WO2023229378A1 - Heterocyclic compound as diacylglycerol kinase inhibitor and use thereof - Google Patents

Heterocyclic compound as diacylglycerol kinase inhibitor and use thereof Download PDF

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Publication number
WO2023229378A1
WO2023229378A1 PCT/KR2023/007097 KR2023007097W WO2023229378A1 WO 2023229378 A1 WO2023229378 A1 WO 2023229378A1 KR 2023007097 W KR2023007097 W KR 2023007097W WO 2023229378 A1 WO2023229378 A1 WO 2023229378A1
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WIPO (PCT)
Prior art keywords
methyl
dihydropyrido
chloro
pyrazine
piperidin
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PCT/KR2023/007097
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French (fr)
Korean (ko)
Inventor
윤수영
장창영
곽영신
김병규
김윤영
김형진
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주식회사 엘지화학
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Publication of WO2023229378A1 publication Critical patent/WO2023229378A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a heterocyclic compound represented by Formula 1 that exhibits diacylglycerol kinase inhibitor activity, a pharmaceutical composition containing the same as an active ingredient, and its use.
  • T cell therapy tumor-induced T cell suppression
  • T cell anergy exists.
  • the effect may be greatly halved because the tumor has a mechanism to disable the T cells. Therefore, understanding the mechanism of T cell inactivation by tumors and developing measures to prevent it can greatly improve the treatment efficiency of anticancer T cell therapy.
  • the DGK enzyme is attracting great interest as an immune-anticancer target.
  • DGKs diacylglycerol kinases
  • DAG diacylglycerol
  • PA phosphatidic acid
  • a substance that inhibits DGK if developed, it can act as an immunotherapy agent such as T cell reactivation. Excellent anticancer efficacy can be expected through the dual pharmacological effect of simultaneously exhibiting cell death effects. Additionally, since DGK is known to be involved in not only T cell anergy but also NK cell anergy, the additional benefit of eliminating cancer cells by NK cells may be obtained when developing an inhibitor.
  • the purpose of the present invention is to provide a novel heterocycle compound represented by Formula 1 that exhibits diacylglycerol kinase inhibitor activity.
  • Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of diacylglycerol kinase-related diseases, such as cancer, containing the above compound as an active ingredient.
  • Another object of the present invention is to provide a method for preventing or treating diacylglycerol kinase-related diseases, such as cancer, in a subject using the above compound as an active ingredient.
  • the present invention provides a compound of the following formula (1), or a pharmaceutically acceptable salt or stereoisomer thereof:
  • n 0, 1 or 2;
  • X represents N or CH
  • R 1 represents hydrogen, halo, cyano(-CN), alkyl, alkoxy or aryl unsubstituted or substituted with halo;
  • R 2 represents hydrogen, halo, alkyl, alkylcarbonyl or alkoxycarbonyl
  • R 3 represents hydrogen or alkyl
  • R 4 represents alkyl
  • R 5 represents alkyl, and when m is 2, they can combine with each other to form a ring;
  • R 7 represents cycloalkyl, aryl, aralkyl, heterocycloalkyl or heterocyclyl;
  • R 8 represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl;
  • heterocycloalkyl, heterocyclyl and heteroaryl may have one or more heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms.
  • the compound of Formula 1 according to the present invention can form a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.; Organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; Acid addition salts formed with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid are included.
  • carboxylic acid salts include, for example, alkali metal or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc.; Amino acid salts such as lysine, arginine, and guanidine; Organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc. are included.
  • the compound of formula 1 according to the present invention can be converted into its salt by conventional methods.
  • the compounds according to the present invention may have an asymmetric carbon center and an asymmetric axis or an asymmetric plane, and therefore may exist as E or Z isomers, R or S isomers, racemates, diastereomeric mixtures, and individual diastereomers. All these isomers and mixtures are included within the scope of the present invention.
  • the compound of Formula 1 is used to include the compound of Formula 1, pharmaceutically acceptable salts and stereoisomers thereof.
  • halo used herein when used alone or in combination with additional terms (e.g., haloalkyl or haloalkoxy), fluorine (F), chlorine (Cl) , represents a radical that is bromine (Br) or iodine (I).
  • cyano herein means -CN.
  • alkyl when used alone or in combination with additional terms (e.g. haloalkyl), refers to a straight-chain or branched alkyl group, e.g. It refers to a radical of a group of saturated aliphatic hydrocarbons having from 7 to 7 carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, It includes, but is not limited to, 2-methylbutyl, 1-ethylpropyl, and 1,2-dimethylpropyl.
  • alkoxy herein means alkyloxy, eg, alkyloxy having 1 to 7 carbon atoms.
  • alkylene herein means a radical of the group of divalent straight-chain or branched, saturated aliphatic hydrocarbons, e.g., having 1 to 5 carbon atoms.
  • cycloalkyl refers to a radical of the group of cyclic, saturated, aliphatic hydrocarbons having, for example, 3 to 7 carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • cycloalkylene herein refers to a radical of the group of divalent cyclic, saturated, aliphatic hydrocarbons having, for example, 3 to 6 carbon atoms.
  • heterocycloalkyl herein includes one or more heteroatoms selected from N, O and S, preferably 1 to 3 heteroatoms selected from N and O as reducing elements and is entirely saturated. refers to hydrocarbons.
  • aryl refers to an aromatic hydrocarbon, for example, an aromatic hydrocarbon having 6 to 10 carbon atoms.
  • aryl groups include, but are not limited to, phenyl, naphthyl, etc.
  • heteroaryl refers to an aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S as a reducing member, for example, a 5 to 10 membered aromatic hydrocarbon.
  • heteroaryls include pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, triazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, thiazolyl, Isothiazolyl, furanyl, benzofuranyl, imidazolyl, thiophenyl, benzthiazole, benzimidazole, quinolinyl, indolinyl, 1,2,3,4-tetrahydroisoquinolyl, 3,4 -Dihydroisoquinolyl, thiazolopyridyl, 2,3
  • Ochroman 1,2,3,4-tetrahydroquinoline, 4H-benzo[1,3]dioxin, 2,3-dihydrobenzo[1,4]dioxin, 6,7-dihydro-5H-cyclopenta [d] Pyrimidine, etc. are included, but are not limited thereto.
  • heterocyclyl refers to an unsaturated or partially saturated single or fused ring having one or more heteroatoms selected from N, O and S, for example 1 to 3 heteroatoms. It refers to hydrocarbons that form a ring. Specifically, the heterocyclyl may be a 5- to 12-membered hydrocarbon having 1 to 3 heteroatoms. The unsaturated heterocyclyl may include an aromatic hydrocarbon such as heteroaryl.
  • n 0, 1 or 2;
  • X represents N or CH
  • R 1 represents hydrogen, halo, cyano, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or C 6 -C 10 aryl unsubstituted or substituted with halo;
  • R 2 represents hydrogen, halo, C 1 -C 7 alkyl, C 1 -C 7 alkylcarbonyl or C 1 -C 7 alkoxycarbonyl;
  • R 3 represents hydrogen or C 1 -C 7 alkyl
  • R 4 represents C 1 -C 7 alkyl
  • R 5 represents C 1 -C 7 alkyl, and when m is 2, they may combine with each other to form a C 2 -C 4 ring;
  • R 7 is 5 to 3 heteroatoms selected from C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryl-C 1 -C 7 alkyl, N and O.
  • R 8 represents hydrogen, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl-C 1 -C 7 alkyl;
  • the cycloalkyl, aryl, heterocycloalkyl and heterocyclyl are unsubstituted or halo, cyano, oxo, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, halo-C 1 -C 7 alkyl, halo-C 1 -C 7 alkoxy, C 1 -C 7 alkylcarbonyl, di(C 1 -C 7 alkyl)amino, C 6 -C 10 aryl, C 6 -C 10 aryloxy and unsubstituted or halo substituted N and It may be substituted with 1 to 3 substituents selected from the group consisting of 5 to 10 membered heteroaryl having 1 to 3 heteroatoms selected from O.
  • Representative compounds of Formula 1 according to the present invention may include, but are not limited to, the following compounds:
  • the compound of Formula 1 can be prepared according to the following Schemes 1 to 5.
  • R 1 to R 6 are as defined herein.
  • the compound of Formula 1 according to the present invention has diacylglycerol kinases (DGKs) inhibitor activity. Accordingly, the present invention provides a pharmaceutical composition for the prevention or treatment of diseases related to diacylglycerol kinase, comprising the compound of Formula 1, or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable carrier. do.
  • DGKs diacylglycerol kinases
  • the diacylglycerol kinase-related disease is cancer.
  • cancer that can be prevented or treated with the pharmaceutical composition according to the present invention include gastrointestinal cancer, pancreatic cancer, breast cancer, colon cancer, retinoblastoma, liver cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, brain tumor, testicular cancer, laryngeal cancer, and prostate cancer.
  • Cancer includes, but is not limited to, neuroblastoma, kidney cancer, thyroid cancer, esophageal cancer, skin cancer, osteosarcoma, and bladder cancer.
  • “pharmaceutical composition” may include other chemical components such as carriers, diluents, excipients, etc. in addition to the active compound according to the present invention. Accordingly, the pharmaceutical composition may include a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof, if necessary. Pharmaceutical compositions facilitate administration of the active compound into an organism. There are a variety of techniques for administering compounds, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.
  • carrier refers to a compound that facilitates the introduction of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • carrier facilitates the introduction of many organic compounds into the cells or tissues of an organism.
  • diluent is defined as a compound diluted in water that not only stabilizes the biologically active form of the compound of interest, but also dissolves the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer is phosphate buffered saline, which mimics the salt form of human solutions. Because buffer salts can control the pH of a solution at low concentrations, it is rare for buffer diluents to modify the biological activity of a compound.
  • pharmaceutically acceptable means a property that does not impair the biological activity and physical properties of a compound.
  • the compounds of the present invention can be formulated into various pharmaceutical dosage forms depending on the purpose.
  • the active ingredient specifically the compound of Formula 1, a pharmaceutically acceptable salt or stereoisomer thereof, is mixed with various pharmaceutically acceptable salts or stereoisomers that can be selected depending on the formulation to be prepared.
  • the pharmaceutical composition according to the present invention may be formulated into an injectable formulation, an oral formulation, etc., depending on the purpose.
  • the compounds of the present invention can be formulated by known methods using known pharmaceutical carriers and excipients and placed in unit dosage form or multi-dose containers.
  • the form of the preparation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium and may contain customary dispersing, suspending or stabilizing agents. Additionally, for example, it may be in the form of a dry powder that is dissolved in sterile, pyrogen-free water before use.
  • the compounds of the present invention may also be formulated in suppository form using conventional suppository bases such as cocoa butter or other glycerides.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules, and capsules and tablets are particularly useful.
  • Solid dosage forms can be prepared by mixing the compounds of the present invention with one or more inert diluents such as sucrose, lactose, starch, etc. and carriers such as lubricants such as magnesium stearate, disintegrants, binders, etc.
  • inert diluents such as sucrose, lactose, starch, etc.
  • carriers such as lubricants such as magnesium stearate, disintegrants, binders, etc.
  • the compound according to the present invention or a pharmaceutical composition containing the same can be administered in combination with other drugs, for example, other anticancer immunotherapy agents.
  • the dosage of the compound of formula 1 of the present invention is determined according to the doctor's prescription depending on factors such as the patient's weight, age, and the specific nature and severity of the disease.
  • the dosage required for adult treatment typically ranges from about 0.3 to 500 mg per day, depending on the frequency and intensity of administration.
  • a total dose of approximately 1 to 300 mg per day, divided into single doses will usually be sufficient, although higher daily doses may be desirable for some patients.
  • treatment means stopping, delaying, or alleviating the progression of a disease when used in a subject showing symptoms of the disease.
  • the heterocycle compound represented by Formula 1 according to the present invention can be usefully used for the prevention or treatment of diseases related to diacylglycerol kinases, such as cancer, by inhibiting diacylglycerol kinases (DGKs).
  • DGKs diacylglycerol kinases
  • DIAD diisopropyl azodicarboxylate
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • Step A Preparation of tert-butyl 4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((3-aminopyridin-2-yl)amino)piperidine-1-carboxylate
  • Step C Preparation of tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)pyridin-2-yl)amino)piperidine-1-carboxylate
  • Step D of tert-butyl 4-(2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate manufacturing
  • Step E Tert-Butyl 4-(1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates
  • Step F Preparation of 1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
  • Step A Preparation of tert-butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B Preparation of 6-tert-butyl 4-((3-amino-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate
  • Step C Tert-Butyl 4-((3-(2-ethoxy-2-oxoacetamido)-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate
  • Step D Tert-Butyl 4-(6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates
  • Step E Tert-Butyl 4-(1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -Preparation of 1-carboxylate
  • Step F Preparation of 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
  • Step A Preparation of tert-butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((6-cyano-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step C of tert-butyl 4-(N-(6-cyano-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate manufacturing
  • reaction was terminated by slowly adding water to the reaction product, diluted with EtOAc, and washed with 0.5 N aqueous NaOH solution, aqueous sodium bicarbonate solution, and brine.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (1.02 g).
  • Step D Tert-Butyl 4-(6-cyano-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1 -Manufacture of carboxylates
  • Step E tert-butyl 4-(6-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p Preparation of peridine-1-carboxylate
  • Step F 1-Methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-car Manufacturing of Bonitrile
  • Step A Preparation of tert-butyl 4-((5-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-(N-(5-chloro-3-aminopyridin-2-yl)-2-ethoxy-2-oxoacetoamido)piperidine-1-carboxylate
  • Step C Tert-Butyl 4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates
  • Step D Tert-Butyl 4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi Preparation of dine-1-carboxylate
  • Step E Preparation of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
  • Step A Preparation of tert-butyl 4-((5-chloro-3-nitropyridin-2-yl)amino)-3,3-dimethylpiperidine-1-carboxylate
  • Step B Tert-Butyl 4-(N-(5-chloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)-3,3-dimethylpiperidine- Preparation of 1-carboxylate
  • Step C Tert-Butyl 4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-3,3-di Preparation of methylpiperidine-1-carboxylate
  • Step D Tert-Butyl 4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-3 , Preparation of 3-dimethylpiperidine-1-carboxylate
  • Step E 7-Chloro-4-(3,3-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3- Manufacturing of dione
  • Step A tert-butyl (1R,3s,5S)-3-((5-chloro-3-nitropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-car Preparation of boxylate
  • Step B Tert-Butyl (1R,3s,5S)-3-(N-(5-chloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)-8- Preparation of azabicyclo[3.2.1]octane-8-carboxylate
  • Step C tert-butyl (1R,3s,5S)-3-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)- 1) Preparation of -8-azabicyclo[3.2.1]octane-8-carboxylate
  • Step D tert-butyl (1R,3s,5S)-3-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4 Preparation of (1H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate
  • Step E 4-(8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2, Preparation of 3-dione
  • Step A Preparation of tert-butyl 4-((6-methoxy-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((3-amino-6-methoxypyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B of Preparation Example 1 using tert-butyl 4-((6-methoxy-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.80 g, 5.11 mmol)
  • the title compound (1.65 g) was obtained in a similar manner and used directly in the next reaction without purification.
  • Step C Tert-Butyl 4-(6-methoxy-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 -Manufacture of carboxylates
  • Step D tert-butyl 4-(6-methoxy-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p Preparation of peridine-1-carboxylate
  • Step E Preparation of 6-methoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
  • Step A Preparation of tert-butyl 4-((4-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((3-amino-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate
  • Step C Preparation of tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate
  • Step D Tert-Butyl 4-(8-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates
  • Step E Tert-Butyl 4-(1,8-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -Preparation of 1-carboxylate
  • Step F Preparation of 1,8-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
  • Step A Preparation of tert-butyl 4-((6-isopropoxy-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((3-amino-6-isopropoxypyridin-2-yl)amino)piperidine-1-carboxylate
  • the title compound (1.07 g) was synthesized in a similar manner.
  • Step C Tert-Butyl 4-(6-isopropoxy-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- Preparation of 1-carboxylate
  • Step C of Preparation Example 7 using tert-butyl 4-((3-amino-6-isopropoxypyridin-2-yl)amino)piperidine-1-carboxylate (1.07 g, 3.05 mmol)
  • the title compound (1.2 g) was synthesized in a similar manner.
  • Step D Tert-Butyl 4-(6-isopropoxy-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl) Preparation of piperidine-1-carboxylate
  • Step E Preparation of 6-isopropoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
  • Step A Preparation of tert-butyl 4-((5-fluoro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((3-amino-5-fluoropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B of Preparation Example 1 using tert-butyl 4-((5-fluoro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (4.2 g, 12.34 mmol)
  • the title compound (2.67 g) was synthesized in a similar manner.
  • Step C Tert-Butyl 4-(7-fluoro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 -Manufacture of carboxylates
  • Step D tert-butyl 4-(7-fluoro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p Preparation of peridine-1-carboxylate
  • Step E Preparation of 7-fluoro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
  • Step A Preparation of methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-5-nitronicotinate
  • Step B Preparation of methyl 5-amino-6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)nicotinate
  • Step C Methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3- b]Preparation of pyrazine-7-carboxylate
  • Step D Methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[ Preparation of 2,3-b]pyrazine-7-carboxylate
  • Step E Methyl 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7- Preparation of carboxylates
  • Step A Preparation of tert-butyl 4-((5-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((3-amino-5-methylpyridin-2-yl)amino)piperidine-1-carboxylate
  • Step C Tert-Butyl 4-(7-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates
  • Step D Tert-Butyl 4-(1,7-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -Manufacture of 1-carboxylate
  • Step E Preparation of 1,7-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
  • Step A Preparation of tert-butyl 4-((5-bromo-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • NBS 0.552 g, 3.10 mmol
  • the reaction solution was concentrated under reduced pressure, and the residue was diluted with EtOAc and washed with aqueous sodium bicarbonate solution.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (1.23 g).
  • Step B of tert-butyl 4-(N-(5-bromo-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate manufacturing
  • Step C Tert-Butyl 4-(7-bromo-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 -Manufacture of carboxylates
  • Step D Tert-Butyl 4-(7-bromo-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)- Preparation of 3,3-dimethylpiperidine-1-carboxylate
  • Step E Preparation of 7-bromo-4-(piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
  • Step A Preparation of 4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexan-1-one
  • Step B Preparation of 4-((3-amino-5-chloropyridin-2-yl)amino)cyclohexan-1-one
  • Step C Preparation of 7-chloro-4-(4-oxocyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
  • Step D Preparation of 7-chloro-1-methyl-4-(4-oxocyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
  • Step A Preparation of tert-butyl 4-((3-amino-6-chloropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B Tert-Butyl 4-(6-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates
  • Step C Tert-Butyl 4-(6-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi Preparation of dine-1-carboxylate
  • Step D Preparation of 6-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
  • Step A tert-butyl (1R,3r,5S)-3-((5-chloro-3-nitropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-car Preparation of boxylate
  • Step B tert-butyl (1R,3r,5S)-3-((3-amino-5-chloropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxyl
  • Step C tert-butyl (1R,3r,5S)-3-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4 Preparation of (1H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate
  • tert-butyl (1R,3r,5S)-3-((3-amino-5-chloropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.88 g, 5.33 mmol) and DIPEA (5.58 mL, 32.00 mmol) were dissolved in DCM (300 mL) and then ethyl 2-chloro-2-oxoacetate (1.79 mL, 15.98 mmol) was slowly added while maintaining the temperature at 0°C. Next, it was heated to 50°C and stirred for 18 hours.
  • Step D 4-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2, 3-b] Preparation of pyrazine-2,3-dione
  • Step A Preparation of tert-butyl (4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexyl)carbamate
  • the title compound (1.92 g) was synthesized in a similar manner.
  • Step B Preparation of tert-butyl (4-((3-amino-5-chloropyridin-2-yl)amino)cyclohexyl)carbamate
  • Step C tert-butyl (4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)cyclohexyl)carbamate manufacture of
  • Step D tert-butyl (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)cyclo Preparation of hexyl)carbamate
  • Step E Preparation of 4-(4-aminocyclohexyl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
  • Step A Preparation of tert-butyl 4-((5,6-dichloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B Tert-Butyl 4-(N-(5,6-dichloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxyl
  • Step C of Preparation Example 3 using tert-butyl 4-((5,6-dichloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (0.920 g, 2.351)
  • the title compound (1.05 g) was obtained in the same manner.
  • Step C Tert-Butyl 4-(6,7-dichloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -Preparation of 1-carboxylate
  • Step D Tert-Butyl 4-(6,7-dichloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl ) Preparation of piperidine-1-carboxylate
  • Step E Tert-Butyl 4-(7-chloro-6-(2-fluorophenyl)-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine Preparation of -4(1H)-yl)piperidine-1-carboxylate
  • Step F 7-Chloro-6-(2-fluorophenyl)-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- Preparation of 2,3-dione hydrochloride
  • Step A Preparation of tert-butyl 4-((5-bromo-6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((5-bromo-6-cyano-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step C Tert-Butyl 4-(N-(5-bromo-6-cyano-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1 -Manufacture of carboxylates
  • Step D tert-Butyl 4-(7-bromo-6-cyano-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl) Preparation of piperidine-1-carboxylate
  • Step E tert-butyl 4-(7-bromo-6-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H )-yl) Preparation of piperidine-1-carboxylate
  • Step F 7-Bromo-1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]
  • Step A Preparation of (1r,4r)-4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexan-1-ol
  • Step B Preparation of N-((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5-chloro-3-nitropyridin-2-amine
  • Step C Ethyl 2-(((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)(5-chloro-3-nitropyridin-2-yl)amino)-2- Manufacture of oxoacetate
  • Step D 4-((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3- b] Preparation of pyrazine-2,3-dione
  • Step E 7-Chloro-4-((1r,4r)-4-hydroxycyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da Preparation of ions
  • Step A Preparation of tert-butyl (2R,5S)-4-((5-chloro-3-nitropyridin-2-yl)amino)-2,5-dimethylpiperidine-1-carboxylate
  • Step B Preparation of tert-butyl (2R,5S)-4-((3-amino-5-chloropyridin-2-yl)amino)-2,5-dimethylpiperidine-1-carboxylate
  • Step C tert-butyl (2R,5S)-4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H )-yl)-2,5-dimethylpiperidine-1-carboxylate
  • Step D tert-butyl (2R,5S)-4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl) -Preparation of 2,5-dimethylpiperidine-1-carboxylate
  • Step E 7-Chloro-4-((2R,5S)-2,5-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]
  • Step A Preparation of tert-butyl 4-((5-chloro-6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((3-amino-5-chloro-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate
  • Step C Tert-Butyl 4-(7-chloro-6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi Preparation of dine-1-carboxylate
  • Step D Tert-Butyl 4-(7-chloro-1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl ) Preparation of piperidine-1-carboxylate
  • Step E 7-Chloro-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione 2
  • Step A Preparation of tert-butyl 4-((5-bromo-6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((3-amino-5-bromo-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate
  • Step C Tert-Butyl 4-(7-bromo-6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p Preparation of peridine-1-carboxylate
  • Step D Tert-Butyl 4-(7-bromo-1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)- 1) Preparation of piperidine-1-carboxylate

Abstract

The present invention relates to: a heterocyclic compound represented by chemical formula 1 and exhibiting diacylglycerol kinase inhibitor activity; a pharmaceutical composition comprising same as an active ingredient; and a use thereof.

Description

다이아실글리세롤 키나아제 저해제로서 헤테로사이클 화합물 및 이의 용도Heterocyclic compounds and uses thereof as diacylglycerol kinase inhibitors
본 발명은 다이아실글리세롤 키나아제 저해제 활성을 나타내는 화학식 1로 표시되는 헤테로사이클 화합물, 이를 활성성분으로 포함하는 약제학적 조성물 및 이의 용도에 관한 것이다.The present invention relates to a heterocyclic compound represented by Formula 1 that exhibits diacylglycerol kinase inhibitor activity, a pharmaceutical composition containing the same as an active ingredient, and its use.
최근 항암면역치료, 특히 T세포치료법이 악성흑색종 등 일부 종양에서 큰 효과를 보이면서 관심의 대상이 되고 있으나, 항암T세포요법이 극복해야 할 큰 장애요인으로 종양에 의한 T세포억제현상 (T세포관용, T세포 anergy)이 존재한다. 즉, 다수의 항암T세포가 종양에 접근한다 할지라도, 종양이 T세포를 불능화시키는 기전이 존재하므로, 그 효과가 크게 반감될 수 있다. 따라서 종양에 의한 T세포불능화의 기전을 이해하고 이를 방지할 수 있는 대책을 마련하는 것은 항암T세포요법의 치료효율을 크게 증진시킬 수 있을 것이다. 이를 극복하기 위한 면역 항암 target으로써 DGK 효소가 큰 관심을 불러일으키고 있으며 T 세포가 anergy에 빠질 때 과발현되어 T세포의 활성을 불능화 시키는 역할을 한다. 구체적으로, 다이아실글리세롤 키나아제(diacylglycerol kinases, DGKs)는 신호전달에 중요한 인자인 다이아실글리세롤(DAG)을 포스파티딘산(phosphatidic acid, PA)으로 전환하는 반응을 통해서 세포내 checkpoint 역할을 하는데 이러한 DGK를 저해하면 축적된 DAG가 T 세포의 TCR signaling pathway를 향상시켜 anergy에 빠진 T 세포를 재활성화(reactivation) 시킨다고 알려져 있어서 단독 또는 PD-(L)1과 같은 면역항암제와 병용시 시너지를 기대할 수 있다. 또한, DGK는 각종 암세포에 과발현 되어 있으며 암세포 생존(survival), 이동(migration), 약물 내성(drug resistance)을 일으킨다고 알려져 있어서 DGK를 저해하는 물질을 개발하면 T 세포 재활성화와 같은 면역항암제 역할과 세포 사멸 효과를 동시에 나타내는 이중 약리 효과를 통해 우수한 항암 효능을 기대할 수 있다. 추가적으로, DGK는 T cell anergy뿐만 아니라 NK cell anergy에 관여하는 것으로 알려져 있기에 저해제 개발시 NK세포에 의한 암세포 제거라는 부가적인 잇점도 얻을 수 있을 것이다.Recently, anti-cancer immunotherapy, especially T-cell therapy, has been attracting attention as it has shown great effectiveness in some tumors such as malignant melanoma. However, a major obstacle that anti-cancer T-cell therapy must overcome is the phenomenon of tumor-induced T cell suppression (T cell therapy). Tolerance, T cell anergy) exists. In other words, even if a large number of anti-cancer T cells approach the tumor, the effect may be greatly halved because the tumor has a mechanism to disable the T cells. Therefore, understanding the mechanism of T cell inactivation by tumors and developing measures to prevent it can greatly improve the treatment efficiency of anticancer T cell therapy. To overcome this, the DGK enzyme is attracting great interest as an immune-anticancer target. It is overexpressed when T cells fall into anergy and plays a role in disabling the activity of T cells. Specifically, diacylglycerol kinases (DGKs) act as intracellular checkpoints through a reaction that converts diacylglycerol (DAG), an important factor in signal transduction, into phosphatidic acid (PA). When inhibited, accumulated DAG is known to enhance the TCR signaling pathway of T cells and reactivate anergic T cells, so synergy can be expected when used alone or in combination with anticancer immunotherapy drugs such as PD-(L)1. . In addition, DGK is overexpressed in various cancer cells and is known to cause cancer cell survival, migration, and drug resistance. Therefore, if a substance that inhibits DGK is developed, it can act as an immunotherapy agent such as T cell reactivation. Excellent anticancer efficacy can be expected through the dual pharmacological effect of simultaneously exhibiting cell death effects. Additionally, since DGK is known to be involved in not only T cell anergy but also NK cell anergy, the additional benefit of eliminating cancer cells by NK cells may be obtained when developing an inhibitor.
본 발명의 목적은 다이아실글리세롤 키나아제 저해제 활성을 나타내는 화학식 1로 표시되는 신규한 헤테로사이클 화합물을 제공하는 것이다.The purpose of the present invention is to provide a novel heterocycle compound represented by Formula 1 that exhibits diacylglycerol kinase inhibitor activity.
본 발명의 또 다른 목적은 활성성분으로 상기 화합물을 포함하는, 암과 같은 다이아실글리세롤 키나아제 관련 질환의 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of diacylglycerol kinase-related diseases, such as cancer, containing the above compound as an active ingredient.
본 발명의 또 다른 목적은 활성성분으로 상기 화합물을 사용하여 대상의 암과 같은 다이아실글리세롤 키나아제 관련 질환을 예방 또는 치료하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing or treating diacylglycerol kinase-related diseases, such as cancer, in a subject using the above compound as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명에서는 하기 화학식 1의 화합물, 또는 이의 약제학적으로 허용되는 염 또는 입체이성질체를 제공한다:In order to achieve the above object, the present invention provides a compound of the following formula (1), or a pharmaceutically acceptable salt or stereoisomer thereof:
[화학식 1][Formula 1]
Figure PCTKR2023007097-appb-img-000001
Figure PCTKR2023007097-appb-img-000001
상기 화학식 1에서,In Formula 1,
m은 0, 1 또는 2를 나타내고;m represents 0, 1 or 2;
X는 N 또는 CH를 나타내며;X represents N or CH;
R1은 수소, 할로, 시아노(-CN), 알킬, 알콕시 또는 비치환되거나 할로로 치환된 아릴을 나타내고;R 1 represents hydrogen, halo, cyano(-CN), alkyl, alkoxy or aryl unsubstituted or substituted with halo;
R2는 수소, 할로, 알킬, 알킬카르보닐 또는 알콕시카르보닐을 나타내며;R 2 represents hydrogen, halo, alkyl, alkylcarbonyl or alkoxycarbonyl;
R3는 수소 또는 알킬을 나타내고;R 3 represents hydrogen or alkyl;
R4는 알킬을 나타내며;R 4 represents alkyl;
R5는 알킬을 나타내고, m이 2일 경우 서로 결합하여 고리를 형성할 수 있으며;R 5 represents alkyl, and when m is 2, they can combine with each other to form a ring;
R6는 -C(=O)-R7, -S(=O)2-R7, -C(=O)-알킬렌-R7, -O-R7,
Figure PCTKR2023007097-appb-img-000002
, -C(=O)-사이클로알킬렌-R7, -알킬렌-C(=O)-R7,
Figure PCTKR2023007097-appb-img-000003
또는 -NH-C(=O)-R7이고; 여기에서 R7은 사이클로알킬, 아릴, 아르알킬, 헤테로사이클로알킬 또는 헤테로사이클릴을 나타내며; R8은 수소, 알킬, 사이클로알킬 또는 사이클로알킬-알킬을 나타내고;R 6 is -C(=O)-R 7 , -S(=O) 2 -R 7 , -C(=O)-alkylene-R 7 , -OR 7 ,
Figure PCTKR2023007097-appb-img-000002
, -C(=O)-cycloalkylene-R 7 , -alkylene-C(=O)-R 7 ,
Figure PCTKR2023007097-appb-img-000003
or -NH-C(=O)-R 7 ; where R 7 represents cycloalkyl, aryl, aralkyl, heterocycloalkyl or heterocyclyl; R 8 represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl;
상기 사이클로알킬, 아릴, 헤테로사이클로알킬 및 헤테로사이클릴은 할로, 시아노, 옥소(=O), 알킬, 알콕시, 할로알킬, 할로알콕시, 알킬카르보닐, 다이알킬아미노, 아릴, 아릴옥시 및 비치환되거나 할로로 치환된 헤테로아릴로 이루어지는 그룹에서 선택되는 하나 이상의 치환기로 임의로 치환될 수 있으며;The cycloalkyl, aryl, heterocycloalkyl and heterocyclyl include halo, cyano, oxo (=O), alkyl, alkoxy, haloalkyl, haloalkoxy, alkylcarbonyl, dialkylamino, aryl, aryloxy and unsubstituted. or may be optionally substituted with one or more substituents selected from the group consisting of heteroaryl substituted with halo;
상기 헤테로사이클로알킬, 헤테로사이클릴 및 헤테로아릴은 질소(N), 산소(O) 및 황(S) 원자로부터 선택되는 하나 이상의 헤테로원자를 가질 수 있다.The heterocycloalkyl, heterocyclyl and heteroaryl may have one or more heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms.
본 발명에 따른 화학식 1의 화합물은 약제학적으로 허용되는 염을 형성할 수 있다. 약제학적으로 허용되는 염에는 약제학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들면 염산, 황산, 질산, 인산, 브롬화수소산, 요오드화수소산 등과 같은 무기산; 타타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산, 트리플루오로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산, 살리실산 등과 같은 유기산; 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염이 포함된다. 또한, 약제학적으로 허용되는 카복실산 염에는, 예를 들어 리튬, 나트륨, 칼륨, 칼슘, 마그네슘 등에 의해 형성된 알칼리 금속 또는 알칼리 토금속 염; 라이신, 아르기닌, 구아니딘 등의 아미노산 염; 디사이클로헥실아민, N-메틸-D-글루카민, 트리스(하이드록시메틸) 메틸아민, 디에탄올아민, 콜린, 트리에틸아민 등과 같은 유기염 등이 포함된다. 본 발명에 따른 화학식 1의 화합물은 통상적인 방법에 의해 그의 염으로 전환될 수 있다.The compound of Formula 1 according to the present invention can form a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.; Organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; Acid addition salts formed with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid are included. Additionally, pharmaceutically acceptable carboxylic acid salts include, for example, alkali metal or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc.; Amino acid salts such as lysine, arginine, and guanidine; Organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc. are included. The compound of formula 1 according to the present invention can be converted into its salt by conventional methods.
