3-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(tri fluoromethyl)pyrimidin-2-yl)amino)benzamide;
3-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드,3-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(tri fluoromethyl)pyrimidin-2-yl)amino)benzamide;
이소프로필 2-((4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)-3-메톡시페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트,Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-3-methoxyphenyl)amino)-4-((2-(N-methylmethylsulfonamido )phenyl)amino)pyrimidine-5-carboxylate,
이소프로필 2-((3-플루오로-4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트,Isopropyl 2-((3-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethylsulfonamido )phenyl)amino)pyrimidine-5-carboxylate,
이소프로필 2-((4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트,Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethylsulfonamido)phenyl)amino) pyrimidine-5-carboxylate;
이소프로필 2-((4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)-2-메톡시페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트,Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-2-methoxyphenyl)amino)-4-((2-(N-methylmethylsulfonamido )phenyl)amino)pyrimidine-5-carboxylate,
이소프로필 2-((2-플루오로-4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트,Isopropyl 2-((2-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethylsulfonamido )phenyl)amino)pyrimidine-5-carboxylate,
4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-3-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)벤즈아미드,4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-fluoro-N-(7-(hydroxy amino)-7-oxoheptyl)benzamide;
4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-2-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)벤즈아미드,4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-(7-(hydroxy amino)-7-oxoheptyl)benzamide;
2-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)벤즈아미드,2-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidine-2- yl) amino) benzamide,
4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-N-(7-(히드록시아미노)-7-옥소헵틸)벤즈아미드,4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino)-7- oxoheptyl)benzamide,
4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-N-(7-(히드록시아미노)-7-옥소헵틸)-3-메톡시벤즈아미드, 또는4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino)-7- oxoheptyl)-3-methoxybenzamide, or
4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-N-(7-(히드록시아미노)-7-옥소헵틸)-2-메톡시벤즈아미드, 또는 이의 약학적으로 허용 가능한 염이다. 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino)-7- oxoheptyl)-2-methoxybenzamide, or a pharmaceutically acceptable salt thereof.
더욱 바람직하게, 본 개시에 있어 상기 화학식 1의 화합물은 이소프로필 2-((4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트 또는 이의 약학적으로 허용 가능한 염이다.More preferably, in the present disclosure, the compound of Formula 1 is isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2 -(N-methylmethylsulfonamido)phenyl)amino)pyrimidine-5-carboxylate or a pharmaceutically acceptable salt thereof.
본 발명의 다른 측면은 상기 화학식 1의 화합물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 섬유증의 치료, 개선 또는 예방용 약학 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for treating, improving or preventing fibrosis, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 다른 측면은 또한 상기 화학식 1의 화합물, 또는 이의 약학적으로 허용 가능한 염의 치료학적으로 또는 예방학적으로 유효한 양을 섬유증의 치료, 개선 또는 예방이 필요한 개체에게 투여하는 것을 포함하는, 섬유증의 치료, 개선 또는 예방 방법을 제공한다. 즉, 본 개시는 상기 화학식 1의 화합물, 또는 이의 약학적으로 허용 가능한 염의 섬유증 치료, 개선 또는 예방의 의약 용도를 제공한다.Another aspect of the present invention is also a treatment for fibrosis, comprising administering a therapeutically or prophylactically effective amount of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment, improvement or prevention of fibrosis. Methods of treatment, improvement or prevention are provided. That is, the present disclosure provides a pharmaceutical use of the compound of Formula 1 or a pharmaceutically acceptable salt thereof for treating, improving or preventing fibrosis.
본 명세서에서 사용된 "예방(prevention)"은 환자(개체)에 있어 섬유화의 재발의 방지, 확장 또는 발병의 예방을 포함한다.As used herein, “prevention” includes prevention of recurrence, expansion or development of fibrosis in a patient (subject).
본 명세서에서 사용된 "치료"는 섬유화의 근절, 제거, 또는 통제를 포함하고, 섬유화의 확장을 최소화하거나 지연시키는 것이다.As used herein, "treatment" includes eradication, elimination, or control of fibrosis, and minimizing or delaying the spread of fibrosis.
본 개시에 있어, 섬유증은 심장, 간, 폐, 골격근, 신장, 또는 혈관 섬유증이다. 본 발명의 바람직한 일 태양에 있어, 섬유증은 간 또는 폐 섬유증이다. 본 발명의 다른 태양에 있어, 섬유증은 폐 섬유증이다. For purposes of this disclosure, fibrosis is cardiac, liver, lung, skeletal muscle, kidney, or vascular fibrosis. In one preferred aspect of the invention, the fibrosis is liver or pulmonary fibrosis. In another aspect of the invention, the fibrosis is pulmonary fibrosis.
본 개시에 따른 상기 화학식 1의 화합물, 또는 이의 약학적으로 허용 가능한 염은 일반적으로 치료적으로 또는 예방학적으로 유효한 양으로 투여된다. The compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present disclosure is generally administered in a therapeutically or prophylactically effective amount.
본 발명의 화합물(들)은 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 0.01 내지 약 50 mg/체중kg/일이고, 바람직하게는 약 0.05 내지 약 20 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.The compound(s) of the present invention can be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in a dosage effective for the intended treatment. An effective dosage is generally from about 0.01 to about 50 mg/kg of body weight/day, preferably from about 0.05 to about 20 mg/kg/day, in single or divided administration. Dosage levels below the lower end 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 detrimental side effects. Larger doses may be divided into several smaller doses for administration throughout the day. Methods for determining the appropriate dosage are well known in the art.
본 개시는 또한 본 개시의 화합물 (상기 화학식 1의 화합물, 또는 이의 약학적으로 허용 가능한 염) 및 약학적으로 허용 가능한 첨가제를 포함하는 조성물, 바람직하게는 약학 조성물을 제공한다.The present disclosure also provides a composition, preferably a pharmaceutical composition, comprising a compound of the present disclosure (a compound of Formula 1 above, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient.
섬유증의 치료, 개선 또는 예방을 위하여, 본 명세서에서 설명된 상기 유효 성분은 다음과 같이 투여될 수 있다. For the treatment, improvement or prevention of fibrosis, the active ingredient described herein can be administered as follows.
비강 내 투여(Intranasal administration)Intranasal administration
본 발명에 따른 유효 성분은 비강으로 투여될 수 있으며, 특히 본 개시의 의약 용도상 비강 투여가 바람직할 수 있다. 본 발명에 있어, 이러한 비강 투여는 통상적인 흡입제 투여를 포함하는 개념이다. The active ingredient according to the present invention may be administered intranasally, and nasal administration may be particularly preferable for the pharmaceutical use of the present disclosure. In the present invention, such nasal administration is a concept including conventional inhalant administration.
이러한 “비강 내 투여(intranasal administration)”는 코 또는 비강 중 하나 또는 둘 다를 통한 코 및 비강 내로의 조성물의 전달을 의미하고, 분무 메커니즘 또는 액적 메커니즘에 의한 전달 또는 유효 성분의 에어로졸화를 통한 전달을 포함한다. 흡입제에 의한 조성물의 투여는 분무 또는 액적 메커니즘에 의한 전달을 통해 코 또는 입을 통해 이루어질 수 있다. By “intranasal administration” is meant delivery of a composition into the nose and nasal cavities through one or both of the nose or nasal passages, and includes delivery by a spray mechanism or droplet mechanism or delivery by aerosolization of an active ingredient. include Administration of the composition by inhalation may be through the nose or mouth via delivery by a nebulizer or droplet mechanism.
비강 또는 흡입 전달을 위하여, 본 발명의 조성물은 통상의 기술자에게 잘 알려진 방법에 의해 제형화될 수 있고, 예를 들어, 대표적인 가용화, 희석, 또는 분산 물질, 예컨대, 식염수, 보존제, 예컨대, 벤질알코올, 흡수촉진제 등을 포함할 수 있지만, 이에 제한되는 것은 아니다. 이러한 액체 제약 조성물은 후술하는 구강 투여 조성물 등과 동일한 방법으로 제조될 수도 있다. For nasal or inhalation delivery, the compositions of the present invention may be formulated by methods well known to those skilled in the art, for example, with representative solubilizing, diluting, or dispersing substances such as saline, preservatives such as benzyl alcohol. , absorption enhancers and the like, but is not limited thereto. Such a liquid pharmaceutical composition may be prepared by the same method as an oral administration composition described later.
이러한 비강 투여는 본 발명이 속한 분야에서 이미 잘 알려진 비강내 전달 장치를 이용해 수행될 수 있으며, 이러한 장치에서는 플루오로카본, 하이드로플루오로알칸 등의 분사제가 사용될 수도 있다. Such nasal administration may be performed using an intranasal delivery device well known in the art to which the present invention pertains, and propellants such as fluorocarbon and hydrofluoroalkane may be used in such a device.
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 can be administered orally, and oral is a concept including swallowing. Oral administration allows the compounds of the present invention to enter the gastrointestinal tract or be directly absorbed from the mouth into the bloodstream, eg, 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. Compositions suitable for oral administration may be in solid, liquid, gel, or powder form, and may have formulations such as tablets, lozenges, capsules, granules, powders, and the like. .
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 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 include a pharmaceutically acceptable carrier such as 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 active ingredient drug may be present from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight of the total weight of the tablet. Tablets may also contain a disintegrant comprising from about 0.5% to about 35% by weight, more usually from about 2% to about 25% by weight of the dosage form. Examples of disintegrants 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 making into tablets may be present in amounts 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. It can be used as a lubricant, but the present invention is not limited to these types of 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, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. may be used as a binder for preparing tablets. Mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc. may be used as suitable diluents for preparing tablets, but the present invention is not limited to these types of 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, HCORTM(Nikkol), 올레일에스테르, 젤루시어(GelucireTM), 카프릴릭/카프릴산 모노/디글리세리드, 소르비탄지방산에스테르, 솔루톨HSTM 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 based on 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 mono/ Diglyceride, sorbitan fatty acid ester, Solutol HS TM and the like can be used in the pharmaceutical composition according to the present invention, but the present invention is not limited to the specific types of these solubilizing agents.
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.Compounds of the present invention may be administered directly into the bloodstream, muscle, or intestine. Suitable methods for parenteral administration include intravenous, intramuscular, 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 these liquid compositions are aqueous solutions containing the active ingredient, salt, buffer, tonicity agent and the like according to the present invention.
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.
본 개시에 따른 화합물은 섬유증의 치료, 개선 또는 예방에 유용하다. 즉, 본 개시는 본 개시에 따른 화합물의 섬유증 치료, 개선 또는 예방을 위한 의약 용도를 제공한다. 본 개시의 또 다른 측면은 본 개시에 따른 화합물의 치료적 또는 예방적 유효량을 이를 필요로 하는 개체(바람직하게는 인간)에게 투여하는 단계를 포함하는 섬유증을 치료 또는 완화하는 방법을 제공한다.Compounds according to the present disclosure are useful for the treatment, amelioration or prevention of fibrosis. That is, the present disclosure provides a pharmaceutical use for treating, ameliorating or preventing fibrosis of a compound according to the present disclosure. Another aspect of the present disclosure provides a method for treating or alleviating fibrosis comprising administering to a subject (preferably a human) in need thereof a therapeutically or prophylactically effective amount of a compound according to the present disclosure.
본 명세서에 첨부되는 다음의 도면들은 본 발명의 바람직한 실시예를 예시하는 것이며, 전술한 발명의 내용과 함께 본 발명의 기술사상을 더욱 이해시키는 역할을 하는 것이므로, 본 발명은 그러한 도면에 기재된 사항에만 한정되어 해석되어서는 아니 된다.The following drawings attached to this specification illustrate preferred embodiments of the present invention, and serve to further understand the technical idea of the present invention together with the contents of the above-described invention, so the present invention is limited to those described in the drawings. It should not be construed as limiting.
도 1은 본 발명에 따른 일 실시예 화합물들의 HDAC 효소 억제 활성을 평가한 결과이다.1 is a result of evaluating the HDAC enzyme inhibitory activity of the compounds of one example according to the present invention.
도 2-4는 본 발명에 따른 일 실시예 화합물들의 동물 모델 평가 결과이다.2-4 are animal model evaluation results of compounds of one example according to the present invention.
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 aid understanding of the present invention. However, the embodiments according to the present invention can be modified in many different forms, and the scope of the present invention should not be construed as being limited to the following examples. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.
실시예 1: N-(7-(히드록시아미노)-7-옥소헵틸)-2-메톡시-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드의 제조Example 1: N-(7-(hydroxyamino)-7-oxoheptyl)-2-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)- Preparation of 5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide
단계 1: N-(2-((2-클로로-5-(트리플루오로메틸)피리미딘-4-일)아미노)페닐)-N-메틸메탄술폰아미드의 제조 (1-1)Step 1: Preparation of N-(2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (1-1)
Figure PCTKR2022020882-appb-img-000002
Figure PCTKR2022020882-appb-img-000002
N-(2-아미노페닐)-N-메틸메탄술폰아미드 (18 g, 89.88 mmol)와 2,4-디클로로-5-(트리플루오로메틸)피리미딘 (19.50 g, 89.88 mmol)의 이프로필알콜 (360 mL) 혼합물에 디이소프로필에틸아민 (46.47 g, 359.53 mmol)을 넣고 7시간 동안 환류 교반하였다. 반응 혼합물을 농축하고 디클로로메탄과 물로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조, 여과, 농축하였다. 잔류물을 디클로로메탄, 삼차 부틸메틸 에테르와 시클로헥산으로 재결정하여 표제 화합물 (16.47 g, %)을 수득하였다. Ipropyl alcohol of N-(2-aminophenyl)-N-methylmethanesulfonamide (18 g, 89.88 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (19.50 g, 89.88 mmol) (360 mL) into the mixture was added diisopropylethylamine (46.47 g, 359.53 mmol) and stirred at reflux for 7 hours. The reaction mixture was concentrated and extracted with dichloromethane and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was recrystallized from dichloromethane, tertiary butylmethyl ether and cyclohexane to give the title compound (16.47 g, %).
1H NMR (400 MHz, CDCl3): δ 8.58 (s, 1H), 8.45 (s, 1H), 8.35 (dd, 1H), 7.44 (m, 1H), 7.33 (m, 1H), 7.22 (m, 1H), 3.28 (s, 1H), 2.98 (s, 3H) 1 H NMR (400 MHz, CDCl 3 ): δ 8.58 (s, 1H), 8.45 (s, 1H), 8.35 (dd, 1H), 7.44 (m, 1H), 7.33 (m, 1H), 7.22 (m , 1H), 3.28 (s, 1H), 2.98 (s, 3H)
단계 2: 2-메톡시-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤조익 애시드의 제조 (1-2)Step 2: 2-Methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzo Preparation of ripe acid (1-2)
Figure PCTKR2022020882-appb-img-000003
Figure PCTKR2022020882-appb-img-000003
단계 1의 물질 (3 g, 7.88 mmol), 4-아미노-2-메톡시벤조익 애시드 (1.32 g, 7.88 mmol)와 파라-톨루엔술포닉 애시드 (1.50 g, 7.88 mmol)의 이소프로필알콜 (240 mL) 혼합물을 6시간 동안 환류 교반하였다. 반응 혼합물을 농축하고 디클로로메탄과 물로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조, 여과, 농축하였다. 잔류물을 디클로로메탄과 시클로헥산으로 재결정하여 표제 화합물 (1.26 g, %)을 수득하였다.The material from step 1 (3 g, 7.88 mmol), 4-amino-2-methoxybenzoic acid (1.32 g, 7.88 mmol) and para-toluenesulfonic acid (1.50 g, 7.88 mmol) in isopropyl alcohol (240 mL) The mixture was stirred at reflux for 6 hours. The reaction mixture was concentrated and extracted with dichloromethane and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was recrystallized from dichloromethane and cyclohexane to give the title compound (1.26 g, %).
1H NMR (400 MHz, DMSO-d6): δ 8.88 (br s, 1H), 8.40 (s, 1H), 7.98 (m, 1H), 7.53 (d, 1H), 7.26 (m, 1H), 7.10 (m, 3H), 7.03 (dd, 1H), 6.80 (dd, 1H), 3.71 (s, 1H), 3.14 (3H), 3.06 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.88 (br s, 1H), 8.40 (s, 1H), 7.98 (m, 1H), 7.53 (d, 1H), 7.26 (m, 1H), 7.10 (m, 3H), 7.03 (dd, 1H), 6.80 (dd, 1H), 3.71 (s, 1H), 3.14 (3H), 3.06 (s, 3H)
단계 3: 삼차 부틸 (7-((벤질옥시)아미노)-7-옥소헵틸)카바메이트의 제조 (1-3)Step 3: Preparation of tertiary butyl (7-((benzyloxy)amino)-7-oxoheptyl)carbamate (1-3)
Figure PCTKR2022020882-appb-img-000004
Figure PCTKR2022020882-appb-img-000004
O-벤질히드록실아민 염산 염 (1.07 g, 6.73 mmol), 7-((삼차 부톡시카르보닐)아미노)헵타노익 애시드 (1.50 g, 6.11 mmol), 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 (EDC, 1.76 g, 9.17 mmol)와 히드록시벤조트리아졸 (HOBt, 1.24 g, 9.17 mmol)의 디클로로메탄 (30 mL) 혼합물에 디이소프로필에틸아민 (4.2 mL, 24.40 mmol)을 넣고 밤새 교반하였다. 반응 혼합물을 디클로로메탄으로 희석하고 물, 1N HCl 수용액, 그리고 NaHCO3 수용액으로 차례로 씻었다. 유기층을 무수 황산 마그네슘으로 건조, 여과, 농축하였다. 잔류물을 칼럼 크로마토그래피로 정제하여 표제 화합물 (1.0 g, 47%)을 수득하였다.O-benzylhydroxylamine hydrochloride salt (1.07 g, 6.73 mmol), 7-((tert-butoxycarbonyl)amino)heptanoic acid (1.50 g, 6.11 mmol), 1-ethyl-3-(3-dimethylamino) Diisopropylethylamine (4.2 mL, 24.40 mmol) in dichloromethane (30 mL) mixture of propyl) carbodiimide (EDC, 1.76 g, 9.17 mmol) and hydroxybenzotriazole (HOBt, 1.24 g, 9.17 mmol) was added and stirred overnight. The reaction mixture was diluted with dichloromethane and washed sequentially with water, 1N HCl aqueous solution, and NaHCO3 aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography to give the title compound (1.0 g, 47%).
1H NMR (400 MHz, CDCl3): δ 8.31 (br s, 1H), 7.38 (s, 5H), 4.92 (s, 2H), 4.51 (s, 1H), 3.08 (m, 2H), 2.03 (br s, 1H), 1.63 (m, 3H), 1.44 (s, 11H), 1.31 (s, 4H) 1 H NMR (400 MHz, CDCl 3 ): δ 8.31 (br s, 1H), 7.38 (s, 5H), 4.92 (s, 2H), 4.51 (s, 1H), 3.08 (m, 2H), 2.03 ( br s, 1H), 1.63 (m, 3H), 1.44 (s, 11H), 1.31 (s, 4H)
단계 4: 7-아미노-N-(벤질옥시)헵탄아미드 염산 염의 제조 (1-4)Step 4: Preparation of 7-amino-N-(benzyloxy)heptanamide hydrochloric acid salt (1-4)
Figure PCTKR2022020882-appb-img-000005
Figure PCTKR2022020882-appb-img-000005
단계 3의 물질 (1.0 g, 2.86 mmol)의 1,4-디옥산 (3 mL) 용액에 4N HCl 1,4-디옥산 용액 (7.0 mL, 28.57 mmol)을 넣고 6시간 동안 교반하였다. 삼차 부틸메틸 에테르 (10 mL)를 넣고 1시간 동안 교반한 후 여과, 진공 건조하여 표제 화합물 (0.8 g, 98%)를 수득하였다.A 4N HCl 1,4-dioxane solution (7.0 mL, 28.57 mmol) was added to a solution of the material of step 3 (1.0 g, 2.86 mmol) in 1,4-dioxane (3 mL) and stirred for 6 hours. After adding tertiary butylmethyl ether (10 mL) and stirring for 1 hour, the mixture was filtered and dried under vacuum to obtain the title compound (0.8 g, 98%).
1H NMR (400 MHz, DMSO-d6): δ 11.03 (br s, 1H), 7.64 (bs, 3H), 7.38 (m, 5H), 4.78 (s, 2H), 2.75 (m, 2H), 1.96 (t, 2H), 1.51 (m, 4H), 1.25 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.03 (br s, 1H), 7.64 (bs, 3H), 7.38 (m, 5H), 4.78 (s, 2H), 2.75 (m, 2H), 1.96 (t, 2H), 1.51 (m, 4H), 1.25 (m, 4H)
단계 5: N-(7-((벤질옥시)아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드의 제조 (1-5)Step 5: N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(tri Preparation of fluoromethyl) pyrimidin-2-yl) amino) benzamide (1-5)
Figure PCTKR2022020882-appb-img-000006
Figure PCTKR2022020882-appb-img-000006
단계 4의 물질 (0.51 g, 0.53 mmol), 단계 2의 물질 (0.27 g, 0.53 mmol), 2-(1H-7-아자벤조트리아졸-1-일)-1,1,3,3-테트라메틸 유로늄 헥사플루오로포스페이트 (HATU, 0.22 g, 0.58 mmol)의 N,N-디메틸포름아미드 (2.6 mL) 혼합물에 디이소프로필에틸아민 (0.28 mL, 1.58 mmol)을 넣고 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트와 물로 추출하고, 유기층을 포화 염화 나트륨 수용액으로 씻었다. 유기층을 무수 황산 마그네슘으로 건조, 여과, 농축하였다. 잔류물을 칼럼 크로마토그래피로 정제하여 표제 화합물 (47 mg, 12%)을 수득하였다.Material from Step 4 (0.51 g, 0.53 mmol), Material from Step 2 (0.27 g, 0.53 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetra To a mixture of methyl euronium hexafluorophosphate (HATU, 0.22 g, 0.58 mmol) in N,N-dimethylformamide (2.6 mL) was added diisopropylethylamine (0.28 mL, 1.58 mmol) and stirred overnight. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography to give the title compound (47 mg, 12%).
단계 6: N-(7-(히드록시아미노)-7-옥소헵틸)-2-메톡시-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드의 제조 (1-6)Step 6: N-(7-(hydroxyamino)-7-oxoheptyl)-2-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5 Preparation of -(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (1-6)
Figure PCTKR2022020882-appb-img-000007
Figure PCTKR2022020882-appb-img-000007
단계 5의 물질 (45 mg, 0.061 mmol)의 메틸알콜 (1.2 mL) 혼합물을 아르곤 가스로 치환하고 10% Pd/C (7 mg, 15 wt%)를 첨가하였다. 반응 혼합물을 수소 가스로 치환하여 밤새 교반하였다. 반응 혼합물을 디클로로메탄으로 묽히고 셀라이트로 여과, 농축하였다. 잔류물을 칼럼 크로마토그래피로 정제하여 표제 화합물 (28 mg, 72%)을 수득하였다.A mixture of the materials from step 5 (45 mg, 0.061 mmol) in methyl alcohol (1.2 mL) was purged with argon gas and 10% Pd/C (7 mg, 15 wt%) was added. The reaction mixture was purged with hydrogen gas and stirred overnight. The reaction mixture was diluted with dichloromethane, filtered through celite, and concentrated. The residue was purified by column chromatography to give the title compound (28 mg, 72%).
1H NMR (400 MHz, DMSO): δ 10.34 (br s, 1H), 8.83 (br s, 1H), 8.66 (s, 1H), 8.44 (d, 2H), 8.09 (t, 1H), 7.98 (d, 1H), 7.73 (d, 1H), 7.54 (dd, 1H), 7.40 (br s, 1H), 7.14-7.24 (m, 3H), 3.77 (s, 3H), 3.27 (m, 2H), 3.14 (s, 3H), 3.06 (s, 3H), 1.95 (t, 2H), 1.52 (m, 4H), 1.31 (m, 4H) 1 H NMR (400 MHz, DMSO): δ 10.34 (br s, 1H), 8.83 (br s, 1H), 8.66 (s, 1H), 8.44 (d, 2H), 8.09 (t, 1H), 7.98 ( d, 1H), 7.73 (d, 1H), 7.54 (dd, 1H), 7.40 (br s, 1H), 7.14-7.24 (m, 3H), 3.77 (s, 3H), 3.27 (m, 2H), 3.14 (s, 3H), 3.06 (s, 3H), 1.95 (t, 2H), 1.52 (m, 4H), 1.31 (m, 4H)
실시예 2: 2-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드의 제조Example 2: 2-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)- Preparation of 5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide
단계 1: 2-플루오로-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤조익 애시드의 제조 (2-1)Step 1: 2-Fluoro-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzo Preparation of ripe acid (2-1)
Figure PCTKR2022020882-appb-img-000008
Figure PCTKR2022020882-appb-img-000008
4-아미노-2-메톡시벤조익 애시드 대신에 4-아미노-2-플루오로벤조익 애시드를 사용하고, 상기 실시예 1의 단계 2 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-2-fluorobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
1H NMR (400 MHz, DMSO-d6): δ 8.96 (br s, 1H), 8.68 (br s, 1H), 8.47 (s, 1H), 7.87 (dd, 1H), 7.77 (t, 1H), 7.62 (m, 1H), 7.55 (dd, 1H), 7.47 (m, 1H), 7.23 (m, 2H), 3.14 (s, 3H), 3.05 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.96 (br s, 1H), 8.68 (br s, 1H), 8.47 (s, 1H), 7.87 (dd, 1H), 7.77 (t, 1H) , 7.62 (m, 1H), 7.55 (dd, 1H), 7.47 (m, 1H), 7.23 (m, 2H), 3.14 (s, 3H), 3.05 (s, 3H)
단계 2: N-(7-((벤질옥시)아미노)-7-옥소헵틸)-2-플루오로-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드의 제조 (2-2)Step 2: N-(7-((benzyloxy)amino)-7-oxoheptyl)-2-fluoro-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino) Preparation of -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (2-2)
Figure PCTKR2022020882-appb-img-000009
Figure PCTKR2022020882-appb-img-000009
7-아미노-N-(벤질옥시)헵탄아미드 염산 염 (1-4)와 단계 1의 물질을 사용하고, 상기 실시예 1의 단계 5 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained using a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloric acid salt (1-4) and the materials of Step 1.