한편, 본 발명에 따른 화합물들은 비대칭 탄소중심과 비대칭축 또는 비대칭평면을 가질 수 있으므로 E 또는 Z 이성질체, R 또는 S 이성질체, 라세미체, 부분입체이성질체 혼합물 및 개개의 부분입체이성질체로서 존재할 수 있으며, 이들 모든 이성질체 및 혼합물은 본 발명의 범위에 포함된다.Meanwhile, the compounds according to the present invention may have an asymmetric carbon center and an asymmetric axis or an asymmetric plane, and therefore may exist as E or Z isomers, R or S isomers, racemates, diastereomeric mixtures, and individual diastereomers. All these isomers and mixtures are included within the scope of the present invention.
본 명세서에서는 편의상 달리 명시되지 않는 한, 화학식 1의 화합물은 화학식 1의 화합물, 이의 약제학적으로 허용되는 염 및 입체이성질체 모두를 포함하는 의미로 사용된다.In this specification, unless otherwise specified for convenience, the compound of Formula 1 is used to include the compound of Formula 1, pharmaceutically acceptable salts and stereoisomers thereof.
본 명세서를 통하여 화학식 1의 화합물을 정의함에 있어서는 다음과 같은 치환체에 대해 정의된 개념들이 사용된다.In defining the compound of Formula 1 throughout this specification, the following concepts defined for substituents are used.
다르게 기술되지 않는 한, 본원에서 용어 "할로"는 단독으로 사용되는 경우 또는 그 밖에 추가적인 용어와의 조합으로 사용되는 경우 (예를 들면, 할로알킬 또는 할로알콕시) 불소(F), 염소(Cl), 브롬(Br) 또는 요오드(I)인 라디칼을 나타낸다.Unless otherwise stated, the term “halo” used herein when used alone or in combination with additional terms (e.g., haloalkyl or haloalkoxy), fluorine (F), chlorine (Cl) , represents a radical that is bromine (Br) or iodine (I).
다르게 기술되지 않는 한, 본원에서 용어 "시아노"는 -CN을 의미한다.Unless otherwise stated, the term “cyano” herein means -CN.
다르게 기술되지 않는 한, 본원에서 용어 "옥소"는 =O를 의미한다.Unless otherwise stated, the term “oxo” herein means =O.
다르게 기술되지 않는 한, 본원에서 용어 "알킬"은 단독으로 사용되는 경우 또는 그 밖에 추가적인 용어와의 조합으로 사용되는 경우(예를 들면, 할로알킬) 직쇄형 또는 분지형의, 예를 들면 1개 내지 7개의 탄소 원자를 갖는 포화된 지방족 탄화수소 군의 라디칼을 의미한다. 알킬 그룹의 예로는 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 세크-부틸, 터트-부틸, n-펜틸, 이소펜틸, 네오펜틸, 터트-펜틸, 1-메틸부틸, 2-메틸부틸, 1-에틸프로필 및 1,2-디메틸프로필 등을 포함하나 이에 제한되는 것은 아니다.Unless otherwise stated, the term "alkyl" herein, when used alone or in combination with additional terms (e.g. haloalkyl), refers to a straight-chain or branched alkyl group, e.g. It refers to a radical of a group of saturated aliphatic hydrocarbons having from 7 to 7 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, It includes, but is not limited to, 2-methylbutyl, 1-ethylpropyl, and 1,2-dimethylpropyl.
다르게 기술되지 않는 한, 본원에서 용어 "알콕시"는 알킬옥시, 예를 들면 1개 내지 7개의 탄소 원자를 가지는 알킬옥시를 의미한다.Unless otherwise stated, the term “alkoxy” herein means alkyloxy, eg, alkyloxy having 1 to 7 carbon atoms.
다르게 기술되지 않는 한, 본원에서 용어 “알킬렌(alkylene)”은 2가의 직쇄형 또는 측쇄형의, 예를 들면 1개 내지 5개의 탄소 원자를 갖는 포화된 지방족 탄화수소 군의 라디칼을 의미한다.Unless otherwise stated, the term “alkylene” herein means a radical of the group of divalent straight-chain or branched, saturated aliphatic hydrocarbons, e.g., having 1 to 5 carbon atoms.
다르게 기술되지 않는 한, 본원에서 용어 “사이클로알킬”은 고리형의, 예를 들면 3개 내지 7개의 탄소 원자를 갖는 포화된 지방족 탄화수소 군의 라디칼을 의미한다. 사이클로알킬 그룹의 예로는 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실 등을 포함하나 이에 제한되는 것은 아니다.Unless otherwise stated, the term “cycloalkyl” herein refers to a radical of the group of cyclic, saturated, aliphatic hydrocarbons having, for example, 3 to 7 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
다르게 기술되지 않는 한, 본원에서 용어 “사이클로알킬렌”은 2가의 고리형의, 예를 들면 3개 내지 6개의 탄소 원자를 갖는 포화된 지방족 탄화수소 군의 라디칼을 의미한다.Unless stated otherwise, the term “cycloalkylene” herein refers to a radical of the group of divalent cyclic, saturated, aliphatic hydrocarbons having, for example, 3 to 6 carbon atoms.
다르게 기술되지 않는 한, 본원에서 용어 “헤테로사이클로알킬”은 N, O 및 S 중에서 선택된 하나 이상의 헤테로원자, 바람직하게는 N 및 O로부터 선택되는 1 내지 3개의 헤테로원자를 환원자로서 포함하고 전체적으로 포화된 탄화수소를 의미한다.Unless otherwise stated, the term “heterocycloalkyl” herein includes one or more heteroatoms selected from N, O and S, preferably 1 to 3 heteroatoms selected from N and O as reducing elements and is entirely saturated. refers to hydrocarbons.
다르게 기술되지 않는 한, 본원에서 용어 “아릴”은 방향족 탄화수소를 의미하며, 예를 들면 6개 내지 10개의 탄소 원자를 갖는 방향족 탄화수소를 의미한다. 아릴 그룹의 예로는 페닐, 나프틸 등을 포함하지만, 이에 한정되는 것은 아니다.Unless otherwise stated, the term “aryl” herein refers to an aromatic hydrocarbon, for example, an aromatic hydrocarbon having 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, etc.
다르게 기술되지 않는 한, 본원에서 용어 “헤테로아릴”은 N, O 및 S 중에서 선택된 하나 이상의 헤테로 원자를 환원자로서 포함하는 방향족 탄화수소를 의미하며, 예를 들면 5 내지 10원 방향족 탄화수소를 의미한다. 헤테로아릴의 예로는 피리디닐, 피리미디닐, 피리다지닐, 피라지닐, 옥사디아졸릴, 이속사디아졸릴, 테트라졸릴, 트리아졸릴, 인돌릴, 인다졸릴, 이속사졸릴, 옥사졸릴, 티아졸릴, 아이소티아졸릴, 퓨라닐, 벤조퓨라닐, 이미다졸릴, 티오페닐, 벤즈티아졸, 벤즈이미다졸, 퀴놀리닐, 인돌리닐, 1,2,3,4-테트라하이드로이소퀴놀릴, 3,4-다이하이드로아이소퀴놀릴, 티아졸로피리딜, 2,3-다이하이드로벤조퓨란, 2,3-다이하이드로티오펜, 2,3-다이하이드로인돌, 벤조[1,3]다이옥산, 크로만, 싸이오크로만, 1,2,3,4-테트라하이드로퀴놀린, 4H-벤조[1,3]다이옥신, 2,3-다이하이드로벤조[1,4]다이옥신, 6,7-다이하이드로-5H-사이클로펜타[d]피리미딘 등을 포함하지만, 이에 한정되는 것은 아니다.Unless otherwise stated, the term “heteroaryl” herein refers to an aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S as a reducing member, for example, a 5 to 10 membered aromatic hydrocarbon. Examples of heteroaryls include pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, triazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, thiazolyl, Isothiazolyl, furanyl, benzofuranyl, imidazolyl, thiophenyl, benzthiazole, benzimidazole, quinolinyl, indolinyl, 1,2,3,4-tetrahydroisoquinolyl, 3,4 -Dihydroisoquinolyl, thiazolopyridyl, 2,3-dihydrobenzofuran, 2,3-dihydrothiophene, 2,3-dihydroindole, benzo[1,3]dioxane, chroman, cy. Ochroman, 1,2,3,4-tetrahydroquinoline, 4H-benzo[1,3]dioxin, 2,3-dihydrobenzo[1,4]dioxin, 6,7-dihydro-5H-cyclopenta [d] Pyrimidine, etc. are included, but are not limited thereto.
다르게 기술되지 않는 한, 본원에서 용어 “헤테로사이클릴”은 N, O 및 S 중에서 선택된 하나 이상의 헤테로원자, 예를 들면 1개 내지 3개의 헤테로원자를 갖는, 불포화되거나 부분적으로 포화된 단일 또는 융합고리환을 이루는 탄화수소를 의미한다. 구체적으로, 상기 헤테로사이클릴은 1 내지 3개의 헤테로 원자를 갖는 5원 내지 12원의 탄화수소일 수 있다. 상기 불포화 헤테로사이클릴은 헤테로아릴 등의 방향족 탄화수소를 포함할 수 있다.Unless otherwise stated, the term “heterocyclyl” herein refers to an unsaturated or partially saturated single or fused ring having one or more heteroatoms selected from N, O and S, for example 1 to 3 heteroatoms. It refers to hydrocarbons that form a ring. Specifically, the heterocyclyl may be a 5- to 12-membered hydrocarbon having 1 to 3 heteroatoms. The unsaturated heterocyclyl may include an aromatic hydrocarbon such as heteroaryl.
본 발명의 일 구체예에 따르면, 상기 화학식 1에서According to one embodiment of the present invention, in Formula 1
m은 0, 1 또는 2를 나타내고;m represents 0, 1 or 2;
X는 N 또는 CH를 나타내며;X represents N or CH;
R1은 수소, 할로, 시아노, C1-C7 알킬, C1-C7 알콕시 또는 비치환되거나 할로로 치환된 C6-C10 아릴을 나타내고;R 1 represents hydrogen, halo, cyano, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or C 6 -C 10 aryl unsubstituted or substituted with halo;
R2는 수소, 할로, C1-C7 알킬, C1-C7 알킬카르보닐 또는 C1-C7 알콕시카르보닐을 나타내며;R 2 represents hydrogen, halo, C 1 -C 7 alkyl, C 1 -C 7 alkylcarbonyl or C 1 -C 7 alkoxycarbonyl;
R3는 수소 또는 C1-C7 알킬을 나타내고;R 3 represents hydrogen or C 1 -C 7 alkyl;
R4는 C1-C7 알킬을 나타내며;R 4 represents C 1 -C 7 alkyl;
R5는 C1-C7 알킬을 나타내고, m이 2일 경우 서로 결합하여 C2-C4 고리를 형성할 수 있으며;R 5 represents C 1 -C 7 alkyl, and when m is 2, they may combine with each other to form a C 2 -C 4 ring;
R6는 -C(=O)-R7, -S(=O)2-R7, -C(=O)-C1-C5 알킬렌-R7, -O-R7,
Figure PCTKR2023007097-appb-img-000004
, -C(=O)-C3-C6 사이클로알킬렌-R7, -C1-C5 알킬렌-C(=O)-R7,
Figure PCTKR2023007097-appb-img-000005
또는 -NH-C(=O)-R7이고; 여기에서 R7은 C3-C7 사이클로알킬, C6-C10 아릴, C6-C10 아릴-C1-C7 알킬, N 및 O로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 10원 헤테로사이클로알킬, 또는 N, O 및 S로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 12원 헤테로사이클릴을 나타내며; R8은 수소, C1-C7 알킬, C3-C7 사이클로알킬 또는 C3-C7 사이클로알킬-C1-C7 알킬을 나타내고;R 6 is -C(=O)-R 7 , -S(=O) 2 -R 7 , -C(=O)-C 1 -C 5 alkylene-R 7 , -OR 7 ,
Figure PCTKR2023007097-appb-img-000004
, -C(=O)-C 3 -C 6 cycloalkylene-R 7 , -C 1 -C 5 alkylene-C(=O)-R 7 ,
Figure PCTKR2023007097-appb-img-000005
or -NH-C(=O)-R 7 ; Here, R 7 is 5 to 3 heteroatoms selected from C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryl-C 1 -C 7 alkyl, N and O. represents a 10-membered heterocycloalkyl, or a 5- to 12-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S; R 8 represents hydrogen, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl-C 1 -C 7 alkyl;
상기 사이클로알킬, 아릴, 헤테로사이클로알킬 및 헤테로사이클릴은 비치환되거나 할로, 시아노, 옥소, C1-C7 알킬, C1-C7 알콕시, 할로-C1-C7 알킬, 할로-C1-C7 알콕시, C1-C7 알킬카르보닐, 다이(C1-C7 알킬)아미노, C6-C10 아릴, C6-C10 아릴옥시 및 비치환되거나 할로로 치환된 N 및 O로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 10원 헤테로아릴로 이루어지는 그룹에서 선택되는 1 내지 3개의 치환기로 치환될 수 있다.The cycloalkyl, aryl, heterocycloalkyl and heterocyclyl are unsubstituted or halo, cyano, oxo, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, halo-C 1 -C 7 alkyl, halo-C 1 -C 7 alkoxy, C 1 -C 7 alkylcarbonyl, di(C 1 -C 7 alkyl)amino, C 6 -C 10 aryl, C 6 -C 10 aryloxy and unsubstituted or halo substituted N and It may be substituted with 1 to 3 substituents selected from the group consisting of 5 to 10 membered heteroaryl having 1 to 3 heteroatoms selected from O.
본 발명에 따른 상기 화학식 1의 화합물 중 대표적인 것에는 하기 화합물들이 포함될 수 있으나, 이들만으로 한정되는 것은 아니다:Representative compounds of Formula 1 according to the present invention may include, but are not limited to, the following compounds:
1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3- Dion;
1,6-다이메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
1,6-다이메틸-4-(1-토실피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;1,6-dimethyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
4-(1-((3-클로로페닐)설포닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;4-(1-((3-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;
4-(1-((3,4-다이클로로페닐)설포닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;4-(1-((3,4-dichlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2, 3-dione;
1-메틸-4-(1-((4-페녹시페닐)설포닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;1-methyl-4-(1-((4-phenoxyphenyl)sulfonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3- Dion;
1-메틸-2,3-다이옥소-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-6-카르보나이트릴;1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2 ,3-b]pyrazine-6-carbonitrile;
7-클로로-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;
7-클로로-1-메틸-4-(1-토실피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
7-클로로-4-(3,3-다이메틸-1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(3,3-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2 ,3-b]pyrazine-2,3-dione;
7-클로로-1-메틸-4-((1R,3s,5S)-8-(4-(트라이플루오로메톡시)벤조일)-8-아자바이사이클로[3.2.1]옥탄-3-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-((1R,3s,5S)-8-(4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl)- 1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
7-브로모-1-메틸-2,3-다이옥소-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-6-카르보나이트릴;7-Bromo-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetra Hydropyrido[2,3-b]pyrazine-6-carbonitrile;
7-클로로-1-메틸-4-(1-(2-(4-(트라이플루오로메톡시)페닐)아세틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
7-클로로-4-(4-(3-클로로페녹시)사이클로헥실)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(4-(3-chlorophenoxy)cyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-(tri fluoromethoxy)phenyl)piperidine-1-carboxamide;
7-클로로-1-메틸-4-(1-(2-(피리딘-2-일)아세틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Chloro-1-methyl-4-(1-(2-(pyridin-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
7-클로로-1-메틸-4-(1-(2-(티오펜-2-일)아세틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(2-(thiophen-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
7-클로로-4-(1-(2-(2-플루오로페닐)아세틸)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(2-(2-fluorophenyl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
7-클로로-4-(1-(2-(퓨란-2-일)아세틸)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(2-(furan-2-yl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
7-클로로-6-(2-플루오로페닐)-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Chloro-6-(2-fluorophenyl)-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyri do[2,3-b]pyrazine-2,3-dione;
7-클로로-1-메틸-4-(1-(2-페닐아세틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(2-phenylacetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;
7-클로로-1-메틸-4-(1-(1-페닐사이클로프로판-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Chloro-1-methyl-4-(1-(1-phenylcyclopropane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
7-클로로-4-(1-(2-(2-플루오로페닐)-2-메틸프로파노일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(2-(2-fluorophenyl)-2-methylpropanoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2 ,3-b]pyrazine-2,3-dione;
7-클로로-4-(1-(4-클로로벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(4-chlorobenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;
7-클로로-1-메틸-4-(1-(4-(트라이플루오로메틸)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;
4-((4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-일)설포닐)벤조나이트릴;4-((4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- 1-yl)sulfonyl)benzonitrile;
4-(4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르보닐)벤조나이트릴;4-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 -carbonyl)benzonitrile;
4-(1-((4-(터트-부틸)페닐)설포닐)피페리딘-4-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;4-(1-((4-(tert-butyl)phenyl)sulfonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione;
7-클로로-4-(1-(2,3-다이하이드로벤조[b][1,4]다이옥신-6-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-carbonyl)piperidin-4-yl)-1-methyl-1,4-di hydropyrido[2,3-b]pyrazine-2,3-dione;
4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-(트라이플루오로메틸)페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-(tri fluoromethyl)phenyl)piperidine-1-carboxamide;
4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-클로로페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-chlorophenyl ) piperidine-1-carboxamide;
4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-시아노페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-cyano phenyl)piperidine-1-carboxamide;
7-클로로-4-(1-(사이클로헥산카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(cyclohexanecarbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;
7-클로로-1-메틸-4-(1-(2-옥소-2-페닐에틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Chloro-1-methyl-4-(1-(2-oxo-2-phenylethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
7-클로로-1-메틸-4-((1s,4s)-4-(4-(트라이플루오로메톡시)페녹시)사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-((1s,4s)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
7-클로로-4-(1-((4-클로로페닐)설포닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Chloro-4-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
7-클로로-4-(1-(2-(4-클로로페닐)-2-옥소에틸)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione;
4-(2-(4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-일)아세틸)벤조나이트릴;4-(2-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi din-1-yl)acetyl)benzonitrile;
7-클로로-1-메틸-4-(1-(2-옥소-2-(4-(트라이플루오로메틸)페닐)에틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)piperidin-4-yl)-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione;
7-클로로-1-메틸-4-(4-((4-(트라이플루오로메톡시)페닐)아미노)사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(4-((4-(trifluoromethoxy)phenyl)amino)cyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2, 3-dione;
7-클로로-1-메틸-4-((1r,4r)-4-((5-메틸피리미딘-2-일)옥시)사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-((1r,4r)-4-((5-methylpyrimidin-2-yl)oxy)cyclohexyl)-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione;
4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-메틸-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-methyl-N-( 4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;
7-클로로-4-((2R,5S)-2,5-다이메틸-1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-((2R,5S)-2,5-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1-methyl-1,4- Dihydropyrido[2,3-b]pyrazine-2,3-dione;
7-클로로-4-(1-(4-플루오로-3-(트라이플루오로메틸)벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(4-fluoro-3-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
7-클로로-1-메틸-4-(1-(4-(트라이플루오로메틸)사이클로헥산-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(4-(trifluoromethyl)cyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido [2, 3-b]pyrazine-2,3-dione;
7-클로로-4-(1-(5-플루오로-2-(트라이플루오로메틸)벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(5-fluoro-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
4-(1-(4-브로모-2-(트라이플루오로메틸)벤조일)피페리딘-4-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;4-(1-(4-bromo-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
7-클로로-4-(1-(5-플루오로-2-메틸벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(5-fluoro-2-methylbenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;
4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-에틸-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-ethyl-N-( 4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;
7-클로로-1,6-다이메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione;
7-브로모-1,6-다이메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Bromo-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione;
4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(사이클로프로필메틸)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(cyclopropylmethyl) -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;
4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(사이클로헥실메틸)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(cyclohexylmethyl) -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;
7-클로로-1-메틸-4-(1-(5-메틸-1-페닐-1H-피라졸-4-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(5-methyl-1-phenyl-1H-pyrazole-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[ 2,3-b]pyrazine-2,3-dione;
7-클로로-4-(1-(1-(5-클로로피리딘-2-일)-5-(트라이플루오로메틸)-1H-피라졸-4-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(1-(5-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl)piperidin-4-yl) -1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
7-클로로-1-메틸-4-(1-(피페리딘-4-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 염산염;7-chloro-1-methyl-4-(1-(piperidine-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione hydrochloride;
N-((1r,4r)-4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)사이클로헥실)-4-(트라이플루오로메톡시)벤즈아마이드;N-((1r,4r)-4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl )Cyclohexyl)-4-(trifluoromethoxy)benzamide;
7-클로로-4-(1-(5-클로로피리미딘e-2-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Chloro-4-(1-(5-chloropyrimidinee-2-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
7-클로로-4-(1-(6-클로로니코티노일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(6-chloronicotinoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3 -Dion;
7-클로로-4-(1-(1-아이소부틸피페리딘-4-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(1-isobutylpiperidine-4-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione;
4-(1-(1-아세틸피페리딘-4-카르보닐)피페리딘-4-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;4-(1-(1-acetylpiperidine-4-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(사이클로부틸메틸)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(cyclobutylmethyl) -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;
6-메톡시-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;6-methoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
6-클로로-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;
7-클로로-1-메틸-4-(1-(피페라진-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(piperazine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2, 3-dione;
4-(1-(1H-인돌-3-카르보닐)피페리딘-4-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;4-(1-(1H-indole-3-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
6-클로로-1-메틸-4-(1-(4-옥소사이클로헥산-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;6-chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
7-클로로-1-메틸-4-(1-(4-옥소사이클로헥산-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
6-클로로-4-(1-(4-(다이메틸아미노)사이클로헥산-1-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;6-chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
7-클로로-4-(1-(4-(다이메틸아미노)사이클로헥산-1-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
7-클로로-4-(1-(4-아이소부틸피페라진-1-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(4-isobutylpiperazine-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
7-클로로-1-메틸-4-(1-(피롤리딘-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(pyrrolidine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(3-클로로페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(3-chlorophenyl ) piperidine-1-carboxamide;
4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-클로로벤질)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-chlorobenzyl ) piperidine-1-carboxamide;
1,8-다이메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;1,8-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
7-클로로-1-메틸-4-((1R,3r,5S)-8-(4-(트라이플루오로메톡시)벤조일)-8-아자바이사이클로[3.2.1]옥탄-3-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-((1R,3r,5S)-8-(4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl)- 1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
6-아이소프로폭시-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;6-isopropoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
7-플루오로-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Fluoro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
메틸 1-메틸-2,3-다이옥소-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-7-카르복시레이트;Methyl 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[ 2,3-b]pyrazine-7-carboxylate;
1,7-다이메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온; 및1,7-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione; and
7-브로모-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온.7-Bromo-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione.
본 명세서에서 사용된 용어와 약어들은 달리 정의되지 않는 한 그 본래의 의미를 갖는다.Terms and abbreviations used in this specification have their original meanings unless otherwise defined.
이하에서는 본 발명에 대한 이해를 돕기 위해 화학식 1의 화합물의 제조방법을 예시적인 반응식에 기초하여 설명한다. 그러나 본 발명이 속한 기술분야에서 통상의 지식을 가진 자라면 화학식 1의 구조를 바탕으로 다양한 방법에 의해 화학식 1의 화합물을 제조할 수 있으며, 이러한 방법들은 모두 본 발명의 범주에 포함되는 것으로 해석되어야 한다. 즉, 본 명세서에 기재되거나 선행기술에 개시된 여러 합성법들을 임의로 조합하여 화학식 1의 화합물을 제조할 수 있으며, 이는 본 발명의 범위 내에 속하는 것으로 이해되고, 화학식 1의 화합물의 제조방법이 하기 설명된 것으로 제한되는 것은 아니다.Hereinafter, to facilitate understanding of the present invention, a method for preparing the compound of Formula 1 will be described based on an exemplary reaction scheme. However, those skilled in the art to which the present invention pertains can prepare the compound of Formula 1 by various methods based on the structure of Formula 1, and all of these methods should be interpreted as falling within the scope of the present invention. do. That is, the compound of Formula 1 can be prepared by arbitrarily combining various synthetic methods described in this specification or disclosed in the prior art, and this is understood to be within the scope of the present invention, and the method for producing the compound of Formula 1 is described below. It is not limited.
예를 들면, 상기 화학식 1의 화합물은 다음의 반응식 1 내지 5에 따라 제조될 수 있다.For example, the compound of Formula 1 can be prepared according to the following Schemes 1 to 5.
[반응식 1][Scheme 1]
Figure PCTKR2023007097-appb-img-000006
Figure PCTKR2023007097-appb-img-000006
[반응식 2][Scheme 2]
Figure PCTKR2023007097-appb-img-000007
Figure PCTKR2023007097-appb-img-000007
[반응식 3][Scheme 3]
Figure PCTKR2023007097-appb-img-000008
Figure PCTKR2023007097-appb-img-000008
[반응식 4][Scheme 4]
Figure PCTKR2023007097-appb-img-000009
Figure PCTKR2023007097-appb-img-000009
[반응식 5][Scheme 5]
Figure PCTKR2023007097-appb-img-000010
Figure PCTKR2023007097-appb-img-000010
상기 반응식 1 내지 5에서, R1 내지 R6는 본원에서 정의된 바와 같다.In Schemes 1 to 5, R 1 to R 6 are as defined herein.
본 발명에 따른 화학식 1의 화합물은 다이아실글리세롤 키나아제 (diacylglycerol kinases, DGKs) 저해제 활성을 갖는다. 이에 따라 본 발명은 화학식 1의 화합물, 또는 이의 약제학적으로 허용되는 염 또는 입체이성질체를, 약제학적으로 허용되는 담체와 함께 포함하는 다이아실글리세롤 키나아제와 관련된 질환의 예방 또는 치료용 약제학적 조성물을 제공한다.The compound of Formula 1 according to the present invention has diacylglycerol kinases (DGKs) inhibitor activity. Accordingly, the present invention provides a pharmaceutical composition for the prevention or treatment of diseases related to diacylglycerol kinase, comprising the compound of Formula 1, or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable carrier. do.
본 발명에 따른 일 구체예에서, 다이아실글리세롤 키나아제 관련 질환은 암이다. 본 발명에 따른 약제학적 조성물로 예방 또는 치료할 수 있는 암의 예로는 위장관암, 췌장암, 유방암, 결장암, 망막모세포종, 간암, 폐암, 난소암, 자궁경부암, 자궁내막암, 뇌종양, 고환암, 후두암, 전립선암, 신경모세포종, 신장암, 갑상선암, 식도암, 피부암, 골육종 및 방광암을 포함하나, 이들만으로 한정되는 것은 아니다.In one embodiment according to the present invention, the diacylglycerol kinase-related disease is cancer. Examples of cancer that can be prevented or treated with the pharmaceutical composition according to the present invention include gastrointestinal cancer, pancreatic cancer, breast cancer, colon cancer, retinoblastoma, liver cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, brain tumor, testicular cancer, laryngeal cancer, and prostate cancer. Cancer includes, but is not limited to, neuroblastoma, kidney cancer, thyroid cancer, esophageal cancer, skin cancer, osteosarcoma, and bladder cancer.
본 발명에서 "약제학적 조성물(pharmaceutical composition)"은 본 발명에 따른 활성 화합물에 추가하여 담체, 희석제, 부형제 등과 같은 다른 화학 성분들을 포함할 수 있다. 따라서, 상기 약제학적 조성물에는 필요에 따라 약제학적으로 허용되는 담체, 희석제, 부형제, 또는 이들의 조합이 포함될 수 있다. 약제학적 조성물은 생물체 내로 활성 화합물의 투여를 용이하게 한다. 화합물을 투여하는 다양한 기술이 존재하며, 여기에는 경구, 주사, 에어로졸, 비경구, 및 국소 투여 등이 포함되지만, 이들만으로 한정되는 것은 아니다.In the present invention, “pharmaceutical composition” may include other chemical components such as carriers, diluents, excipients, etc. in addition to the active compound according to the present invention. Accordingly, the pharmaceutical composition may include a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof, if necessary. Pharmaceutical compositions facilitate administration of the active compound into an organism. There are a variety of techniques for administering compounds, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.
본 명세서에서 “담체(carrier)”란 세포 또는 조직 내로 화합물의 투입을 용이하게 하는 화합물을 의미한다. 예를 들어, 디메틸설폭사이드(DMSO)는 생물체의 세포 또는 조직 내로 많은 유기 화합물의 투입을 용이하게 하는 통상의 담체이다.As used herein, “carrier” refers to a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a common carrier that facilitates the introduction of many organic compounds into the cells or tissues of an organism.
본 명세서에서 “희석제(diluent)”란 대상 화합물의 생물학적 활성 형태를 안정화시킬 뿐만 아니라, 화합물을 용해시키는 물에서 희석되는 화합물로 정의된다. 완충액에 용해되어 있는 염은 당해 분야에서 희석제로 사용된다. 통상 사용되는 완충액은 인체 용액의 염 형태를 모방하고 있는 포스페이트 완충 식염수이다. 완충제 염은 낮은 농도에서 용액의 pH를 제어할 수 있기 때문에, 완충 희석제가 화합물의 생물학적 활성을 변형시키는 일은 드물다.As used herein, “diluent” is defined as a compound diluted in water that not only stabilizes the biologically active form of the compound of interest, but also dissolves the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer is phosphate buffered saline, which mimics the salt form of human solutions. Because buffer salts can control the pH of a solution at low concentrations, it is rare for buffer diluents to modify the biological activity of a compound.
본 명세서에서 “약제학적으로 허용되는(pharmaceutically acceptable)”이란, 화합물의 생물학적 활성과 물성들을 손상시키지 않는 성질을 의미한다.As used herein, “pharmaceutically acceptable” means a property that does not impair the biological activity and physical properties of a compound.
본 발명의 화합물은 목적하는 바에 따라 다양한 약제학적 투여 형태로 제형화될 수 있다. 본 발명에 따른 약제학적 조성물을 제조하는 경우, 유효 성분, 구체적으로 화학식 1의 화합물, 이의 약제학적으로 허용되는 염 또는 입체이성질체를, 제조하고자 하는 제형에 따라 선택될 수 있는 다양한 약제학적으로 허용되는 담체와 함께 혼합한다. 예를 들어, 본 발명에 따른 약제학적 조성물은 목적하는 바에 따라 주사용 제제, 경구용 제제 등으로 제형화될 수 있다.The compounds of the present invention can be formulated into various pharmaceutical dosage forms depending on the purpose. When preparing a pharmaceutical composition according to the present invention, the active ingredient, specifically the compound of Formula 1, a pharmaceutically acceptable salt or stereoisomer thereof, is mixed with various pharmaceutically acceptable salts or stereoisomers that can be selected depending on the formulation to be prepared. Mix with the carrier. For example, the pharmaceutical composition according to the present invention may be formulated into an injectable formulation, an oral formulation, etc., depending on the purpose.
본 발명의 화합물은 공지된 제약용 담체와 부형제를 이용하는 공지의 방법으로 제제화되어 단위 용량 형태 또는 다용량 용기에 내입될 수 있다. 제제의 형태는 오일 또는 수성 매질 중의 용액, 현탁액 또는 유화액 형태일 수 있으며, 통상의 분산제, 현탁제 또는 안정화제를 함유할 수 있다. 또한, 예를 들어, 사용 전에 무균, 발열물질이 제거된 물에 녹여 사용하는 건조 분말의 형태일 수도 있다. 본 발명의 화합물은 또한, 코코아버터 또는 기타 글리세리드와 같은 통상의 좌약 기제를 이용하여 좌약형으로 제제화될 수도 있다. 경구 투여용 고체투여 형태는 캅셀제, 정제, 환제, 산제 및 과립제가 가능하고, 특히 캅셀제와 정제가 유용하다. 정제 및 환제는 장용피제로 제조하는 것이 바람직하다. 고체투여 형태는 본 발명의 화합물을 수크로오즈, 락토오즈, 전분 등과 같은 하나 이상의 불활성 희석제 및 마그네슘 스테아레이트와 같은 윤활제, 붕해제, 결합제 등과 같은 담체와 혼합시킴으로써 제조할 수 있다.The compounds of the present invention can be formulated by known methods using known pharmaceutical carriers and excipients and placed in unit dosage form or multi-dose containers. The form of the preparation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium and may contain customary dispersing, suspending or stabilizing agents. Additionally, for example, it may be in the form of a dry powder that is dissolved in sterile, pyrogen-free water before use. The compounds of the present invention may also be formulated in suppository form using conventional suppository bases such as cocoa butter or other glycerides. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules, and capsules and tablets are particularly useful. Tablets and pills are preferably manufactured as enteric coating agents. Solid dosage forms can be prepared by mixing the compounds of the present invention with one or more inert diluents such as sucrose, lactose, starch, etc. and carriers such as lubricants such as magnesium stearate, disintegrants, binders, etc.
필요에 따라, 본 발명에 따른 화합물 또는 이를 함유하는 약제학적 조성물은 기타의 약제, 예를 들어, 다른 면역항암제와 조합하여 투여할 수 있다.If necessary, the compound according to the present invention or a pharmaceutical composition containing the same can be administered in combination with other drugs, for example, other anticancer immunotherapy agents.