1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 8.23 (m, 3H), 8.04 (t, 1H), 7.77 (m, 1H), 7.32-7.40 (m, 7H), 7.17-7.21 (m, 2H), 7.01 (br s, 1H), 6.72 (m, 1H), 4.93 (s, 2H), 3.44 (m, 2H), 3.27 (s, 3H), 2.98 (s, 3H), 2.05 (br s, 1H), 1.62 (m, 5H), 1.38 (m, 4H) 1 H NMR (400 MHz, CDCl 3 ): δ 8.40 (s, 1H), 8.23 (m, 3H), 8.04 (t, 1H), 7.77 (m, 1H), 7.32-7.40 (m, 7H), 7.17 -7.21 (m, 2H), 7.01 (br s, 1H), 6.72 (m, 1H), 4.93 (s, 2H), 3.44 (m, 2H), 3.27 (s, 3H), 2.98 (s, 3H) , 2.05 (br s, 1H), 1.62 (m, 5H), 1.38 (m, 4H)
단계 3: 2-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드의 제조 (2-3)Step 3: 2-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5 Preparation of -(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (2-3)
Figure PCTKR2022020882-appb-img-000010
Figure PCTKR2022020882-appb-img-000010
단계 2의 물질을 사용하고, 상기 실시예 1의 단계 6 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by using the materials of Step 2 and using a method similar to the synthesis method of Step 6 of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 8.91 (s, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 8.18 (m, 1H), 7.90 (dd, 1H), 7.52-7.57 (m, 3H), 7.43 (dd, 1H), 7.25 (t, 1H), 7.17 (m, 1H), 3.24 (m, 2H), 3.14 (s, 3H), 3.05 (s, 3H), 1.95 (t, 2H), 1.51 (m, 4H), 1.30 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.34 (s, 1H), 8.91 (s, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 8.18 (m, 1H), 7.90 (dd, 1H), 7.52-7.57 (m, 3H), 7.43 (dd, 1H), 7.25 (t, 1H), 7.17 (m, 1H), 3.24 (m, 2H), 3.14 (s, 3H), 3.05 (s, 3H), 1.95 (t, 2H), 1.51 (m, 4H), 1.30 (m, 4H)
실시예 3: N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드의 제조Example 3: N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoro Preparation of romethyl) pyrimidin-2-yl) amino) benzamide
단계 1: 4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤조익 애시드의 제조 (3-1)Step 1: Preparation of 4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid ( 3-1)
Figure PCTKR2022020882-appb-img-000011
Figure PCTKR2022020882-appb-img-000011
4-아미노-2-메톡시벤조익 애시드 대신에 4-아미노벤조익 애시드를 사용하고, 상기 실시예 1의 단계 2 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-aminobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
1H NMR (400 MHz, DMSO-d6): δ 9.43 (br s, 1H), 8.92 (br s, 1H), 8.56 (br s, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.82 (dd, 1H), 7.61 (d, 1H), 7.54 (dd, 1H), 7.20 (m, 1H), 7.13 (m, 1H), 3.13 (s, 3H), 3.07 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.43 (br s, 1H), 8.92 (br s, 1H), 8.56 (br s, 1H), 7.92 (s, 1H), 7.90 (s, 1H) ), 7.82 (dd, 1H), 7.61 (d, 1H), 7.54 (dd, 1H), 7.20 (m, 1H), 7.13 (m, 1H), 3.13 (s, 3H), 3.07 (s, 3H)
단계 2: N-(7-((벤질옥시)아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드의 제조 (3-2)Step 2: N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(tri Preparation of fluoromethyl) pyrimidin-2-yl) amino) benzamide (3-2)
Figure PCTKR2022020882-appb-img-000012
Figure PCTKR2022020882-appb-img-000012
7-아미노-N-(벤질옥시)헵탄아미드 염산 염 (1-4)와 단계 1의 물질을 사용하고, 상기 실시예 1의 단계 5 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
1H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 8.92 (s, 1H), 8.39-8.45 (m, 3H), 7.90 (m, 1H), 7.84 (d, 2H), 7.57 (d, 2H), 7.51 (m, 1H), 7.36 (m, 5H), 7.12 (m, 2H), 4.76 (s, 2H), 3.26 (m, 2H), 3.13 (s, 3H), 3.05 (s, 3H), 1.97 (t, 2H), 1.52 (m, 4H), 1.29 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.95 (s, 1H), 8.92 (s, 1H), 8.39-8.45 (m, 3H), 7.90 (m, 1H), 7.84 (d, 2H) , 7.57 (d, 2H), 7.51 (m, 1H), 7.36 (m, 5H), 7.12 (m, 2H), 4.76 (s, 2H), 3.26 (m, 2H), 3.13 (s, 3H), 3.05 (s, 3H), 1.97 (t, 2H), 1.52 (m, 4H), 1.29 (m, 4H)
단계 3: N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드의 제조 (3-3)Step 3: N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoro Preparation of methyl) pyrimidin-2-yl) amino) benzamide (3-3)
Figure PCTKR2022020882-appb-img-000013
Figure PCTKR2022020882-appb-img-000013
단계 2의 물질을 사용하고, 상기 실시예 1의 단계 6 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by using the materials of Step 2 and using a method similar to the synthesis method of Step 6 of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 8.91 (s, 1H), 8.66, (d, 1H), 8.39-8.44 (m, 3H), 7.90 (m, 1H), 7.84 (d, 2H), 7.57 (d, 2H), 7.52 (m, 1H), 7.12 (m, 2H), 3.26 (m, 2H), 3.14 (s, 3H), 3.06 (s, 3H), 1.95 (t, 2H), 1.52 (m, 4H), 1.30 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.34 (s, 1H), 8.91 (s, 1H), 8.66, (d, 1H), 8.39-8.44 (m, 3H), 7.90 (m, 1H) ), 7.84 (d, 2H), 7.57 (d, 2H), 7.52 (m, 1H), 7.12 (m, 2H), 3.26 (m, 2H), 3.14 (s, 3H), 3.06 (s, 3H) , 1.95 (t, 2H), 1.52 (m, 4H), 1.30 (m, 4H)
실시예 4: N-(7-(히드록시아미노)-7-옥소헵틸)-3-메톡시-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드의 제조Example 4: N-(7-(hydroxyamino)-7-oxoheptyl)-3-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)- Preparation of 5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide
단계 1: 3-메톡시-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤조익 애시드의 제조 (4-1)Step 1: 3-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzo Preparation of ripe acid (4-1)
Figure PCTKR2022020882-appb-img-000014
Figure PCTKR2022020882-appb-img-000014
4-아미노-2-메톡시벤조익 애시드 대신에 4-아미노-3-메톡시-벤조익 애시드를 사용하고, 상기 실시예 1의 단계 2 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-3-methoxy-benzoic acid instead of 4-amino-2-methoxybenzoic acid.
1H NMR (400 MHz, DMSO-d6): δ 8.67 (br s, 1H), 8.44 (s, 1H), 8.32 (br s, 1H), 7.92 (br s, 1H), 7.76 (m, 1H), 7.58 (m, 1H), 7.47 (dd, 1H), 7.20 (m, 2H), 3.88 (s, 3H), 3.13 (s, 3H), 3.05 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.67 (br s, 1H), 8.44 (s, 1H), 8.32 (br s, 1H), 7.92 (br s, 1H), 7.76 (m, 1H) ), 7.58 (m, 1H), 7.47 (dd, 1H), 7.20 (m, 2H), 3.88 (s, 3H), 3.13 (s, 3H), 3.05 (s, 3H)
단계 2: N-(7-((벤질옥시)아미노)-7-옥소헵틸)―3-메톡시-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드의 제조 (4-2)Step 2: N-(7-((benzyloxy)amino)-7-oxoheptyl)-3-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino) Preparation of -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (4-2)
Figure PCTKR2022020882-appb-img-000015
Figure PCTKR2022020882-appb-img-000015
7-아미노-N-(벤질옥시)헵탄아미드 염산 염 (1-4)와 단계 1의 물질을 사용하고, 상기 실시예 1의 단계 5 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
1H NMR (400 MHz, CDCl3): δ 8.46 (d, 1H), 8.37 (s, 1H), 8.29 (d, 1H), 8.14 (s, 1H), 7.94 (br s, 1H), 7.48 (d, 1H), 7.31-7.40 (m, 7H), 7.15-7.24 (m, 2H), 6.25 (br s, 1H), 4.92 (s, 2H), 3.98 (s, 3H), 3.44 (m, 2H), 3.27 (s, 3H), 2.98 (s, 3H), 2.06 (br s, 1H), 1.65 (m, 5H), 1.39 (m, 4H) 1 H NMR (400 MHz, CDCl 3 ): δ 8.46 (d, 1H), 8.37 (s, 1H), 8.29 (d, 1H), 8.14 (s, 1H), 7.94 (br s, 1H), 7.48 ( d, 1H), 7.31-7.40 (m, 7H), 7.15-7.24 (m, 2H), 6.25 (br s, 1H), 4.92 (s, 2H), 3.98 (s, 3H), 3.44 (m, 2H) ), 3.27 (s, 3H), 2.98 (s, 3H), 2.06 (br s, 1H), 1.65 (m, 5H), 1.39 (m, 4H)
단계 3: N-(7-(히드록시아미노)-7-옥소헵틸)-3-메톡시-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드의 제조 (4-3)Step 3: N-(7-(hydroxyamino)-7-oxoheptyl)-3-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5 Preparation of (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (4-3)
Figure PCTKR2022020882-appb-img-000016
Figure PCTKR2022020882-appb-img-000016
단계 2의 물질을 사용하고, 상기 실시예 1의 단계 6 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by using the materials of Step 2 and using a method similar to the synthesis method of Step 6 of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 8.66 (d, 1H), 8.52 (s, 1H), 8.48 (t, 1H), 8.40 (s, 1H), 8.35 (s, 1H), 7.79 (m, 2H), 7.57 (dd, 1H), 7.54 (m, 1H), 7.44 (dd, 1H), 7.15 (m, 1H), 3.87 (s, 3H), 3.27 (m, 2H), 3.14 (s, 3H), 3.05 (s, 3H), 1.95 (t, 2H), 1.53 (m, 4H), 1.31 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.34 (s, 1H), 8.66 (d, 1H), 8.52 (s, 1H), 8.48 (t, 1H), 8.40 (s, 1H), 8.35 (s, 1H), 7.79 (m, 2H), 7.57 (dd, 1H), 7.54 (m, 1H), 7.44 (dd, 1H), 7.15 (m, 1H), 3.87 (s, 3H), 3.27 ( m, 2H), 3.14 (s, 3H), 3.05 (s, 3H), 1.95 (t, 2H), 1.53 (m, 4H), 1.31 (m, 4H)
실시예 5: 3-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드의 제조Example 5: 3-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)- Preparation of 5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide
단계 1: 3-플루오로-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤조익 애시드의 제조 (5-1)Step 1: 3-Fluoro-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzo Preparation of ripe acid (5-1)
Figure PCTKR2022020882-appb-img-000017
Figure PCTKR2022020882-appb-img-000017
4-아미노-2-메톡시벤조익 애시드 대신에 4-아미노-3-플루오로-벤조익 애시드를 사용하고, 상기 실시예 1의 단계 2 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-3-fluoro-benzoic acid instead of 4-amino-2-methoxybenzoic acid.
1H NMR (400 MHz, DMSO-d6): δ 9.08 (br s, 1H), 8.81 (br s, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 7.79 (m, 2H), 7.70 (d, 1H), 7.58 (m, 2H), 7.49 (m, 1H), 7.06 (m, 1H), 3.13 (s, 3H), 3.07 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.08 (br s, 1H), 8.81 (br s, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 7.79 (m, 2H) , 7.70 (d, 1H), 7.58 (m, 2H), 7.49 (m, 1H), 7.06 (m, 1H), 3.13 (s, 3H), 3.07 (s, 3H)
단계 2: N-(7-((벤질옥시)아미노)-7-옥소헵틸)―3-플루오로-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드의 제조 (5-2)Step 2: N-(7-((benzyloxy)amino)-7-oxoheptyl)-3-fluoro-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino) Preparation of -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (5-2)
Figure PCTKR2022020882-appb-img-000018
Figure PCTKR2022020882-appb-img-000018
7-아미노-N-(벤질옥시)헵탄아미드 염산 염 (1-4)와 단계 1의 물질을 사용하고, 상기 실시예 1의 단계 5 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained using a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloric acid salt (1-4) and the materials of Step 1.
1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 8.31-8.37 (m, 2H), 8.17-2.11 (m, 2H), 7.63 (dd, 1H), 7.49 (d, 1H), 7.30-7.37 (m, 7H), 7.17 (m, 1H), 6.27 (br s, 1H), 4.92 (s, 2H), 3.44 (m, 2H), 3.27 (s, 3H), 2.98 (s, 3H), 2.06 (br s, 1H), 1.65 (m, 5H), 1.39 (m, 4H) 1 H NMR (400 MHz, CDCl 3 ): δ 8.40 (s, 1H), 8.31-8.37 (m, 2H), 8.17-2.11 (m, 2H), 7.63 (dd, 1H), 7.49 (d, 1H) , 7.30-7.37 (m, 7H), 7.17 (m, 1H), 6.27 (br s, 1H), 4.92 (s, 2H), 3.44 (m, 2H), 3.27 (s, 3H), 2.98 (s, 3H), 2.06 (br s, 1H), 1.65 (m, 5H), 1.39 (m, 4H)
단계 3: 3-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드의 제조 (5-3)Step 3: 3-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5 Preparation of -(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (5-3)
Figure PCTKR2022020882-appb-img-000019
Figure PCTKR2022020882-appb-img-000019
단계 2의 물질을 사용하고, 상기 실시예 1의 단계 6 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by using the materials of Step 2 and using a method similar to the synthesis method of Step 6 of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.05 (s, 1H), 8.66 (d, 1H), 859 (t, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 7.74-7.82 (m, 2H), 7.68 (d, 1H), 7.47-7.54 (m, 2H), 7.03 (m, 1H), 6.91 (t, 1H), 3.30 (m, 2H), 3.12 (s, 3H), 3.05 (s, 3H), 1.96 (t, 2H), 1.53 (m, 4H), 1.31 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.34 (s, 1H), 9.05 (s, 1H), 8.66 (d, 1H), 859 (t, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 7.74-7.82 (m, 2H), 7.68 (d, 1H), 7.47-7.54 (m, 2H), 7.03 (m, 1H), 6.91 (t, 1H), 3.30 (m, 2H) ), 3.12 (s, 3H), 3.05 (s, 3H), 1.96 (t, 2H), 1.53 (m, 4H), 1.31 (m, 4H)
실시예 6: 이소프로필 2-((4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)-3-메톡시페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조Example 6: Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-3-methoxyphenyl)amino)-4-((2-(N-methyl Preparation of methylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate
단계 1: 이소프로필 2-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조 (6-1)Step 1: Preparation of isopropyl 2-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidine-5-carboxylate (6-1)
Figure PCTKR2022020882-appb-img-000020
Figure PCTKR2022020882-appb-img-000020
2,4-디클로로-5-(트리플루오로메틸)피리미딘 대신에 이소프로필 2,4-디클로로피리미딘-5-카르복실레이트를 사용하고, 상기 실시예 1의 단계 1 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.Isopropyl 2,4-dichloropyrimidine-5-carboxylate was used instead of 2,4-dichloro-5-(trifluoromethyl)pyrimidine, and a method similar to the step 1 synthesis method of Example 1 was used. The title compound was obtained.
1H NMR (400 MHz, CDCl3): δ 11.15 (br s, 1H), 8.84 (s, 1H), 8.45 (dd, 1H), 7.42 (m, 2H), 7.24 (m, 1H), 5.34 (m, 1H), 3.29 (s, 3H), 3.03 (s, 3H), 1.38 (d, 6H) 1 H NMR (400 MHz, CDCl 3 ): δ 11.15 (br s, 1H), 8.84 (s, 1H), 8.45 (dd, 1H), 7.42 (m, 2H), 7.24 (m, 1H), 5.34 ( m, 1H), 3.29 (s, 3H), 3.03 (s, 3H), 1.38 (d, 6H)
단계 2: 4-((5-(이소프로필카르보닐)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-2-메톡시벤조익 애시드의 제조 (6-2)Step 2: 4-((5-(isopropylcarbonyl)-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-methoxybenzo Preparation of ripe acid (6-2)
Figure PCTKR2022020882-appb-img-000021
Figure PCTKR2022020882-appb-img-000021
N-(2-((2-클로로-5-(트리플루오로메틸)피리미딘-4-일)아미노)페닐)-N-메틸메탄술폰아미드 대신에 단계 1의 물질을 사용하고, 상기 실시예 1의 단계 2 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.Substitute N-(2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide with the material from Step 1, The title compound was obtained using a method similar to the step 2 synthesis method of 1.
1H NMR (400 MHz, DMSO-d6): δ 10.63 (br s, 1H), 10.18 (br s, 1H), 8.80 (s, 1H), 8.36 (br s, 1H), 7.60 (m, 2H), 7.46 (m, 1H), 7.38 (m, 2H), 7.27 (m, 1H), 7.11 (m, 1H), 5.17 (m, 1H), 3.94 (s, 3H), 3.18 (s, 3H), 3.12 (s, 3H), 1.34 (d, 6H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.63 (br s, 1H), 10.18 (br s, 1H), 8.80 (s, 1H), 8.36 (br s, 1H), 7.60 (m, 2H) ), 7.46 (m, 1H), 7.38 (m, 2H), 7.27 (m, 1H), 7.11 (m, 1H), 5.17 (m, 1H), 3.94 (s, 3H), 3.18 (s, 3H) , 3.12 (s, 3H), 1.34 (d, 6H)
단계 3: 이소프로필 2-((4-((7-((벤질옥시)아미노)-7-옥소헵틸)카바모일)-3-메톡시페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조 (6-3)Step 3: Isopropyl 2-((4-((7-((benzyloxy)amino)-7-oxoheptyl)carbamoyl)-3-methoxyphenyl)amino)-4-((2-(N- Preparation of methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate (6-3)
Figure PCTKR2022020882-appb-img-000022
Figure PCTKR2022020882-appb-img-000022
7-아미노-N-(벤질옥시)헵탄아미드 염산 염 (1-4)와 단계 2의 물질을 사용하고, 상기 실시예 1의 단계 5 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 2.
1H NMR (400 MHz, CDCl3): δ 10.85 (s, 1H), 8.83 (s, 1H), 8.49 (br s, 1H), 8.34 (d, 1H), 8.09 (d, 1H), 7.81 (t, 1H), 7.34-7.49 (m, 9H), 7.20 (m, 1H), 7.11 (d, 1H), 5.30 (m, 1H), 4.93 (s, 2H), 3.75 (s, 3H), 3.42 (m, 2H), 3.29 (s, 3H), 3.07 (s, 3H), 2.05 (br s, 1H), 1.63 (m, 5H), 1.38 (m, 10H) 1 H NMR (400 MHz, CDCl 3 ): δ 10.85 (s, 1H), 8.83 (s, 1H), 8.49 (br s, 1H), 8.34 (d, 1H), 8.09 (d, 1H), 7.81 ( t, 1H), 7.34-7.49 (m, 9H), 7.20 (m, 1H), 7.11 (d, 1H), 5.30 (m, 1H), 4.93 (s, 2H), 3.75 (s, 3H), 3.42 (m, 2H), 3.29 (s, 3H), 3.07 (s, 3H), 2.05 (br s, 1H), 1.63 (m, 5H), 1.38 (m, 10H)
단계 4: 이소프로필 2-((4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)-3-메톡시페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조 (6-4)Step 4: Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-3-methoxyphenyl)amino)-4-((2-(N-methylmethyl Preparation of sulfonamido) phenyl) amino) pyrimidine-5-carboxylate (6-4)
Figure PCTKR2022020882-appb-img-000023
Figure PCTKR2022020882-appb-img-000023
단계 3의 물질을 사용하고, 상기 실시예 1의 단계 6 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by using the materials of Step 3 and using a method similar to the synthesis method of Step 6 of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 10.64 (br s, 1H), 10.35 (s, 1H), 10.13 (s, 1H), 8.79 (s, 1H), 8.67 (s, 1H), 8.02 (t, 1H), 7.69 (d, 1H), 7.61 (d, 1H), 7.49 (br s, 1H), 7.39 (m, 1H), 7.26 (t, 1H), 5.17 (m, 1H), 3.70 (s, 3H), 3.25 (m, 2H), 3.18 (s, 3H), 3.12 (s, 3H), 1.94 (t, 2H), 1.49 (m, 4H), 1.34 (d, 6H), 1.28 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.64 (br s, 1H), 10.35 (s, 1H), 10.13 (s, 1H), 8.79 (s, 1H), 8.67 (s, 1H), 8.02 (t, 1H), 7.69 (d, 1H), 7.61 (d, 1H), 7.49 (br s, 1H), 7.39 (m, 1H), 7.26 (t, 1H), 5.17 (m, 1H), 3.70 (s, 3H), 3.25 (m, 2H), 3.18 (s, 3H), 3.12 (s, 3H), 1.94 (t, 2H), 1.49 (m, 4H), 1.34 (d, 6H), 1.28 (m, 4H)
실시예 7: 이소프로필 2-((3-플루오로-4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조Example 7: Isopropyl 2-((3-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methyl Preparation of methylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate
단계 1: 2-플루오로-4-((5-(이소프로필카르보닐)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)벤조익 애시드의 제조 (7-1)Step 1: 2-Fluoro-4-((5-(isopropylcarbonyl)-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)benzo Preparation of ripe acid (7-1)
Figure PCTKR2022020882-appb-img-000024
Figure PCTKR2022020882-appb-img-000024
4-아미노-2-메톡시벤조익 애시드 대신에 4-아미노-2-플루오로벤조익 애시드를 사용하고, 상기 실시예 1의 단계 2 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-2-fluorobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
1H NMR (400 MHz, DMSO-d6): δ 10.59 (br s, 1H), 10.48 (br s, 1H), 8.81 (s, 1H), 8.28 (br s, 1H), 7.73 (m, 2H), 7.63 (dd, 1H), 7.43 (m, 2H), 7.30 (m, 1H), 5.17 (m, 1H), 3.17 (s, 3H), 3.12 (s, 3H), 1.34 (d, 6H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.59 (br s, 1H), 10.48 (br s, 1H), 8.81 (s, 1H), 8.28 (br s, 1H), 7.73 (m, 2H) ), 7.63 (dd, 1H), 7.43 (m, 2H), 7.30 (m, 1H), 5.17 (m, 1H), 3.17 (s, 3H), 3.12 (s, 3H), 1.34 (d, 6H)
단계 2: 이소프로필 2-((4-((7-((벤질옥시)아미노)-7-옥소헵틸)카바모일)-3-플루오로페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조 (7-2)Step 2: Isopropyl 2-((4-((7-((benzyloxy)amino)-7-oxoheptyl)carbamoyl)-3-fluorophenyl)amino)-4-((2-(N- Preparation of methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate (7-2)
Figure PCTKR2022020882-appb-img-000025
Figure PCTKR2022020882-appb-img-000025
7-아미노-N-(벤질옥시)헵탄아미드 염산 염 (1-4)와 단계 1의 물질을 사용하고, 상기 실시예 1의 단계 5 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
1H NMR (400 MHz, CDCl3): δ 10.85 (s, 1H), 8.82 (s, 1H), 8.29 (d, 2H), 7.97 (t, 1H), 7.79 (d, 1H), 7.37-7.51 (m, 8H), 7.26 (m, 1H), 7.13 (d, 1H), 6.69 (m, 1H), 5.31 (m, 1H), 4.93 (s, 2H), 3.45 (m, 2H), 3.28 (s, 3H), 3.06 (s, 3H), 2.05 (br s, 1H), 1.63 (m, 5H), 1.38 (m, 10H) 1 H NMR (400 MHz, CDCl 3 ): δ 10.85 (s, 1H), 8.82 (s, 1H), 8.29 (d, 2H), 7.97 (t, 1H), 7.79 (d, 1H), 7.37-7.51 (m, 8H), 7.26 (m, 1H), 7.13 (d, 1H), 6.69 (m, 1H), 5.31 (m, 1H), 4.93 (s, 2H), 3.45 (m, 2H), 3.28 ( s, 3H), 3.06 (s, 3H), 2.05 (br s, 1H), 1.63 (m, 5H), 1.38 (m, 10H)
단계 3: 이소프로필 2-((3-플루오로-4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조 (7-3)Step 3: Isopropyl 2-((3-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethyl Preparation of sulfonamido) phenyl) amino) pyrimidine-5-carboxylate (7-3)
Figure PCTKR2022020882-appb-img-000026
Figure PCTKR2022020882-appb-img-000026
단계 2의 물질을 사용하고, 상기 실시예 1의 단계 6 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by using the materials of Step 2 and using a method similar to the synthesis method of Step 6 of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 10.62 (br s, 1H), 10.33 (m, 2H), 8.79 (s, 1H), 8.67 (s, 1H), 8.66 (s, 1H), 8.33 (br s, 1H), 8.04 (m, 1H), 7.75 (d, 1H), 7.61 (dd, 1H), 7.41-7.52 (m, 3H), 7.29 (t, 1H), 5.18 (m, 1H), 3.22 (m, 2H), 3.17 (s, 3H), 3.12 (s, 3H), 1.95 (t, 2H), 1.50 (m, 4H), 1.34 (d, 6H), 1.28 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.62 (br s, 1H), 10.33 (m, 2H), 8.79 (s, 1H), 8.67 (s, 1H), 8.66 (s, 1H), 8.33 (br s, 1H), 8.04 (m, 1H), 7.75 (d, 1H), 7.61 (dd, 1H), 7.41-7.52 (m, 3H), 7.29 (t, 1H), 5.18 (m, 1H) ), 3.22 (m, 2H), 3.17 (s, 3H), 3.12 (s, 3H), 1.95 (t, 2H), 1.50 (m, 4H), 1.34 (d, 6H), 1.28 (m, 4H)
실시예 8: 이소프로필 2-((4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조Example 8: Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethylsulfonamido) Preparation of phenyl) amino) pyrimidine-5-carboxylate
단계 1: 4-((5-(이소프로필카르보닐)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)벤조익 애시드의 제조 (8-1)Step 1: Preparation of 4-((5-(isopropylcarbonyl)-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid ( 8-1)
Figure PCTKR2022020882-appb-img-000027
Figure PCTKR2022020882-appb-img-000027
4-아미노-2-메톡시벤조익 애시드 대신에 4-아미노벤조익 애시드를 사용하고, 상기 실시예 1의 단계 2 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-aminobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
1H NMR (400 MHz, DMSO-d6): δ 10.60 (br s, 1H), 10.31 (br s, 1H), 8.78 (s, 1H), 8.32 (br s, 1H), 7.78 (m, 4H), 7.61 (dd, 1H), 7.43 (m, 2H), 7.30 (m, 1H), 5.17 (m, 1H), 3.17 (s, 3H), 3.12 (s, 3H), 1.34 (d, 6H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.60 (br s, 1H), 10.31 (br s, 1H), 8.78 (s, 1H), 8.32 (br s, 1H), 7.78 (m, 4H) ), 7.61 (dd, 1H), 7.43 (m, 2H), 7.30 (m, 1H), 5.17 (m, 1H), 3.17 (s, 3H), 3.12 (s, 3H), 1.34 (d, 6H)
단계 2: 이소프로필 2-((4-((7-((벤질옥시)아미노)-7-옥소헵틸)카바모일)페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조 (8-2)Step 2: Isopropyl 2-((4-((7-((benzyloxy)amino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethylsulfonamido Preparation of )phenyl)amino)pyrimidine-5-carboxylate (8-2)
Figure PCTKR2022020882-appb-img-000028
Figure PCTKR2022020882-appb-img-000028
7-아미노-N-(벤질옥시)헵탄아미드 염산 염 (1-4)와 단계 1의 물질을 사용하고, 상기 실시예 1의 단계 5 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
1H NMR (400 MHz, CDCl3): δ 10.87 (s, 1H), 8.79 (s, 1H), 8.48 (br s, 1H), 8.37 (d, 2H), 7.56-7.68 (m, 5H), 7.35-7.45 (m, 7H), 7.20 (m, 1H), 6.24 (t, 1H), 5.30 (m, 1H), 4.92 (s, 2H), 3.43 (m, 2H), 3.27 (s, 3H), 3.07 (s, 3H), 2.04 (br s, 1H), 1.62 (m, 5H), 1.38 (m, 10H) 1 H NMR (400 MHz, CDCl 3 ): δ 10.87 (s, 1H), 8.79 (s, 1H), 8.48 (br s, 1H), 8.37 (d, 2H), 7.56-7.68 (m, 5H), 7.35-7.45 (m, 7H), 7.20 (m, 1H), 6.24 (t, 1H), 5.30 (m, 1H), 4.92 (s, 2H), 3.43 (m, 2H), 3.27 (s, 3H) , 3.07 (s, 3H), 2.04 (br s, 1H), 1.62 (m, 5H), 1.38 (m, 10H)
단계 3: 이소프로필 2-((4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조 (8-3)Step 3: Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethylsulfonamido)phenyl Preparation of )amino)pyrimidine-5-carboxylate (8-3)
Figure PCTKR2022020882-appb-img-000029
Figure PCTKR2022020882-appb-img-000029
단계 2의 물질을 사용하고, 상기 실시예 1의 단계 6 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by using the materials of Step 2 and using a method similar to the synthesis method of Step 6 of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 10.66 (br s, 1H), 10.33 (br s, 1H), 10.16 (br s, 1H), 8.77 (s, 1H), 8.66 (s, 1H), 8.40 (br s, 1H), 8.30 (t, 1H), 7.73 (s, 4H), 7.60 (dd, 1H), 7.44 (m, 1H), 7.28 (t, 1H), 5.17 (m, 1H), 3.22 (m, 2H), 3.18 (s, 3H), 3.13 (s, 3H), 1.94 (t, 2H), 1.50 (m, 4H), 1.34 (d, 6H), 1.28 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.66 (br s, 1H), 10.33 (br s, 1H), 10.16 (br s, 1H), 8.77 (s, 1H), 8.66 (s, 1H) ), 8.40 (br s, 1H), 8.30 (t, 1H), 7.73 (s, 4H), 7.60 (dd, 1H), 7.44 (m, 1H), 7.28 (t, 1H), 5.17 (m, 1H) ), 3.22 (m, 2H), 3.18 (s, 3H), 3.13 (s, 3H), 1.94 (t, 2H), 1.50 (m, 4H), 1.34 (d, 6H), 1.28 (m, 4H)
실시예 9: 이소프로필 2-((4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)-2-메톡시페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조Example 9: Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-2-methoxyphenyl)amino)-4-((2-(N-methyl Preparation of methylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate
단계 1: 4-((5-(이소프로필카르보닐)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-3-메톡시벤조익 애시드의 제조 (9-1)Step 1: 4-((5-(isopropylcarbonyl)-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxybenzo Manufacture of ripe acid (9-1)
Figure PCTKR2022020882-appb-img-000030
Figure PCTKR2022020882-appb-img-000030
4-아미노-2-메톡시벤조익 애시드 대신에 4-아미노-3-메톡시벤조익 애시드를 사용하고, 상기 실시예 1의 단계 2 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-3-methoxybenzoic acid instead of 4-amino-2-methoxybenzoic acid.