본 발명의 화학식 1의 화합물의 투여량은 환자의 체중, 나이 및 질병의 특수한 성질과 심각성과 같은 요인에 따라 의사의 처방에 따라 결정된다. 그러나, 성인 치료에 필요한 투여량은 투여의 빈도와 강도에 따라 하루에 약 0.3 내지 500 ㎎ 범위가 통상적이다. 성인에게 근육 내 또는 정맥 내 투여 시 일회 투여량으로 분리하여 하루에 보통 약 1 내지 300 ㎎의 전체 투여량이면 충분할 것이나, 일부 환자의 경우 더 높은 일일 투여량이 바람직할 수 있다.The dosage of the compound of formula 1 of the present invention is determined according to the doctor's prescription depending on factors such as the patient's weight, age, and the specific nature and severity of the disease. However, the dosage required for adult treatment typically ranges from about 0.3 to 500 mg per day, depending on the frequency and intensity of administration. When administered intramuscularly or intravenously to adults, a total dose of approximately 1 to 300 mg per day, divided into single doses, will usually be sufficient, although higher daily doses may be desirable for some patients.
본 명세서에서 “치료”란 발병 증상을 보이는 객체에 사용될 때 질병의 진행을 중단, 지연 또는 완화시키는 것을 의미한다.As used herein, “treatment” means stopping, delaying, or alleviating the progression of a disease when used in a subject showing symptoms of the disease.
본 발명에 따른 화학식 1로 표시되는 헤테로사이클 화합물은 다이아실글리세롤 키나아제(diacylglycerol kinases, DGKs)를 저해함으로써 암과 같은 다이아실글리세롤 키나아제와 관련된 질환의 예방 또는 치료를 위해 유용하게 사용될 수 있다.The heterocycle compound represented by Formula 1 according to the present invention can be usefully used for the prevention or treatment of diseases related to diacylglycerol kinases, such as cancer, by inhibiting diacylglycerol kinases (DGKs).
이하 제조예 및 실시예를 통하여 본 발명을 더욱 구체적으로 설명한다. 단, 이들 실시예는 본 발명의 예시일 뿐, 본 발명의 범위가 이들에 의해 한정되는 것은 아니다.The present invention will be described in more detail below through preparation examples and examples. However, these examples are only illustrative of the present invention, and the scope of the present invention is not limited thereto.
하기 제조예 및 실시예에서 사용되는 약어와 용어의 설명은 다음과 같다:An explanation of the abbreviations and terms used in the following preparation examples and examples is as follows:
ACN: 아세토나이트릴ACN: Acetonitrile
DCE: 다이클로로에탄DCE: Dichloroethane
DCM: 다이클로로메탄DCM: dichloromethane
DIAD: 다이아이소프로필 아조다이카르복실레이트DIAD: diisopropyl azodicarboxylate
DIPEA: N,N-다이아이소프로필에틸아민DIPEA: N,N-diisopropylethylamine
DMAP: 다이메틸아미노피리딘DMAP: Dimethylaminopyridine
DMF: N,N-다이메틸포름아미드DMF: N,N-dimethylformamide
EDC: 1-에틸-3-(3-다이메틸아미노프로필)카보디이미드EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
EtOAc: 에틸 아세테이트EtOAc: ethyl acetate
EtOH: 에탄올EtOH: Ethanol
Et3N: 트라이에틸아민Et 3 N: triethylamine
HATU: 헥사플루오로포스페이트 아자벤조트리아졸 테트라메틸 유로늄HATU: Hexafluorophosphate Azabenzotriazole Tetramethyl Euronium
HOBt: 하이드록시벤조트리아졸HOBt: Hydroxybenzotriazole
IPA: 아이소프로필알코올IPA: Isopropyl Alcohol
MeOH: 메탄올MeOH: methanol
MPLC: 중압 액체 크로마토그래피(medium pressure liquid chromatography)MPLC: medium pressure liquid chromatography
NaH: 소듐 하이드라이드NaH: sodium hydride
NBS: N-브로모숙신이미드NBS: N-bromosuccinimide
NCS: N-클로로숙신이미드NCS: N-chlorosuccinimide
Pd2(dba)3: 트리스(다이벤질리덴아세톤)다이팔라듐(0)Pd 2 (dba) 3 : Tris(dibenzylideneacetone)dipalladium (0)
(PPh4)4Pd: 테트라키스(트라이페닐포스핀)팔라듐(0)(PPh 4 ) 4 Pd: tetrakis(triphenylphosphine)palladium (0)
TBSCl: 터트-부틸다이메틸실릴 클로라이드TBSCl: tert-butyldimethylsilyl chloride
TEA: 트라이에틸아민TEA: triethylamine
THF: 테트라하이드로퓨란THF: tetrahydrofuran
TLC: 박막 크로마토그래피TLC: thin layer chromatography
Xantphos: (9,9-다이메틸-9H-크산텐-4,5-다이일)비스(다이페닐포스판)Xantphos: (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)
제조예 1: 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 1: Preparation of 1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000011
Figure PCTKR2023007097-appb-img-000011
단계 A: 터트-부틸 4-((3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000012
Figure PCTKR2023007097-appb-img-000012
터트-뷰틸 4-아미도피페리딘-1-카르복실레이트 (1.00 g, 5.00 mmol)와 2-플루오로-3-나이트로피리딘 (0.71 g, 5.00 mmol)을 DMF(15 ml)에 녹인 후 다이아이소프로필아민 (1.75 mL, 10.00 mmol)을 가한 후 60℃에서 4시간 교반하였다. 반응물을 상온으로 식히고, EtOAc로 희석한 다음, brine으로 2번 세척 후 무수 마그네슘설페이트로 건조하고 감압농축하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (1.53 g)을 수득하였다.Dissolve tert-butyl 4-amidopiperidine-1-carboxylate (1.00 g, 5.00 mmol) and 2-fluoro-3-nitropyridine (0.71 g, 5.00 mmol) in DMF (15 ml) and add dia. Isopropylamine (1.75 mL, 10.00 mmol) was added and stirred at 60°C for 4 hours. The reaction was cooled to room temperature, diluted with EtOAc, washed twice with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (1.53 g).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.46~8.41 (m, 2H), 8.19 (dd, 1H), 6.68 (dd, 1H), 4.41~4.38 (m, 1H), 4.09 (br s, 2H), 3.03 (br s, 2H), 2.11~2.07 (m, 2H), 1.55~1.53 (m, 2H), 1.50 (s, 9H) 1 H-NMR (500 MHz, CHLOROFORM-D) δ 8.46~8.41 (m, 2H), 8.19 (dd, 1H), 6.68 (dd, 1H), 4.41~4.38 (m, 1H), 4.09 (br s, 2H), 3.03 (br s, 2H), 2.11~2.07 (m, 2H), 1.55~1.53 (m, 2H), 1.50 (s, 9H)
LC/MS: 267 (M+H-t-Bu)LC/MS: 267 (M+H-t-Bu)
단계 B: 터트-부틸 4-((3-아미노피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((3-aminopyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000013
Figure PCTKR2023007097-appb-img-000013
터트-부틸 4-((3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (0.50 g, 1.55 mmol)를 MeOH (10 mL)에 녹인 후 0℃에서 Zn (2. 24 g, 34.4 mmol)과 암모늄 클로라이드 (0.92 g, 17.14 mmol)를 천천히 넣어 준 후 70℃에서 20 시간 동안 환류하며 교반하였다. 반응 종결 후 혼합물을 상온으로 식힌 뒤 Celite pad로 필터해준 후 감압농축시켰다. 혼합물을 DCM으로 묽힌 뒤 포화 NaHCO3 수용액을 이용하여 추출하였다. 유기층을 무수 MgSO4를 이용하여 건조 후 감압증류하여 표제 화합물 (440 mg)을 수득하였다.Tert-butyl 4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (0.50 g, 1.55 mmol) was dissolved in MeOH (10 mL) and then dissolved in Zn (2) at 0°C. 24 g, 34.4 mmol) and ammonium chloride (0.92 g, 17.14 mmol) were slowly added and stirred under reflux at 70°C for 20 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through a Celite pad, and concentrated under reduced pressure. The mixture was diluted with DCM and extracted using saturated aqueous NaHCO 3 solution. The organic layer was dried using anhydrous MgSO 4 and then distilled under reduced pressure to obtain the title compound (440 mg).
LC/MS: 293 (M+H)LC/MS: 293 (M+H)
단계 C: 터트-부틸 4-((3-(2-에톡시-2-옥소아세트아미도)피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step C: Preparation of tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)pyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000014
Figure PCTKR2023007097-appb-img-000014
터트-부틸 4-((3-아미노피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (130 mg, 0.18 mmol)와 다이아이소프로필아민 (0.23 mL, 1.33 mmol)을 디클로로메탄 (10 mL)에 녹인 후 0℃에서 에틸 옥살릴 클로라이드 (0.075 mL, 0.67 mmol)를 가한 후 상온에서 2시간 동안 교반하였다. 반응물을 물로 희석 후 EtOAc로 추출하였다. 유기층을 무수 마그네슘설페이트로 건조한 다음 감압농축하여 표제 화합물 (146 mg)을 수득하였고 정제하지 않고 다음 반응에 바로 사용하였다.Tert-butyl 4-((3-aminopyridin-2-yl)amino)piperidine-1-carboxylate (130 mg, 0.18 mmol) and diisopropylamine (0.23 mL, 1.33 mmol) were dissolved in dichloromethane ( After dissolving in 10 mL), ethyl oxalyl chloride (0.075 mL, 0.67 mmol) was added at 0°C and stirred at room temperature for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound (146 mg), which was used directly in the next reaction without purification.
LC/MS: 393 (M+H)LC/MS: 393 (M+H)
단계 D: 터트-부틸 4-(2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step D: of tert-butyl 4-(2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate manufacturing
Figure PCTKR2023007097-appb-img-000015
Figure PCTKR2023007097-appb-img-000015
터트-부틸 4-((3-(2-에톡시-2-옥소아세트아미도)피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (70 mg, 0.18 mmol)를 EtOH (6 mL)에 녹인 후 소듐에톡사이드 (0.35 mL, 0.89 mmol, 20 wt% in EtOH)을 첨가한 후 70℃에서 0.5 시간 동안 교반하였다. 반응물을 상온으로 식히고 물로 희석 후 1 N HCl로 ~pH 5 정도로 산성화한 후, EtOAc로 2번 추출하였다. 유기층을 무수 마그네슘설페이트로 건조한 다음 감압농축하여 표제 화합물 (42 mg)을 수득하였고 정제하지 않고 다음 반응에 바로 사용하였다.Tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)pyridin-2-yl)amino)piperidine-1-carboxylate (70 mg, 0.18 mmol) was dissolved in EtOH (6 mL) and then added sodium ethoxide (0.35 mL, 0.89 mmol, 20 wt% in EtOH) and stirred at 70°C for 0.5 hours. The reaction was cooled to room temperature, diluted with water, acidified to pH 5 with 1 N HCl, and extracted twice with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (42 mg), which was used directly in the next reaction without purification.
LC/MS: 347 (M+H), 369 (M+Na)LC/MS: 347 (M+H), 369 (M+Na)
단계 E: 터트-부틸 4-(1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step E: Tert-Butyl 4-(1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates
Figure PCTKR2023007097-appb-img-000016
Figure PCTKR2023007097-appb-img-000016
터트-부틸 4-(2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (42 mg, 0.12 mmol)를 DMF (5 mL)에 녹인 후 세슘카보네이트 (158 mg, 0.49 mmol)와 아이도메탄 (0.011 mL, 0.18 mmol)을 첨가한 후 상온에서 0.5 시간 동안 교반하였다. 반응물을 물로 희석 후 EtOAc로 3번 추출하였다. 유기층을 무수 마그네슘설페이트로 건조 후 감압농축시키고 잔류물을 Preparatory TLC로 정제하여 표제 화합물 (19 mg)을 수득하였다.Tert-butyl 4-(2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate (42 mg, 0.12 mmol) was dissolved in DMF (5 mL), cesium carbonate (158 mg, 0.49 mmol) and idomethane (0.011 mL, 0.18 mmol) were added, and the mixture was stirred at room temperature for 0.5 hours. The reaction was diluted with water and extracted three times with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by Preparatory TLC to obtain the title compound (19 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.27~8.26 (m, 1H), 7.53~7.51 (m, 1H), 7.25~7.23 (m, 1H), 5.58 (s, 1H), 4.29 (br s, 2H), 3.64 (s, 3H), 2.91~2.87 (m, 4H), 1.65 (br s, 2H), 1.51 (s, 9H) 1 H-NMR (500 MHz, CHLOROFORM-D) δ 8.27~8.26 (m, 1H), 7.53~7.51 (m, 1H), 7.25~7.23 (m, 1H), 5.58 (s, 1H), 4.29 (br s, 2H), 3.64 (s, 3H), 2.91~2.87 (m, 4H), 1.65 (br s, 2H), 1.51 (s, 9H)
LC/MS: 383 (M+Na)LC/MS: 383 (M+Na)
단계 F: 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step F: Preparation of 1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000017
Figure PCTKR2023007097-appb-img-000017
터트-부틸 4-(1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (19 mg, 0.053 mmol)를 디클로로메탄 (4 mL)에 녹인 후 HCl (0.26 mL, 1.05 mmol, 4 M in 1,4-다이옥산)을 첨가한 후 상온에서 16 시간 동안 교반하였다. 혼합물을 감압증류한 뒤 10% MeOH/DCM (v/v) 용액과 0.3 N NaOH 수용액을 이용하여 추출하였다. 유기층을 무수 MgSO4를 이용하여 건조한 뒤 감압증류하여 표제 화합물 (18 mg)을 수득하였다.Tert-Butyl 4-(1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate (19 mg, 0.053 mmol) was dissolved in dichloromethane (4 mL), HCl (0.26 mL, 1.05 mmol, 4 M in 1,4-dioxane) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was distilled under reduced pressure and extracted using 10% MeOH/DCM (v/v) solution and 0.3 N NaOH aqueous solution. The organic layer was dried using anhydrous MgSO 4 and then distilled under reduced pressure to obtain the title compound (18 mg).
LC/MS: 261 (M+H)LC/MS: 261 (M+H)
제조예 2: 1,6-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 2: Preparation of 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000018
Figure PCTKR2023007097-appb-img-000018
단계 A: 터트-부틸 4-((6-메틸-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000019
Figure PCTKR2023007097-appb-img-000019
2-플루오로-6-메틸-3-나이트로피리딘 (0.781 g, 5.00 mmol)을 제조예 1의 단계 A와 같은 방법을 이용하여 표제 화합물 (1.61 g)을 수득하였다.The title compound (1.61 g) was obtained by using 2-fluoro-6-methyl-3-nitropyridine (0.781 g, 5.00 mmol) in the same manner as Step A of Preparation Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.31 (d, J = 8.5 Hz, 1H), 8.24 (d, J = 7.0 Hz, 1H), 6.51 (d, J = 8.5 Hz, 1H), 4.45-4.40 (m, 1H), 4.07 (s, 2H), 3.07-3.02 (m, 2H), 2.48 (s, 3H), 2.08 (d, J = 10.4 Hz, 2H), 1.58-1.52 (m, 2H), 1.50 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.31 (d, J = 8.5 Hz, 1H), 8.24 (d, J = 7.0 Hz, 1H), 6.51 (d, J = 8.5 Hz, 1H), 4.45- 4.40 (m, 1H), 4.07 (s, 2H), 3.07-3.02 (m, 2H), 2.48 (s, 3H), 2.08 (d, J = 10.4 Hz, 2H), 1.58-1.52 (m, 2H) , 1.50 (s, 9H)
LC/MS: 337 (M+H)LC/MS: 337 (M+H)
단계 B: 6-터트-부틸 4-((3-아미노-6-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of 6-tert-butyl 4-((3-amino-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000020
Figure PCTKR2023007097-appb-img-000020
터트-부틸 4-((6-메틸-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (800 mg, 2.38 mmol)를 제조예 1의 단계 B와 같은 방법을 이용하여 표제 화합물 (720 mg)을 수득하였다.Tert-butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (800 mg, 2.38 mmol) was prepared in the same manner as Step B of Preparation Example 1. The title compound (720 mg) was obtained.
LC/MS: 307 (M+H), 329 (M+Na)LC/MS: 307 (M+H), 329 (M+Na)
단계 C: 터트-부틸 4-((3-(2-에톡시-2-옥소아세트아미도)-6-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트Step C: Tert-Butyl 4-((3-(2-ethoxy-2-oxoacetamido)-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000021
Figure PCTKR2023007097-appb-img-000021
6-터트-부틸 4-((3-아미노-6-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (720 mg, 2.35 mmol)를 제조예 1의 단계 C와 같은 방법을 이용하여 표제 화합물 (898 mg)을 수득하였다6-tert-butyl 4-((3-amino-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate (720 mg, 2.35 mmol) was prepared in the same manner as Step C of Preparation Example 1. The title compound (898 mg) was obtained using
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.43 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.28 (s, 2H), 6.53 (d, J = 7.9 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 4.28 (d, J = 7.0 Hz, 1H), 4.18-4.12 (m, 2H), 4.06 (s, 1H), 2.98 (t, J = 11.3 Hz, 2H), 2.41 (s, 4H), 2.09-2.05 (m, 4H), 1.49 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.43 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.28 (s, 2H), 6.53 (d, J = 7.9 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 4.28 (d, J = 7.0 Hz, 1H), 4.18-4.12 (m, 2H), 4.06 (s, 1H), 2.98 (t, J = 11.3 Hz, 2H) ), 2.41 (s, 4H), 2.09-2.05 (m, 4H), 1.49 (s, 9H)
LC/MS: 408 (M+H).LC/MS: 408 (M+H).
단계 D: 터트-부틸 4-(6-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step D: Tert-Butyl 4-(6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates
Figure PCTKR2023007097-appb-img-000022
Figure PCTKR2023007097-appb-img-000022
터트-부틸 4-((3-(2-에톡시-2-옥소아세트아미도)-6-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (898 mg, 2.21 mmol)를 제조예 1의 단계 D와 같은 방법을 이용하여 표제 화합물 (781 mg)을 수득하였다.Tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate (898 mg, 2.21 mmol) The title compound (781 mg) was obtained using the same method as Step D of Preparation Example 1.
LC/MS: 383 (M+Na), 743 (2M+Na)LC/MS: 383 (M+Na), 743 (2M+Na)
단계 E: 터트-부틸 4-(1,6-다이메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step E: Tert-Butyl 4-(1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -Preparation of 1-carboxylate
Figure PCTKR2023007097-appb-img-000023
Figure PCTKR2023007097-appb-img-000023
터트-부틸 4-(6-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (660 mg, 1.83 mmol)를 제조예 1의 단계 E와 같은 방법을 이용하여 표제 화합물 (322 mg)을 수득하였다.Tert-Butyl 4-(6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate (660 mg, 1.83 mmol) was obtained using the same method as Step E of Preparation Example 1 to obtain the title compound (322 mg).
1H-NMR (500 MHz, DMSO-D6) δ 7.71 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 5.47 (s, 1H), 4.09 (s, 2H), 3.50-3.43 (m, 3H), 2.85 (s, 1H), 2.66-2.60 (m, 2H), 2.48-2.35 (m, 4H), 1.60 (d, J = 9.5 Hz, 2H), 1.50-1.24 (m, 9H)1H-NMR (500 MHz, DMSO-D6) δ 7.71 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 5.47 (s, 1H), 4.09 (s, 2H), 3.50-3.43 (m, 3H), 2.85 (s, 1H), 2.66-2.60 (m, 2H), 2.48-2.35 (m, 4H), 1.60 (d, J = 9.5 Hz, 2H), 1.50-1.24 ( m, 9H)
LC/MS: 375 (M+H)LC/MS: 375 (M+H)
단계 F: 1,6-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step F: Preparation of 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000024
Figure PCTKR2023007097-appb-img-000024
터트-부틸 4-(1,6-다이메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (300 mg, 0.83 mmol)를 제조예 1의 단계 F와 같은 방법을 이용해여 표제 화합물 (256 mg)을 수득하였다.Tert-Butyl 4-(1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Carboxylate (300 mg, 0.83 mmol) was reacted using the same method as Step F of Preparation Example 1 to obtain the title compound (256 mg).
LC/MS: 275 (M+H)LC/MS: 275 (M+H)
제조예 3: 1-메틸-2,3-다이옥소-4-(피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-6-카르보나이트릴의 제조Preparation Example 3: 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6- Manufacture of carbonitrile
Figure PCTKR2023007097-appb-img-000025
Figure PCTKR2023007097-appb-img-000025
단계 A: 터트-부틸 4-((6-클로로-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000026
Figure PCTKR2023007097-appb-img-000026
터트-뷰틸 4-아미도피페리딘-1-카르복실레이트 (4.21 g, 21.0 mmol)와 2,6-다이클로로-3-나이트로피리딘 (4.20 g, 20.0 mmol)을 이용하여 제조예 1의 단계 A와 같은 방법으로 표제 화합물 (6.21 g)을 수득하였다.Preparation Example 1 using tert-butyl 4-amidopiperidine-1-carboxylate (4.21 g, 21.0 mmol) and 2,6-dichloro-3-nitropyridine (4.20 g, 20.0 mmol) The title compound (6.21 g) was obtained in the same manner as A.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.37 (d, J = 8.5 Hz, 1H), 8.30 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 9.0 Hz, 1H), 4.37~4.33 (m, 1H), 4.09 (br s, 2H), 3.04 (br s, 2H), 2.08 (d, J = 10.0 Hz, 2H), 1.57-1.52 (m, 2H), 1.50 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.37 (d, J = 8.5 Hz, 1H), 8.30 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 9.0 Hz, 1H), 4.37~ 4.33 (m, 1H), 4.09 (br s, 2H), 3.04 (br s, 2H), 2.08 (d, J = 10.0 Hz, 2H), 1.57-1.52 (m, 2H), 1.50 (s, 9H)
LC/MS: 379 (M+Na)LC/MS: 379 (M+Na)
단계 B: 터트-부틸 4-((6-시아노-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((6-cyano-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000027
Figure PCTKR2023007097-appb-img-000027
터트-부틸 4-((6-클로로-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (2.0 g, 5.61 mmol), Zn(CN)2 (0.987 g, 8.41 mmol), (PPh4)4Pd (0.648 g, 0.561 mmol)을 DMF (50 mL)에 녹이고 100℃에서 1 시간 동안 교반하였다. 반응물을 상온으로 식히고 EtOAc로 희석 후 소듐바이카보네이트 수용액과 brine으로 세척하였다. 유기층을 무수 소듐설페이트로 건조 후 감압농축시키고 잔류물을 MPLC로 정제하여 표제 화합물 (1.84 g)을 수득하였다.Tert-butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (2.0 g, 5.61 mmol), Zn(CN) 2 (0.987 g, 8.41 mmol), (PPh 4 ) 4 Pd (0.648 g, 0.561 mmol) was dissolved in DMF (50 mL) and stirred at 100°C for 1 hour. The reaction was cooled to room temperature, diluted with EtOAc, and washed with aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (1.84 g).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.55 (d, J = 8.5 Hz, 1H), 8.14 (d, J = 7.5 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 4.39~4.33 (m, 1H), 4.17~4.12 (m, 2H), 3.06~3.01 (m, 2H), 2.10~2.08 (m, 2H), 1.57-1.52 (m, 2H), 1.51 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.55 (d, J = 8.5 Hz, 1H), 8.14 (d, J = 7.5 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 4.39~ 4.33 (m, 1H), 4.17~4.12 (m, 2H), 3.06~3.01 (m, 2H), 2.10~2.08 (m, 2H), 1.57-1.52 (m, 2H), 1.51 (s, 9H)
LC/MS: 370 (M+Na)LC/MS: 370 (M+Na)
단계 C: 터트-부틸 4-(N-(6-시아노-3-나이트로피리딘-2-일)-2-에톡시-2-옥소아세트아미도)피페리딘-1-카르복실레이트의 제조Step C: of tert-butyl 4-(N-(6-cyano-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate manufacturing
Figure PCTKR2023007097-appb-img-000028
Figure PCTKR2023007097-appb-img-000028
터트-부틸 4-((6-시아노-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (1.04 g, 2.99 mmol)를 THF (34 mL)에 녹인 후 0℃에서 NaH (179 mg, 4.48 mmol, 60% in dispersion oil)를 천천히 가한 후 30분 동안 교반하였다. 에틸 옥살릴 클로라이드 (0.66 mL, 5.97 mmol)를 0℃에서 반응물에 첨가한 후 상온에서 1 시간 동안 교반하였다. 반응물에 물을 천천히 첨가하여 반응을 종료시키고 EtOAc로 묽힌 후 0.5 N NaOH 수용액, 소듐바이카보네이트 수용액 및 brine으로 세척하였다. 유기층을 무수 소듐설페이트로 건조 후 감압농축시키고 잔류물을 MPLC로 정제하여 표제 화합물 (1.02 g)을 수득하였다.After dissolving tert-butyl 4-((6-cyano-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.04 g, 2.99 mmol) in THF (34 mL), 0 NaH (179 mg, 4.48 mmol, 60% in dispersion oil) was slowly added at ℃ and stirred for 30 minutes. Ethyl oxalyl chloride (0.66 mL, 5.97 mmol) was added to the reaction at 0°C and stirred at room temperature for 1 hour. The reaction was terminated by slowly adding water to the reaction product, diluted with EtOAc, and washed with 0.5 N aqueous NaOH solution, aqueous sodium bicarbonate solution, and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (1.02 g).
LC/MS: 470 (M+Na)LC/MS: 470 (M+Na)
단계 D: 터트-부틸 4-(6-시아노-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step D: Tert-Butyl 4-(6-cyano-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1 -Manufacture of carboxylates
Figure PCTKR2023007097-appb-img-000029
Figure PCTKR2023007097-appb-img-000029
터트-부틸 4-(N-(6-시아노-3-나이트로피리딘-2-일)-2-에톡시-2-옥소아세트아미도)피페리딘-1-카르복실레이트 (0.51 g, 1.14 mmol)를 EtOH (10 mL)에 녹인 후 물 (10 mL), Iron (0.77 g, 13.9 mmol) 및 암모늄클로라이드 (1.35 g, 25 mmol)를 상온에서 첨가한 후 70℃에서 4시간 동안 교반하였다. 반응물을 상온으로 식힌 후 Celite로 감압 필터 후 EtOAc로 추출하였다. 유기층을 무수 소듐설페이트로 건조한 다음 감압농축하여 표제 화합물 (0.39 g)을 수득하였고 정제하지 않고 다음 반응에 바로 사용하였다.tert-butyl 4-(N-(6-cyano-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate (0.51 g, 1.14 mmol) was dissolved in EtOH (10 mL), water (10 mL), iron (0.77 g, 13.9 mmol), and ammonium chloride (1.35 g, 25 mmol) were added at room temperature and stirred at 70°C for 4 hours. . The reaction product was cooled to room temperature, filtered under reduced pressure with Celite, and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound (0.39 g), which was used directly in the next reaction without purification.
LC/MS: 394 (M+Na)LC/MS: 394 (M+Na)
단계 E: 터트-부틸 4-(6-시아노-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step E: tert-butyl 4-(6-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p Preparation of peridine-1-carboxylate
Figure PCTKR2023007097-appb-img-000030
Figure PCTKR2023007097-appb-img-000030
터트-부틸 4-(6-시아노-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (0.388 g, 1.045 mmol)를 제조예 1의 단계 E와 같은 방법을 이용하여 얻어진 잔류물을 MPLC로 정제하여 표제 화합물 (0.368 g)을 수득하였다.Tert-Butyl 4-(6-cyano-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxyl Rate (0.388 g, 1.045 mmol) was obtained using the same method as Step E of Preparation Example 1. The residue was purified by MPLC to obtain the title compound (0.368 g).
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.64 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 5.50~5.47 (m, 1H), 4.37~4.29 (m, 2H), 3.67 (s, 3H), 2.91 (m, 2H), 2.84~2.80 (m, 2H), 1.68-1.65 (m, 2H), 1.53 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.64 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 5.50~5.47 (m, 1H), 4.37~4.29 (m , 2H), 3.67 (s, 3H), 2.91 (m, 2H), 2.84~2.80 (m, 2H), 1.68-1.65 (m, 2H), 1.53 (s, 9H)
LC/MS: 408 (M+Na)LC/MS: 408 (M+Na)
단계 F: 1-메틸-2,3-다이옥소-4-(피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-6-카르보나이트릴의 제조Step F: 1-Methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-car Manufacturing of Bonitrile
Figure PCTKR2023007097-appb-img-000031
Figure PCTKR2023007097-appb-img-000031
터트-부틸 4-(6-시아노-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (0.300 g, 0.778 mmol)를 제조예 1의 단계 F와 같은 방법으로 표제 화합물 (250 mg)을 수득하였다.tert-butyl 4-(6-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- 1-Carboxylate (0.300 g, 0.778 mmol) was prepared in the same manner as Step F of Preparation Example 1 to obtain the title compound (250 mg).
LC/MS: 286 (M+H), 308 (M+Na)LC/MS: 286 (M+H), 308 (M+Na)
제조예 4: 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 4: Preparation of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000032
Figure PCTKR2023007097-appb-img-000032
단계 A: 터트-부틸 4-((5-클로로-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((5-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000033
Figure PCTKR2023007097-appb-img-000033
터트-부틸 4-아미도피페리딘-1-카르복실레이트 (5.96 g, 29.7 mmol)와 5-클로로-2-플루오로-3-나이트로피리딘 (5.00 g, 28.3 mmol)을 이용하여 제조예 1의 단계 A와 같은 방법으로 표제 화합물 (10.0 g)을 수득하였다.Preparation Example 1 using tert-butyl 4-amidopiperidine-1-carboxylate (5.96 g, 29.7 mmol) and 5-chloro-2-fluoro-3-nitropyridine (5.00 g, 28.3 mmol) The title compound (10.0 g) was obtained in the same manner as step A.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.40 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 2.7 Hz, 1H), 8.09 (d, J = 7.3 Hz, 1H), 4.30 (tt, J = 10.7, 3.5 Hz, 1H), 4.18-3.95 (m, 2H), 2.98 (t, J = 12.1 Hz, 2H), 2.05 (d, J = 10.5 Hz, 2H), 1.53-1.48 (2H), 1.46 (s, 9H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.40 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 2.7 Hz, 1H), 8.09 (d, J = 7.3 Hz, 1H), 4.30 ( tt, J = 10.7, 3.5 Hz, 1H), 4.18-3.95 (m, 2H), 2.98 (t, J = 12.1 Hz, 2H), 2.05 (d, J = 10.5 Hz, 2H), 1.53-1.48 (2H) ), 1.46 (s, 9H)
LC/MS: 357 (M+H), 379 (M+Na)LC/MS: 357 (M+H), 379 (M+Na)
단계 B: 터트-부틸 4-(N-(5-클로로-3-아미노피리딘-2-일)-2-에톡시-2-옥소아세토아미도)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-(N-(5-chloro-3-aminopyridin-2-yl)-2-ethoxy-2-oxoacetoamido)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000034
Figure PCTKR2023007097-appb-img-000034
터트-부틸 4-((5-클로로-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (3.20 g, 8.97 mmol)를 이용하여 제조예 3의 단계 C와 같은 방법으로 표제화합물 (1.32 g)을 수득하였다.The same as step C of Preparation Example 3 using tert-butyl 4-((5-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (3.20 g, 8.97 mmol) The title compound (1.32 g) was obtained through this method.
LC/MS: 479 (M+Na)LC/MS: 479 (M+Na)
단계 C: 터트-부틸 4-(7-클로로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step C: Tert-Butyl 4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates
Figure PCTKR2023007097-appb-img-000035
Figure PCTKR2023007097-appb-img-000035
터트-부틸 4-(N-(5-클로로-3-아미노피리딘-2-일)-2-에톡시-2-옥소아세토아미도)피페리딘-1-카르복실레이트 (1.90 g, 4.16 mmol)를 이용하여 제조예 3의 단계 D와 같은 방법으로 표제 화합물 (1.28 g)을 수득하였다.Tert-butyl 4-(N-(5-chloro-3-aminopyridin-2-yl)-2-ethoxy-2-oxoacetoamido)piperidine-1-carboxylate (1.90 g, 4.16 mmol) ) was used to obtain the title compound (1.28 g) in the same manner as Step D of Preparation Example 3.
LC/MS: 325 (M+H-t-Bu)LC/MS: 325 (M+H-t-Bu)
단계 D: 터트-부틸 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step D: Tert-Butyl 4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi Preparation of dine-1-carboxylate
Figure PCTKR2023007097-appb-img-000036
Figure PCTKR2023007097-appb-img-000036
터트-부틸 4-(7-클로로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (1.28 g, 3.36 mmol)를 제조예 1의 단계 E와 같은 방법을 이용하여 얻어진 잔류물을 MPLC로 정제하여 표제 화합물 (1.08 g)을 수득하였다.Tert-Butyl 4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate (1.28 g, 3.36 mmol) was obtained using the same method as Step E of Preparation Example 1. The residue was purified by MPLC to obtain the title compound (1.08 g).
LC/MS: 417 (M+Na)LC/MS: 417 (M+Na)
단계 E: 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step E: Preparation of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000037
Figure PCTKR2023007097-appb-img-000037
터트-부틸 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (1.08 g, 2.74 mmol)를 제조예 1의 단계 F와 같은 방법을 이용하여 표제 화합물 (1,000 mg)을 수득하였다.Tert-Butyl 4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 -Carboxylate (1.08 g, 2.74 mmol) was prepared using the same method as Step F of Preparation Example 1 to obtain the title compound (1,000 mg).