1H NMR (400 MHz, DMSO-d6): δ 10.78 (br s, 1H), 9.18 (br s, 1H), 8.79 (s, 1H), 8.22 (br s, 1H), 7.91 (d, 1H), 7.60 (dd, 1H), 7.55 (d, 1H), 7.48 (dd, 1H), 7.30 (m, 2H), 5.19 (m, 1H), 3.89 (s, 3H), 3.16 (s, 3H), 3.11 (s, 3H), 1.34 (d, 6H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.78 (br s, 1H), 9.18 (br s, 1H), 8.79 (s, 1H), 8.22 (br s, 1H), 7.91 (d, 1H) ), 7.60 (dd, 1H), 7.55 (d, 1H), 7.48 (dd, 1H), 7.30 (m, 2H), 5.19 (m, 1H), 3.89 (s, 3H), 3.16 (s, 3H) , 3.11 (s, 3H), 1.34 (d, 6H)
단계 2: 이소프로필 2-((4-((7-((벤질옥시)아미노)-7-옥소헵틸)카바모일)-2-메톡시페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조 (9-2)Step 2: Isopropyl 2-((4-((7-((benzyloxy)amino)-7-oxoheptyl)carbamoyl)-2-methoxyphenyl)amino)-4-((2-(N- Preparation of methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate (9-2)
Figure PCTKR2022020882-appb-img-000031
Figure PCTKR2022020882-appb-img-000031
7-아미노-N-(벤질옥시)헵탄아미드 염산 염 (1-4)와 단계 1의 물질을 사용하고, 상기 실시예 1의 단계 5 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
1H NMR (400 MHz, CDCl3): δ 10.83 (s, 1H), 8.82 (s, 1H), 8.37 (m, 3H), 7.94 (s, 1H), 7.37-7.47 (m, 8H), 7.24 (m, 1H), 7.15 (d, 1H), 6.20 (br s, 1H), 5.23 (m, 1H), 4.91 (s, 2H), 3.95 (s, 3H), 3.42 (m, 2H), 3.27 (s, 3H), 3.06 (s, 3H), 2.05 (br s, 1H), 1.63 (m, 5H), 1.38 (m, 10H) 1 H NMR (400 MHz, CDCl 3 ): δ 10.83 (s, 1H), 8.82 (s, 1H), 8.37 (m, 3H), 7.94 (s, 1H), 7.37-7.47 (m, 8H), 7.24 (m, 1H), 7.15 (d, 1H), 6.20 (br s, 1H), 5.23 (m, 1H), 4.91 (s, 2H), 3.95 (s, 3H), 3.42 (m, 2H), 3.27 (s, 3H), 3.06 (s, 3H), 2.05 (br s, 1H), 1.63 (m, 5H), 1.38 (m, 10H)
단계 3: 이소프로필 2-((4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)-2-메톡시페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조 (9-3)Step 3: Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-2-methoxyphenyl)amino)-4-((2-(N-methylmethyl) Preparation of sulfonamido) phenyl) amino) pyrimidine-5-carboxylate (9-3)
Figure PCTKR2022020882-appb-img-000032
Figure PCTKR2022020882-appb-img-000032
단계 2의 물질을 사용하고, 상기 실시예 1의 단계 6 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by using the materials of Step 2 and using a method similar to the synthesis method of Step 6 of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 10.34 (s, 1H), 8.84 (s, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 8.43 (t, 1H), 8.31 (br s, 1H), 7.84 (d, 1H), 7.54 (m, 2H), 7.42 (dd, 1H), 7.26 (t, 1H), 7.19 (m, 1H), 5.16 (m, 1H), 3.87 (s, 3H), 3.27 (m, 2H), 3.16 (s, 3H), 3.12 (s, 3H), 1.95 (t, 2H), 1.52 (m, 4H), 1.29-1.34 (m, 10H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.72 (s, 1H), 10.34 (s, 1H), 8.84 (s, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 8.43 (t, 1H), 8.31 (br s, 1H), 7.84 (d, 1H), 7.54 (m, 2H), 7.42 (dd, 1H), 7.26 (t, 1H), 7.19 (m, 1H), 5.16 (m, 1H), 3.87 (s, 3H), 3.27 (m, 2H), 3.16 (s, 3H), 3.12 (s, 3H), 1.95 (t, 2H), 1.52 (m, 4H), 1.29- 1.34 (m, 10H)
실시예 10: 이소프로필 2-((2-플루오로-4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조Example 10: Isopropyl 2-((2-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methyl Preparation of methylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate
단계 1: 3-플루오로-4-((5-(이소프로필카르보닐)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)벤조익 애시드의 제조 (10-1)Step 1: 3-Fluoro-4-((5-(isopropylcarbonyl)-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)benzo Preparation of ripe acid (10-1)
Figure PCTKR2022020882-appb-img-000033
Figure PCTKR2022020882-appb-img-000033
4-아미노-2-메톡시벤조익 애시드 대신에 4-아미노-3-플루오로벤조익 애시드를 사용하고, 상기 실시예 1의 단계 2 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-3-fluorobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
1H NMR (400 MHz, DMSO-d6): δ 10.81 (br s, 1H), 9.96 (br s, 1H), 8.76 (s, 1H), 8.33 (br s, 1H), 7.85 (m, 1H), 7.30 (m, 2H), 7.55 (m, 1H), 7.19 (m, 2H), 5.16 (m, 1H), 3.17 (s, 3H), 3.12 (s, 3H), 1.34 (d, 6H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.81 (br s, 1H), 9.96 (br s, 1H), 8.76 (s, 1H), 8.33 (br s, 1H), 7.85 (m, 1H) ), 7.30 (m, 2H), 7.55 (m, 1H), 7.19 (m, 2H), 5.16 (m, 1H), 3.17 (s, 3H), 3.12 (s, 3H), 1.34 (d, 6H)
단계 2: 이소프로필 2-((4-((7-((벤질옥시)아미노)-7-옥소헵틸)카바모일)-2-플루오로페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조 (10-2)Step 2: Isopropyl 2-((4-((7-((benzyloxy)amino)-7-oxoheptyl)carbamoyl)-2-fluorophenyl)amino)-4-((2-(N- Preparation of methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate (10-2)
Figure PCTKR2022020882-appb-img-000034
Figure PCTKR2022020882-appb-img-000034
7-아미노-N-(벤질옥시)헵탄아미드 염산 염 (1-4)와 단계 1의 물질을 사용하고, 상기 실시예 1의 단계 5 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
1H NMR (400 MHz, CDCl3): δ 10.85 (s, 1H), 8.84 (s, 1H), 8.42 (t, 1H), 8.31 (d, 1H), 8.25 (br s, 1H), 7.56 (dd, 1H), 7.38-7.50 (m, 9H), 7.24 (m, 1H), 6.18 (br s, 1H), 5.31 (m, 1H), 4.92 (s, 2H), 3.43 (m, 2H), 3.27 (s, 3H), 3.06 (s, 3H), 2.05 (br s, 1H), 1.63 (m, 5H), 1.39 (m, 10H) 1 H NMR (400 MHz, CDCl 3 ): δ 10.85 (s, 1H), 8.84 (s, 1H), 8.42 (t, 1H), 8.31 (d, 1H), 8.25 (br s, 1H), 7.56 ( dd, 1H), 7.38-7.50 (m, 9H), 7.24 (m, 1H), 6.18 (br s, 1H), 5.31 (m, 1H), 4.92 (s, 2H), 3.43 (m, 2H), 3.27 (s, 3H), 3.06 (s, 3H), 2.05 (br s, 1H), 1.63 (m, 5H), 1.39 (m, 10H)
단계 3: 이소프로필 2-((2-플루오로-4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트의 제조 (10-3)Step 3: Isopropyl 2-((2-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethyl Preparation of sulfonamido) phenyl) amino) pyrimidine-5-carboxylate (10-3)
Figure PCTKR2022020882-appb-img-000035
Figure PCTKR2022020882-appb-img-000035
단계 2의 물질을 사용하고, 상기 실시예 1의 단계 6 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by using the materials of Step 2 and using a method similar to the synthesis method of Step 6 of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 10.34 (br s, 1H), 9.80 (br s, 1H), 8.74 (s, 1H), 8.66 (s, 1H), 8.50 (t, 1H), 8.35 (br s, 1H), 7.67-7.78 (m, 3H), 7.52 (dd, 1H), 7.14 (m, 2H), 5.16 (m, 1H), 3.27 (m, 2H), 3.17 (s, 3H), 3.12 (s, 3H), 1.95 (t, 2H), 1.49 (m, 4H), 1.29-1.34 (m, 10H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.81 (s, 1H), 10.34 (br s, 1H), 9.80 (br s, 1H), 8.74 (s, 1H), 8.66 (s, 1H) , 8.50 (t, 1H), 8.35 (br s, 1H), 7.67-7.78 (m, 3H), 7.52 (dd, 1H), 7.14 (m, 2H), 5.16 (m, 1H), 3.27 (m, 2H), 3.17 (s, 3H), 3.12 (s, 3H), 1.95 (t, 2H), 1.49 (m, 4H), 1.29-1.34 (m, 10H)
실시예 11: 4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-3-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)벤즈아미드의 제조Example 11: 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-fluoro-N-(7 Preparation of (hydroxyamino)-7-oxoheptyl)benzamide
단계 1: 4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-3-플루오로벤조익 애시드의 제조 (11-1)Step 1: Preparation of 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-fluorobenzoic acid (11 -One)
Figure PCTKR2022020882-appb-img-000036
Figure PCTKR2022020882-appb-img-000036
N-(2-((2-클로로-5-(트리플루오로메틸)피리미딘-4-일)아미노)페닐)-N-메틸메탄술폰아미드 대신에 N-(2-((2,5-디클로로피리미딘-4-일)아미노)페닐)-N-메틸메탄술폰아미드을 사용하고, 상기 실시예 1의 단계 2 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.N-(2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide instead of N-(2-((2,5- The title compound was obtained using dichloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide and using a method similar to the step 2 synthesis method of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 13.03 (br s, 1H), 9.36 (br s, 1H), 8.47 (br s, 1H), 8.27 (s, 1H), 8.26 (m, 1H), 7.96 (t, 1H), 7.62-7.70 (m, 3H), 7.34 (m, 1H), 7.25 (m, 1H), 3.19 (s, 3H), 3.10 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 13.03 (br s, 1H), 9.36 (br s, 1H), 8.47 (br s, 1H), 8.27 (s, 1H), 8.26 (m, 1H) ), 7.96 (t, 1H), 7.62-7.70 (m, 3H), 7.34 (m, 1H), 7.25 (m, 1H), 3.19 (s, 3H), 3.10 (s, 3H)
단계 2: N-(7-((벤질옥시)아미노)-7-옥소헵틸)-4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)-3-플루오로벤즈아미드의 제조 (11-2)Step 2: N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)- Preparation of 5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-fluorobenzamide (11-2)
Figure PCTKR2022020882-appb-img-000037
Figure PCTKR2022020882-appb-img-000037
7-아미노-N-(벤질옥시)헵탄아미드 염산 염 (1-4)와 단계 1의 물질을 사용하고, 상기 실시예 1의 단계 5 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
단계 3: 4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-3-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)벤즈아미드의 제조 (11-3)Step 3: 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-fluoro-N-(7- Preparation of (hydroxyamino) -7-oxoheptyl) benzamide (11-3)
Figure PCTKR2022020882-appb-img-000038
Figure PCTKR2022020882-appb-img-000038
단계 2의 물질을 사용하고, 상기 실시예 1의 단계 6 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by using the materials of Step 2 and using a method similar to the synthesis method of Step 6 of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 10.33 (br s, 1H), 9.25 (br s, 1H), 8.31 (s, 1H), 8.20 (br d, 1H), 7.97 (m, 1H), 7.72 (dd, 1H), 7.66 (dd, 1H), 7.46-7.52 (m, 2H), 7.32-7.38 (m, 2H), 7.23 (br s, 1H), 6.69 (br s, 1H), 3.24 (m, 2H), 3.19 (s, 3H), 3.10 (s, 3H), 1.95 (t, 2H), 1.49 (m, 4H), 1.28 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.33 (br s, 1H), 9.25 (br s, 1H), 8.31 (s, 1H), 8.20 (br d, 1H), 7.97 (m, 1H) ), 7.72 (dd, 1H), 7.66 (dd, 1H), 7.46-7.52 (m, 2H), 7.32-7.38 (m, 2H), 7.23 (br s, 1H), 6.69 (br s, 1H), 3.24 (m, 2H), 3.19 (s, 3H), 3.10 (s, 3H), 1.95 (t, 2H), 1.49 (m, 4H), 1.28 (m, 4H)
실시예 12: 4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-2-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)벤즈아미드의 제조Example 12: 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-(7 Preparation of (hydroxyamino)-7-oxoheptyl)benzamide
단계 1: 4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-2-플루오로벤조익 애시드의 제조 (12-1)Step 1: Preparation of 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorobenzoic acid (12 -One)
Figure PCTKR2022020882-appb-img-000039
Figure PCTKR2022020882-appb-img-000039
4-아미노-2-메톡시벤조익 애시드 대신에 4-아미노-2-플루오로벤조익 애시드를 사용하고, 상기 실시예 1의 단계 2 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-2-fluorobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
1H NMR (400 MHz, DMSO-d6): δ 12.81 (br s, 1H), 8.53 (br s, 1H), 8.33 (s, 1H), 8.15 (m, 1H), 7.65-7.78 (m, 4H), 7.47 (td, 1H), 7.37 (dd, 1H), 7.34 (td, 1H), 3.19 (s, 3H), 3.09 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.81 (br s, 1H), 8.53 (br s, 1H), 8.33 (s, 1H), 8.15 (m, 1H), 7.65-7.78 (m, 4H), 7.47 (td, 1H), 7.37 (dd, 1H), 7.34 (td, 1H), 3.19 (s, 3H), 3.09 (s, 3H)
단계 2: N-(7-((벤질옥시)아미노)-7-옥소헵틸)-4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-2-플루오로벤즈아미드의 제조 (12-2)Step 2: N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrid Preparation of midin-2-yl) amino) -2-fluorobenzamide (12-2)
Figure PCTKR2022020882-appb-img-000040
Figure PCTKR2022020882-appb-img-000040
7-아미노-N-(벤질옥시)헵탄아미드 염산 염 (1-4)와 단계 1의 물질을 사용하고, 상기 실시예 1의 단계 5 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
단계 3: 4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-2-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)벤즈아미드의 제조 (12-3)Step 3: 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-(7- Preparation of (hydroxyamino) -7-oxoheptyl) benzamide (12-3)
Figure PCTKR2022020882-appb-img-000041
Figure PCTKR2022020882-appb-img-000041
단계 2의 물질을 사용하고, 상기 실시예 1의 단계 6 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by using the materials of Step 2 and using a method similar to the synthesis method of Step 6 of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 9.89 (br s, 1H), 8.50 (br s, 1H), 8.31 (s, 1H), 8.20 (br d, 1H), 7.97 (m, 1H), 7.72 (dd, 1H), 7.66 (dd, 1H), 7.46-7.52 (m, 2H), 7.32-7.38 (m, 2H), 7.23 (br s, 1H), 6.69 (br s, 1H), 3.22 (m, 2H), 3.19 (s, 3H), 3.10 (s, 3H), 2.03 (t, 2H), 1.49 (m, 4H), 1.28 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.89 (br s, 1H), 8.50 (br s, 1H), 8.31 (s, 1H), 8.20 (br d, 1H), 7.97 (m, 1H) ), 7.72 (dd, 1H), 7.66 (dd, 1H), 7.46-7.52 (m, 2H), 7.32-7.38 (m, 2H), 7.23 (br s, 1H), 6.69 (br s, 1H), 3.22 (m, 2H), 3.19 (s, 3H), 3.10 (s, 3H), 2.03 (t, 2H), 1.49 (m, 4H), 1.28 (m, 4H)
실시예 13: 2-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)벤즈아미드의 제조Example 13: 2-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrid Preparation of midin-2-yl) amino) benzamide
단계 1: 2-플루오로-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)벤조익 애시드의 제조 (13-1)Step 1: Preparation of 2-fluoro-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid (13-1)
Figure PCTKR2022020882-appb-img-000042
Figure PCTKR2022020882-appb-img-000042
4-아미노-2-메톡시벤조익 애시드 대신에 4-아미노-2-플루오로벤조익 애시드를 사용하고, 상기 실시예 1의 단계 2 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-2-fluorobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
1H NMR (400 MHz, DMSO-d6): δ 12.74 (br s, 1H), 9.79 (br s, 1H), 8.69 (br s, 1H), 8.10 (d, 1H), 7.92 (d, 1H), 7.84 (m, 1H), 7.69 (t, 1H), 7.57 (d, 1H), 7.41 (m, 2H), 7.26 (d, 1H), 6.49 (d, 1H), 3.15 (s, 3H), 3.05 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.74 (br s, 1H), 9.79 (br s, 1H), 8.69 (br s, 1H), 8.10 (d, 1H), 7.92 (d, 1H) ), 7.84 (m, 1H), 7.69 (t, 1H), 7.57 (d, 1H), 7.41 (m, 2H), 7.26 (d, 1H), 6.49 (d, 1H), 3.15 (s, 3H) , 3.05 (s, 3H)
단계 2: N-(7-((벤질옥시)아미노)-7-옥소헵틸)-2-플루오로-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)벤즈아미드의 제조 (13-2)Step 2: N-(7-((benzyloxy)amino)-7-oxoheptyl)-2-fluoro-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino) Preparation of pyrimidin-2-yl) amino) benzamide (13-2)
Figure PCTKR2022020882-appb-img-000043
Figure PCTKR2022020882-appb-img-000043
7-아미노-N-(벤질옥시)헵탄아미드 염산 염 (1-4)와 단계 1의 물질을 사용하고, 상기 실시예 1의 단계 5 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
단계 3: 2-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)벤즈아미드의 제조 (13-3)Step 3: 2-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidine Preparation of -2-yl) amino) benzamide (13-3)
Figure PCTKR2022020882-appb-img-000044
Figure PCTKR2022020882-appb-img-000044
단계 2의 물질을 사용하고, 상기 실시예 1의 단계 6 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by using the materials of Step 2 and using a method similar to the synthesis method of Step 6 of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 9.63 (br s, 1H), 8.62 (br s, 1H), 8.09 (d, 1H), 7.96 (dd, 1H), 7.94 (m, 1H), 7.82 (dd, 1H), 7.57 (dd, 2H), 7.48 (t, 2H), 7.38-7.43 (m, 2H), 7.23-7.27 (m, 2H), 6.69 (br s, 1H), 6.47 (d, 2H), 3.21 (m, 2H), 3.16 (s, 3H), 3.05 (s, 3H), 2.04 (t, 2H), 1.49 (m, 4H), 1.28 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.63 (br s, 1H), 8.62 (br s, 1H), 8.09 (d, 1H), 7.96 (dd, 1H), 7.94 (m, 1H) , 7.82 (dd, 1H), 7.57 (dd, 2H), 7.48 (t, 2H), 7.38–7.43 (m, 2H), 7.23–7.27 (m, 2H), 6.69 (br s, 1H), 6.47 ( d, 2H), 3.21 (m, 2H), 3.16 (s, 3H), 3.05 (s, 3H), 2.04 (t, 2H), 1.49 (m, 4H), 1.28 (m, 4H)
실시예 14: 4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-N-(7-(히드록시아미노)-7-옥소헵틸)벤즈아미드의 제조Example 14: 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of )-7-oxoheptyl)benzamide
단계 1: 4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)벤조익 애시드의 제조 (14-1)Step 1: Preparation of 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid (14-1)
Figure PCTKR2022020882-appb-img-000045
Figure PCTKR2022020882-appb-img-000045
4-아미노-2-메톡시벤조익 애시드 대신에 4-아미노벤조익 애시드를 사용하고, 상기 실시예 1의 단계 2 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-aminobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
1H NMR (400 MHz, DMSO-d6): δ 12.58 (br s, 1H), 9.87 (br s, 1H), 8.49 (br s, 1H), 8.30 (s, 1H), 8.22 (m, 1H), 7.72-7.80 (m, 4H), 7.67 (dd, 1H), 7.48 (td, 1H), 7.34 (td, 1H), 3.19 (s, 3H), 3.10 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.58 (br s, 1H), 9.87 (br s, 1H), 8.49 (br s, 1H), 8.30 (s, 1H), 8.22 (m, 1H) ), 7.72-7.80 (m, 4H), 7.67 (dd, 1H), 7.48 (td, 1H), 7.34 (td, 1H), 3.19 (s, 3H), 3.10 (s, 3H)
단계 2: N-(7-((벤질옥시)아미노)-7-옥소헵틸)-4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)벤즈아미드의 제조 (14-2)Step 2: N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrid Preparation of midin-2-yl) amino) benzamide (14-2)
Figure PCTKR2022020882-appb-img-000046
Figure PCTKR2022020882-appb-img-000046
7-아미노-N-(벤질옥시)헵탄아미드 염산 염 (1-4)와 단계 1의 물질을 사용하고, 상기 실시예 1의 단계 5 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
단계 3: 4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-N-(7-(히드록시아미노)-7-옥소헵틸)벤즈아미드의 제조 (14-3)Step 3: 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of -7-oxoheptyl)benzamide (14-3)
Figure PCTKR2022020882-appb-img-000047
Figure PCTKR2022020882-appb-img-000047
단계 2의 물질을 사용하고, 상기 실시예 1의 단계 6 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by using the materials of Step 2 and using a method similar to the synthesis method of Step 6 of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 10.34 (br s, 1H), 9.72 (br s, 1H), 8.67 (br s, 1H), 8.46 (br s, 1H), 8.28 (m, 3H), 8.20 (br d, 1H), 7.70 (m, 4H), 7.68 (t, 1H), 7.48 (t, 1H), 7.31 (t, 1H), 3.22 (m, 2H), 3.20 (s, 3H), 3.10 (s, 3H), 1.94 (t, 2H), 1.50 (m, 4H), 1.28 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.34 (br s, 1H), 9.72 (br s, 1H), 8.67 (br s, 1H), 8.46 (br s, 1H), 8.28 (m, 3H), 8.20 (br d, 1H), 7.70 (m, 4H), 7.68 (t, 1H), 7.48 (t, 1H), 7.31 (t, 1H), 3.22 (m, 2H), 3.20 (s, 3H), 3.10 (s, 3H), 1.94 (t, 2H), 1.50 (m, 4H), 1.28 (m, 4H)
실시예 15: 4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-N-(7-(히드록시아미노)-7-옥소헵틸)-3-메톡시벤즈아미드의 제조Example 15: 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of )-7-oxoheptyl)-3-methoxybenzamide
단계 1: 4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-3-메톡시벤조익 애시드의 제조 (15-1)Step 1: Preparation of 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxybenzoic acid ( 15-1)
Figure PCTKR2022020882-appb-img-000048
Figure PCTKR2022020882-appb-img-000048
4-아미노-2-메톡시벤조익 애시드 대신에 4-아미노-3-메톡시벤조익 애시드를 사용하고, 상기 실시예 1의 단계 2 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-3-methoxybenzoic acid instead of 4-amino-2-methoxybenzoic acid.