1H-NMR (400 MHz, METHANOL-D4) δ 8.23 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 5.72 (t, J = 11.7 Hz, 1H), 3.59 (s, 4H), 3.54 (d, J = 12.3 Hz, 2H), 3.22-3.02 (m, 3H), 1.97 (d, J = 15.6 Hz, 2H)1H-NMR (400 MHz, METHANOL-D4) δ 8.23 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 5.72 (t, J = 11.7 Hz, 1H), 3.59 ( s, 4H), 3.54 (d, J = 12.3 Hz, 2H), 3.22-3.02 (m, 3H), 1.97 (d, J = 15.6 Hz, 2H)
LC/MS: 295 (M+H)LC/MS: 295 (M+H)
제조예 5: 7-클로로-4-(3,3-다이메틸피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 5: 7-Chloro-4-(3,3-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3 -Manufacture of dione
Figure PCTKR2023007097-appb-img-000038
Figure PCTKR2023007097-appb-img-000038
단계 A: 터트-부틸 4-((5-클로로-3-나이트로피리딘-2-일)아미노)-3,3-다이메틸피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((5-chloro-3-nitropyridin-2-yl)amino)-3,3-dimethylpiperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000039
Figure PCTKR2023007097-appb-img-000039
터트-부틸 4-아미도-3,3-다이메틸피페리딘-1-카르복실레이트 (0.951 g, 4.16 mmol)와 5-클로로-2-플루오로-3-나이트로피리딘 (0.700 g, 3.97 mmol)을 이용하여 제조예 1의 단계 A와 같은 방법으로 표제 화합물 (1.36 g)을 수득하였다.Tert-butyl 4-amido-3,3-dimethylpiperidine-1-carboxylate (0.951 g, 4.16 mmol) and 5-chloro-2-fluoro-3-nitropyridine (0.700 g, 3.97 mmol) The title compound (1.36 g) was obtained in the same manner as Step A of Preparation Example 1 using mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.44 (d, J = 2.5 Hz, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.28 (d, J = 8.5 Hz, 1H), 4.36~4.31 (m, 1H), 4.19~4.06 (m, 1H), 3.88~3.76 (m, 1H), 2.95 (br s, 1H), 2.78~2.74 (m, 1H), 1.84 (br s, 1H), 1.68-1.61 (m, 1H), 1.50 (s, 9H), 1.04 (s, 3H), 0.96 (s, 3H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.44 (d, J = 2.5 Hz, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.28 (d, J = 8.5 Hz, 1H), 4.36~ 4.31 (m, 1H), 4.19~4.06 (m, 1H), 3.88~3.76 (m, 1H), 2.95 (br s, 1H), 2.78~2.74 (m, 1H), 1.84 (br s, 1H), 1.68-1.61 (m, 1H), 1.50 (s, 9H), 1.04 (s, 3H), 0.96 (s, 3H)
LC/MS: 407 (M+Na)LC/MS: 407 (M+Na)
단계 B: 터트-부틸 4-(N-(5-클로로-3-나이트로피리딘-2-일)-2-에톡시-2-옥소아세트아미도)-3,3-다이메틸피페리딘-1-카르복실레이트의 제조Step B: Tert-Butyl 4-(N-(5-chloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)-3,3-dimethylpiperidine- Preparation of 1-carboxylate
Figure PCTKR2023007097-appb-img-000040
Figure PCTKR2023007097-appb-img-000040
터트-부틸 4-((5-클로로-3-나이트로피리딘-2-일)아미노)-3,3-다이메틸피페리딘-1-카르복실레이트 (1.01 g, 2.62 mmol)를 이용하여 제조예 3의 단계 C와 같은 방법으로 표제 화합물 (0.120 g)을 수득하였다.Prepared using tert-butyl 4-((5-chloro-3-nitropyridin-2-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (1.01 g, 2.62 mmol) The title compound (0.120 g) was obtained in the same manner as Step C of Example 3.
LC/MS: 507 (M+Na)LC/MS: 507 (M+Na)
단계 C: 터트-부틸 4-(7-클로로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-3,3-다이메틸피페리딘-1-카르복실레이트의 제조Step C: Tert-Butyl 4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-3,3-di Preparation of methylpiperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000041
Figure PCTKR2023007097-appb-img-000041
터트-부틸 4-(N-(5-클로로-3-나이트로피리딘-2-일)-2-에톡시-2-옥소아세트아미도)-3,3-다이메틸피페리딘-1-카르복실레이트 (0.23 g, 0.474 mmol)를 이용하여 제조예 3의 단계 D와 같은 방법으로 표제 화합물 (0.161 g)을 수득하였고 정제하지 않고 다음 반응에 바로 사용하였다.Tert-Butyl 4-(N-(5-chloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)-3,3-dimethylpiperidine-1-car The title compound (0.161 g) was obtained in the same manner as Step D of Preparation Example 3 using boxylate (0.23 g, 0.474 mmol), and was used directly in the next reaction without purification.
LC/MS: 431 (M+Na)LC/MS: 431 (M+Na)
단계 D: 터트-부틸 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-3,3-다이메틸피페리딘-1-카르복실레이트의 제조Step D: Tert-Butyl 4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-3 , Preparation of 3-dimethylpiperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000042
Figure PCTKR2023007097-appb-img-000042
터트-부틸 4-(7-클로로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-3,3-다이메틸피페리딘-1-카르복실레이트 (0.161 g, 0.394 mmol)를 제조예 1의 단계 E와 같은 방법을 이용하여 얻어진 잔류물을 MPLC로 정제하여 표제 화합물 (0.100 g)을 수득하였다.Tert-butyl 4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-3,3-dimethylpiperi Dean-1-carboxylate (0.161 g, 0.394 mmol) was obtained using the same method as Step E of Preparation Example 1, and the residue was purified by MPLC to obtain the title compound (0.100 g).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 7.5, 2.0 Hz, 1H), 5.68~5.32 (2 dd, 1H), 4.42~4.29 (m, 1H), 3.96~3.81 (m, 1H), 3.64 (s, 3H), 3.49~3.37 (m, 1H), 2.84~2.74 (m, 2H), 1.58~1.52 (m, 1H), 1.50 (s, 9H), 1.12~1.05 (2 s, 3H), 0.94~0.83 (2 s, 3H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 7.5, 2.0 Hz, 1H), 5.68~5.32 (2 dd, 1H), 4.42~ 4.29 (m, 1H), 3.96~3.81 (m, 1H), 3.64 (s, 3H), 3.49~3.37 (m, 1H), 2.84~2.74 (m, 2H), 1.58~1.52 (m, 1H), 1.50 (s, 9H), 1.12~1.05 (2 s, 3H), 0.94~0.83 (2 s, 3H)
LC/MS: 445 (M+Na)LC/MS: 445 (M+Na)
단계 E: 7-클로로-4-(3,3-다이메틸피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step E: 7-Chloro-4-(3,3-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3- Manufacturing of dione
Figure PCTKR2023007097-appb-img-000043
Figure PCTKR2023007097-appb-img-000043
터트-부틸 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-3,3-다이메틸피페리딘-1-카르복실레이트 (0.100 g, 0.236 mmol)를 제조예 1의 단계 F와 같은 방법을 이용하여 표제 화합물 (0.094 g)을 수득하였고 정제하지 않고 다음 반응에 바로 사용하였다.Tert-Butyl 4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-3,3- The title compound (0.094 g) was obtained from dimethylpiperidine-1-carboxylate (0.100 g, 0.236 mmol) using the same method as Step F of Preparation Example 1, and was used directly in the next reaction without purification.
LC/MS: 323 (M+H)LC/MS: 323 (M+H)
제조예 6: 4-(8-아자바이사이클로[3.2.1]옥탄-3-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 6: 4-(8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,Manufacture of 3-dione
Figure PCTKR2023007097-appb-img-000044
Figure PCTKR2023007097-appb-img-000044
단계 A: 터트-부틸 (1R,3s,5S)-3-((5-클로로-3-나이트로피리딘-2-일)아미노)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트의 제조Step A: tert-butyl (1R,3s,5S)-3-((5-chloro-3-nitropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-car Preparation of boxylate
Figure PCTKR2023007097-appb-img-000045
Figure PCTKR2023007097-appb-img-000045
5-클로로-2-플루오로-3-나이트로피리딘 (5.00 g, 28.3 mmol)과 터트-부틸 (1R,3s,5S)-3-아미노-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트 (6.41 g, 28.30 mmol)를 제조예 1의 단계 A와 같은 방법을 이용하여 표제 화합물 (10.71 g)을 수득하였다. 5-Chloro-2-fluoro-3-nitropyridine (5.00 g, 28.3 mmol) and tert-butyl (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8 -Carboxylate (6.41 g, 28.30 mmol) was prepared using the same method as Step A of Preparation Example 1 to obtain the title compound (10.71 g).
1H-NMR (500 MHz, DMSO-D6) δ 8.67 (d, J = 6.7 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H), 4.44 (q, J = 6.4 Hz, 1H), 4.13 (s, 2H), 2.15 (d, J = 12.2 Hz, 2H), 1.98 (s, 4H), 1.82 (d, J = 13.7 Hz, 2H), 1.43 (s, 9H)1H-NMR (500 MHz, DMSO-D6) δ 8.67 (d, J = 6.7 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H), 4.44 ( q, J = 6.4 Hz, 1H), 4.13 (s, 2H), 2.15 (d, J = 12.2 Hz, 2H), 1.98 (s, 4H), 1.82 (d, J = 13.7 Hz, 2H), 1.43 ( s, 9H)
LC/MS: 405 (M+Na)LC/MS: 405 (M+Na)
단계 B: 터트-부틸 (1R,3s,5S)-3-(N-(5-클로로-3-나이트로피리딘-2-일)-2-에톡시-2-옥소아세트아미도)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트의 제조Step B: Tert-Butyl (1R,3s,5S)-3-(N-(5-chloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)-8- Preparation of azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTKR2023007097-appb-img-000046
Figure PCTKR2023007097-appb-img-000046
터트-부틸 (1R,3s,5S)-3-((5-클로로-3-나이트로피리딘-2-일)아미노)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트 (3.20 g, 8.36 mmol)를 제조예 3의 단계 C와 같은 방법을 이용하여 표제 화합물 (1.17 g)을 수득하였다.tert-Butyl (1R,3s,5S)-3-((5-chloro-3-nitropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate ( The title compound (1.17 g) was obtained using the same method as Step C of Preparation Example 3 (3.20 g, 8.36 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.68 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 4.29 (d, J = 29.6 Hz, 2H), 4.16-4.12 (m, 2H), 3.94 (t, J = 8.5 Hz, 1H), 2.56 (d, J = 27.2 Hz, 1H), 1.98 (s, 2H), 1.72-1.65 (m, 3H), 1.52-1.49 (m, 1H), 1.46 (s, 9H), 1.33-1.24 (m, 4H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.68 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 4.29 (d, J = 29.6 Hz, 2H), 4.16-4.12 (m, 2H) ), 3.94 (t, J = 8.5 Hz, 1H), 2.56 (d, J = 27.2 Hz, 1H), 1.98 (s, 2H), 1.72-1.65 (m, 3H), 1.52-1.49 (m, 1H) , 1.46 (s, 9H), 1.33-1.24 (m, 4H)
LC/MS: 483 (M+H), 505 (M+Na)LC/MS: 483 (M+H), 505 (M+Na)
단계 C: 터트-부틸 (1R,3s,5S)-3-(7-클로로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트의 제조Step C: tert-butyl (1R,3s,5S)-3-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)- 1) Preparation of -8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTKR2023007097-appb-img-000047
Figure PCTKR2023007097-appb-img-000047
터트-부틸 (1R,3s,5S)-3-(N-(5-클로로-3-나이트로피리딘-2-일)-2-에톡시-2-옥소아세트아미도)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트 (1.17 g, 2.42 mmol)를 제조예 3의 단계 D와 같은 방법을 이용하여 표제 화합물 (0.77 g)을 수득하였다.tert-butyl (1R,3s,5S)-3-(N-(5-chloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)-8-azabicyclo [3.2.1] Octane-8-carboxylate (1.17 g, 2.42 mmol) was prepared using the same method as Step D of Preparation Example 3 to obtain the title compound (0.77 g).
1H-NMR (500 MHz, DMSO-D6) δ 12.14 (br s, 1H), 8.14 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 5.27 (q, J = 9.6 Hz, 1H), 4.22 (d, J = 34.2 Hz, 2H), 2.26-2.18 (m, 4H), 1.95 (d, J = 39.7 Hz, 2H), 1.85 (s, 2H), 1.47 (s, 9H)1H-NMR (500 MHz, DMSO-D6) δ 12.14 (br s, 1H), 8.14 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 5.27 (q, J = 9.6 Hz, 1H), 4.22 (d, J = 34.2 Hz, 2H), 2.26-2.18 (m, 4H), 1.95 (d, J = 39.7 Hz, 2H), 1.85 (s, 2H), 1.47 (s, 9H)
LC/MS: 407 (M+H)LC/MS: 407 (M+H)
단계 D: 터트-부틸 (1R,3s,5S)-3-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트의 제조Step D: tert-butyl (1R,3s,5S)-3-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4 Preparation of (1H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTKR2023007097-appb-img-000048
Figure PCTKR2023007097-appb-img-000048
터트-부틸 (1R,3s,5S)-3-(7-클로로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-8-아자바이사이클로[3.2.1]옥탄e-8-카르복실레이트 (0.72 g, 1.78 mmol)를 제조예 1의 단계 E와 같은 방법을 이용하여 표제 화합물 (0.75 g)을 수득 하였다.tert-butyl (1R,3s,5S)-3-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)- 8-azabicyclo[3.2.1]octane e-8-carboxylate (0.72 g, 1.78 mmol) was prepared using the same method as Step E of Preparation Example 1 to obtain the title compound (0.75 g).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.17 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 5.59-5.51 (m, 1H), 4.36 (d, J = 58.0 Hz, 1H), 3.64 (s, 3H), 2.37 (m, 3H), 2.27-2.19 (m, 2H), 2.12-1.98 (m, 4H), 1.56 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.17 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 5.59-5.51 (m, 1H), 4.36 (d, J = 58.0 Hz, 1H), 3.64 (s, 3H), 2.37 (m, 3H), 2.27-2.19 (m, 2H), 2.12-1.98 (m, 4H), 1.56 (s, 9H)
LC/MS: 443 (M+Na)LC/MS: 443 (M+Na)
단계 E: 4-(8-아자바이사이클로[3.2.1]옥탄-3-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step E: 4-(8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2, Preparation of 3-dione
Figure PCTKR2023007097-appb-img-000049
Figure PCTKR2023007097-appb-img-000049
터트-부틸 (1R,3s,5S)-3-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트 (590 mg, 1.40 mmol)를 제조예 1의 단계 F와 같은 방법을 이용하여 표제 화합물 (440 mg)을 수득하였다.Tert-Butyl (1R,3s,5S)-3-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H) -I)-8-azabicyclo[3.2.1]octane-8-carboxylate (590 mg, 1.40 mmol) was prepared using the same method as Step F of Preparation Example 1 to obtain the title compound (440 mg). .
LC/MS: 321 (M+H)LC/MS: 321 (M+H)
제조예 7: 6-메톡시-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 7: Preparation of 6-methoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000050
Figure PCTKR2023007097-appb-img-000050
단계 A: 터트-부틸 4-((6-메톡시-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((6-methoxy-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000051
Figure PCTKR2023007097-appb-img-000051
2-클로로-6-메톡시-3-나이트로피리딘 (1.00 g, 5.30 mmol)을 이용하여 제조예 1의 단계 A와 같은 방법으로 표제 화합물 (1.80 g)을 합성하였다.The title compound (1.80 g) was synthesized in the same manner as Step A of Preparation Example 1 using 2-chloro-6-methoxy-3-nitropyridine (1.00 g, 5.30 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.66 (d, J = 7.0 Hz, 1H), 8.33 (d, J = 9.2 Hz, 1H), 6.09 (d, J = 9.2 Hz, 1H), 4.33-4.26 (m, 1H), 4.07 (br s, 2H), 3.97 (s, 3H), 3.04 (t, J = 11.3 Hz, 2H), 2.09 (d, J = 10.1 Hz, 2H), 1.62-1.57 (m, 2H), 1.50 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.66 (d, J = 7.0 Hz, 1H), 8.33 (d, J = 9.2 Hz, 1H), 6.09 (d, J = 9.2 Hz, 1H), 4.33- 4.26 (m, 1H), 4.07 (br s, 2H), 3.97 (s, 3H), 3.04 (t, J = 11.3 Hz, 2H), 2.09 (d, J = 10.1 Hz, 2H), 1.62-1.57 ( m, 2H), 1.50 (s, 9H)
LC/MS: 375 (M+Na)LC/MS: 375 (M+Na)
단계 B: 터트-부틸 4-((3-아미노-6-메톡시피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((3-amino-6-methoxypyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000052
Figure PCTKR2023007097-appb-img-000052
터트-부틸 4-((6-메톡시-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (1.80 g, 5.11 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (1.65 g)을 수득하였고, 정제하지 않고 다음 반응에 바로 사용하였다.Step B of Preparation Example 1 using tert-butyl 4-((6-methoxy-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.80 g, 5.11 mmol) The title compound (1.65 g) was obtained in a similar manner and used directly in the next reaction without purification.
LC/MS: 345 (M+Na)LC/MS: 345 (M+Na)
단계 C: 터트-부틸 4-(6-메톡시-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step C: Tert-Butyl 4-(6-methoxy-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 -Manufacture of carboxylates
Figure PCTKR2023007097-appb-img-000053
Figure PCTKR2023007097-appb-img-000053
터트-부틸 4-((3-아미노-6-메톡시피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (1.21 g, 3.72 mmol)를 이용하여 DCE (50 mL)에 녹인 후 에틸 2-클로로-2-옥소아세테이트 (0.625 mL, 5.60 mmol)와 DIPEA (1.95 mL, 2.57 mmol)를 넣어준 후 상온에서 12시간 동안 교반한 후 70℃에서 2 일 동안 교반하였다. 반응물에 물을 넣어 반응을 종결시킨 후 DCM으로 3번 추출하였다. 유기층을 무수 마그네슘설페이트로 건조 후 감압 농축시켜 표제 화합물 (750 mg)을 수득하였고, 다음 반응에 바로 사용하였다.Tert-butyl 4-((3-amino-6-methoxypyridin-2-yl)amino)piperidine-1-carboxylate (1.21 g, 3.72 mmol) was dissolved in DCE (50 mL). Ethyl 2-chloro-2-oxoacetate (0.625 mL, 5.60 mmol) and DIPEA (1.95 mL, 2.57 mmol) were added and stirred at room temperature for 12 hours and then at 70°C for 2 days. The reaction was terminated by adding water to the reactant, and then extracted three times with DCM. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (750 mg), which was immediately used in the next reaction.
LC/MS: 399 (M+Na)LC/MS: 399 (M+Na)
단계 D: 터트-부틸 4-(6-메톡시-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step D: tert-butyl 4-(6-methoxy-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p Preparation of peridine-1-carboxylate
Figure PCTKR2023007097-appb-img-000054
Figure PCTKR2023007097-appb-img-000054
터트-부틸 4-(6-메톡시-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (750 mg, 3.72 mmol)를 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (600 mg)을 합성하였다.Tert-Butyl 4-(6-methoxy-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxyl The title compound (600 mg) was synthesized in a manner similar to Step E of Preparation Example 1 using 750 mg, 3.72 mmol.
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.50 (d, J = 8.9 Hz, 1H), 6.68 (d, J = 8.9 Hz, 1H), 5.49-5.44 (m, 1H), 4.33 (d, J = 61.0 Hz, 2H), 3.94 (s, 3H), 3.63 (s, 3H), 2.99-2.82 (m, 4H), 1.71 (d, J = 10.1 Hz, 2H), 1.49 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.50 (d, J = 8.9 Hz, 1H), 6.68 (d, J = 8.9 Hz, 1H), 5.49-5.44 (m, 1H), 4.33 (d, J = 61.0 Hz, 2H), 3.94 (s, 3H), 3.63 (s, 3H), 2.99-2.82 (m, 4H), 1.71 (d, J = 10.1 Hz, 2H), 1.49 (s, 9H)
LC/MS: 335 (M+Na-tBu), 413 (M+Na)LC/MS: 335 (M+Na-tBu), 413 (M+Na)
단계 E: 6-메톡시-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step E: Preparation of 6-methoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000055
Figure PCTKR2023007097-appb-img-000055
터트-부틸 4-(6-메톡시-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (600 mg, 1.54 mmol)를 이용하여 제조예 1의 단계 F와 유사한 방법으로 표제 화합물 (450 mg)을 수득하였다.Tert-Butyl 4-(6-methoxy-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- The title compound (450 mg) was obtained in a manner similar to Step F of Preparation Example 1 using 1-carboxylate (600 mg, 1.54 mmol).
LC/MS: 291 (M+H)LC/MS: 291 (M+H)
제조예 8: 1,8-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 8: Preparation of 1,8-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000056
Figure PCTKR2023007097-appb-img-000056
단계 A: 터트-부틸 4-((4-메틸-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((4-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000057
Figure PCTKR2023007097-appb-img-000057
2-플루오로-4-메틸-3-나이트로피리딘 (1.56 g, 9.99 mmol)을 이용하여 제조예 1의 단계 A와 같은 방법으로 표제 화합물 (3.32 g)을 합성하였다.The title compound (3.32 g) was synthesized in the same manner as Step A of Preparation Example 1 using 2-fluoro-4-methyl-3-nitropyridine (1.56 g, 9.99 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.14 (d, J = 5.0 Hz, 1H), 7.45 (d, J = 7.0 Hz, 1H), 6.50 (d, J = 5.0 Hz, 1H), 4.31~4.28 (m, 1H), 4.06 (br s, 2H), 3.04~2.99 (m, 2H), 2.56 (s, 3H), 2.08~2.06 (m, 2H), 1.52 (s, 9H), 1.51~1.44 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.14 (d, J = 5.0 Hz, 1H), 7.45 (d, J = 7.0 Hz, 1H), 6.50 (d, J = 5.0 Hz, 1H), 4.31~ 4.28 (m, 1H), 4.06 (br s, 2H), 3.04~2.99 (m, 2H), 2.56 (s, 3H), 2.08~2.06 (m, 2H), 1.52 (s, 9H), 1.51~1.44 (m, 2H)
LC/MS: 337 (M+H)LC/MS: 337 (M+H)
단계 B: 터트-부틸 4-((3-아미노-4-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((3-amino-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000058
Figure PCTKR2023007097-appb-img-000058
터트-부틸 4-((4-메틸-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (1.5 g, 4.46 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (1.35 g)을 수득하였고, 정제하지 않고 다음 반응에 바로 사용하였다.Similar to step B of Preparation Example 1 using tert-butyl 4-((4-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.5 g, 4.46 mmol) The title compound (1.35 g) was obtained by this method, and was used directly in the next reaction without purification.
LC/MS: 307 (M+H)LC/MS: 307 (M+H)
단계 C: 터트-부틸 4-((3-(2-에톡시-2-옥소아세트아미도)-4-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step C: Preparation of tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000059
Figure PCTKR2023007097-appb-img-000059
터트-부틸 4-((3-아미노-4-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (1.35 g, 4.41 mmol)를 이용하여 제조예 1의 단계 C와 유사한 방법으로 표제 화합물 (1.67 g)을 수득하였다.Similar method to Step C of Preparation Example 1 using tert-butyl 4-((3-amino-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate (1.35 g, 4.41 mmol) The title compound (1.67 g) was obtained.
LC/MS: 407 (M+H)LC/MS: 407 (M+H)
단계 D: 터트-부틸 4-(8-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step D: Tert-Butyl 4-(8-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates
Figure PCTKR2023007097-appb-img-000060
Figure PCTKR2023007097-appb-img-000060
터트-부틸 4-((3-(2-에톡시-2-옥소아세트아미도)-4-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (930 mg, 2.29 mmol)을 제조예 1의 단계 D와 유사한 방법으로 표제 화합물 (34 mg)을 수득하였다.Tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate (930 mg, 2.29 mmol) The title compound (34 mg) was obtained in a similar manner to Step D of Preparation Example 1.
LC/MS: 305 (M+H-t-Bu)LC/MS: 305 (M+H-t-Bu)
단계 E: 터트-부틸 4-(1,8-다이메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step E: Tert-Butyl 4-(1,8-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -Preparation of 1-carboxylate
Figure PCTKR2023007097-appb-img-000061
Figure PCTKR2023007097-appb-img-000061
터트-부틸 4-(8-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (34 mg, 0.094 mmol)를 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (35 mg)을 합성하였다.Tert-Butyl 4-(8-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate The title compound (35 mg) was synthesized in a similar manner to Step E of Preparation Example 1 using (34 mg, 0.094 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.24 (d, J = 5.0 Hz, 1H), 7.12 (d, J = 5.0 Hz, 1H), 5.74 (br s, 1H), 4.31~4.22 (m, 2H), 4.13 (s, 3H), 2.96~2.94 (m, 4H), 2.61 (s, 3H), 1.65~1.62 (m, 2H), 1.52 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.24 (d, J = 5.0 Hz, 1H), 7.12 (d, J = 5.0 Hz, 1H), 5.74 (br s, 1H), 4.31~4.22 (m, 2H), 4.13 (s, 3H), 2.96~2.94 (m, 4H), 2.61 (s, 3H), 1.65~1.62 (m, 2H), 1.52 (s, 9H)
LC/MS: 397 (M+Na)LC/MS: 397 (M+Na)
단계 F: 1,8-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step F: Preparation of 1,8-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000062
Figure PCTKR2023007097-appb-img-000062
터트-부틸 4-(1,8-다이메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (35 mg, 0.093 mmol)를 이용하여 제조예 1의 단계 F와 유사한 방법으로 표제 화합물 (29 mg)을 합성하였다.Tert-Butyl 4-(1,8-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- The title compound (29 mg) was synthesized in a manner similar to Step F of Preparation Example 1 using carboxylate (35 mg, 0.093 mmol).
LC/MS: 275 (M+H)LC/MS: 275 (M+H)
제조예 9: 6-아이소프로폭시-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 9: 6-isopropoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione manufacturing
Figure PCTKR2023007097-appb-img-000063
Figure PCTKR2023007097-appb-img-000063
단계 A: 터트-부틸 4-((6-아이소프로폭시-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((6-isopropoxy-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000064
Figure PCTKR2023007097-appb-img-000064
2,6-다이플루오로-3-나이트로피리딘 (2 g, 12.49 mmol)과 터트-부틸 4-아미노피페리딘-1-카르복실레이트 (2.502 g, 12.49 mmol)를 IPA에 녹이고, DIPEA (4.36 ml, 24.99 mmol)를 넣어준 후 70℃에서 4 시간 동안 교반하였다. 반응물을 상온으로 식히고 감압농축 후 MPLC를 이용하여 표제 화합물 (3.78 g)을 수득하였다.2,6-Difluoro-3-nitropyridine (2 g, 12.49 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (2.502 g, 12.49 mmol) were dissolved in IPA, and DIPEA ( 4.36 ml, 24.99 mmol) was added and stirred at 70°C for 4 hours. The reaction product was cooled to room temperature and concentrated under reduced pressure to obtain the title compound (3.78 g) using MPLC.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.28 (d, J = 9.1 Hz, 1H), 6.00 (d, J = 9.1 Hz, 1H), 5.25 (t, J = 6.2 Hz, 1H), 3.85-4.45 (4H), 3.01 (s, 2H), 2.03 (q, J = 4.1 Hz, 2H), 1.46 (s, 9H), 1.35 (d, 6H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.28 (d, J = 9.1 Hz, 1H), 6.00 (d, J = 9.1 Hz, 1H), 5.25 (t, J = 6.2 Hz, 1H), 3.85- 4.45 (4H), 3.01 (s, 2H), 2.03 (q, J = 4.1 Hz, 2H), 1.46 (s, 9H), 1.35 (d, 6H)
LC/MS: 381 (M+H)LC/MS: 381 (M+H)
단계 B: 터트-부틸 4-((3-아미노-6-아이소프로폭시피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((3-amino-6-isopropoxypyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000065
Figure PCTKR2023007097-appb-img-000065
터트-부틸 4-((6-아이소프로폭시-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (3.76 g, 9.87 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (1.07 g)을 합성하였다.Step B of Preparation Example 1 using tert-butyl 4-((6-isopropoxy-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (3.76 g, 9.87 mmol) The title compound (1.07 g) was synthesized in a similar manner.
1H-NMR (400 MHz, CHLOROFORM-D) δ 6.87 (d, J = 7.8 Hz, 1H), 5.87 (d, J = 8.2 Hz, 1H), 5.07-5.00 (m, 1H), 4.29 (s, 1H), 4.00 (d, J = 10.5 Hz, 3H), 2.94 (t, J = 11.4 Hz, 2H), 2.74 (s, 1H), 2.06 (q, J = 4.1 Hz, 2H), 1.46 (s, 9H), 1.38 (d, J = 9.1 Hz, 2H), 1.34-1.30 (m, 6H)1H-NMR (400 MHz, CHLOROFORM-D) δ 6.87 (d, J = 7.8 Hz, 1H), 5.87 (d, J = 8.2 Hz, 1H), 5.07-5.00 (m, 1H), 4.29 (s, 1H) ), 4.00 (d, J = 10.5 Hz, 3H), 2.94 (t, J = 11.4 Hz, 2H), 2.74 (s, 1H), 2.06 (q, J = 4.1 Hz, 2H), 1.46 (s, 9H) ), 1.38 (d, J = 9.1 Hz, 2H), 1.34-1.30 (m, 6H)
LC/MS: 351 (M+H)LC/MS: 351 (M+H)
단계 C: 터트-부틸 4-(6-아이소프로폭시-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step C: Tert-Butyl 4-(6-isopropoxy-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- Preparation of 1-carboxylate
Figure PCTKR2023007097-appb-img-000066
Figure PCTKR2023007097-appb-img-000066
터트-부틸 4-((3-아미노-6-아이소프로폭시피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (1.07 g, 3.05 mmol)를 이용하여 제조예 7의 단계 C와 유사한 방법으로 표제 화합물 (1.2 g)을 합성하였다.Step C of Preparation Example 7 using tert-butyl 4-((3-amino-6-isopropoxypyridin-2-yl)amino)piperidine-1-carboxylate (1.07 g, 3.05 mmol) The title compound (1.2 g) was synthesized in a similar manner.
LC/MS: 405 (M+H)LC/MS: 405 (M+H)
단계 D: 터트-부틸 4-(6-아이소프로폭시-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step D: Tert-Butyl 4-(6-isopropoxy-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl) Preparation of piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000067
Figure PCTKR2023007097-appb-img-000067
터트-부틸 4-(6-아이소프로폭시-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (1.256 g, 3.11 mmol)를 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (870 mg)을 합성하였다.Tert-Butyl 4-(6-isopropoxy-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-car The title compound (870 mg) was synthesized in a manner similar to Step E of Preparation Example 1 using boxylate (1.256 g, 3.11 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.48 (d, J = 8.9 Hz, 1H), 6.64-6.62 (m, 1H), 5.43 (s, 1H), 5.17-5.13 (m, 1H), 4.29 (d, J = 29.3 Hz, 2H), 3.62 (s, 3H), 2.89 (d, J = 11.0 Hz, 4H), 1.67 (d, J = 20.8 Hz, 2H), 1.51 (s, 9H), 1.40 (d, J = 6.1 Hz, 6H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.48 (d, J = 8.9 Hz, 1H), 6.64-6.62 (m, 1H), 5.43 (s, 1H), 5.17-5.13 (m, 1H), 4.29 (d, J = 29.3 Hz, 2H), 3.62 (s, 3H), 2.89 (d, J = 11.0 Hz, 4H), 1.67 (d, J = 20.8 Hz, 2H), 1.51 (s, 9H), 1.40 (d, J = 6.1 Hz, 6H)
LC/MS: 419 (M+H)LC/MS: 419 (M+H)
단계 E: 6-아이소프로폭시-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step E: Preparation of 6-isopropoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000068
Figure PCTKR2023007097-appb-img-000068
터트-부틸 4-(6-아이소프로폭시-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (870 mg, 2.079 mmol)를 이용하여 제조예 1의 단계 F와 유사한 방법으로 표제 화합물 (668 mg)을 합성하였다.Tert-Butyl 4-(6-isopropoxy-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine The title compound (668 mg) was synthesized in a manner similar to Step F of Preparation Example 1 using -1-carboxylate (870 mg, 2.079 mmol).