1H NMR (400 MHz, DMSO-d6): δ 12.81 (br s, 1H), 8.51 (br s, 1H), 8.27 (s, 1H), 8.19 (d, 1H), 8.15 (dd, H), 8.09 (dd, 1H), 7.66 (dd, 1H), 7.49 (d, 1H), 7.41-7.46 (m, 2H), 7.33 (td, 1H), 3.90 (s, 3H), 3.18 (s, 3H), 3.09 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.81 (br s, 1H), 8.51 (br s, 1H), 8.27 (s, 1H), 8.19 (d, 1H), 8.15 (dd, H) , 8.09 (dd, 1H), 7.66 (dd, 1H), 7.49 (d, 1H), 7.41-7.46 (m, 2H), 7.33 (td, 1H), 3.90 (s, 3H), 3.18 (s, 3H) ), 3.09 (s, 3H)
단계 2: N-(7-((벤질옥시)아미노)-7-옥소헵틸)-4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-3-메톡시벤즈아미드의 제조 (15-2)Step 2: N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrid Preparation of midin-2-yl) amino) -3-methoxybenzamide (15-2)
Figure PCTKR2022020882-appb-img-000049
Figure PCTKR2022020882-appb-img-000049
7-아미노-N-(벤질옥시)헵탄아미드 염산 염 (1-4)와 단계 1의 물질을 사용하고, 상기 실시예 1의 단계 5 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
단계 3: 4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-N-(7-(히드록시아미노)-7-옥소헵틸)-3-메톡시벤즈아미드의 제조 (15-3)Step 3: 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of -7-oxoheptyl) -3-methoxybenzamide (15-3)
Figure PCTKR2022020882-appb-img-000050
Figure PCTKR2022020882-appb-img-000050
단계 2의 물질을 사용하고, 상기 실시예 1의 단계 6 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by using the materials of Step 2 and using a method similar to the synthesis method of Step 6 of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 8.46 (br s, 1H), 8.36 (br t, 1H), 8.25 (s, 1H), 8.19 (dd, 1H), 8.16 (br s, 1H), 8.01 (d, 1H), 7.65 (dd, 1H), 7.49 (d, 1H), 7.37-7.43 (d, 2H), 7.29 (td, 1H), 7.23 (br s, 1H), 6.69 (br s, 1H), 3.89 (s, 3H), 3.25 (m, 2H), 3.19 (s, 3H), 3.10 (s, 3H), 2.04 (t, 2H), 1.51 (m, 4H), 1.30 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.46 (br s, 1H), 8.36 (br t, 1H), 8.25 (s, 1H), 8.19 (dd, 1H), 8.16 (br s, 1H) ), 8.01 (d, 1H), 7.65 (dd, 1H), 7.49 (d, 1H), 7.37-7.43 (d, 2H), 7.29 (td, 1H), 7.23 (br s, 1H), 6.69 (br s, 1H), 3.89 (s, 3H), 3.25 (m, 2H), 3.19 (s, 3H), 3.10 (s, 3H), 2.04 (t, 2H), 1.51 (m, 4H), 1.30 (m , 4H)
실시예 16: 4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-N-(7-(히드록시아미노)-7-옥소헵틸)-2-메톡시벤즈아미드의 제조Example 16: 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of )-7-oxoheptyl)-2-methoxybenzamide
단계 1: 4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-2-메톡시벤조익 애시드의 제조 (16-1)Step 1: Preparation of 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-methoxybenzoic acid ( 16-1)
Figure PCTKR2022020882-appb-img-000051
Figure PCTKR2022020882-appb-img-000051
상기 실시예 1의 단계 2 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained using a method similar to the step 2 synthesis method of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 12.11 (br s, 1H), 9.76 (br s, 1H), 8.49 (br s, 1H), 8.30 (s, 1H), 8.21 (m, 1H), 7.65 (dd, H), 7.58 (dd, 1H), 7.42-7.46 (m, 2H), 7.27-7.35 (m, 2H), 3.60 (s, 3H), 3.19 (s, 3H), 3.10 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.11 (br s, 1H), 9.76 (br s, 1H), 8.49 (br s, 1H), 8.30 (s, 1H), 8.21 (m, 1H) ), 7.65 (dd, H), 7.58 (dd, 1H), 7.42-7.46 (m, 2H), 7.27-7.35 (m, 2H), 3.60 (s, 3H), 3.19 (s, 3H), 3.10 ( s, 3H)
단계 2: N-(7-((벤질옥시)아미노)-7-옥소헵틸)-4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-2-메톡시벤즈아미드의 제조 (16-2)Step 2: N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrid Preparation of midin-2-yl) amino) -2-methoxybenzamide (16-2)
Figure PCTKR2022020882-appb-img-000052
Figure PCTKR2022020882-appb-img-000052
7-아미노-N-(벤질옥시)헵탄아미드 염산 염 (1-4)와 단계 1의 물질을 사용하고, 상기 실시예 1의 단계 5 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
단계 3: 4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-N-(7-(히드록시아미노)-7-옥소헵틸)-2-메톡시벤즈아미드의 제조 (16-3)Step 3: 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of -7-oxoheptyl) -2-methoxybenzamide (16-3)
Figure PCTKR2022020882-appb-img-000053
Figure PCTKR2022020882-appb-img-000053
단계 2의 물질을 사용하고, 상기 실시예 1의 단계 6 합성법과 유사한 방법을 사용하여 표제화합물을 수득하였다.The title compound was obtained by using the materials of Step 2 and using a method similar to the synthesis method of Step 6 of Example 1 above.
1H NMR (400 MHz, DMSO-d6): δ 9.70 (br s, 1H), 8.47 (br s, 1H), 8.29 (s, 1H), 8.22 (m, 1H), 7.98 (br t, 1H), 7.67 (m, 2H), 7.44 (m, 1H), 7.37 (dd, 1H), 7.32 (td, 1H), 7.24 (br s, 1H), 6.69 (br s, 1H), 3.69 (s, 3H), 3.24 (m, 2H), 3.19 (s, 3H), 3.10 (s, 3H), 2.04 (t, 2H), 1.49 (m, 4H), 1.28 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.70 (br s, 1H), 8.47 (br s, 1H), 8.29 (s, 1H), 8.22 (m, 1H), 7.98 (br t, 1H) ), 7.67 (m, 2H), 7.44 (m, 1H), 7.37 (dd, 1H), 7.32 (td, 1H), 7.24 (br s, 1H), 6.69 (br s, 1H), 3.69 (s, 3H), 3.24 (m, 2H), 3.19 (s, 3H), 3.10 (s, 3H), 2.04 (t, 2H), 1.49 (m, 4H), 1.28 (m, 4H)
실험예 1: EGFR 효소 억제 활성 평가Experimental Example 1: Evaluation of EGFR enzyme inhibitory activity
본 발명의 화합물들에 대해 사람 유래 EGFR 키나아제 야생형 및 삼중 돌연변이 형태인 EGFR wt, EGFR del19/T790M/C797S, EGFR L858R/T790M/C797S에 대하여 억제 활성을 나타내는지를 확인하였다. 효소 활성 억제 평가는 Reaction Biology 社(미국, MA)에서 수행되었으며, 구체적인 시험 방법은 다음과 같다.It was confirmed whether the compounds of the present invention exhibit inhibitory activity against human-derived EGFR kinase wild-type and triple mutant EGFR wt, EGFR del19/T790M/C797S, and EGFR L858R/T790M/C797S. Enzyme activity inhibition was evaluated by Reaction Biology (USA, MA), and the specific test method is as follows.
실험에 사용하는 화합물은 최고 농도 1 μM로 준비하여 3배 희석을 순차적으로 진행하였다. 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05 nM의 농도를 사용하였다. 효소 반응 조건의 확인을 위한 대조물질로는 Staurosporine을 사용하였다. 반응에 사용한 ATP의 농도는 각각의 단백질별 Km에 해당하는 농도를 사용하였다. 반응에 사용할 기질은 반응 완충 용액인 assay buffer에(조성: 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01%, Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO) 혼합하여 준비하였다. 기질반응에 필요한 보조인자를 첨가하였다. 각 효소를 기질 혼합액에 첨가한 뒤 시험 물질을 농도별로 처리하고 33P-ATP를 처리하여 반응을 개시하였다. 2시간 동안 반응을 진행한 뒤 P81 Filter plate 통과 후 남아 있는 방사능의 양을 측정하여 분석함으로써 키나아제 활성을 분석하였다. 발명의 화합물에 대한 키나아제 활성 저해 활성 결과는 표 1에 나타내었다.The compound used in the experiment was prepared at the highest concentration of 1 μM and was sequentially diluted 3-fold. Concentrations of 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, and 0.05 nM were used. Staurosporine was used as a control material to confirm the enzymatic reaction conditions. The concentration of ATP used in the reaction was the concentration corresponding to Km for each protein. Substrates to be used for the reaction were mixed in assay buffer, a reaction buffer solution (composition: 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01%, Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO) was prepared by mixing. Cofactors required for substrate reaction were added. After each enzyme was added to the substrate mixture, the test substance was treated by concentration and the reaction was initiated by treatment with 33 P-ATP. After the reaction for 2 hours, the kinase activity was analyzed by measuring and analyzing the amount of remaining radioactivity after passing through the P81 Filter plate. The kinase activity inhibitory activity results for the compounds of the invention are shown in Table 1.
실시예Example IC50, nMIC50, nM
EGFR
(WT)EGFR
(WT) 		EGFR
(d746-750/T790M/C797S)EGFR
(d746-750/T790M/C797S) 		EGFR (T790M/C797S/L858R)EGFR (T790M/C797S/L858R)
1111 84.0584.05 1.541.54 12.3012.30
1212 59.1559.15 0.370.37 6.706.70
1313 140.50140.50 5.815.81 85.5585.55
1414 9.129.12 0.110.11 0.640.64
1515 106.85106.85 1.281.28 19.6519.65
1616 70.7570.75 0.640.64 7.707.70
실험예 2: HDAC 효소 억제 활성 평가Experimental Example 2: Evaluation of HDAC enzyme inhibitory activity
본 발명의 화합물 중 2종에 대해 사람 유래 HDAC 단백질에 대한 활성 억제 효과를 나타내는지를 확인하였다. 효소 활성 억제 평가는 Eurofins Cerep 사(프랑스)에서 수행되었으며, 구체적인 시험 방법은 다음과 같다. It was confirmed whether two of the compounds of the present invention had an activity inhibitory effect on human-derived HDAC protein. Enzyme activity inhibition was evaluated by Eurofins Cerep (France), and the specific test method is as follows.
정제된 사람 유래 HDAC 1, 2, 3, 4, 6 단백질과 HDAC에 대한 기질을 사용하여 효소 활성 저해능을 확인하였다. 화합물 2종을 1000, 100, 10, 1 nM의 농도로 준비하였다. 기질은 형광표지 된 HDAC class 2a를 20 μM농도로 사용하였다. 효소 반응 조건의 확인을 위한 대조물질로는 Trichostatin A를 사용하였다. 효소, 화합물, 기질을 혼합한 뒤 실온에서 30분 동안 반응을 진행하였으며, 최종 형광값 측정을 통해 HDAC 활성 저해 정도를 상대적으로 분석하였다. 발명의 화합물에 대한 HDAC 활성 저해 활성 결과는 도 1에 나타내었다. Enzyme activity inhibition was confirmed using purified human-derived HDAC 1, 2, 3, 4, and 6 proteins and substrates for HDAC. Two compounds were prepared at concentrations of 1000, 100, 10, and 1 nM. As a substrate, fluorescently labeled HDAC class 2a was used at a concentration of 20 μM. Trichostatin A was used as a control material for confirmation of the enzyme reaction conditions. After mixing the enzyme, compound, and substrate, the reaction was carried out at room temperature for 30 minutes, and the degree of inhibition of HDAC activity was relatively analyzed by measuring the final fluorescence value. HDAC activity inhibitory activity results for the compounds of the invention are shown in Figure 1.
실험예 3: 동물모델에서의 폐섬유화 억제 시험Experimental Example 3: Pulmonary Fibrosis Inhibition Test in Animal Model
본 발명의 화합물의 방사선 치료 후 발생되는 폐섬유화 증상에 대한 억제 효과를 확인하기 위해 동물실험을 진행하였다. C57BL/6 마우스(8주령)의 폐 부위에 90 Gy의 국소 방사선을 조사하여 폐섬유화를 유발하였다. 방사선 조사 1시간 전에 양성대조물질(Nintedanib, 30 mg/kg)과 본 발명의 화합물 (30 mg/kg)을 경구 투여하였다. 약물 투여는 하루 1회, 14일 동안 반복 투여하였다. Animal experiments were conducted to confirm the inhibitory effect of the compound of the present invention on the symptoms of pulmonary fibrosis occurring after radiation treatment. Lung fibrosis was induced by irradiating 90 Gy of local radiation to the lungs of C57BL/6 mice (8 weeks old). A positive control (Nintedanib, 30 mg/kg) and a compound of the present invention (30 mg/kg) were orally administered 1 hour before irradiation. Drug administration was repeated once a day for 14 days.
실험방법Experiment method
(1) 생체조직에 대한 헤마톡실린(hematoxilin) 및 에오신(Eosin) 염색법(H&E)(1) Hematoxylin and Eosin staining method (H&E) for living tissue
마우스 조직은 먼저 10%의 중성 포르말린으로 5일 고정시키고 파라핀 블럭을 만들었다. 조직 내에 침투된 파라핀을 제거하는 과정으로 자일렌(xylene) 반응시키는 과정을 거치고, 100, 95, 70, 50% 에탄올 용액에 각각 3분씩 반응시켰다. 50% 에탄올 과정이 끝나면 흐르는 물에 10분 동안 세척하였다. 헤마톡실린 용액은 2분간 반응시켜 핵을 염색하고 흐르는 물에 10분간 세척하였다. 그런 뒤 에오신 용액에 30초 반응시켜 세포질을 염색하고 50,70,95,100% 에탄올 과정을 각각 1분씩 반응시켰다. 마지막으로 자일렌 용액에 반응시킨 후, 마운팅 용액을 한 방울 떨어트린 후 커버 슬라이드를 덮고 현미경으로 관찰하였다.Mouse tissues were first fixed in 10% neutral formalin for 5 days and then made into paraffin blocks. As a process of removing paraffin penetrating into tissue, xylene was reacted, followed by reaction in 100, 95, 70, and 50% ethanol solutions for 3 minutes, respectively. After the 50% ethanol process was completed, it was washed with running water for 10 minutes. The hematoxylin solution was reacted for 2 minutes to stain the nuclei, and washed with running water for 10 minutes. Then, the cytoplasm was stained by reacting with an eosin solution for 30 seconds, and 50, 70, 95, and 100% ethanol were reacted for 1 minute each. Finally, after reacting with the xylene solution, a drop of the mounting solution was applied, and the cover slide was covered and observed under a microscope.
(2) 생체조직에 대한 트라이크롬(Trichrome) 염색법(2) Trichrome staining method for living tissue
마우스 조직은 먼저 10%의 중성 포르말린으로 5일 고정시키고 파라핀 블럭을 만들었다. 조직내의 파라핀을 제거하기 위해 자일렌(xylene)에 반응시키고, 100, 95, 70, 50% 에탄올 용액에 3분씩 각각 반응시켰으며, 마지막 과정이 끝난 뒤 흐르는 물에 10분간 세척을 진행하였다. 먼저 Bouin's Solution에 60분간 60℃ 워터베스에서 반응시키고, 반응 후 흐르는 물에 10분간 세척하였다. 세척 후, Weigert's hematoxylin A와 B용액을 1:1 비율로 섞은 뒤 10분간 반응시켰다. 마찬가지로 염색 후 흐르는 물에 10분간 세척을 진행 후, Biebrich Scarlet-Acid Fuschin solution은 3분간 반응시키고 3차 증류수로 한번 헹궈주었다. 그 다음 Phosphotumstic/Phosphomolydic acid에 20분간, 세척과정 없이 아닐린 블루 30분간 반응을 진행하였다. 마지막 염색과정이 끝나면 3차 증류수로 3번 헹궈 준 뒤, 1% 아세트산 용액에 1분 동안 반응시켰다. 95, 100% 에탄올 용액을 통해 탈수과정을 거친 뒤, 자일렌 용액을 마지막으로 마무리한 후 마운팅 용액을 한 방울 떨어트린 후 커버 슬라이드를 덮은 후 현미경으로 관찰하였다.Mouse tissues were first fixed in 10% neutral formalin for 5 days and then made into paraffin blocks. In order to remove paraffin in the tissue, it was reacted with xylene, reacted with 100, 95, 70, and 50% ethanol solutions for 3 minutes each, and after the last process was finished, washed with running water for 10 minutes. First, Bouin's Solution was reacted in a water bath at 60 ° C for 60 minutes, and after the reaction, it was washed with running water for 10 minutes. After washing, Weigert's hematoxylin A and B solutions were mixed in a 1:1 ratio and reacted for 10 minutes. Likewise, after washing in running water for 10 minutes after dyeing, the Biebrich Scarlet-Acid Fuschin solution was reacted for 3 minutes and rinsed once with tertiary distilled water. Then, the reaction was carried out in Phosphotumstic/Phosphomolydic acid for 20 minutes and aniline blue for 30 minutes without washing. After the last dyeing process was finished, it was rinsed 3 times with tertiary distilled water and reacted in 1% acetic acid solution for 1 minute. After dehydration through 95 and 100% ethanol solutions, xylene solution was finally finished, a drop of mounting solution was dropped, and a cover slide was covered and observed under a microscope.
방사선 조사 2주 후, Micro-CT 촬영을 통해 마우스 폐의 염증 정도와 섬유화 진행 정도를 영상으로 확인하였다. 도 2에서 보는 바와 같이, Micro-CT 촬영 단면을 통해 방사선에 조사 후, 염증반응과 폐 섬유화가 진행된 것을 확인하였고, 약물 처리군에서 양성대조물질 (Nitedanib, 30mg/kg)과 본 발명의 화합물 (30mg/kg)에서 염증과 섬유화 정도가 완화되는 것을 확인할 수 있었다. 도 3은 마우스 폐를 적출한 후 염증세포의 침윤 및 염증 정도와 섬유화 시 나타나는 단백질인 콜라겐을 분석하기 위해 H&E 염색과 트라이크롬 염색법으로 확인한 결과이다. 도 4는 도 3의 결과를 토대로 Ashcorft score를 적용하여 폐섬유화 정도를 평가하였고, 각 그룹(n=4) 모두 방사선 조사 부위 5곳을 현미경으로 찍은 뒤 Image J 프로그램을 이용하여 콜라겐 침착 정도를 정량 분석한 결과이다. Two weeks after irradiation, the degree of inflammation and fibrosis in the lungs of mice were confirmed through micro-CT images. As shown in FIG. 2, after irradiation with radiation through the Micro-CT cross-section, it was confirmed that the inflammatory reaction and pulmonary fibrosis progressed, and in the drug-treated group, the positive control substance (Nitedanib, 30 mg/kg) and the compound of the present invention ( 30mg/kg), it was confirmed that the degree of inflammation and fibrosis were alleviated. Figure 3 is the result confirmed by H&E staining and trichrome staining to analyze the degree of infiltration and inflammation of inflammatory cells and collagen, a protein that appears during fibrosis, after removing mouse lungs. Figure 4 evaluates the degree of pulmonary fibrosis by applying the Ashcorft score based on the results of Figure 3, and each group (n = 4) takes pictures of 5 irradiated areas under a microscope and quantifies the degree of collagen deposition using the Image J program. is the result of the analysis.
대조군(Vehicle) 대비 양성대조물질(Nintedanib)과 실시예 8 화합물은 방사선에 의한 폐섬유화 현상을 현저히 저해하는 것으로 나타났다.Compared to the control group (Vehicle), the positive control material (Nintedanib) and the compound of Example 8 were found to significantly inhibit radiation-induced pulmonary fibrosis.

Claims (7)

  1. 하기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염. A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
    [화학식 1][Formula 1]
    Figure PCTKR2022020882-appb-img-000054
    Figure PCTKR2022020882-appb-img-000054
    상기 화학식 1에서, In Formula 1,
    R1 및 R2는 서로 독립적으로 수소, C1~C6알킬, 또는 C1~C6할로알킬,R 1 and R 2 independently of each other are hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
    R3는 수소, 할로겐, C1~C6할로알킬, 또는 -C(=O)O-C1~C6알킬,R 3 is hydrogen, halogen, C 1 -C 6 haloalkyl, or -C(=O)OC 1 -C 6 alkyl;
    R4는 수소, 할로겐, 시아노, C1~C6알킬, C1~C6알콕시, 또는 C1~C6할로알킬, R 4 is hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl;
    n은 0, 1, 2, 3, 또는 4,n is 0, 1, 2, 3, or 4;
    R5 및 R6는 서로 독립적으로 수소, 하이드록사믹 애시드(hydroxamic acid)로 치환된 C1~C6알킬, 또는 하이드록사믹 애시드로 치환된 C2~C6알켄임.R 5 and R 6 independently represent hydrogen, C 1 -C 6 alkyl substituted with hydroxamic acid, or C 2 -C 6 alkene substituted with hydroxamic acid.
  2. 제1항에 있어서, 상기 화합물은The method of claim 1, wherein the compound
    N-(7-(히드록시아미노)-7-옥소헵틸)-2-메톡시-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드, N-(7-(hydroxyamino)-7-oxoheptyl)-2-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(tri fluoromethyl)pyrimidin-2-yl)amino)benzamide;
    2-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드,2-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(tri fluoromethyl)pyrimidin-2-yl)amino)benzamide;
    N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드,N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoromethyl)pyridine midin-2-yl) amino) benzamide;
    N-(7-(히드록시아미노)-7-옥소헵틸)-3-메톡시-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드,N-(7-(hydroxyamino)-7-oxoheptyl)-3-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(tri fluoromethyl)pyrimidin-2-yl)amino)benzamide;
    3-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)벤즈아미드,3-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(tri fluoromethyl)pyrimidin-2-yl)amino)benzamide;
    이소프로필 2-((4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)-3-메톡시페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트,Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-3-methoxyphenyl)amino)-4-((2-(N-methylmethylsulfonamido )phenyl)amino)pyrimidine-5-carboxylate,
    이소프로필 2-((3-플루오로-4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트,Isopropyl 2-((3-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethylsulfonamido )phenyl)amino)pyrimidine-5-carboxylate,
    이소프로필 2-((4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트,Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethylsulfonamido)phenyl)amino) pyrimidine-5-carboxylate;
    이소프로필 2-((4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)-2-메톡시페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트,Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-2-methoxyphenyl)amino)-4-((2-(N-methylmethylsulfonamido )phenyl)amino)pyrimidine-5-carboxylate,
    이소프로필 2-((2-플루오로-4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트,Isopropyl 2-((2-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethylsulfonamido )phenyl)amino)pyrimidine-5-carboxylate,
    4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-3-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)벤즈아미드,4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-fluoro-N-(7-(hydroxy amino)-7-oxoheptyl)benzamide;
    4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-2-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)벤즈아미드,4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-(7-(hydroxy amino)-7-oxoheptyl)benzamide;
    2-플루오로-N-(7-(히드록시아미노)-7-옥소헵틸)-4-((4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)벤즈아미드,2-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidine-2- yl) amino) benzamide,
    4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-N-(7-(히드록시아미노)-7-옥소헵틸)벤즈아미드,4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino)-7- oxoheptyl)benzamide,
    4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-N-(7-(히드록시아미노)-7-옥소헵틸)-3-메톡시벤즈아미드, 또는4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino)-7- oxoheptyl)-3-methoxybenzamide, or
    4-((5-클로로-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-2-일)아미노)-N-(7-(히드록시아미노)-7-옥소헵틸)-2-메톡시벤즈아미드인 화합물 또는 이의 약학적으로 허용 가능한 염.4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino)-7- A compound that is oxoheptyl)-2-methoxybenzamide or a pharmaceutically acceptable salt thereof.
  3. 제1항 또는 제2항에 있어서, 상기 화합물은 이소프로필 2-((4-((7-(히드록시아미노)-7-옥소헵틸)카바모일)페닐)아미노)-4-((2-(N-메틸메틸술폰아미도)페닐)아미노)피리미딘-5-카르복실레이트인, 화합물 또는 이의 약학적으로 허용 가능한 염.3. The compound according to claim 1 or 2, wherein the compound is isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2- (N-methylmethylsulfonamido)phenyl)amino)pyrimidine-5-carboxylate, a compound or a pharmaceutically acceptable salt thereof.
  4. 제1항 내지 제3항 중 어느 한 항에 있어서, 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 섬유증 치료 또는 예방용 약학 조성물. The pharmaceutical composition for treating or preventing fibrosis according to any one of claims 1 to 3, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  5. 제4항에 있어서, 상기 섬유증은 폐 섬유증인 약학 조성물.The pharmaceutical composition according to claim 4, wherein the fibrosis is pulmonary fibrosis.
  6. 제1항 내지 제3항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염의 치료학적으로 또는 예방학적으로 유효한 양을 섬유증의 치료, 개선 또는 예방이 필요한 개체에게 투여하는 것을 포함하는, 섬유증의 치료, 개선 또는 예방 방법.Treatment of fibrosis, comprising administering a therapeutically or prophylactically effective amount of the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof to a subject in need of treatment, improvement or prevention of fibrosis. , improvement or prevention methods.
  7. 제6항에 있어서, 상기 섬유증은 폐 섬유증인 방법. 7. The method of claim 6, wherein the fibrosis is pulmonary fibrosis.
PCT/KR2022/020882 2021-12-21 2022-12-20 Egfr and hdac dual inhibitor compounds and medical use thereof WO2023121251A1 (en)

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WO2009112490A1 (en) * 2008-03-11 2009-09-17 Cellzome Limited Sulfonamides as zap-70 inhibitors
US20110028405A1 (en) * 2007-12-20 2011-02-03 Richard John Harrison Sulfamides as zap-70 inhibitors
US20120172385A1 (en) * 2009-09-11 2012-07-05 Richard John Harrison Ortho substituted pyrimidine compounds as jak inhibitors
US20200190068A1 (en) * 2017-08-28 2020-06-18 Zhihong Chen Substituted pyrimidines, pharmaceutical compositions and therapeutic methods thereof
CN113754591A (en) * 2020-06-05 2021-12-07 山东大学 HDAC, JAK and BET three-target inhibitor and preparation method and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110028405A1 (en) * 2007-12-20 2011-02-03 Richard John Harrison Sulfamides as zap-70 inhibitors
WO2009112490A1 (en) * 2008-03-11 2009-09-17 Cellzome Limited Sulfonamides as zap-70 inhibitors
US20120172385A1 (en) * 2009-09-11 2012-07-05 Richard John Harrison Ortho substituted pyrimidine compounds as jak inhibitors
US20200190068A1 (en) * 2017-08-28 2020-06-18 Zhihong Chen Substituted pyrimidines, pharmaceutical compositions and therapeutic methods thereof
CN113754591A (en) * 2020-06-05 2021-12-07 山东大学 HDAC, JAK and BET three-target inhibitor and preparation method and application thereof

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