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.44 (d, J = 8.7 Hz, 1H), 6.59 (dd, J = 8.7, 0.9 Hz, 1H), 5.41 (d, J = 7.8 Hz, 1H), 5.18 (q, J = 6.1 Hz, 1H), 3.69 (d, J = 0.9 Hz, 2H), 3.59 (s, 3H), 3.27 (d, J = 10.1 Hz, 2H), 2.80-2.70 (m, 4H), 1.67 (d, J = 9.6 Hz, 2H), 1.40-1.39 (m, 6H)1H-NMR (400 MHz, CHLOROFORM-D) δ 7.44 (d, J = 8.7 Hz, 1H), 6.59 (dd, J = 8.7, 0.9 Hz, 1H), 5.41 (d, J = 7.8 Hz, 1H), 5.18 (q, J = 6.1 Hz, 1H), 3.69 (d, J = 0.9 Hz, 2H), 3.59 (s, 3H), 3.27 (d, J = 10.1 Hz, 2H), 2.80-2.70 (m, 4H) ), 1.67 (d, J = 9.6 Hz, 2H), 1.40-1.39 (m, 6H)
LC/MS: 319 (M+H)LC/MS: 319 (M+H)
제조예 10: 7-플루오로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 10: Preparation of 7-fluoro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000069
Figure PCTKR2023007097-appb-img-000069
단계 A: 터트-부틸 4-((5-플루오로-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((5-fluoro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000070
Figure PCTKR2023007097-appb-img-000070
2,6-다이플루오로-3-나이트로피리딘 (2 g, 12.49 mmol)과 터트-부틸 4-아미노피페리딘-1-카르복실레이트 (2.502 g, 12.49 mmol)를 이용하여 제조예 1의 단계 A와 유사한 방법으로 표제 화합물 (4.2 g)을 합성하였다.Preparation Example 1 using 2,6-difluoro-3-nitropyridine (2 g, 12.49 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (2.502 g, 12.49 mmol) The title compound (4.2 g) was synthesized in a manner similar to Step A.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.35 (d, J = 3.2 Hz, 1H), 8.18 (dd, J = 8.0, 3.0 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 4.31-4.27 (m, 1H), 4.05 (d, J = 11.0 Hz, 2H), 2.98 (t, J = 11.9 Hz, 2H), 2.04 (d, J = 10.5 Hz, 2H), 1.52-1.49 (m, 2H), 1.46 (s, 9H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.35 (d, J = 3.2 Hz, 1H), 8.18 (dd, J = 8.0, 3.0 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 4.31-4.27 (m, 1H), 4.05 (d, J = 11.0 Hz, 2H), 2.98 (t, J = 11.9 Hz, 2H), 2.04 (d, J = 10.5 Hz, 2H), 1.52-1.49 (m , 2H), 1.46 (s, 9H)
LC/MS: 341 (M+H)LC/MS: 341 (M+H)
단계 B: 터트-부틸 4-((3-아미노-5-플루오로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((3-amino-5-fluoropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000071
Figure PCTKR2023007097-appb-img-000071
터트-부틸 4-((5-플루오로-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (4.2 g, 12.34 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (2.67 g)을 합성하였다.Step B of Preparation Example 1 using tert-butyl 4-((5-fluoro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (4.2 g, 12.34 mmol) The title compound (2.67 g) was synthesized in a similar manner.
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.56 (d, J = 2.7 Hz, 1H), 6.67 (dd, J = 8.9, 2.5 Hz, 1H), 4.00 (d, J = 11.9 Hz, 2H), 3.70 (s, 1H), 3.32 (s, 2H), 2.94 (t, J = 12.1 Hz, 2H), 2.08-2.03 (m, 2H), 1.45 (s, 9H), 1.35-1.29 (m, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 7.56 (d, J = 2.7 Hz, 1H), 6.67 (dd, J = 8.9, 2.5 Hz, 1H), 4.00 (d, J = 11.9 Hz, 2H), 3.70 (s, 1H), 3.32 (s, 2H), 2.94 (t, J = 12.1 Hz, 2H), 2.08-2.03 (m, 2H), 1.45 (s, 9H), 1.35-1.29 (m, 2H)
LC/MS: 311 (M+H)LC/MS: 311 (M+H)
단계 C: 터트-부틸 4-(7-플루오로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step C: Tert-Butyl 4-(7-fluoro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 -Manufacture of carboxylates
Figure PCTKR2023007097-appb-img-000072
Figure PCTKR2023007097-appb-img-000072
터트-부틸 4-((3-아미노-5-플루오로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (2.67 g, 8.60 mmol)를 이용하여 제조예 7의 단계 C와 유사한 방법으로 표제 화합물 (3.0 g)을 합성하였다.Similar to Step C of Preparation Example 7 using tert-butyl 4-((3-amino-5-fluoropyridin-2-yl)amino)piperidine-1-carboxylate (2.67 g, 8.60 mmol) The title compound (3.0 g) was synthesized using this method.
LC/MS: 365 (M+H)LC/MS: 365 (M+H)
단계 D: 터트-부틸 4-(7-플루오로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step D: tert-butyl 4-(7-fluoro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p Preparation of peridine-1-carboxylate
Figure PCTKR2023007097-appb-img-000073
Figure PCTKR2023007097-appb-img-000073
터트-부틸 4-(7-플루오로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (3 g, 8.23 mmol)를 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (1.92 g)을 합성하였다.Tert-Butyl 4-(7-fluoro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxyl The title compound (1.92 g) was synthesized in a manner similar to Step E of Preparation Example 1 using nitrate (3 g, 8.23 mmol).
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.09 (d, J = 2.7 Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 5.46 (s, 1H), 4.28 (s, 2H), 3.59 (s, 3H), 2.88-2.80 (m, 4H), 1.62 (s, 2H), 1.47 (d, J = 15.1 Hz, 9H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.09 (d, J = 2.7 Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 5.46 (s, 1H), 4.28 (s, 2H), 3.59 (s, 3H), 2.88-2.80 (m, 4H), 1.62 (s, 2H), 1.47 (d, J = 15.1 Hz, 9H)
LC/MS: 379 (M+H)LC/MS: 379 (M+H)
단계 E: 7-플루오로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step E: Preparation of 7-fluoro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000074
Figure PCTKR2023007097-appb-img-000074
터트-부틸 4-(7-플루오로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (1.915 g, 5.06 mmol)를 이용하여 제조예 1의 단계 F와 유사한 방법으로 표제 화합물 (1.27 g)을 합성하였다.Tert-Butyl 4-(7-fluoro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- The title compound (1.27 g) was synthesized in a similar manner to Step F of Preparation Example 1 using 1-carboxylate (1.915 g, 5.06 mmol).
LC/MS: 279 (M+H)LC/MS: 279 (M+H)
제조예 11: 메틸 1-메틸-2,3-다이옥소-4-(피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-7-카르복시레이트의 제조Preparation Example 11: Methyl 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7 -Manufacture of carboxylates
Figure PCTKR2023007097-appb-img-000075
Figure PCTKR2023007097-appb-img-000075
단계 A: 메틸 6-((1-(터트-부톡시카르보닐)피페리딘-4-일)아미노)-5-나이트로니코티네이트의 제조Step A: Preparation of methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-5-nitronicotinate
Figure PCTKR2023007097-appb-img-000076
Figure PCTKR2023007097-appb-img-000076
메틸 6-클로로-5-니코티네이트 (10.00 g, 46.20 mmol)를 이용하여 제조예 1의 단계 A와 같은 방법으로 표제 화합물 (17.56 g, 98%)을 합성하였다.The title compound (17.56 g, 98%) was synthesized in the same manner as Step A of Preparation Example 1 using methyl 6-chloro-5-nicotinate (10.00 g, 46.20 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 9.01 (d, J = 10.1 Hz, 2H), 8.47 (d, J = 7.0 Hz, 1H), 4.47 (br s, 1H), 4.12 (br s, 2H), 3.95 (s, 3H), 3.03 (t, J = 11.1 Hz, 2H), 2.10 (d, J = 12.2 Hz, 2H), 1.61-1.51 (m, 2H), 1.50 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 9.01 (d, J = 10.1 Hz, 2H), 8.47 (d, J = 7.0 Hz, 1H), 4.47 (br s, 1H), 4.12 (br s, 2H) ), 3.95 (s, 3H), 3.03 (t, J = 11.1 Hz, 2H), 2.10 (d, J = 12.2 Hz, 2H), 1.61-1.51 (m, 2H), 1.50 (s, 9H)
LC/MS: 325 (M-tBu+2H), 403.2 (M+Na)LC/MS: 325 (M-tBu+2H), 403.2 (M+Na)
단계 B: 메틸 5-아미노-6-((1-(터트-부톡시카르보닐)피페리딘-4-일)아미노)니코티네이트의 제조Step B: Preparation of methyl 5-amino-6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)nicotinate
Figure PCTKR2023007097-appb-img-000077
Figure PCTKR2023007097-appb-img-000077
메틸 6-((1-(터트-부톡시카르보닐)피페리딘-4-일)아미노)-5-나이트로니코티네이트 (17.20 g, 45.20 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (15.84 g, 99%)을 수득하였다.Similar to step B of Preparation Example 1 using methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-5-nitronicotinate (17.20 g, 45.20 mmol) This method gave the title compound (15.84 g, 99%).
LC/MS: 351 (M+H)LC/MS: 351 (M+H)
단계 C: 메틸 4-(1-(터트-부톡시카르보닐)피페리딘-4-일)-2,3-다이옥소-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-7-카르복실레이트의 제조Step C: Methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3- b]Preparation of pyrazine-7-carboxylate
Figure PCTKR2023007097-appb-img-000078
Figure PCTKR2023007097-appb-img-000078
메틸 5-아미노-6-((1-(터트-부톡시카르보닐)피페리딘-4-일)아미노)니코티네이트 (15.84 g, 45.20 mmol)를 이용하여 제조예 7의 단계 C와 유사한 방법으로 표제 화합물 (8.50 g, 46%)을 합성하였다.Similar to Step C of Preparation Example 7 using methyl 5-amino-6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)nicotinate (15.84 g, 45.20 mmol) The title compound (8.50 g, 46%) was synthesized using this method.
LC/MS: 427 (M+Na)LC/MS: 427 (M+Na)
단계 D: 메틸 4-(1-(터트-부톡시카르보닐)피페리딘-4-일)-1-메틸-2,3-다이옥소-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-7-카르복실레이트의 제조Step D: Methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[ Preparation of 2,3-b]pyrazine-7-carboxylate
Figure PCTKR2023007097-appb-img-000079
Figure PCTKR2023007097-appb-img-000079
메틸 4-(1-(터트-부톡시카르보닐)피페리딘-4-일)-2,3-다이옥소-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-7-카르복실레이트 (8.50 g, 21.02 mmol)를 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (4.51 g, 51%)을 합성하였다.Methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine The title compound (4.51 g, 51%) was synthesized in a similar manner to Step E of Preparation Example 1 using -7-carboxylate (8.50 g, 21.02 mmol).
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.82 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 1.8 Hz, 1H), 5.55 (br s, 1H), 4.27 (br s, 2H), 3.98 (s, 3H), 3.66 (s, 3H), 2.86-2.81 (m, 4H), 1.67-1.59 (m, 2H), 1.49 (s, 9H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.82 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 1.8 Hz, 1H), 5.55 (br s, 1H), 4.27 (br s, 2H) ), 3.98 (s, 3H), 3.66 (s, 3H), 2.86-2.81 (m, 4H), 1.67-1.59 (m, 2H), 1.49 (s, 9H)
LC/MS: 431 (M+Na)LC/MS: 431 (M+Na)
단계 E: 메틸 1-메틸-2,3-다이옥소-4-(피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-7-카르복실레이트의 제조Step E: Methyl 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7- Preparation of carboxylates
Figure PCTKR2023007097-appb-img-000080
Figure PCTKR2023007097-appb-img-000080
메틸 4-(1-(터트-부톡시카르보닐)피페리딘-4-일)-1-메틸-2,3-다이옥소-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-7-카르복실레이트 (4.50 g, 10.75 mmol)를 이용하여 제조예 1의 단계 F와 유사한 방법으로 표제 화합물 (3.8 g)을 합성하였다.Methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3 -b] The title compound (3.8 g) was synthesized in a similar manner to Step F of Preparation Example 1 using pyrazine-7-carboxylate (4.50 g, 10.75 mmol).
LC/MS: 319 (M+H)LC/MS: 319 (M+H)
제조예 12: 1,7-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 12: Preparation of 1,7-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000081
Figure PCTKR2023007097-appb-img-000081
단계 A: 터트-부틸 4-((5-메틸-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복시레이트의 제조Step A: Preparation of tert-butyl 4-((5-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000082
Figure PCTKR2023007097-appb-img-000082
2-클로로-5-메틸-3-나이트로피리딘 (10 g, 57.9 mmol)을 이용하여 제조예 1의 단계 A와 유사한 방법으로 표제 화합물 (4.21 g)을 얻었다.The title compound (4.21 g) was obtained in a similar manner to Step A of Preparation Example 1 using 2-chloro-5-methyl-3-nitropyridine (10 g, 57.9 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.27 (d, J = 8.5 Hz, 2H), 8.05 (d, J = 6.4 Hz, 1H), 4.36-4.35 (m, 1H), 4.08 (br s, 2H), 3.03 (t, J = 11.4 Hz, 2H), 2.29 (s, 3H), 2.12-2.04 (m, 2H), 1.54-1.50 (m, 11H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.27 (d, J = 8.5 Hz, 2H), 8.05 (d, J = 6.4 Hz, 1H), 4.36-4.35 (m, 1H), 4.08 (br s, 2H), 3.03 (t, J = 11.4 Hz, 2H), 2.29 (s, 3H), 2.12-2.04 (m, 2H), 1.54-1.50 (m, 11H)
LC/MS: 403.2 (M+Na), 325.1 (M-tbu+2H)LC/MS: 403.2 (M+Na), 325.1 (M-tbu+2H)
단계 B: 터트-부틸 4-((3-아미노-5-메틸피리딘-2-일)아미노)피페리딘-1-카르복시레이트의 제조Step B: Preparation of tert-butyl 4-((3-amino-5-methylpyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000083
Figure PCTKR2023007097-appb-img-000083
터트-부틸 4-((5-메틸-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복시레이트 (4.21 g, 12.52 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (3.64 g)을 수득하였다.Similar method to step B of Preparation Example 1 using tert-butyl 4-((5-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (4.21 g, 12.52 mmol) The title compound (3.64 g) was obtained.
LC/MS: 307.2 (M+H)LC/MS: 307.2 (M+H)
단계 C: 터트-부틸 4-(7-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복시레이트의 제조Step C: Tert-Butyl 4-(7-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates
Figure PCTKR2023007097-appb-img-000084
Figure PCTKR2023007097-appb-img-000084
터트-부틸 4-((3-아미노-5-메틸피리딘-2-일)아미노)피페리딘-1-카르복시레이트 (3.64 g, 11.88 mmol)를 이용하여 제조예 7의 단계 C와 유사한 방법으로 표제화합물 (2.1 g)을 수득하였고 추가 정제 없이 다음 반응에 사용하였다.In a similar manner to Step C of Preparation Example 7 using tert-butyl 4-((3-amino-5-methylpyridin-2-yl)amino)piperidine-1-carboxylate (3.64 g, 11.88 mmol) The title compound (2.1 g) was obtained and used in the next reaction without further purification.
LC/MS: 361.2 (M+H)LC/MS: 361.2 (M+H)
단계 D: 터트-부틸 4-(1,7-다이메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복시레이트의 제조Step D: Tert-Butyl 4-(1,7-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -Manufacture of 1-carboxylate
Figure PCTKR2023007097-appb-img-000085
Figure PCTKR2023007097-appb-img-000085
터트-부틸 4-(7-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복시레이트 (2.1 g, 5.83 mmol)를 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (1.8 g)을 수득하였다.Tert-butyl 4-(7-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate ( The title compound (1.8 g) was obtained in a similar manner to Step E of Preparation Example 1 using 2.1 g, 5.83 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.08 (s, 1H), 7.32 (s, 1H), 5.55 (br s, 1H), 4.43-4.12 (m, 3H), 3.63 (s, 3H), 2.95-2.81 (m, 5H), 2.44 (s, 3H), 1.52 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.08 (s, 1H), 7.32 (s, 1H), 5.55 (br s, 1H), 4.43-4.12 (m, 3H), 3.63 (s, 3H), 2.95-2.81 (m, 5H), 2.44 (s, 3H), 1.52 (s, 9H)
LC/MS: 397.2 (M+Na)LC/MS: 397.2 (M+Na)
단계 E: 1,7-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step E: Preparation of 1,7-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000086
Figure PCTKR2023007097-appb-img-000086
터트-부틸 4-(1,7-다이메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복시레이트 (1.8 g, 4.81 mmol)를 이용하여 제조예 1의 단계 F와 유사한 방법으로 표제 화합물 (1.2 g)을 수득하였다.Tert-Butyl 4-(1,7-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- The title compound (1.2 g) was obtained in a similar manner to Step F of Preparation Example 1 using carboxylate (1.8 g, 4.81 mmol).
LC/MS: 275.1 (M+H)LC/MS: 275.1 (M+H)
제조예 13: 7-브로모-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 13: Preparation of 7-bromo-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000087
Figure PCTKR2023007097-appb-img-000087
단계 A: 터트-부틸 4-((5-브로모-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((5-bromo-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000088
Figure PCTKR2023007097-appb-img-000088
터트-뷰틸 4-((3-나이트로피리딘-2-일)아미노)아미도피페리딘-1-카르복실레이트(1.00 g, 3.10 mmol)를 CH3CN (20 mL)에 녹인 용액에 NBS (0.552 g, 3.10 mmol)를 가한 후 상온에서 18시간 동안 교반하였다. 반응액을 감압 농축 후 잔류물을 EtOAc로 희석하고 소듐바이카보네이트 수용액으로 세척하였다. 유기층을 무수 소듐설페이트로 건조 후 감압농축시키고 잔류물을 MPLC 정제하여 표제 화합물 (1.23 g)을 수득하였다. NBS ( 0.552 g, 3.10 mmol) was added and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with EtOAc and washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (1.23 g).
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.53 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 4.31~4.28 (m, 1H), 4.10-4.04 (m, 2H), 3.01~2.95 (m, 2H), 2.05~2.03 (m, 2H), 1.52-1.48 (2H), 1.46 (s, 9H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.53 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 4.31~ 4.28 (m, 1H), 4.10-4.04 (m, 2H), 3.01~2.95 (m, 2H), 2.05~2.03 (m, 2H), 1.52-1.48 (2H), 1.46 (s, 9H)
LC/MS: 433, 435 (M+Na)LC/MS: 433, 435 (M+Na)
단계 B: 터트-부틸 4-(N-(5-브로모-3-나이트로피리딘-2-일)-2-에톡시-2-옥소아세트아미도)피페리딘-1-카르복실레이트의 제조Step B: of tert-butyl 4-(N-(5-bromo-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate manufacturing
Figure PCTKR2023007097-appb-img-000089
Figure PCTKR2023007097-appb-img-000089
터트-부틸 4-((5-브로모-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (1.23 g, 3.07 mmol)를 이용하여 제조예 3의 단계 C와 같은 방법으로 표제 화합물 (0.880 g)을 수득하였다.Step C of Preparation Example 3 using tert-butyl 4-((5-bromo-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.23 g, 3.07 mmol) The title compound (0.880 g) was obtained in the same manner.
LC/MS: 523, 525 (M+Na)LC/MS: 523, 525 (M+Na)
단계 C: 터트-부틸 4-(7-브로모-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step C: Tert-Butyl 4-(7-bromo-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 -Manufacture of carboxylates
Figure PCTKR2023007097-appb-img-000090
Figure PCTKR2023007097-appb-img-000090
터트-부틸 4-(N-(5-브로모-3-나이트로피리딘-2-일)-2-에톡시-2-옥소아세트아미도)피페리딘-1-카르복실레이트 (0.880 g, 1.755 mmol)를 이용하여 제조예 3의 단계 D와 같은 방법으로 표제 화합물 (0.480 g)을 수득하였고 정제하지 않고 다음 반응에 바로 사용하였다.Tert-butyl 4-(N-(5-bromo-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate (0.880 g, The title compound (0.480 g) was obtained in the same manner as Step D of Preparation Example 3 using 1.755 mmol) and used directly in the next reaction without purification.
LC/MS: 447, 449 (M+Na)LC/MS: 447, 449 (M+Na)
단계 D: 터트-부틸 4-(7-브로모-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-3,3-다이메틸피페리딘-1-카르복실레이트의 제조Step D: Tert-Butyl 4-(7-bromo-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)- Preparation of 3,3-dimethylpiperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000091
Figure PCTKR2023007097-appb-img-000091
터트-부틸 4-(7-브로모-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (0.480 g, 1.129 mmol)를 제조예 1의 단계 E와 같은 방법을 이용하여 얻어진 잔류물을 MPLC로 정제하여 표제 화합물 (0.335 g)을 수득하였다.Tert-Butyl 4-(7-bromo-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxyl Rate (0.480 g, 1.129 mmol) was obtained using the same method as Step E of Preparation Example 1. The residue was purified by MPLC to obtain the title compound (0.335 g).
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.29 (d, J = 1.2 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 5.51~5.49 (m, 1H), 4.31~4.27 (m, 2H), 3.63 (s, 3H), 2.87~2.83 (m, 4H), 1.65 (br s, 2H), 1.52 (s, 9H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.29 (d, J = 1.2 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 5.51~5.49 (m, 1H), 4.31~4.27 (m , 2H), 3.63 (s, 3H), 2.87~2.83 (m, 4H), 1.65 (br s, 2H), 1.52 (s, 9H)
LC/MS: 461, 463 (M+Na)LC/MS: 461, 463 (M+Na)
단계 E: 7-브로모-4-(피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step E: Preparation of 7-bromo-4-(piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000092
Figure PCTKR2023007097-appb-img-000092
터트-부틸 4-(7-브로모-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (0.335 g, 0.763 mmol)를 제조예 1의 단계 F와 같은 방법을 이용하여 표제 화합물 (0.314 g)을 수득하였다.tert-butyl 4-(7-bromo-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- 1-Carboxylate (0.335 g, 0.763 mmol) was prepared using the same method as Step F of Preparation Example 1 to obtain the title compound (0.314 g).
LC/MS: 338, 340 (M+H)LC/MS: 338, 340 (M+H)
제조예 14: 7-클로로-1-메틸-4-(4-옥소사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 14: Preparation of 7-chloro-1-methyl-4-(4-oxocyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000093
Figure PCTKR2023007097-appb-img-000093
단계 A: 4-((5-클로로-3-나이트로피리딘-2-일)아미노)사이클로헥산-1-온의 제조Step A: Preparation of 4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexan-1-one
Figure PCTKR2023007097-appb-img-000094
Figure PCTKR2023007097-appb-img-000094
5-클로로-2-플루오로-3-나이트로피리딘 (6 g, 34.0 mmol) 과 4-아미노사이클로헥산-1-온 염산염 (5.09 g, 34.0 mmol)을 이용하여 제조예 1의 단계 A와 유사한 방법으로 표제 화합물 (8.9 g)을 얻었다.Similar to step A of Preparation Example 1 using 5-chloro-2-fluoro-3-nitropyridine (6 g, 34.0 mmol) and 4-aminocyclohexan-1-one hydrochloride (5.09 g, 34.0 mmol) The title compound (8.9 g) was obtained by this method.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.44 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 6.1 Hz, 1H), 4.64-4.62 (m, 1H), 2.54-2.51 (m, 4H), 2.40-2.37 (m, 2H), 1.94-1.89 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.44 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 6.1 Hz, 1H), 4.64- 4.62 (m, 1H), 2.54-2.51 (m, 4H), 2.40-2.37 (m, 2H), 1.94-1.89 (m, 2H)
LC/MS: 270.0 (M+H)LC/MS: 270.0 (M+H)
단계 B: 4-((3-아미노-5-클로로피리딘-2-일)아미노)사이클로헥산-1-온의 제조Step B: Preparation of 4-((3-amino-5-chloropyridin-2-yl)amino)cyclohexan-1-one
Figure PCTKR2023007097-appb-img-000095
Figure PCTKR2023007097-appb-img-000095
4-((5-클로로-3-나이트로피리딘-2-일)아미노)사이클로헥산-1-온 (8.5 g, 31.5 mmol)을 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (5.1 g)을 얻었다.4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexan-1-one (8.5 g, 31.5 mmol) was used to prepare the title compound (5.1 g) was obtained.
LC/MS: 240.1 (M+H)LC/MS: 240.1 (M+H)
단계 C: 7-클로로-4-(4-옥소사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step C: Preparation of 7-chloro-4-(4-oxocyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000096
Figure PCTKR2023007097-appb-img-000096
4-((3-아미노-5-클로로피리딘-2-일)아미노)사이클로헥산-1-one (5 g, 20.86 mmol)을 이용하여 제조예 7의 단계 C와 유사한 방법으로 표제 화합물 (4.39 g)을 얻었다.The title compound (4.39 g) was prepared in a manner similar to Step C of Preparation Example 7 using 4-((3-amino-5-chloropyridin-2-yl)amino)cyclohexane-1-one (5 g, 20.86 mmol). ) was obtained.
LC/MS: 294.1 (M+H), 316.1 (M+Na)LC/MS: 294.1 (M+H), 316.1 (M+Na)
단계 D: 7-클로로-1-메틸-4-(4-옥소사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step D: Preparation of 7-chloro-1-methyl-4-(4-oxocyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000097
Figure PCTKR2023007097-appb-img-000097
7-클로로-4-(4-옥소사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (4.4 g, 14.98 mmol)을 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제화합물 (2.55 g)을 얻었다.Preparation Example 1 using 7-chloro-4-(4-oxocyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (4.4 g, 14.98 mmol) The title compound (2.55 g) was obtained in a similar manner to step E of .
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.20 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 5.86-5.81 (m, 1H), 3.62 (d, J = 7.6 Hz, 3H), 3.07 (qd, J = 12.3, 5.5 Hz, 2H), 2.61-2.51 (m, 4H), 2.04-2.01 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.20 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 5.86-5.81 (m, 1H), 3.62 (d, J = 7.6 Hz, 3H), 3.07 (qd, J = 12.3, 5.5 Hz, 2H), 2.61-2.51 (m, 4H), 2.04-2.01 (m, 2H)
LC/MS: 308.0 (M+H), 330.0 (M+Na)LC/MS: 308.0 (M+H), 330.0 (M+Na)
제조예 15: 6-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 15: Preparation of 6-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000098
Figure PCTKR2023007097-appb-img-000098
단계 A: 터트-부틸 4-((3-아미노-6-클로로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((3-amino-6-chloropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000099
Figure PCTKR2023007097-appb-img-000099
제조예 3의 단계 A에서 얻은 터트-부틸 4-((6-클로로-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (7.86 g, 22.03 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (4.4 g)을 합성하였다.Using tert-butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (7.86 g, 22.03 mmol) obtained in Step A of Preparation Example 3 The title compound (4.4 g) was synthesized in a manner similar to Step B of Preparation Example 1.
LC/MS: 271 (M+H-t-Bu), 349 (M+Na)LC/MS: 271 (M+H-t-Bu), 349 (M+Na)
단계 B: 터트-부틸 4-(6-클로로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step B: Tert-Butyl 4-(6-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates
Figure PCTKR2023007097-appb-img-000100
Figure PCTKR2023007097-appb-img-000100
터트-부틸 4-((3-아미노-6-클로로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (4.4 g, 13.46 mmol)를 이용하여 제조예 7의 단계 C와 유사한 방법으로 표제 화합물 (5.13 g)을 합성하였고, 다음 반응에 바로 사용하였다.Similar method to Step C of Preparation Example 7 using tert-butyl 4-((3-amino-6-chloropyridin-2-yl)amino)piperidine-1-carboxylate (4.4 g, 13.46 mmol) The title compound (5.13 g) was synthesized and used directly in the next reaction.
LC/MS: 281 (M+H-t-Bu)LC/MS: 281 (M+H-t-Bu)
단계 C: 터트-부틸 4-(6-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step C: Tert-Butyl 4-(6-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi Preparation of dine-1-carboxylate
Figure PCTKR2023007097-appb-img-000101
Figure PCTKR2023007097-appb-img-000101
터트-부틸 4-(6-클로로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (5.13 g, 13.47 mmol)를 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (3.91 g, 74%)을 합성하였다.Tert-Butyl 4-(6-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate The title compound (3.91 g, 74%) was synthesized in a similar manner to Step E of Preparation Example 1 using (5.13 g, 13.47 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.47 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.47~5.42 (m, 1H), 4.36~4.26 (m, 2H), 3.64 (s, 3H), 2.91~2.84 (m, 4H), 1.66~1.65 (m, 2H), 1.52 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.47 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.47~5.42 (m, 1H), 4.36~4.26 (m , 2H), 3.64 (s, 3H), 2.91~2.84 (m, 4H), 1.66~1.65 (m, 2H), 1.52 (s, 9H)
LCMS: 417 (M+Na)LCMS: 417 (M+Na)
단계 D: 6-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step D: Preparation of 6-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000102
Figure PCTKR2023007097-appb-img-000102
터트-부틸 4-(6-클로로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (500 mg, 1.27 mmol)를 제조예 1의 단계 F와 같은 방법으로 표제 화합물 (450 mg, 99%)을 수득하였다.Tert-Butyl 4-(6-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate (500 mg, 1.27 mmol) was obtained in the same manner as Step F of Preparation Example 1 to obtain the title compound (450 mg, 99%).
LC/MS: 337 (M+H)LC/MS: 337 (M+H)
제조예 16: 4-((1R,3r,5S)-8-아자바이사이클로[3.2.1]옥탄-3-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 16: 4-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2 ,3-b] Production of pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000103
Figure PCTKR2023007097-appb-img-000103
단계 A: 터트-부틸 (1R,3r,5S)-3-((5-클로로-3-나이트로피리딘-2-일)아미노)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트의 제조Step A: tert-butyl (1R,3r,5S)-3-((5-chloro-3-nitropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-car Preparation of boxylate
Figure PCTKR2023007097-appb-img-000104
Figure PCTKR2023007097-appb-img-000104
5-클로로-2-플루오로-3-나이트로피리딘 (1.00 g, 5.66 mmol)과 터트-부틸 3-아미노-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트 (1.41 g, 6.23 mmol)를 이용하여 제조예 1의 단계 A와 같은 방법으로 표제 화합물 (2.11 g)을 합성하였다.5-chloro-2-fluoro-3-nitropyridine (1.00 g, 5.66 mmol) and tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (1.41 g, The title compound (2.11 g) was synthesized in the same manner as Step A of Preparation Example 1 using 6.23 mmol).
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.38 (d, J = 2.7 Hz, 1H), 8.32 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 4.74-4.69 (m, 1H), 4.31 (br s, 2H), 2.04-2.01 (m, 4H), 1.80 (q, J = 7.0 Hz, 2H), 1.71-1.60 (m, 2H), 1.48 (s, 9H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.38 (d, J = 2.7 Hz, 1H), 8.32 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 4.74- 4.69 (m, 1H), 4.31 (br s, 2H), 2.04-2.01 (m, 4H), 1.80 (q, J = 7.0 Hz, 2H), 1.71-1.60 (m, 2H), 1.48 (s, 9H) )
LC/MS: 383 (M+H)LC/MS: 383 (M+H)
단계 B: 터트-부틸 (1R,3r,5S)-3-((3-아미노-5-클로로피리딘-2-일)아미노)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트의 제조Step B: tert-butyl (1R,3r,5S)-3-((3-amino-5-chloropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxyl Manufacture of rate
Figure PCTKR2023007097-appb-img-000105
Figure PCTKR2023007097-appb-img-000105
터트-부틸 (1R,3r,5S)-3-((5-클로로-3-나이트로피리딘-2-일)아미노)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트 (2.11 g, 5.49 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (1.88 g)을 수득하였고, 정제하지 않고 다음 반응에 바로 사용하였다.tert-butyl (1R,3r,5S)-3-((5-chloro-3-nitropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate ( The title compound (1.88 g) was obtained in a similar manner to Step B of Preparation Example 1 using 2.11 g, 5.49 mmol), and was used directly in the next reaction without purification.
LC/MS: 375 (M+Na)LC/MS: 375 (M+Na)
단계 C: 터트-부틸 (1R,3r,5S)-3-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트의 제조Step C: tert-butyl (1R,3r,5S)-3-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4 Preparation of (1H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTKR2023007097-appb-img-000106
Figure PCTKR2023007097-appb-img-000106
터트-부틸 (1R,3r,5S)-3-((3-아미노-5-클로로피리딘-2-일)아미노)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트 (1.88 g, 5.33 mmol)와 DIPEA (5.58 mL, 32.00 mmol)를 DCM (300 mL)에 녹인 후 0℃로 유지한 상태에서 에틸 2-클로로-2-옥소아세테이트 (1.79 mL, 15.98 mmol)를 천천히 첨가한 다음 50℃로 가열한 상태로 18 시간 동안 교반하였다. 반응 종결 후, 혼합물을 포화 NH4Cl 수용액을 사용하여 추출한 이후 유기층을 MgSO4를 이용하여 건조하고 나서 감압증류하여 농축된 혼합물을 수득하였다. 수득한 혼합물을 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (1.50 g)을 합성하였다.tert-butyl (1R,3r,5S)-3-((3-amino-5-chloropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.88 g, 5.33 mmol) and DIPEA (5.58 mL, 32.00 mmol) were dissolved in DCM (300 mL) and then ethyl 2-chloro-2-oxoacetate (1.79 mL, 15.98 mmol) was slowly added while maintaining the temperature at 0°C. Next, it was heated to 50°C and stirred for 18 hours. After completion of the reaction, the mixture was extracted using a saturated NH 4 Cl aqueous solution, and the organic layer was dried using MgSO 4 and then distilled under reduced pressure to obtain a concentrated mixture. The obtained mixture was synthesized in a similar manner to Step E of Preparation Example 1 to obtain the title compound (1.50 g).
1H-NMR (500 MHz, DMSO-D6) δ 8.20 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 5.83 (br s, 1H), 4.16 (br s, 2H), 3.48 (s, 3H), 2.81-2.72 (m, 2H), 2.01-1.98 (m, 2H), 1.81-1.68 (m, 2H), 1.49 (s, 9H)1H-NMR (500 MHz, DMSO-D6) δ 8.20 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 5.83 (br s, 1H), 4.16 (br s, 2H), 3.48 (s) , 3H), 2.81-2.72 (m, 2H), 2.01-1.98 (m, 2H), 1.81-1.68 (m, 2H), 1.49 (s, 9H)
LC/MS: 421 (M+H)LC/MS: 421 (M+H)
단계 D: 4-((1R,3r,5S)-8-아자바이사이클로[3.2.1]옥탄-3-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step D: 4-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2, 3-b] Preparation of pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000107
Figure PCTKR2023007097-appb-img-000107
터트-부틸 (1R,3r,5S)-3-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트 (1.50 g, 3.56 mmol)를 이용하여 제조예 1의 단계 F와 유사한 방법으로 표제 화합물 (1.25 g)을 얻었다.Tert-Butyl (1R,3r,5S)-3-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H) The title compound (1.25 g) was obtained in a similar manner to Step F of Preparation Example 1 using -yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.50 g, 3.56 mmol).
LC/MS: 321 (M+H)LC/MS: 321 (M+H)
제조예 17: 4-(4-아미노사이클로헥실)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 17: Preparation of 4-(4-aminocyclohexyl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000108
Figure PCTKR2023007097-appb-img-000108
단계 A: 터트-부틸 (4-((5-클로로-3-나이트로피리딘-2-일)아미노)사이클로헥실)카바메이트의 제조Step A: Preparation of tert-butyl (4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexyl)carbamate
Figure PCTKR2023007097-appb-img-000109
Figure PCTKR2023007097-appb-img-000109
5-클로로-2-플루오로-3-나이트로피리딘 (1 g, 5.66 mmol)과 터트-부틸 (4-아미노사이클로헥실)카바메이트 (1.214 g, 5.66 mmol)를 이용하여 제조예 1의 단계 A와 유사한 방법으로 표제 화합물 (1.92 g)을 합성하였다.Step A of Preparation Example 1 using 5-chloro-2-fluoro-3-nitropyridine (1 g, 5.66 mmol) and tert-butyl (4-aminocyclohexyl) carbamate (1.214 g, 5.66 mmol) The title compound (1.92 g) was synthesized in a similar manner.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.38 (d, J = 2.3 Hz, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 4.40 (s, 1H), 3.49 (s, 1H), 2.13 (dd, J = 32.0, 16.9 Hz, 4H), 1.44 (s, 10H), 1.35 (dd, J = 24.0, 10.7 Hz, 4H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.38 (d, J = 2.3 Hz, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 4.40 ( s, 1H), 3.49 (s, 1H), 2.13 (dd, J = 32.0, 16.9 Hz, 4H), 1.44 (s, 10H), 1.35 (dd, J = 24.0, 10.7 Hz, 4H)
LC/MS: 371 (M+H)LC/MS: 371 (M+H)
단계 B: 터트-부틸 (4-((3-아미노-5-클로로피리딘-2-일)아미노)사이클로헥실)카바메이트의 제조Step B: Preparation of tert-butyl (4-((3-amino-5-chloropyridin-2-yl)amino)cyclohexyl)carbamate
Figure PCTKR2023007097-appb-img-000110
Figure PCTKR2023007097-appb-img-000110
터트-부틸 (4-((5-클로로-3-나이트로피리딘-2-일)아미노)사이클로헥실)카바메이트 (1.21 g, 3.26 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (717 mg)을 합성하였다.Tert-butyl (4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexyl)carbamate (1.21 g, 3.26 mmol) was used in a similar manner to Step B of Preparation Example 1. Compound (717 mg) was synthesized.
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.65 (d, J = 2.3 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 4.40 (d, J = 6.9 Hz, 1H), 3.89-3.82 (m, 2H), 3.46 (s, 1H), 3.19 (s, 2H), 2.17-2.14 (m, 2H), 2.03 (t, J = 3.9 Hz, 2H), 1.43 (s, 9H)1H-NMR (400 MHz, CHLOROFORM-D) δ 7.65 (d, J = 2.3 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 4.40 (d, J = 6.9 Hz, 1H), 3.89- 3.82 (m, 2H), 3.46 (s, 1H), 3.19 (s, 2H), 2.17-2.14 (m, 2H), 2.03 (t, J = 3.9 Hz, 2H), 1.43 (s, 9H)
LC/MS: 341 (M+H)LC/MS: 341 (M+H)
단계 C: 터트-부틸 (4-(7-클로로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)사이클로헥실)카바메이트의 제조Step C: tert-butyl (4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)cyclohexyl)carbamate manufacture of
Figure PCTKR2023007097-appb-img-000111
Figure PCTKR2023007097-appb-img-000111
터트-부틸 (4-((3-아미노-5-클로로피리딘-2-일)아미노)사이클로헥실)카바메이트 (717 mg, 2.104 mmol)를 이용하여 제조예 7의 단계 C와 유사한 방법으로 표제 화합물 (630 mg)을 합성하였다.The title compound was prepared in a manner similar to Step C of Preparation Example 7 using tert-butyl (4-((3-amino-5-chloropyridin-2-yl)amino)cyclohexyl)carbamate (717 mg, 2.104 mmol). (630 mg) was synthesized.
1H-NMR (400 MHz, METHANOL-D4) δ 8.16 (d, J = 2.3 Hz, 1H), 7.54-7.50 (m, 1H), 5.31 (s, 1H), 3.46-3.38 (m, 1H), 2.74 (d, J = 11.9 Hz, 2H), 2.01 (d, J = 11.0 Hz, 2H), 1.71 (d, J = 10.1 Hz, 2H), 1.42 (s, 10H), 1.37 (d, J = 12.3 Hz, 2H)1H-NMR (400 MHz, METHANOL-D4) δ 8.16 (d, J = 2.3 Hz, 1H), 7.54-7.50 (m, 1H), 5.31 (s, 1H), 3.46-3.38 (m, 1H), 2.74 (d, J = 11.9 Hz, 2H), 2.01 (d, J = 11.0 Hz, 2H), 1.71 (d, J = 10.1 Hz, 2H), 1.42 (s, 10H), 1.37 (d, J = 12.3 Hz) , 2H)
LC/MS: 395 (M+H)LC/MS: 395 (M+H)
단계 D: 터트-부틸 (4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)사이클로헥실)카바메이트의 제조Step D: tert-butyl (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)cyclo Preparation of hexyl)carbamate
Figure PCTKR2023007097-appb-img-000112
Figure PCTKR2023007097-appb-img-000112
터트-부틸 (4-(7-클로로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)사이클로헥실)카바메이트 (630 mg, 1.596 mmol)를 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (1.92 g)을 합성하였다.Tert-butyl (4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)cyclohexyl)carbamate (630 mg , 1.596 mmol), the title compound (1.92 g) was synthesized in a similar manner to Step E of Preparation Example 1.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.16 (s, 1H), 7.45 (d, J = 2.3 Hz, 1H), 5.27 (s, 1H), 4.41 (s, 1H), 3.59 (s,3H), 2.82-2.77 (m, 2H), 2.13 (d, J = 12.8 Hz, 2H), 1.68 (d, J = 11.4 Hz, 2H), 1.45 (s, 9H), 1.33-1.27 (m, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.16 (s, 1H), 7.45 (d, J = 2.3 Hz, 1H), 5.27 (s, 1H), 4.41 (s, 1H), 3.59 (s,3H) ), 2.82-2.77 (m, 2H), 2.13 (d, J = 12.8 Hz, 2H), 1.68 (d, J = 11.4 Hz, 2H), 1.45 (s, 9H), 1.33-1.27 (m, 2H)
LC/MS: 409 (M+H)LC/MS: 409 (M+H)
단계 E: 4-(4-아미노사이클로헥실)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step E: Preparation of 4-(4-aminocyclohexyl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000113
Figure PCTKR2023007097-appb-img-000113
터트-부틸 (4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)사이클로헥실)카바메이트 (720 mg, 1.761 mmol)를 이용하여 제조예 1의 단계 F와 유사한 방법으로 표제 화합물 (635 mg)을 합성하였다.tert-butyl (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)cyclohexyl)carba The title compound (635 mg) was synthesized in a manner similar to Step F of Preparation Example 1 using mate (720 mg, 1.761 mmol).
1H-NMR (400 MHz, METHANOL-D4) δ 8.21 (d, J = 2.3 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 5.22-5.57 (1H), 3.64 (s, 4H), 3.57 (d, J = 3.7 Hz, 3H), 3.20 (s, 1H), 2.76 (d, J = 11.0 Hz, 2H), 2.16 (d, J = 12.3 Hz, 2H), 1.84 (d, J = 10.5 Hz, 2H), 1.58 (dd, J = 12.6, 3.9 Hz, 2H)1H-NMR (400 MHz, METHANOL-D4) δ 8.21 (d, J = 2.3 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 5.22-5.57 (1H), 3.64 (s, 4H), 3.57 (d, J = 3.7 Hz, 3H), 3.20 (s, 1H), 2.76 (d, J = 11.0 Hz, 2H), 2.16 (d, J = 12.3 Hz, 2H), 1.84 (d, J = 10.5 Hz, 2H), 1.58 (dd, J = 12.6, 3.9 Hz, 2H)
LC/MS: 309 (M+H)LC/MS: 309 (M+H)
제조예 18: 7-클로로-6-(2-플루오로페닐)-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 염산염의 제조Preparation Example 18: 7-Chloro-6-(2-fluorophenyl)-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine Preparation of -2,3-dione hydrochloride
Figure PCTKR2023007097-appb-img-000114
Figure PCTKR2023007097-appb-img-000114
단계 A: 터트-부틸 4-((5,6-다이클로로-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((5,6-dichloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000115
Figure PCTKR2023007097-appb-img-000115
제조예 3의 단계 A에서 수득한 터트-부틸 4-((6-클로로-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (1.5 g, 4.20 mmol)를 CH3CN(50 mL)에 녹인 후 NCS (0.842 g, 6.31 mmol)를 가한 다음 50℃에서 5시간 동안 교반하였다. 반응물을 감압농축하고 EtOAc로 희석 후 소듐바이카보네이트 수용액과 brine으로 세척하였다. 유기층을 무수 소듐설페이트로 건조 후 감압농축시키고 잔류물을 MPLC로 정제하여 표제 화합물 (1.57 g)을 수득하였다.Tert-butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.5 g, 4.20 mmol) obtained in step A of Preparation Example 3 was reacted with CH 3 After dissolving in CN (50 mL), NCS (0.842 g, 6.31 mmol) was added and stirred at 50°C for 5 hours. The reaction was concentrated under reduced pressure, diluted with EtOAc, and washed with aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (1.57 g).
LC/MS: 413, 415 (M+Na)LC/MS: 413, 415 (M+Na)
단계 B: 터트-부틸 4-(N-(5,6-다이클로로-3-나이트로피리딘-2-일)-2-에톡시-2-옥소아세트아미도)피페리딘-1-카르복실레이트의 제조Step B: Tert-Butyl 4-(N-(5,6-dichloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxyl Manufacture of rate
Figure PCTKR2023007097-appb-img-000116
Figure PCTKR2023007097-appb-img-000116
터트-부틸 4-((5,6-다이클로로-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (0.920 g, 2.351)를 이용하여 제조예 3의 단계 C와 같은 방법으로 표제 화합물 (1.05 g)을 수득하였다.Step C of Preparation Example 3 using tert-butyl 4-((5,6-dichloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (0.920 g, 2.351) The title compound (1.05 g) was obtained in the same manner.
LC/MS: 513, 515 (M+Na) LC/MS: 513, 515 (M+Na)
단계 C: 터트-부틸 4-(6,7-다이클로로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step C: Tert-Butyl 4-(6,7-dichloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -Preparation of 1-carboxylate
Figure PCTKR2023007097-appb-img-000117
Figure PCTKR2023007097-appb-img-000117
터트-부틸 4-(N-(5,6-다이클로로-3-나이트로피리딘-2-일)-2-에톡시-2-옥소아세트아미도)피페리딘-1-카르복실레이트 (220 mg, 0.448 mol)를 이용하여 제조예 3의 단계 D와 같은 방법으로 표제 화합물 (0.186 g)을 수득하였고 정제하지 않고 다음 반응에 바로 사용하였다.Tert-Butyl 4-(N-(5,6-dichloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate (220 mg, 0.448 mol) to obtain the title compound (0.186 g) in the same manner as Step D of Preparation Example 3 and used directly in the next reaction without purification.
LC/MS: 437, 439 (M+Na)LC/MS: 437, 439 (M+Na)
단계 D: 터트-부틸 4-(6,7-다이클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step D: Tert-Butyl 4-(6,7-dichloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl ) Preparation of piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000118
Figure PCTKR2023007097-appb-img-000118
터트-부틸 4-(6,7-다이클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (0.186 g, 0.448 mmol)를 제조예 1의 단계 E와 같은 방법을 이용하여 얻어진 잔류물을 MPLC로 정제하여 표제 화합물 (0.121 g)을 수득하였다.Tert-Butyl 4-(6,7-dichloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi Dean-1-carboxylate (0.186 g, 0.448 mmol) was obtained using the same method as Step E of Preparation Example 1. The residue was purified by MPLC to obtain the title compound (0.121 g).
LC/MS: 451. 453 (M+Na)LC/MS: 451. 453 (M+Na)
단계 E: 터트-부틸 4-(7-클로로-6-(2-플루오로페닐)-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step E: Tert-Butyl 4-(7-chloro-6-(2-fluorophenyl)-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine Preparation of -4(1H)-yl)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000119
Figure PCTKR2023007097-appb-img-000119
터트-부틸 4-(6,7-다이클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (0.090 g, 0.210 mmol), (2-플루오로페닐)보론산 (44 mg, 0.314), 2M 소듐카보네이트 수용액 (0.314 mL)과 테트라키스트라이페닐포스핀팔라듐 (24 mg, 0.02 mmol)을 1,4-다이옥산 (5 mL)에 녹인 후 90℃에서 3시간 동안 교반하였다. 반응물을 상온으로 식히고 Celite로 여과한 후 여과액을 감압농축시키고 잔류물을 MPLC로 정제하여 표제 화합물 (89 mg)을 수득하였다.Tert-Butyl 4-(6,7-dichloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi Dean-1-carboxylate (0.090 g, 0.210 mmol), (2-fluorophenyl)boronic acid (44 mg, 0.314), 2M sodium carbonate aqueous solution (0.314 mL) and tetrakistriphenylphosphinepalladium (24 mg) , 0.02 mmol) was dissolved in 1,4-dioxane (5 mL) and stirred at 90°C for 3 hours. The reaction was cooled to room temperature, filtered through Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (89 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.62 (s, 1H), 7.49~7.46 (m, 2H), 7.32~7.28(m, 1H), 7.24~7.20 (m, 2H), 5.48~5.45 (m, 1H), 4.30~4.20 (m, 2H), 3.67 (s, 3H), 2.81 (br s, 4H), 1.67 (br s, 2H), 1.44 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.62 (s, 1H), 7.49~7.46 (m, 2H), 7.32~7.28(m, 1H), 7.24~7.20 (m, 2H), 5.48~5.45 ( m, 1H), 4.30~4.20 (m, 2H), 3.67 (s, 3H), 2.81 (br s, 4H), 1.67 (br s, 2H), 1.44 (s, 9H)
LC/MS: 511 (M+Na)LC/MS: 511 (M+Na)
단계 F: 7-클로로-6-(2-플루오로페닐)-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 염산염의 제조Step F: 7-Chloro-6-(2-fluorophenyl)-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- Preparation of 2,3-dione hydrochloride
Figure PCTKR2023007097-appb-img-000120
Figure PCTKR2023007097-appb-img-000120
터트-부틸 4-(7-클로로-6-(2-플루오로페닐)-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (0.089 g, 0.182 mmol)를 제조예 1의 단계 F와 같은 방법으로 표제 화합물 (80 mg)을 수득하였고 정제하지 않고 다음 반응에 바로 사용하였다.Tert-butyl 4-(7-chloro-6-(2-fluorophenyl)-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4( 1H)-yl)piperidine-1-carboxylate (0.089 g, 0.182 mmol) was obtained in the same manner as Step F of Preparation Example 1 to obtain the title compound (80 mg) and used directly in the next reaction without purification. .
LC/MS: 389 (M+H)LC/MS: 389 (M+H)
제조예 19: 7-브로모-1-메틸-2,3-다이옥소-4-(피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-6-카르보나이트릴 2 염산염의 제조Preparation Example 19: 7-Bromo-1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b ]Preparation of pyrazine-6-carbonitrile 2 hydrochloride
Figure PCTKR2023007097-appb-img-000121
Figure PCTKR2023007097-appb-img-000121
단계 A: 터트-부틸 4-((5-브로모-6-클로로-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((5-bromo-6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000122
Figure PCTKR2023007097-appb-img-000122
제조예 3의 단계 A에서 얻은 터트-부틸 4-((6-클로로-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (1.00 g, 2.80 mmol)와 NBS를 이용하여 제조예 18의 단계 A와 같은 방법으로 표제 화합물 (1.08 g)을 수득하였다.Tert-butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.00 g, 2.80 mmol) obtained in Step A of Preparation Example 3 and NBS The title compound (1.08 g) was obtained in the same manner as Step A of Preparation Example 18.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.62 (s, 1H), 8.16 (d, J = 5.6 Hz, 1H), 4.33~4.27 (m, 1H), 4.15-4.09 (m, 2H), 3.06~3.01 (m, 2H), 2.09~2.07 (m, 2H), 1.55-1.52 (m, 2H), 1.50 (s, 9H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.62 (s, 1H), 8.16 (d, J = 5.6 Hz, 1H), 4.33~4.27 (m, 1H), 4.15-4.09 (m, 2H), 3.06 ~3.01 (m, 2H), 2.09~2.07 (m, 2H), 1.55-1.52 (m, 2H), 1.50 (s, 9H)
LC/MS: 457, 459 (M+Na)LC/MS: 457, 459 (M+Na)
단계 B: 터트-부틸 4-((5-브로모-6-시아노-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((5-bromo-6-cyano-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000123
Figure PCTKR2023007097-appb-img-000123
터트-부틸 4-((5-브로모-6-클로로-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (0.500 g, 1.148 mmol)를 이용하여 제조예 3의 단계 B와 같은 방법으로 표제 화합물 (0.201 g)을 수득하였다.Preparation Example 3 using tert-butyl 4-((5-bromo-6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (0.500 g, 1.148 mmol) The title compound (0.201 g) was obtained in the same manner as step B.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.69 (s, 1H), 8.05 (d, J = 7.5 Hz, 1H), 4.33~4.28 (m, 1H), 4.17-4.12 (m, 2H), 3.05~3.00 (m, 2H), 2.09~2.07 (m, 2H), 1.55-1.52 (m, 2H), 1.50 (s, 9H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.69 (s, 1H), 8.05 (d, J = 7.5 Hz, 1H), 4.33~4.28 (m, 1H), 4.17-4.12 (m, 2H), 3.05 ~3.00 (m, 2H), 2.09~2.07 (m, 2H), 1.55-1.52 (m, 2H), 1.50 (s, 9H)
LC/MS: 523, 525 (M+Na)LC/MS: 523, 525 (M+Na)
단계 C: 터트-부틸 4-(N-(5-브로모-6-시아노-3-나이트로피리딘-2-일)-2-에톡시-2-옥소아세트아미도)피페리딘-1-카르복실레이트의 제조Step C: Tert-Butyl 4-(N-(5-bromo-6-cyano-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1 -Manufacture of carboxylates
Figure PCTKR2023007097-appb-img-000124
Figure PCTKR2023007097-appb-img-000124
터트-부틸 4-((5-브로모-6-시아노-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (0.370 g, 0.868 mmol)를 이용하여 제조예 3의 단계 C와 같은 방법으로 표제 화합물 (0.251 g)을 수득하였다.Preparation example using tert-butyl 4-((5-bromo-6-cyano-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (0.370 g, 0.868 mmol) The title compound (0.251 g) was obtained in the same manner as Step C of 3.
LC/MS: 548, 550 (M+Na)LC/MS: 548, 550 (M+Na)
단계 D: 터트-부틸 4-(7-브로모-6-시아노-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step D: tert-Butyl 4-(7-bromo-6-cyano-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl) Preparation of piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000125
Figure PCTKR2023007097-appb-img-000125
터트-부틸 4-(N-(5-브로모-6-시아노-3-나이트로피리딘-2-일)-2-에톡시-2-옥소아세트아미도)피페리딘-1-카르복실레이트 (0.251 g, 0.477 mmol)를 이용하여 제조예 3의 단계 D와 같은 방법으로 표제 화합물 (0.215 g)을 수득하였고 정제하지 않고 다음 반응에 바로 사용하였다.Tert-Butyl 4-(N-(5-bromo-6-cyano-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxyl The title compound (0.215 g) was obtained in the same manner as in Step D of Preparation Example 3 using a rate (0.251 g, 0.477 mmol) and used directly in the next reaction without purification.
LC/MS: 472, 474 (M+Na)LC/MS: 472, 474 (M+Na)
단계 E: 터트-부틸 4-(7-브로모-6-시아노-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step E: tert-butyl 4-(7-bromo-6-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H )-yl) Preparation of piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000126
Figure PCTKR2023007097-appb-img-000126
터트-부틸 4-(7-브로모-6-시아노-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (0.215 g, 0.477 mmol)를 제조예 1의 단계 E와 같은 방법을 이용하여 얻어진 잔류물을 MPLC로 정제하여 표제 화합물 (0.114 g)을 수득하였다.Tert-Butyl 4-(7-bromo-6-cyano-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -1-Carboxylate (0.215 g, 0.477 mmol) was obtained using the same method as Step E of Preparation Example 1. The residue was purified by MPLC to obtain the title compound (0.114 g).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.29 (d, J = 1.2 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 5.51~5.49 (m, 1H), 4.31~4.27 (m, 2H), 3.63 (s, 3H), 2.87~2.83 (m, 4H), 1.65 (br s, 2H), 1.52 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.29 (d, J = 1.2 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 5.51~5.49 (m, 1H), 4.31~4.27 (m , 2H), 3.63 (s, 3H), 2.87~2.83 (m, 4H), 1.65 (br s, 2H), 1.52 (s, 9H)
LC/MS: 486, 488 (M+Na)LC/MS: 486, 488 (M+Na)
단계 F: 7-브로모-1-메틸-2,3-다이옥소-4-(피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-6-카르보나이트릴 2 염산염의 제조Step F: 7-Bromo-1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b] Preparation of pyrazine-6-carbonitrile 2 hydrochloride
Figure PCTKR2023007097-appb-img-000127
Figure PCTKR2023007097-appb-img-000127
터트-부틸 4-(7-브로모-6-시아노-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (0.114 g, 0.246 mmol)를 제조예 1의 단계 F와 같은 방법을 이용하여 표제 화합물 (0.107 g)을 수득하였고 정제하지 않고 다음 반응에 바로 사용하였다.Tert-Butyl 4-(7-bromo-6-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl ) Piperidine-1-carboxylate (0.114 g, 0.246 mmol) was used in the same manner as Step F of Preparation Example 1 to obtain the title compound (0.107 g), which was used directly in the next reaction without purification.
LC/MS: 364, 366 (M+H)LC/MS: 364, 366 (M+H)
제조예 20: 7-클로로-4-((1r,4r)-4-하이드록시사이클로헥실)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Preparation Example 20: 7-Chloro-4-((1r,4r)-4-hydroxycyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3- Manufacturing of dione
Figure PCTKR2023007097-appb-img-000128
Figure PCTKR2023007097-appb-img-000128
단계 A: (1r,4r)-4-((5-클로로-3-나이트로피리딘-2-일)아미노)사이클로헥산-1-올의 제조Step A: Preparation of (1r,4r)-4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexan-1-ol
Figure PCTKR2023007097-appb-img-000129
Figure PCTKR2023007097-appb-img-000129
5-클로로-2-플루오로-3-나이트로피리딘 (3.53 g, 20.0 mmol)과 trans-4-아미노사이클로헥산-1-ol (2.30 g, 20.00 mmol)를 제조예 1의 단계 A와 유사한 방법을 이용하여 표제 화합물 (5.3 g)을 수득하였다.5-Chloro-2-fluoro-3-nitropyridine (3.53 g, 20.0 mmol) and trans-4-aminocyclohexane-1-ol (2.30 g, 20.00 mmol) were prepared in a manner similar to Step A of Preparation Example 1. The title compound (5.3 g) was obtained using .
단계 B: N-((1r,4r)-4-((터트-부틸다이메틸실릴)옥시)사이클로헥실)-5-클로로-3-나이트로피리딘-2-아민의 제조Step B: Preparation of N-((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5-chloro-3-nitropyridin-2-amine
Figure PCTKR2023007097-appb-img-000130
Figure PCTKR2023007097-appb-img-000130
(1r,4r)-4-((5-클로로-3-나이트로피리딘-2-일)아미노)사이클로헥산-1-올 (1.0 g, 3.68 mmol)을 CH2Cl2 용매 하에서 TBSCl (0.832 g, 5.52 mmol), Et3N (1.54 mL, 11.0 mmol), DMAP (0.045 g, 0.368 mmol)를 첨가한 후 상온에서 18시간 교반하였다. 반응물을 EtOAc로 희석 후 brine으로 세척하고 Na2SO4로 건조 후 감압농축하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (1.35 g)을 수득하였다.(1r,4r)-4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexan-1-ol (1.0 g, 3.68 mmol) was dissolved in TBSCl (0.832 g) in CH 2 Cl 2 solvent. , 5.52 mmol), Et 3 N (1.54 mL, 11.0 mmol), and DMAP (0.045 g, 0.368 mmol) were added and stirred at room temperature for 18 hours. The reaction product was diluted with EtOAc, washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (1.35 g).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.41 (d, J =2.5 Hz, 1H), 8.38 (d, J = 2.5 Hz, 1H), 8.12 (d, J = 7.0 Hz, 1H), 4.19~4.16 (m, 1H), 3.73~3.69 (m, 1H), 2.16~2.13 (m, 2H), 1.94~1.91 (m, 2H), 1.55~1.49 (m, 2H), 1.45~1.38 (m, 2H), 0.91 (s, 9H), 0.08 (s, 3H), 0.02 (s, 3H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.41 (d, J =2.5 Hz, 1H), 8.38 (d, J = 2.5 Hz, 1H), 8.12 (d, J = 7.0 Hz, 1H), 4.19~ 4.16 (m, 1H), 3.73~3.69 (m, 1H), 2.16~2.13 (m, 2H), 1.94~1.91 (m, 2H), 1.55~1.49 (m, 2H), 1.45~1.38 (m, 2H) ), 0.91 (s, 9H), 0.08 (s, 3H), 0.02 (s, 3H)
LC/MS: 386 (M+H)LC/MS: 386 (M+H)
단계 C: 에틸 2-(((1r,4r)-4-((터트-부틸다이메틸실릴)옥시)사이클로헥실)(5-클로로-3-나이트로피리딘-2-일)아미노)-2-옥소아세테이트의 제조Step C: Ethyl 2-(((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)(5-chloro-3-nitropyridin-2-yl)amino)-2- Manufacture of oxoacetate
Figure PCTKR2023007097-appb-img-000131
Figure PCTKR2023007097-appb-img-000131
N-((1r,4r)-4-((터트-부틸다이메틸실릴)옥시)사이클로헥실)-5-클로로-3-나이트로피리딘-2-아민 (1.0 g, 2.59 mmol)을 이용하여 제조예 3의 단계 C와 같은 방법으로 표제 화합물 (0.72 g)을 수득하였다.Prepared using N-((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5-chloro-3-nitropyridin-2-amine (1.0 g, 2.59 mmol) The title compound (0.72 g) was obtained in the same manner as Step C of Example 3.
단계 D: 4-((1r,4r)-4-((터트-부틸다이메틸실릴)옥시)사이클로헥실)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step D: 4-((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3- b] Preparation of pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000132
Figure PCTKR2023007097-appb-img-000132
에틸 2-(((1r,4r)-4-((터트-부틸다이메틸실릴)옥시)사이클로헥실)(5-클로로-3-나이트로피리딘-2-일)아미노)-2-옥소아세테이트 (0.72 g, 1.48 mmol)를 이용하여 제조예 7의 단계 C와 같은 방법으로 표제 화합물 (0.228 g)을 수득하였다.Ethyl 2-(((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)(5-chloro-3-nitropyridin-2-yl)amino)-2-oxoacetate ( The title compound (0.228 g) was obtained in the same manner as Step C of Preparation Example 7 using 0.72 g, 1.48 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.22 (d, J =2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 5.38~5.33 (m, 1H), 3.79~3.73 (m, 1H), 3.62 (s, 3H), 2.76~2.67 (m, 2H), 2.02~2.00 (m, 2H), 1.69~1.67 (m, 2H), 1.55~1.50 (m, 2H), 0.92 (s, 9H), 0.11 (s, 3H), 0.02 (s, 3H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.22 (d, J =2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 5.38~5.33 (m, 1H), 3.79~3.73 (m , 1H), 3.62 (s, 3H), 2.76~2.67 (m, 2H), 2.02~2.00 (m, 2H), 1.69~1.67 (m, 2H), 1.55~1.50 (m, 2H), 0.92 (s) , 9H), 0.11 (s, 3H), 0.02 (s, 3H)
LC/MS: 424 (M+H), 446 (M+Na)LC/MS: 424 (M+H), 446 (M+Na)
단계 E: 7-클로로-4-((1r,4r)-4-하이드록시사이클로헥실)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step E: 7-Chloro-4-((1r,4r)-4-hydroxycyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da Preparation of ions
Figure PCTKR2023007097-appb-img-000133
Figure PCTKR2023007097-appb-img-000133
4-((1r,4r)-4-((터트-부틸다이메틸실릴)옥시)사이클로헥실)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (0.140 g, 0.33 mmol)를 THF 용매하에서 1N HCl (2 mL)을 가한 후 상온에서 3시간 동안 교반하였다. 반응액을 1N NaOH 로 pH 9로 맞춘후 EtOAc로 추출하였다. 유기층을 Na2SO4로 건조 후 감압증류하고 잔류물을 MPLC로 정제하여 표제 화합물 (96 mg)을 수득하였다.4-((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione (0.140 g, 0.33 mmol) was added with 1N HCl (2 mL) in THF solvent and stirred at room temperature for 3 hours. The reaction solution was adjusted to pH 9 with 1N NaOH and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 and distilled under reduced pressure, and the residue was purified by MPLC to obtain the title compound (96 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.22 (d, J =2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 5.40~5.34 (m, 1H), 3.85~3.81 (m, 1H), 3.63 (s, 3H), 2.81~2.73 (m, 2H), 2.15~2.13 (m, 2H), 1.73~1.71 (m, 2H), 1.54~1.49 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.22 (d, J =2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 5.40~5.34 (m, 1H), 3.85~3.81 (m , 1H), 3.63 (s, 3H), 2.81~2.73 (m, 2H), 2.15~2.13 (m, 2H), 1.73~1.71 (m, 2H), 1.54~1.49 (m, 2H)
LC/MS: 310 (M+H), 332 (M+Na)LC/MS: 310 (M+H), 332 (M+Na)
제조예 21: 7-클로로-4-((2R,5S)-2,5-다이메틸피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 2 염산염의 제조Preparation Example 21: 7-chloro-4-((2R,5S)-2,5-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b ]Preparation of pyrazine-2,3-dione 2 hydrochloride
Figure PCTKR2023007097-appb-img-000134
Figure PCTKR2023007097-appb-img-000134
단계 A: 터트-부틸 (2R,5S)-4-((5-클로로-3-나이트로피리딘-2-일)아미노)-2,5-다이메틸피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl (2R,5S)-4-((5-chloro-3-nitropyridin-2-yl)amino)-2,5-dimethylpiperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000135
Figure PCTKR2023007097-appb-img-000135
5-클로로-2-플루오로-3-나이트로피리딘 (306 mg, 1.73 mmol)과 터트-부틸 (2R,5S)-4-아미노-2,5-다이메틸피페리딘-1-카르복실레이트 아세테이트 (500 mg, 1.73 mmol)를 DMF (20 mL)에 녹인 후 DIPEA (0.606 mL, 3.47 mmol)를 넣어준 후 3시간 동안 교반하였다. 반응물에 물을 넣어 반응을 종결시킨 후 EtOAc로 3번 추출하였다. 유기층을 무수 마그네슘설페이트로 건조 후 감압 농축시키고 잔류물을 MPLC로 정제하여 표제 화합물 (500 mg, 75%)을 수득하였다.5-Chloro-2-fluoro-3-nitropyridine (306 mg, 1.73 mmol) with tert-butyl (2R,5S)-4-amino-2,5-dimethylpiperidine-1-carboxylate Acetate (500 mg, 1.73 mmol) was dissolved in DMF (20 mL), then DIPEA (0.606 mL, 3.47 mmol) was added and stirred for 3 hours. The reaction was terminated by adding water to the reactant, and then extracted three times with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (500 mg, 75%).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.53 (d, J = 6.4 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 1.6 Hz, 1H), 4.59~4.55 (m, 1H), 4.39~4.33 (m, 1H), 3.98~3.95 (m, 1H), 2.87~2.81 (m, 1H), 2.13~2.08 (m, 1H), 1.99~1.96 (m, 2H), 1.50 (s, 9H), 1.22 (d, J = 6.0 Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.53 (d, J = 6.4 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 1.6 Hz, 1H), 4.59~ 4.55 (m, 1H), 4.39~4.33 (m, 1H), 3.98~3.95 (m, 1H), 2.87~2.81 (m, 1H), 2.13~2.08 (m, 1H), 1.99~1.96 (m, 2H) ), 1.50 (s, 9H), 1.22 (d, J = 6.0 Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H)
LC/MS: 329 (M+H-t-Bu)LC/MS: 329 (M+H-t-Bu)
단계 B: 터트-부틸 (2R,5S)-4-((3-아미노-5-클로로피리딘-2-일)아미노)-2,5-다이메틸피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl (2R,5S)-4-((3-amino-5-chloropyridin-2-yl)amino)-2,5-dimethylpiperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000136
Figure PCTKR2023007097-appb-img-000136
터트-부틸 (2R,5S)-4-((5-클로로-3-나이트로피리딘-2-일)아미노)-2,5-다이메틸피페리딘-1-카르복실레이트 (330 mg, 0.857 mmol)를 MeOH (10 mL)에 녹인 후 Zn (1.12 g, 17.2 mmol)과 암모늄 클로라이드 (0.460 g, 8.57 mmol)를 넣어 준 후 70℃에서 3시간 동안 교반하였다. Celite pad로 필터해준 후 감압 농축시켜 표제 화합물 (304 mg)을 수득하였고 다음 반응에 바로 사용하였다.Tert-Butyl (2R,5S)-4-((5-chloro-3-nitropyridin-2-yl)amino)-2,5-dimethylpiperidine-1-carboxylate (330 mg, 0.857 mmol) was dissolved in MeOH (10 mL), Zn (1.12 g, 17.2 mmol) and ammonium chloride (0.460 g, 8.57 mmol) were added, and then stirred at 70°C for 3 hours. After filtering with a Celite pad and concentrating under reduced pressure, the title compound (304 mg) was obtained and used immediately in the next reaction.
LC/MS: 355 (M+H)LC/MS: 355 (M+H)
단계 C: 터트-부틸 (2R,5S)-4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-2,5-다이메틸피페리딘-1-카르복실레이트의 제조Step C: tert-butyl (2R,5S)-4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H )-yl)-2,5-dimethylpiperidine-1-carboxylate Preparation
Figure PCTKR2023007097-appb-img-000137
Figure PCTKR2023007097-appb-img-000137
터트-부틸 (2R,5S)-4-((3-아미노-5-클로로피리딘-2-일)아미노)-2,5-다이메틸피페리딘-1-카르복실레이트 (304 mg, 0.857 mmol)를 DCE (10 mL)에 녹인 후 에틸 2-클로로-2-옥소아세테이트 (0.144 mL, 1.29 mmol)와 DIPEA (0.449 mL, 2.57 mmol)를 넣어준 후 상온에서 12시간 동안 교반한 후 70℃에서 주말 동안 교반하였다. 반응물에 물을 넣어 반응을 종결시킨 후 DCM으로 3번 추출하였다. 유기층을 무수 마그네슘설페이트로 건조 후 감압 농축시켜 표제 화합물 (209 mg)을 수득하였고 다음 반응에 바로 사용하였다.Tert-butyl (2R,5S)-4-((3-amino-5-chloropyridin-2-yl)amino)-2,5-dimethylpiperidine-1-carboxylate (304 mg, 0.857 mmol ) was dissolved in DCE (10 mL), then ethyl 2-chloro-2-oxoacetate (0.144 mL, 1.29 mmol) and DIPEA (0.449 mL, 2.57 mmol) were added, stirred at room temperature for 12 hours, and then stirred at 70°C. Stirred over the weekend. The reaction was terminated by adding water to the reactant, and then extracted three times with DCM. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (209 mg), which was immediately used in the next reaction.
LC/MS: 309 (M+H-t-Bu)LC/MS: 309 (M+H-t-Bu)
단계 D: 터트-부틸 (2R,5S)-4-(7-클로로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-2,5-다이메틸피페리딘-1-카르복실레이트의 제조Step D: tert-butyl (2R,5S)-4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl) -Preparation of 2,5-dimethylpiperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000138
Figure PCTKR2023007097-appb-img-000138
터트-부틸 (2R,5S)-4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-2,5-다이메틸피페리딘-1-카르복실레이트 (209 mg, 0.511 mmol)를 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (81 mg, 38%)을 합성하였다.tert-butyl (2R,5S)-4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl The title compound (81 mg, 38%) was synthesized in a similar manner to Step E of Preparation Example 1 using )-2,5-dimethylpiperidine-1-carboxylate (209 mg, 0.511 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 5.36~5.31 (m, 1H), 4.04~3.93 (m, 2H), 3.64 (s, 3H), 3.07~2.95 (m, 2H), 2.76~2.69 (m, 1H), 1.85~1.80 (m, 1H), 1.52 (s, 9H), 1.25 (d, J = 6.0 Hz, 3H), 0.78 (d, J = 6.4 Hz, 3H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 5.36~5.31 (m, 1H), 4.04~3.93 (m , 2H), 3.64 (s, 3H), 3.07~2.95 (m, 2H), 2.76~2.69 (m, 1H), 1.85~1.80 (m, 1H), 1.52 (s, 9H), 1.25 (d, J = 6.0 Hz, 3H), 0.78 (d, J = 6.4 Hz, 3H)
LC/MS: 367 (M+H-t-Bu), 445 (M+Na)LC/MS: 367 (M+H-t-Bu), 445 (M+Na)
단계 E: 7-클로로-4-((2R,5S)-2,5-다이메틸피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 2 염산염의 제조Step E: 7-Chloro-4-((2R,5S)-2,5-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b] Preparation of pyrazine-2,3-dione 2 hydrochloride
Figure PCTKR2023007097-appb-img-000139
Figure PCTKR2023007097-appb-img-000139
터트-부틸 (2R,5S)-4-(7-클로로-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-2,5-다이메틸피페리딘-1-카르복실레이트 (81 mg, 0.192 nnol)를 이용하여 제조예 1의 단계 F와 유사한 방법으로 표제 화합물 (68 mg, 99%)을 합성하였다.tert-butyl (2R,5S)-4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-2, The title compound (68 mg, 99%) was synthesized in a similar manner to Step F of Preparation Example 1 using 5-dimethylpiperidine-1-carboxylate (81 mg, 0.192 nnol).
LC/MS: 323 (M+H)LC/MS: 323 (M+H)
제조예 22: 7-클로로-1,6-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 2 염산염의 제조Preparation Example 22: 7-chloro-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione 2 Preparation of hydrochloride salt
Figure PCTKR2023007097-appb-img-000140
Figure PCTKR2023007097-appb-img-000140
단계 A: 터트-부틸 4-((5-클로로-6-메틸-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((5-chloro-6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000141
Figure PCTKR2023007097-appb-img-000141
제조예 2의 단계 A에서 수득한 터트-부틸 4-((6-메틸-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (1.15 g, 3.42 mmol)를 CH3CN (30 mL)에 녹인 후 NCS를 가한 후 60℃에서 72 시간 동안 교반하였다. 반응물을 상온으로 식힌 후 감압농축하였다. 잔류물을 EtOAc와 소듐 바이카보네이트 수용액으로 희석 후 유기층을 무수 소듐설페이트로 건조한 다음 감압농축하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (770 mg, 61%)을 합성하였다.Tert-butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.15 g, 3.42 mmol) obtained in Step A of Preparation Example 2 was reacted with CH 3 After dissolving in CN (30 mL), NCS was added and stirred at 60°C for 72 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc and an aqueous sodium bicarbonate solution, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by MPLC to synthesize the title compound (770 mg, 61%).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.38 (s, 1H), 8.14 (d, J = 7.0 Hz, 1H), 4.40~4.35 (m, 1H), 4.08 (br s, 2H), 3.03 (d, J = 10.5 Hz, 2H), 2.57 (s, 3H), 2.08~2.06 (m, 2H), 1.55~1.51 (m, 2H), 1.50 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.38 (s, 1H), 8.14 (d, J = 7.0 Hz, 1H), 4.40~4.35 (m, 1H), 4.08 (br s, 2H), 3.03 ( d, J = 10.5 Hz, 2H), 2.57 (s, 3H), 2.08~2.06 (m, 2H), 1.55~1.51 (m, 2H), 1.50 (s, 9H)
LC/MS: 393 (M+H)LC/MS: 393 (M+H)
단계 B: 터트-부틸 4-((3-아미노-5-클로로-6-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((3-amino-5-chloro-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000142
Figure PCTKR2023007097-appb-img-000142
터트-부틸 4-((5-클로로-6-메틸-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (310 mg, 0.836 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (271 mg, 95%)을 합성하였다.Preparation Example 1 using tert-butyl 4-((5-chloro-6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (310 mg, 0.836 mmol) The title compound (271 mg, 95%) was synthesized in a manner similar to Step B.
LC/MS: 341 (M+H)LC/MS: 341 (M+H)
단계 C: 터트-부틸 4-(7-클로로-6-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step C: Tert-Butyl 4-(7-chloro-6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi Preparation of dine-1-carboxylate
Figure PCTKR2023007097-appb-img-000143
Figure PCTKR2023007097-appb-img-000143
터트-부틸 4-((3-아미노-5-클로로-6-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (271 mg, 0.795 mmol)를 이용하여 제조예 7의 단계 C와 유사한 방법으로 표제 화합물 (314 mg, 99%)을 합성하였다.Step of Preparation Example 7 using tert-butyl 4-((3-amino-5-chloro-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate (271 mg, 0.795 mmol) The title compound (314 mg, 99%) was synthesized in a similar manner to C.
LC/MS: 339 (M+H-t-Bu)LC/MS: 339 (M+H-t-Bu)
단계 D: 터트-부틸 4-(7-클로로-1,6-다이메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step D: Tert-Butyl 4-(7-chloro-1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl ) Preparation of piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000144
Figure PCTKR2023007097-appb-img-000144
터트-부틸 4-(7-클로로-6-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (314 mg, 0.795 mmol)를 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (271 mg, 83%)을 합성하였다.Tert-Butyl 4-(7-chloro-6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 The title compound (271 mg, 83%) was synthesized in a similar manner to Step E of Preparation Example 1 using -carboxylate (314 mg, 0.795 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.46 (s, 1H), 5.50 (s, 1H), 4.35~4.24 (m, 2H), 3.61 (s, 3H), 2.87~2.85 (m, 4H), 2.61 (s, 3H), 1.65 (br s, 2H), 1.52 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.46 (s, 1H), 5.50 (s, 1H), 4.35~4.24 (m, 2H), 3.61 (s, 3H), 2.87~2.85 (m, 4H) , 2.61 (s, 3H), 1.65 (br s, 2H), 1.52 (s, 9H)
LC/MS: 431 (M+Na), 353 (M+H-t-Bu)LC/MS: 431 (M+Na), 353 (M+H-t-Bu)
단계 E: 7-클로로-1,6-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 2 염산염의 제조Step E: 7-Chloro-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione 2 Preparation of hydrochloride salt
Figure PCTKR2023007097-appb-img-000145
Figure PCTKR2023007097-appb-img-000145
터트-부틸 4-(7-클로로-1,6-다이메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (271 mg, 0.663 mmol)을 이용하여 제조예 1의 단계 F와 유사한 방법으로 표제 화합물 (221 mg, 97%)을 합성하였다Tert-Butyl 4-(7-chloro-1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi The title compound (221 mg, 97%) was synthesized in a manner similar to Step F of Preparation Example 1 using dine-1-carboxylate (271 mg, 0.663 mmol).
LC/MS: 309 (M+H)LC/MS: 309 (M+H)
제조예 23: 7-브로모-1,6-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 2 염산염의 제조Preparation Example 23: 7-Bromo-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da Preparation of ionic dihydrochloride
Figure PCTKR2023007097-appb-img-000146
Figure PCTKR2023007097-appb-img-000146
단계 A: 터트-부틸 4-((5-브로모-6-메틸-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((5-bromo-6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000147
Figure PCTKR2023007097-appb-img-000147
제조예 2의 단계 A에서 수득한 터트-부틸 4-((6-메틸-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (4.90 g, 14.57 mmol)를 CH3CN (146 mL)에 녹인 후 NBS를 가한 후 상온에서 18 시간 동안 교반하였다. 반응물을 상온으로 식힌 후 감압농축하였다. 잔류물을 EtOAc와 소듐 바이카보네이트 수용액으로 희석 후 유기층을 무수 소듐설페이트로 건조한 다음 감압농축하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (6.05 g, 92%)을 합성하였다.Tert-butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (4.90 g, 14.57 mmol) obtained in Step A of Preparation Example 2 was reacted with CH 3 After dissolving in CN (146 mL), NBS was added and stirred at room temperature for 18 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc and an aqueous sodium bicarbonate solution, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by MPLC to synthesize the title compound (6.05 g, 92%).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.52 (s, 1H), 8.12 (d, J = 7.3 Hz, 1H), 4.37 (m, 1H), 4.08 (br s, 2H), 3.03 (t, J = 11.9 Hz, 2H), 2.61 (s, 3H), 2.08-2.06 (m, 2H), 1.58 (s, 3H), 1.53 (dd, J = 12.8, 4.0 Hz, 2H), 1.50 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.52 (s, 1H), 8.12 (d, J = 7.3 Hz, 1H), 4.37 (m, 1H), 4.08 (br s, 2H), 3.03 (t, J = 11.9 Hz, 2H), 2.61 (s, 3H), 2.08-2.06 (m, 2H), 1.58 (s, 3H), 1.53 (dd, J = 12.8, 4.0 Hz, 2H), 1.50 (s, 9H) )
LC/MS: 437 (M+Na)LC/MS: 437 (M+Na)
단계 B: 터트-부틸 4-((3-아미노-5-브로모-6-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((3-amino-5-bromo-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000148
Figure PCTKR2023007097-appb-img-000148
터트-부틸 4-((5-브로모-6-메틸-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (1000 mg, 2.41 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (811 mg, 87%)을 합성하였다.Preparation Example 1 using tert-butyl 4-((5-bromo-6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1000 mg, 2.41 mmol) The title compound (811 mg, 87%) was synthesized in a manner similar to step B of .
LC/MS: 385, 387 (M+H)LC/MS: 385, 387 (M+H)
단계 C: 터트-부틸 4-(7-브로모-6-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step C: Tert-Butyl 4-(7-bromo-6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p Preparation of peridine-1-carboxylate
Figure PCTKR2023007097-appb-img-000149
Figure PCTKR2023007097-appb-img-000149
터트-부틸 4-((3-아미노-5-브로모-6-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (811 mg, 2.11 mmol)을 이용하여 제조예 7의 단계 C와 유사한 방법으로 표제 화합물 (925 mg, 99%.)을 합성하였다.Preparation Example 7 using tert-butyl 4-((3-amino-5-bromo-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate (811 mg, 2.11 mmol) The title compound (925 mg, 99%.) was synthesized in a manner similar to Step C.
LC/MS: 439, 441 (M+H)LC/MS: 439, 441 (M+H)
단계 D: 터트-부틸 4-(7-브로모-1,6-다이메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step D: Tert-Butyl 4-(7-bromo-1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)- 1) Preparation of piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000150
Figure PCTKR2023007097-appb-img-000150
터트-부틸 4-(7-브로모-6-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (925 mg, 2.11 mmol)를 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (732 mg, 77%)을 합성하였다.Tert-butyl 4-(7-bromo-6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- The title compound (732 mg, 77%) was synthesized in a similar manner to Step E of Preparation Example 1 using 1-carboxylate (925 mg, 2.11 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.61 (s, 1H), 5.49 (s, 1H), 4.35~4.24 (m, 2H), 3.61 (s, 3H), 2.87~2.85 (m, 4H), 2.65 (s, 3H), 1.64 (br s, 2H), 1.52 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.61 (s, 1H), 5.49 (s, 1H), 4.35~4.24 (m, 2H), 3.61 (s, 3H), 2.87~2.85 (m, 4H) , 2.65 (s, 3H), 1.64 (br s, 2H), 1.52 (s, 9H)
LC/MS: 475, 477 (M+Na)LC/MS: 475, 477 (M+Na)
단계 E: 7-브로모-1,6-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 2 염산염의 제조Step E: 7-Bromo-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione 2 Preparation of hydrochloride salt
Figure PCTKR2023007097-appb-img-000151
Figure PCTKR2023007097-appb-img-000151
터트-부틸 4-(7-브로모-1,6-다이메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (732 mg, 1.62 mmol)를 이용하여 제조예 1의 단계 F와 유사한 방법으로 표제 화합물 (631 mg, 100%)을 합성하였다.tert-butyl 4-(7-bromo-1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p The title compound (631 mg, 100%) was synthesized in a similar manner to Step F of Preparation Example 1 using peridine-1-carboxylate (732 mg, 1.62 mmol).
LC/MS: 353, 355 (M+H)LC/MS: 353, 355 (M+H)
제조예 24: 1,8-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 염산염의 제조Preparation Example 24: Preparation of 1,8-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride
Figure PCTKR2023007097-appb-img-000152
Figure PCTKR2023007097-appb-img-000152
단계 A: 터트-부틸 4-((4-메틸-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((4-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000153
Figure PCTKR2023007097-appb-img-000153
2-플루오로-4-메틸-3-나이트로피리딘 (1.56 g, 9.99 mmol)을 이용하여 제조예 1의 단계 A와 같은 방법으로 표제 화합물 (3.32 g, 99%)을 합성하였다.The title compound (3.32 g, 99%) was synthesized in the same manner as Step A of Preparation Example 1 using 2-fluoro-4-methyl-3-nitropyridine (1.56 g, 9.99 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.14 (d, J = 5.0 Hz, 1H), 7.45 (d, J = 7.0 Hz, 1H), 6.50 (d, J = 5.0 Hz, 1H), 4.31~4.28 (m, 1H), 4.06 (br s, 2H), 3.04~2.99 (m, 2H), 2.56 (s, 3H), 2.08~2.06 (m, 2H), 1.52 (s, 9H), 1.51~1.44 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.14 (d, J = 5.0 Hz, 1H), 7.45 (d, J = 7.0 Hz, 1H), 6.50 (d, J = 5.0 Hz, 1H), 4.31~ 4.28 (m, 1H), 4.06 (br s, 2H), 3.04~2.99 (m, 2H), 2.56 (s, 3H), 2.08~2.06 (m, 2H), 1.52 (s, 9H), 1.51~1.44 (m, 2H)
LC/MS: 337 (M+H)LC/MS: 337 (M+H)
단계 B: 터트-부틸 4-((3-아미노-4-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((3-amino-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000154
Figure PCTKR2023007097-appb-img-000154
터트-부틸 4-((4-메틸-3-나이트로피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (1.5 g, 4.46 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (1.35 g, 99%)을 수득하였고, 정제하지 않고 다음 반응에 바로 사용하였다.Similar to step B of Preparation Example 1 using tert-butyl 4-((4-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.5 g, 4.46 mmol) The title compound (1.35 g, 99%) was obtained through this method, and was used directly in the next reaction without purification.
LC/MS: 307 (M+H)LC/MS: 307 (M+H)
단계 C: 터트-부틸 4-((3-(2-에톡시-2-옥소아세트아미도)-4-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step C: Preparation of tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate
Figure PCTKR2023007097-appb-img-000155
Figure PCTKR2023007097-appb-img-000155
터트-부틸 4-((3-아미노-4-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (1.35 g, 4.41 mmol)를 이용하여 제조예 1의 단계 C와 유사한 방법으로 표제 화합물 (1.67 g, 93%)을 수득하였다.Similar method to Step C of Preparation Example 1 using tert-butyl 4-((3-amino-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate (1.35 g, 4.41 mmol) The title compound (1.67 g, 93%) was obtained.
LC/MS: 407 (M+H)LC/MS: 407 (M+H)
단계 D: 터트-부틸 4-(8-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step D: Tert-Butyl 4-(8-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates
Figure PCTKR2023007097-appb-img-000156
Figure PCTKR2023007097-appb-img-000156
터트-부틸 4-((3-(2-에톡시-2-옥소아세트아미도)-4-메틸피리딘-2-일)아미노)피페리딘-1-카르복실레이트 (930 mg, 2.29 mmol)와 DIPEA (2.0 mL, 11.4 mmol) 혼합물을 DCE (15 mL)에 녹인 후 70℃에서 24시간 동안 교반하였다. 반응물을 상온으로 식히고 감압농축 후 MPLC를 이용하여 표제 화합물 (34 mg, 4%)을 수득하였다.Tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate (930 mg, 2.29 mmol) and DIPEA (2.0 mL, 11.4 mmol) were dissolved in DCE (15 mL) and stirred at 70°C for 24 hours. The reaction product was cooled to room temperature and concentrated under reduced pressure to obtain the title compound (34 mg, 4%) using MPLC.
LC/MS: 305 (M+H-t-Bu)LC/MS: 305 (M+H-t-Bu)
단계 E: 터트-부틸 4-(1,8-다이메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트의 제조Step E: Tert-Butyl 4-(1,8-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -Preparation of 1-carboxylate
Figure PCTKR2023007097-appb-img-000157
Figure PCTKR2023007097-appb-img-000157
터트-부틸 4-(8-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (34 mg, 0.094 mmol)를 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (35 mg, 99%)을 합성하였다.Tert-Butyl 4-(8-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate The title compound (35 mg, 99%) was synthesized in a similar manner to Step E of Preparation Example 1 using (34 mg, 0.094 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.24 (d, J = 5.0 Hz, 1H), 7.12 (d, J = 5.0 Hz, 1H), 5.74 (br s, 1H), 4.31~4.22 (m, 2H), 4.13 (s, 3H), 2.96~2.94 (m, 4H), 2.61 (s, 3H), 1.65~1.62 (m, 2H), 1.52 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.24 (d, J = 5.0 Hz, 1H), 7.12 (d, J = 5.0 Hz, 1H), 5.74 (br s, 1H), 4.31~4.22 (m, 2H), 4.13 (s, 3H), 2.96~2.94 (m, 4H), 2.61 (s, 3H), 1.65~1.62 (m, 2H), 1.52 (s, 9H)
LC/MS: 397 (M+Na)LC/MS: 397 (M+Na)
단계 F: 1,8-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 염산염의 제조Step F: Preparation of 1,8-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride
Figure PCTKR2023007097-appb-img-000158
Figure PCTKR2023007097-appb-img-000158
터트-부틸 4-(1,8-다이메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르복실레이트 (35 mg, 0.093 mmol)를 이용하여 제조예 1의 단계 F와 유사한 방법으로 표제 화합물 (29.2 mg, 100%)을 합성하였다.Tert-Butyl 4-(1,8-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- The title compound (29.2 mg, 100%) was synthesized in a manner similar to Step F of Preparation Example 1 using carboxylate (35 mg, 0.093 mmol).
LC/MS: 275 (M+H)LC/MS: 275 (M+H)
실시예 1: 1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 1: 1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione (1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione )Manufacture of
Figure PCTKR2023007097-appb-img-000159
Figure PCTKR2023007097-appb-img-000159
제조예 1에서 얻은 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol), EDC (42 mg, 0.20 mmol), HOBt (31 mg, 0.20 mmol), 4-(트라이플루오로메톡시)벤조산(40 mg, 0.2 mmol)을 DMF (1 mL)에 녹인 후 TEA (42 μL, 0.30 mmol)를 상온에서 가하였다. 반응 혼합물을 상온에서 16 시간 교반 후, EtOAc로 묽힌 뒤 포화 NH4Cl 수용액으로 3회 세척하였다. 유기층을 무수 MgSO4로 건조 후 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (31 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30 mg, 0.10 mmol) obtained in Preparation Example 1 ), EDC (42 mg, 0.20 mmol), HOBt (31 mg, 0.20 mmol), and 4-(trifluoromethoxy)benzoic acid (40 mg, 0.2 mmol) were dissolved in DMF (1 mL) and then added to TEA (42 μL, 0.30 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours, diluted with EtOAc, and washed three times with saturated NH 4 Cl aqueous solution. The organic layer was dried over anhydrous MgSO 4 and then distilled under reduced pressure. The residue was purified by MPLC to give the title compound (31 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.27 (d, J = 4.6 Hz, 1H), 7.53 (dd, J = 8.5, 2.1 Hz, 3H), 7.28-7.24 (m, 3H), 5.71 (br s, 2H), 4.91 (br s, 1H), 3.87 (br s, 1H), 3.64 (s, 3H), 3.21 (br s, 1H), 2.97 (br s, 3H), 1.81 (br s, 1H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.27 (d, J = 4.6 Hz, 1H), 7.53 (dd, J = 8.5, 2.1 Hz, 3H), 7.28-7.24 (m, 3H), 5.71 (br s, 2H), 4.91 (br s, 1H), 3.87 (br s, 1H), 3.64 (s, 3H), 3.21 (br s, 1H), 2.97 (br s, 3H), 1.81 (br s, 1H) )
LC/MS: 449.1 (M+H)LC/MS: 449.1 (M+H)
실시예 2: 1,6-다이메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 2: 1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione (1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine- Preparation of 2,3-dione)
Figure PCTKR2023007097-appb-img-000160
Figure PCTKR2023007097-appb-img-000160
제조예 2에서 얻은 1,6-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.01 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (29 mg)을 얻었다.1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30 mg) obtained in Preparation Example 2 , 0.01 mmol) to obtain the title compound (29 mg) in a similar manner to Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.54-7.52 (m, 2H), 7.41 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 7.3 Hz, 2H), 7.07 (d, J = 8.2 Hz, 1H), 5.73 (br s, 2H), 4.91 (br s, 1H), 3.87 (br s, 1H), 3.61 (s, 3H), 3.23 (br s, 1H), 3.00 (dd, J = 20.3, 11.4 Hz, 2H), 2.57 (s, 3H), 1.74 (d, J = 58.6 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.54-7.52 (m, 2H), 7.41 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 7.3 Hz, 2H), 7.07 (d, J = 8.2 Hz, 1H), 5.73 (br s, 2H), 4.91 (br s, 1H), 3.87 (br s, 1H), 3.61 (s, 3H), 3.23 (br s, 1H), 3.00 (dd, J = 20.3, 11.4 Hz, 2H), 2.57 (s, 3H), 1.74 (d, J = 58.6 Hz, 2H)
LC/MS: 463.1 (M+H)LC/MS: 463.1 (M+H)
실시예 3: 1,6-다이메틸-4-(1-토실피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (1,6-dimethyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 3: 1,6-dimethyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione ( Preparation of 1,6-dimethyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000161
Figure PCTKR2023007097-appb-img-000161
제조예 2에서 얻은 1,6-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.01 mmol)과 DIPEA (0.057 mL, 0.318 mmol)을 DCM (0.9 mL)에 녹인 후 4-메틸벤젠설포닐 클로라이드 (28 mg, 0.15 mmol)를 상온에서 가하였다. 반응 혼합물을 3 시간 동안 상온에서 교반한 뒤, DCM으로 묽히고 brine을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조한 뒤 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (38 mg)을 얻었다.1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30 mg) obtained in Preparation Example 2 , 0.01 mmol) and DIPEA (0.057 mL, 0.318 mmol) were dissolved in DCM (0.9 mL), and then 4-methylbenzenesulfonyl chloride (28 mg, 0.15 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours, then diluted with DCM and extracted using brine. The organic layer was dried with anhydrous MgSO 4 and then distilled under reduced pressure. The residue was purified by MPLC to give the title compound (38 mg).
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.22 (d, J = 5.9 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 6.9 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 5.48-5.43 (m, 1H), 3.59 (s, 3H), 3.11-3.04 (m, 4H), 2.54 (d, J = 14.2 Hz, 3H), 2.36-2.29 (m, 2H), 1.74-1.49 (m, 2H), 1.43 (s, 3H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.22 (d, J = 5.9 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 6.9 Hz, 1H), 7.55 ( t, J = 7.5 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 5.48-5.43 (m, 1H), 3.59 (s, 3H), 3.11-3.04 (m, 4H), 2.54 (d, J = 14.2 Hz, 3H), 2.36-2.29 (m, 2H), 1.74-1.49 (m, 2H), 1.43 (s, 3H)
LC/MS: 429.1 (M+H)LC/MS: 429.1 (M+H)
실시예 4: 4-(1-((3-클로로페닐)설포닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (4-(1-((3-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 4: 4-(1-((3-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione (4-(1-((3-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione) manufacture of
Figure PCTKR2023007097-appb-img-000162
Figure PCTKR2023007097-appb-img-000162
제조예 1에서 얻은 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (20 mg, 0.067 mmol)과 3-클로로벤젠설포닐 클로라이드 (16 mg, 0.074 mmol)를 이용하여 실시예 3과 유사한 방법으로 표제 화합물 (11 mg)을 수득하였다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (20 mg, 0.067 mmol) obtained in Preparation Example 1 ) and 3-chlorobenzenesulfonyl chloride (16 mg, 0.074 mmol) to obtain the title compound (11 mg) in a similar manner to Example 3.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.13 (d, J = 2.3 Hz, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.37-7.33 (m, 1H), 7.26-7.21 (m, 2H), 7.15 (dd, J = 7.3, 6.4 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 5.53-5.46 (m, 1H), 4.85 (d, J = 11.9 Hz, 1H), 4.03 (d, J = 13.7 Hz, 1H), 3.78 (d, J = 5.0 Hz, 2H), 3.59 (s, 3H), 2.75-2.65 (m, 2H), 1.70-1.63 (m, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.13 (d, J = 2.3 Hz, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.37-7.33 (m, 1H), 7.26-7.21 (m , 2H), 7.15 (dd, J = 7.3, 6.4 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 5.53-5.46 (m, 1H), 4.85 (d, J = 11.9 Hz, 1H) , 4.03 (d, J = 13.7 Hz, 1H), 3.78 (d, J = 5.0 Hz, 2H), 3.59 (s, 3H), 2.75-2.65 (m, 2H), 1.70-1.63 (m, 2H)
LC/MS: 435.0 (M+H), 436.0 (M+2H)LC/MS: 435.0 (M+H), 436.0 (M+2H)
실시예 5: 4-(1-((3,4-다이클로로페닐)설포닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (4-(1-((3,4-dichlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 5: 4-(1-((3,4-dichlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b] Pyrazine-2,3-dione (4-(1-((3,4-dichlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b]pyrazine-2 ,3-dione) production
Figure PCTKR2023007097-appb-img-000163
Figure PCTKR2023007097-appb-img-000163
제조예 1에서 얻은 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (20 mg, 0.067 mmol)과 3,4-다이클로로벤젠설포닐 클로라이드 (18 mg, 0.074 mmol)를 이용하여 실시예 3과 유사한 방법으로 표제 화합물 (20 mg)을 수득하였다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (20 mg, 0.067 mmol) obtained in Preparation Example 1 ) and 3,4-dichlorobenzenesulfonyl chloride (18 mg, 0.074 mmol) to obtain the title compound (20 mg) in a similar manner to Example 3.
LC/MS: 469.0 (M+H)LC/MS: 469.0 (M+H)
실시예 6: 1-메틸-4-(1-((4-페녹시페닐)설포닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (1-methyl-4-(1-((4-phenoxyphenyl)sulfonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 6: 1-Methyl-4-(1-((4-phenoxyphenyl)sulfonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione (1-methyl-4-(1-((4-phenoxyphenyl)sulfonyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione )Manufacture of
Figure PCTKR2023007097-appb-img-000164
Figure PCTKR2023007097-appb-img-000164
제조예 1에서 얻은 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (20 mg, 0.067 mmol)과 4-페녹시벤젠설포닐 클로라이드 (20 mg, 0.074 mmol)를 이용하여 실시예 3과 유사한 방법으로 표제 화합물 (1 mg)을 수득하였다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (20 mg, 0.067 mmol) obtained in Preparation Example 1 ) and 4-phenoxybenzenesulfonyl chloride (20 mg, 0.074 mmol) to obtain the title compound (1 mg) in a similar manner to Example 3.
LC/MS:493.1 (M+H), 515.1(M+Na)LC/MS:493.1 (M+H), 515.1(M+Na)
실시예 7: 1-메틸-2,3-다이옥소-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-6-카르보나이트릴 (1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile)의 제조Example 7: 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetrahydro Pyrido[2,3-b]pyrazine-6-carbonitrile (1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2 Manufacture of ,3,4-tetrahydropyrid[2,3-b]pyrazine-6-carbonitrile)
Figure PCTKR2023007097-appb-img-000165
Figure PCTKR2023007097-appb-img-000165
제조예 3에서 얻은 1-메틸-2,3-다이옥소-4-(피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-6-카르보나이트릴 (50 mg, 0.155 mmol)과 4-(트라이플루오로메톡시)벤조일 클로라이드 (0.029 ml, 0.186 mmol)를 이용하여 실시예 8과 같은 방법으로 표제 화합물 (52 mg)을 얻었다.1-Methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6 obtained in Preparation Example 3 The title compound (52 mg) was obtained in the same manner as in Example 8 using -carbonitrile (50 mg, 0.155 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.029 ml, 0.186 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.67 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 8.5Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 2.0 Hz, 2H), 5.67~5.62 (m, 1H), 4.97~4.95 (m, 1H), 3.91 (br s, 1H), 3.68 (s, 3H), 3.23 (br s, 1H), 2.95~2.87 (m, 3H), 1.82~1.70 (d, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.67 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 8.5Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.31 ( d, J = 2.0 Hz, 2H), 5.67~5.62 (m, 1H), 4.97~4.95 (m, 1H), 3.91 (br s, 1H), 3.68 (s, 3H), 3.23 (br s, 1H) , 2.95~2.87 (m, 3H), 1.82~1.70 (d, 2H)
LC/MS: 474 (M+H)LC/MS: 474 (M+H)
실시예 8: 7-클로로-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 8: 7-Chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b ]Manufacture of pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000166
Figure PCTKR2023007097-appb-img-000166
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (800 mg, 2.73 mmol)과 DIPEA (2.1 mL, 12.08 mmol)를 DCM (20 mL)에 녹인 후 4-(트라이플루오로메톡시)벤조일 클로라이드 (0.571 ml, 3.62 mmol)를 0℃에서 가하였다. 반응 혼합물을 6 시간 동안 상온에서 교반 후 DCM으로 묽힌 뒤, 포화 NH4Cl 수용액을 이용해 추출하였다. 유기층을 무수 MgSO4를 이용하여 건조한 뒤 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (860 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (800) obtained in Preparation Example 4 mg, 2.73 mmol) and DIPEA (2.1 mL, 12.08 mmol) were dissolved in DCM (20 mL), and then 4-(trifluoromethoxy)benzoyl chloride (0.571 ml, 3.62 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 6 hours, diluted with DCM, and extracted using a saturated NH 4 Cl aqueous solution. The organic layer was dried using anhydrous MgSO 4 and then distilled under reduced pressure. The residue was purified by MPLC to give the title compound (860 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 1.5 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 5.62 (t, J = 11.6 Hz, 1H), 4.91 (br s, 2H), 3.88 (br s, 1H), 3.62 (br s, 3H), 3.20 (br s, 1H), 2.93 (br s, 2H), 1.90-1.52 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 1.5 Hz, 1H), 7.27 ( d, J = 8.2 Hz, 2H), 5.62 (t, J = 11.6 Hz, 1H), 4.91 (br s, 2H), 3.88 (br s, 1H), 3.62 (br s, 3H), 3.20 (br s , 1H), 2.93 (br s, 2H), 1.90-1.52 (m, 2H)
LC/MS: 483.1 (M+H)LC/MS: 483.1 (M+H)
실시예 9: 7-클로로-1-메틸-4-(1-토실피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 9: 7-Chloro-1-methyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione Preparation of (7-chloro-1-methyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000167
Figure PCTKR2023007097-appb-img-000167
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (23 mg, 0.078 mmol)과 4-메틸벤젠설포닐 클로라이드 (14.88 mg, 0.078 mmol)를 이용하여 실시예 3과 유사한 방법으로 표제 화합물 (13 mg)을 수득하였다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (23) obtained in Preparation Example 4 mg, 0.078 mmol) and 4-methylbenzenesulfonyl chloride (14.88 mg, 0.078 mmol) to obtain the title compound (13 mg) in a similar manner to Example 3.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.12 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 1.8 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 5.16 (tt, J = 12.1, 3.7 Hz, 1H), 3.95 (d, J = 11.9 Hz, 2H), 3.57 (t, J = 15.1 Hz, 3H), 3.04 (qd, J = 12.3, 4.1 Hz, 2H), 2.47 (d, J = 15.1 Hz, 4H), 2.40 (dd, J = 11.9, 1.8 Hz, 2H), 1.66 (d, J = 11.9 Hz, 3H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.12 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 1.8 Hz, 1H), 7.34 ( d, J = 7.8 Hz, 2H), 5.16 (tt, J = 12.1, 3.7 Hz, 1H), 3.95 (d, J = 11.9 Hz, 2H), 3.57 (t, J = 15.1 Hz, 3H), 3.04 ( qd, J = 12.3, 4.1 Hz, 2H), 2.47 (d, J = 15.1 Hz, 4H), 2.40 (dd, J = 11.9, 1.8 Hz, 2H), 1.66 (d, J = 11.9 Hz, 3H)
LC/MS: 449 (M+H)LC/MS: 449 (M+H)
실시예 10: 7-클로로-4-(3,3-다이메틸-1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(3,3-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 10: 7-Chloro-4-(3,3-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydro Pyrido[2,3-b]pyrazine-2,3-dione (7-chloro-4-(3,3-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1- Preparation of methyl-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000168
Figure PCTKR2023007097-appb-img-000168
제조예 5에서 얻은 7-클로로-4-(3,3-다이메틸피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (47 mg, 0.119 mmol)과 4-(트라이플루오로메톡시)벤조일 클로라이드 (0.022 ml, 0.143 mmol)를 이용하여 실시예 8과 같은 방법으로 표제 화합물 (51 mg)을 얻었다.7-chloro-4-(3,3-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 obtained in Preparation Example 5, The title compound (51 mg) was obtained in the same manner as in Example 8 using 3-dione (47 mg, 0.119 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.022 ml, 0.143 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (s, 1H), 7.51~7.50 (m, 3H), 7.29 (d, J = 8.5 Hz, 2H), 5.78, 5.45 (2s, 1H), 4.91, 4.53 (2s, 1H), 3.93~2.85 (m, 3H), 3.65 (s, 3H), 1.72~1.63 (m, 2H), 1.28~0.78 (m, 6H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (s, 1H), 7.51~7.50 (m, 3H), 7.29 (d, J = 8.5 Hz, 2H), 5.78, 5.45 (2s, 1H), 4.91 , 4.53 (2s, 1H), 3.93~2.85 (m, 3H), 3.65 (s, 3H), 1.72~1.63 (m, 2H), 1.28~0.78 (m, 6H)
LC/MS: 511 (M+H)LC/MS: 511 (M+H)
실시예 11: 7-클로로-1-메틸-4-((1R,3s,5S)-8-(4-(트라이플루오로메톡시)벤조일)-8-아자바이사이클로[3.2.1]옥탄-3-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-((1R,3s,5S)-8-(4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 11: 7-Chloro-1-methyl-4-((1R,3s,5S)-8-(4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octane-3 -1)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-((1R,3s,5S)-8-( Preparation of 4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000169
Figure PCTKR2023007097-appb-img-000169
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (20 mg, 0.056 mmol)를 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (24 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (20) obtained in Preparation Example 4 mg, 0.056 mmol) to obtain the title compound (24 mg) in a similar manner to Example 8.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.23 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 2.1 Hz, 1H), 7.32-7.27 (m, 2H), 5.74 (t, J = 9.6 Hz, 1H), 4.99 (br s, 1H), 4.13 (br s, 1H), 3.62 (s, 3H), 2.53 (d, J = 9.2 Hz, 1H), 2.46-2.36 (m, 2H), 2.29 (t, J = 9.0 Hz, 1H), 2.13-2.04 (m, 4H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.23 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 2.1 Hz, 1H), 7.32- 7.27 (m, 2H), 5.74 (t, J = 9.6 Hz, 1H), 4.99 (br s, 1H), 4.13 (br s, 1H), 3.62 (s, 3H), 2.53 (d, J = 9.2 Hz) , 1H), 2.46-2.36 (m, 2H), 2.29 (t, J = 9.0 Hz, 1H), 2.13-2.04 (m, 4H)
LC/MS: 509.1 (M+H), 531.1 (M+Na)LC/MS: 509.1 (M+H), 531.1 (M+Na)
실시예 12: 7-브로모-1-메틸-2,3-다이옥소-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-6-카르보나이트릴 (7-bromo-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile)의 제조Example 12: 7-Bromo-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3 ,4-Tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile (7-bromo-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin Preparation of -4-yl)-1,2,3,4-tetrahydropyrid[2,3-b]pyrazine-6-carbonitrile)
Figure PCTKR2023007097-appb-img-000170
Figure PCTKR2023007097-appb-img-000170
제조예 19에서 얻은 7-브로모-1-메틸-2,3-다이옥소-4-(피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-6-카르보나이트릴 (52 mg, 0.119 mmol)과 4-(트라이플루오로메톡시)벤조일 클로라이드 (0.022 ml, 0.143 mmol)를 이용하여 실시예 8과 같은 방법으로 표제 화합물 (59 mg)을 얻었다.7-Bromo-1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-] obtained in Preparation Example 19 b] The title compound (59 mg) was prepared in the same manner as in Example 8 using pyrazine-6-carbonitrile (52 mg, 0.119 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.022 ml, 0.143 mmol). got it
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.74 (s, 1H), 7.56 (d, J = 8.5Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 5.58~5.53 (m, 1H), 4.94 (br s, 1H), 3.91 (br s, 1H), 3.67 (s, 3H), 3.22 (br s, 1H), 2.97~2.83 (m, 3H), 1.81~1.70 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.74 (s, 1H), 7.56 (d, J = 8.5Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 5.58~5.53 (m, 1H) ), 4.94 (br s, 1H), 3.91 (br s, 1H), 3.67 (s, 3H), 3.22 (br s, 1H), 2.97~2.83 (m, 3H), 1.81~1.70 (m, 2H)
LC/MS: 552, 554 (M+H)LC/MS: 552, 554 (M+H)
실시예 13: 7-클로로-1-메틸-4-(1-(2-(4-(트라이플루오로메톡시)페닐)아세틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 13: 7-Chloro-1-methyl-4-(1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)-1 ,Manufacture of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000171
Figure PCTKR2023007097-appb-img-000171
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol)과 2-(4-(트라이플루오로메톡시)페닐)아세트산 (24 mg, 0.11 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (30 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 2-(4-(trifluoromethoxy)phenyl)acetic acid (24 mg, 0.11 mmol) to obtain the title compound (30 mg) in a similar manner to Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.13 (d, J = 2.1 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 5.54-5.50 (m, 1H), 4.85 (d, J = 11.6 Hz, 1H), 4.01 (d, J = 14.0 Hz, 1H), 3.79 (s, 2H), 3.60 (s, 3H), 3.20-3.15 (m, 1H), 2.84-2.65 (m, 3H), 1.71 (d, J = 12.8 Hz, 1H), 1.65 (d, J = 11.9 Hz, 1H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.13 (d, J = 2.1 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.20 ( d, J = 8.2 Hz, 2H), 5.54-5.50 (m, 1H), 4.85 (d, J = 11.6 Hz, 1H), 4.01 (d, J = 14.0 Hz, 1H), 3.79 (s, 2H), 3.60 (s, 3H), 3.20-3.15 (m, 1H), 2.84-2.65 (m, 3H), 1.71 (d, J = 12.8 Hz, 1H), 1.65 (d, J = 11.9 Hz, 1H)
LC/MS: 497.1 (M+H)LC/MS: 497.1 (M+H)
실시예 14: 7-클로로-4-(4-(3-클로로페녹시)사이클로헥실)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(4-(3-chlorophenoxy)cyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 14: 7-Chloro-4-(4-(3-chlorophenoxy)cyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da Preparation of ion (7-chloro-4-(4-(3-chlorophenoxy)cyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000172
Figure PCTKR2023007097-appb-img-000172
단계 A: 4-((5-클로로-3-나이트로피리딘-2-일)아미노)사이클로헥산-1-올의 제조Step A: Preparation of 4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexan-1-ol
Figure PCTKR2023007097-appb-img-000173
Figure PCTKR2023007097-appb-img-000173
5-클로로-2-플루오로-3-나이트로피리딘 (1 g, 5.66 mmol)과 4-아미노사이클로헥산-1-올 (0.652 g, 5.66 mmol)을 이용하여 제조예 1의 단계 A와 같은 방법으로 표제 화합물 (1.49 g)을 수득하였다.The same method as Step A of Preparation Example 1 using 5-chloro-2-fluoro-3-nitropyridine (1 g, 5.66 mmol) and 4-aminocyclohexan-1-ol (0.652 g, 5.66 mmol) The title compound (1.49 g) was obtained.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.39 (d, J = 2.7 Hz, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.05 (d, J = 5.9 Hz, 1H), 4.18-4.11 (m, 1H), 3.72 (dt, J = 14.5, 5.1 Hz, 1H), 2.17-2.14 (m, 2H), 2.04 (d, J = 11.4 Hz, 2H), 1.51-1.34 (m, 5H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.39 (d, J = 2.7 Hz, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.05 (d, J = 5.9 Hz, 1H), 4.18- 4.11 (m, 1H), 3.72 (dt, J = 14.5, 5.1 Hz, 1H), 2.17-2.14 (m, 2H), 2.04 (d, J = 11.4 Hz, 2H), 1.51-1.34 (m, 5H)
LC/MS: 272 (M+H)LC/MS: 272 (M+H)
단계 B: 5-클로로-N-(4-(3-클로로페녹시)사이클로헥실)-3-나이트로피리딘-2-아민의 제조Step B: Preparation of 5-chloro-N-(4-(3-chlorophenoxy)cyclohexyl)-3-nitropyridin-2-amine
Figure PCTKR2023007097-appb-img-000174
Figure PCTKR2023007097-appb-img-000174
4-((5-클로로-3-나이트로피리딘-2-일)아미노)사이클로헥산-1-ol (500 mg, 1.840 mmol)를 THF (5 ml)에 녹이고 3-클로로페놀 (214 μl, 2.024 mmol), TEA (513 μl, 3.68 mmol)와 트라이페닐포스핀 (965 mg, 3.68 mmol)을 가한 후 DIAD (716 μl, 3.68 mmol)를 서서히 넣어준 후 상온에서 4시간 교반해주었다. 반응물을 물로 희석 후 EtOAc로 추출하였다. 유기층을 무수 마그네슘설페이트로 건조한 다음 감압농축하여 표제 화합물 (174 mg)을 수득하였고 정제하지 않고 다음 반응에 바로 사용하였다.4-((5-Chloro-3-nitropyridin-2-yl)amino)cyclohexane-1-ol (500 mg, 1.840 mmol) was dissolved in THF (5 ml) and 3-chlorophenol (214 μl, 2.024 μl) mmol), TEA (513 μl, 3.68 mmol) and triphenylphosphine (965 mg, 3.68 mmol) were added, DIAD (716 μl, 3.68 mmol) was slowly added, and the mixture was stirred at room temperature for 4 hours. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (174 mg), which was used directly in the next reaction without purification.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.40 (d, J = 2.7 Hz, 1H), 8.34 (d, J = 2.7 Hz, 1H), 8.20 (d, J = 7.3 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 6.93-6.91 (m, 2H), 6.83-6.80 (m, 1H), 4.50 (q, J = 2.3 Hz, 1H), 4.29-4.25 (m, 1H), 2.08-2.03 (m, 2H), 1.94-1.90 (m, 2H), 1.86-1.73 (m, 4H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.40 (d, J = 2.7 Hz, 1H), 8.34 (d, J = 2.7 Hz, 1H), 8.20 (d, J = 7.3 Hz, 1H), 7.19 ( t, J = 8.0 Hz, 1H), 6.93-6.91 (m, 2H), 6.83-6.80 (m, 1H), 4.50 (q, J = 2.3 Hz, 1H), 4.29-4.25 (m, 1H), 2.08 -2.03 (m, 2H), 1.94-1.90 (m, 2H), 1.86-1.73 (m, 4H)
LC/MS: 383 (M+H)LC/MS: 383 (M+H)
단계 C: 에틸 2-((5-클로로-3-나이트로피리딘-2-일)(4-(3-클로로페녹시)사이클로헥실)아미노)-2-옥소아세테이트의 제조Step C: Preparation of ethyl 2-((5-chloro-3-nitropyridin-2-yl)(4-(3-chlorophenoxy)cyclohexyl)amino)-2-oxoacetate
Figure PCTKR2023007097-appb-img-000175
Figure PCTKR2023007097-appb-img-000175
5-클로로-N-(4-(3-클로로페녹시)사이클로헥실)-3-나이트로피리딘-2-아민 (28 mg, 0.073 mmol)을 이용하여 제조예 3의 단계 C와 같은 방법으로 표제 화합물 (15 mg)을 수득하였다.5-Chloro-N-(4-(3-chlorophenoxy)cyclohexyl)-3-nitropyridin-2-amine (28 mg, 0.073 mmol) was used in the same manner as Step C of Preparation Example 3. Compound (15 mg) was obtained.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.75 (d, J = 2.7 Hz, 1H), 8.35 (d, J = 2.3 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.80 (s, 1H), 6.70 (d, J = 8.2 Hz, 1H), 4.54 (s, 1H), 4.45 (s, 1H), 4.12 (q, J = 6.9 Hz, 2H), 2.08 (dd, J = 23.6, 12.6 Hz, 2H), 1.72-1.59 (m, 4H), 1.24 (t, J = 6.9 Hz, 3H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.75 (d, J = 2.7 Hz, 1H), 8.35 (d, J = 2.3 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.89 ( d, J = 8.2 Hz, 1H), 6.80 (s, 1H), 6.70 (d, J = 8.2 Hz, 1H), 4.54 (s, 1H), 4.45 (s, 1H), 4.12 (q, J = 6.9 Hz, 2H), 2.08 (dd, J = 23.6, 12.6 Hz, 2H), 1.72-1.59 (m, 4H), 1.24 (t, J = 6.9 Hz, 3H)
LC/MS: 482 (M+H)LC/MS: 482 (M+H)
단계 D: 7-클로로-4-(4-(3-클로로페녹시)사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step D: Preparation of 7-chloro-4-(4-(3-chlorophenoxy)cyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
Figure PCTKR2023007097-appb-img-000176
Figure PCTKR2023007097-appb-img-000176
에틸 2-((5-클로로-3-나이트로피리딘-2-일)(4-(3-클로로페녹시)사이클로헥실)아미노)-2-옥소아세테이트 (15 mg, 0.031 mmol)를 이용하여 제조예 3의 단계 D와 같은 방법으로 표제 화합물 (2 mg)을 수득하였고 정제하지 않고 다음 반응에 바로 사용하였다.Prepared using ethyl 2-((5-chloro-3-nitropyridin-2-yl)(4-(3-chlorophenoxy)cyclohexyl)amino)-2-oxoacetate (15 mg, 0.031 mmol) The title compound (2 mg) was obtained in the same manner as Step D of Example 3 and used directly in the next reaction without purification.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.23 (s, 1H), 7.69 (s, 1H), 7.20 (t, J = 8.2 Hz, 1H), 7.01 (t, J = 2.1 Hz, 1H), 6.92-6.90 (m, 2H), 5.43 (s, 1H), 4.61 (s, 1H), 3.10 (d, J = 10.1 Hz, 2H), 2.22 (d, J = 12.8 Hz, 2H), 1.71 (t, J = 14.0 Hz, 3H), 1.52 (d, J = 11.4 Hz, 4H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.23 (s, 1H), 7.69 (s, 1H), 7.20 (t, J = 8.2 Hz, 1H), 7.01 (t, J = 2.1 Hz, 1H), 6.92-6.90 (m, 2H), 5.43 (s, 1H), 4.61 (s, 1H), 3.10 (d, J = 10.1 Hz, 2H), 2.22 (d, J = 12.8 Hz, 2H), 1.71 (t , J = 14.0 Hz, 3H), 1.52 (d, J = 11.4 Hz, 4H)
LC/MS: 407 (M+H)LC/MS: 407 (M+H)
단계 E: 7-클로로-4-(4-(3-클로로페녹시)사이클로헥실)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 제조Step E: 7-Chloro-4-(4-(3-chlorophenoxy)cyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione manufacture of
Figure PCTKR2023007097-appb-img-000177
Figure PCTKR2023007097-appb-img-000177
7-클로로-4-(4-(3-클로로페녹시)사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (5 mg, 0.012 mmol)을 이용하여 제조예 1의 단계 F와 같은 방법으로 표제 화합물 (2 mg)을 수득하였다.7-Chloro-4-(4-(3-chlorophenoxy)cyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (5 mg, 0.012 mmol) The title compound (2 mg) was obtained in the same manner as Step F of Preparation Example 1.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.22 (d, J = 1.8 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.20 (t, J = 8.2 Hz, 1H), 7.00 (t, J = 2.3 Hz, 1H), 6.91 (dd, J = 8.2, 2.3 Hz, 2H), 5.39 (d, J = 3.7 Hz, 1H), 4.60 (s, 1H), 3.60 (s, 3H), 3.09 (dd, J = 13.0, 3.0 Hz, 2H), 2.22-2.19 (m, 2H), 1.70 (t, J = 14.0 Hz, 2H), 1.50 (d, J = 12.3 Hz, 3H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.22 (d, J = 1.8 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.20 (t, J = 8.2 Hz, 1H), 7.00 ( t, J = 2.3 Hz, 1H), 6.91 (dd, J = 8.2, 2.3 Hz, 2H), 5.39 (d, J = 3.7 Hz, 1H), 4.60 (s, 1H), 3.60 (s, 3H), 3.09 (dd, J = 13.0, 3.0 Hz, 2H), 2.22-2.19 (m, 2H), 1.70 (t, J = 14.0 Hz, 2H), 1.50 (d, J = 12.3 Hz, 3H)
LC/MS: 421 (M+H)LC/MS: 421 (M+H)
실시예 15: 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드 (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)의 제조Example 15: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( 4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin Preparation of -4(1H)-yl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)
Figure PCTKR2023007097-appb-img-000178
Figure PCTKR2023007097-appb-img-000178
4-(트라이플루오로메톡시)아닐린 (46 mg, 0.257 mmol)과 DIPEA (0.064 mL, 0.37 mmol)를 무수 THF (2.5 mL)에 녹인 후 트라이포스겐 (27 mg, 0.09 mmol)을 0℃에서 가한 뒤 30 분간 교반하였다. 이 후 반응 혼합물에 제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (90 mg, 0.25 mmol)과 DIPEA (0.064 mL, 0.37 mmol)를 가하고 추가로 3 시간 동안 교반하였다. 혼합물을 감압증류하여 농축한 뒤, DCM으로 묽히고 brine으로 추출하였다. 유기층을 무수 MgSO4로 건조 후 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (100 mg)을 얻었다.4-(Trifluoromethoxy)aniline (46 mg, 0.257 mmol) and DIPEA (0.064 mL, 0.37 mmol) were dissolved in anhydrous THF (2.5 mL), and triphosgene (27 mg, 0.09 mmol) was added at 0°C. Stirred for 30 minutes. Afterwards, 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3 obtained in Preparation Example 4 was added to the reaction mixture. -Dione (90 mg, 0.25 mmol) and DIPEA (0.064 mL, 0.37 mmol) were added and stirred for an additional 3 hours. The mixture was concentrated by distillation under reduced pressure, diluted with DCM, and extracted with brine. The organic layer was dried over anhydrous MgSO 4 and then distilled under reduced pressure. The residue was purified by MPLC to give the title compound (100 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (s, 1H), 7.51 (s, 1H), 7.46-7.33 (m, 3H), 7.05 (d, J = 7.9 Hz, 2H), 5.55 (s, 1H), 4.30 (d, J = 12.2 Hz, 2H), 3.59 (s, 3H), 2.99 (t, J = 12.5 Hz, 2H), 2.84 (d, J = 11.6 Hz, 2H), 1.69 (d, J = 11.0 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (s, 1H), 7.51 (s, 1H), 7.46-7.33 (m, 3H), 7.05 (d, J = 7.9 Hz, 2H), 5.55 (s) , 1H), 4.30 (d, J = 12.2 Hz, 2H), 3.59 (s, 3H), 2.99 (t, J = 12.5 Hz, 2H), 2.84 (d, J = 11.6 Hz, 2H), 1.69 (d) , J = 11.0 Hz, 2H)
LC/MS: 498.1 (M+H)LC/MS: 498.1 (M+H)
실시예 16: 7-클로로-1-메틸-4-(1-(2-(피리딘-2-일)아세틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(1-(2-(pyridin-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 16: 7-Chloro-1-methyl-4-(1-(2-(pyridin-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(2-(pyridin-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrid[ Preparation of 2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000179
Figure PCTKR2023007097-appb-img-000179
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol)과 2-(피리딘-2-일)아세트산(13 mg, 0.10 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (31 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 2-(pyridin-2-yl)acetic acid (13 mg, 0.10 mmol) to obtain the title compound (31 mg) in a similar manner to Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.53 (d, J = 4.6 Hz, 1H), 8.14 (d, J = 1.8 Hz, 1H), 7.71 (td, J = 7.8, 1.4 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.18 (dd, J = 7.3, 5.2 Hz, 1H), 5.53-5.49 (m, 1H), 4.84 (d, J = 11.0 Hz, 1H), 4.27 (d, J = 13.7 Hz, 1H), 4.00 (s, 2H), 3.60 (s, 3H), 3.15 (td, J = 13.1, 2.2 Hz, 1H), 2.79-2.59 (m, 3H), 1.69 (d, J = 12.2 Hz, 1H), 1.62 (d, J = 11.9 Hz, 1H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.53 (d, J = 4.6 Hz, 1H), 8.14 (d, J = 1.8 Hz, 1H), 7.71 (td, J = 7.8, 1.4 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.18 (dd, J = 7.3, 5.2 Hz, 1H), 5.53-5.49 (m, 1H), 4.84 (d , J = 11.0 Hz, 1H), 4.27 (d, J = 13.7 Hz, 1H), 4.00 (s, 2H), 3.60 (s, 3H), 3.15 (td, J = 13.1, 2.2 Hz, 1H), 2.79 -2.59 (m, 3H), 1.69 (d, J = 12.2 Hz, 1H), 1.62 (d, J = 11.9 Hz, 1H)
LC/MS: 414.1 (M+H)LC/MS: 414.1 (M+H)
실시예 17: 7-클로로-1-메틸-4-(1-(2-(티오펜-2-일)아세틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(1-(2-(thiophen-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 17: 7-Chloro-1-methyl-4-(1-(2-(thiophen-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2, 3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(2-(thiophen-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrid Preparation of [2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000180
Figure PCTKR2023007097-appb-img-000180
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol)과 2-(티오펜-2-일)아세트산(14 mg, 0.10 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (28 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 2-(thiophen-2-yl)acetic acid (14 mg, 0.10 mmol) to obtain the title compound (28 mg) in a similar manner to Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.15 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 4.9 Hz, 1H), 6.98-6.94 (m, 2H), 5.55-5.50 (m, 1H), 4.84 (d, J = 11.6 Hz, 1H), 4.09-4.01 (m, 1H), 3.97 (d, J = 3.1 Hz, 2H), 3.60 (s, 3H), 3.20 (td, J = 13.2, 2.1 Hz, 1H), 2.82-2.76 (m, 1H), 2.74-2.69 (m, 2H), 1.72-1.65 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.15 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 4.9 Hz, 1H), 6.98- 6.94 (m, 2H), 5.55-5.50 (m, 1H), 4.84 (d, J = 11.6 Hz, 1H), 4.09-4.01 (m, 1H), 3.97 (d, J = 3.1 Hz, 2H), 3.60 (s, 3H), 3.20 (td, J = 13.2, 2.1 Hz, 1H), 2.82-2.76 (m, 1H), 2.74-2.69 (m, 2H), 1.72-1.65 (m, 2H)
LC/MS: 419.1 (M+H)LC/MS: 419.1 (M+H)
실시예 18: 7-클로로-4-(1-(2-(2-플루오로페닐)아세틸)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(2-(2-fluorophenyl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 18: 7-Chloro-4-(1-(2-(2-fluorophenyl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b] pyrazine-2,3-dione (7-chloro-4-(1-(2-(2-fluorophenyl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2, Preparation of 3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000181
Figure PCTKR2023007097-appb-img-000181
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol)과 2-(2-플루오로페닐)아세트산(15 mg, 0.10 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (31 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 2-(2-fluorophenyl)acetic acid (15 mg, 0.10 mmol) to obtain the title compound (31 mg) in a similar manner to Example 1.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.15 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.37 (td, J = 7.5, 1.7 Hz, 1H), 7.28-7.23 (m, 1H), 7.16 (dd, J = 7.3, 6.4 Hz, 1H), 7.06 (t, J = 9.1 Hz, 1H), 5.55-5.49 (m, 1H), 4.86 (d, J = 11.9 Hz, 1H), 4.05 (d, J = 13.7 Hz, 1H), 3.80 (d, J = 5.0 Hz, 2H), 3.60 (s, 3H), 3.22-3.16 (m, 1H), 2.83-2.69 (m, 3H), 1.72-1.64 (m, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.15 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.37 (td, J = 7.5, 1.7 Hz, 1H), 7.28-7.23 (m, 1H), 7.16 (dd, J = 7.3, 6.4 Hz, 1H), 7.06 (t, J = 9.1 Hz, 1H), 5.55-5.49 (m, 1H), 4.86 (d, J = 11.9 Hz, 1H), 4.05 (d, J = 13.7 Hz, 1H), 3.80 (d, J = 5.0 Hz, 2H), 3.60 (s, 3H), 3.22-3.16 (m, 1H), 2.83-2.69 ( m, 3H), 1.72-1.64 (m, 2H)
LC/MS: 431.1 (M+H)LC/MS: 431.1 (M+H)
실시예 19: 7-클로로-4-(1-(2-(퓨란-2-일)아세틸)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(2-(furan-2-yl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 19: 7-Chloro-4-(1-(2-(furan-2-yl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (7-chloro-4-(1-(2-(furan-2-yl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[ Preparation of 2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000182
Figure PCTKR2023007097-appb-img-000182
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol)과 2-(퓨란-2-일)아세트산(12 mg, 0.10 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (27 mg)을 얻었다7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 The title compound (27 mg) was obtained in a similar manner to Example 1 using mg, 0.10 mmol) and 2-(furan-2-yl)acetic acid (12 mg, 0.10 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.17 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 1.8 Hz, 1H), 6.35 (q, J = 1.6 Hz, 1H), 6.25 (d, J = 3.4 Hz, 1H), 5.56-5.51 (m, 1H), 4.85-4.83 (m, 1H), 4.14-4.09 (m, 1H), 3.82 (d, J = 3.7 Hz, 2H), 3.61 (s, 3H), 3.22 (td, J = 13.3, 2.3 Hz, 1H), 2.81-2.72 (m, 3H), 1.72-1.68 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.17 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 1.8 Hz, 1H), 6.35 ( q, J = 1.6 Hz, 1H), 6.25 (d, J = 3.4 Hz, 1H), 5.56-5.51 (m, 1H), 4.85-4.83 (m, 1H), 4.14-4.09 (m, 1H), 3.82 (d, J = 3.7 Hz, 2H), 3.61 (s, 3H), 3.22 (td, J = 13.3, 2.3 Hz, 1H), 2.81-2.72 (m, 3H), 1.72-1.68 (m, 2H)
LC/MS: 431.1 (M+H)LC/MS: 431.1 (M+H)
실시예 20: 7-클로로-6-(2-플루오로페닐)-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-6-(2-fluorophenyl)-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 20: 7-Chloro-6-(2-fluorophenyl)-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4 -Dihydropyrido[2,3-b]pyrazine-2,3-dione (7-chloro-6-(2-fluorophenyl)-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl) Preparation of piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000183
Figure PCTKR2023007097-appb-img-000183
제조예 18에서 얻은 7-클로로-6-(2-플루오로페닐)-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (35 mg, 0.082 mmol)과 4-(트라이플루오로메톡시)벤조일 클로라이드 (0.016 ml, 0.099 mmol)를 이용하여 실시예 8과 같은 방법으로 표제 화합물 (41 mg)을 얻었다.7-Chloro-6-(2-fluorophenyl)-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b] obtained in Preparation Example 18 The title compound (41 mg) was prepared in the same manner as in Example 8 using pyrazine-2,3-dione (35 mg, 0.082 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.016 ml, 0.099 mmol). got it
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.65 (s, 1H), 7.51 (dd, J = 14.5, 7.0, Hz, 2H), 7.36~7.19 (m, 6H), 5.61~5.56 (m, 1H), 4.86 (br s, 1H), 3.77 (br s, 1H), 3.69 (s, 3H), 3.14~3.12 (m, 1H), 3.01~2.89 (m, 3H), 1.83~1.68 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.65 (s, 1H), 7.51 (dd, J = 14.5, 7.0, Hz, 2H), 7.36~7.19 (m, 6H), 5.61~5.56 (m, 1H) ), 4.86 (br s, 1H), 3.77 (br s, 1H), 3.69 (s, 3H), 3.14~3.12 (m, 1H), 3.01~2.89 (m, 3H), 1.83~1.68 (m, 2H) )
LC/MS: 557 (M+H)LC/MS: 557 (M+H)
실시예 21: 7-클로로-1-메틸-4-(1-(2-페닐아세틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(1-(2-phenylacetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 21: 7-Chloro-1-methyl-4-(1-(2-phenylacetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione (7-chloro-1-methyl-4-(1-(2-phenylacetyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione )Manufacture of
Figure PCTKR2023007097-appb-img-000184
Figure PCTKR2023007097-appb-img-000184
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol)과 2-페닐아세트산(12 mg, 0.10 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (26 mg)을 얻었다7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 2-phenylacetic acid (12 mg, 0.10 mmol) to obtain the title compound (26 mg) in a similar manner to Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.13 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.30 (s, 1H), 7.28-7.23 (m, 2H), 5.49 (t, J = 3.7 Hz, 1H), 4.87 (d, J = 11.6 Hz, 1H), 4.02 (d, J = 13.7 Hz, 1H), 3.81 (s, 2H), 3.59 (s, 3H), 3.12 (td, J = 13.1, 1.9 Hz, 1H), 2.81-2.59 (m, 3H), 1.69 (d, J = 12.2 Hz, 1H), 1.58 (d, J = 12.2 Hz, 1H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.13 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.30 ( s, 1H), 7.28-7.23 (m, 2H), 5.49 (t, J = 3.7 Hz, 1H), 4.87 (d, J = 11.6 Hz, 1H), 4.02 (d, J = 13.7 Hz, 1H), 3.81 (s, 2H), 3.59 (s, 3H), 3.12 (td, J = 13.1, 1.9 Hz, 1H), 2.81-2.59 (m, 3H), 1.69 (d, J = 12.2 Hz, 1H), 1.58 (d, J = 12.2 Hz, 1H)
LC/MS: 413.1 (M+H)LC/MS: 413.1 (M+H)
실시예 22: 7-클로로-1-메틸-4-(1-(1-페닐사이클로프로판-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(1-(1-phenylcyclopropane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 22: 7-Chloro-1-methyl-4-(1-(1-phenylcyclopropane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(1-phenylcyclopropane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 Preparation of -b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000185
Figure PCTKR2023007097-appb-img-000185
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol)과 1-페닐사이클로프로판-1-카르복시산 (15 mg, 0.10 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (30 mg)을 얻었다7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 1-phenylcyclopropane-1-carboxylic acid (15 mg, 0.10 mmol) to obtain the title compound (30 mg) in a similar manner to Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.14 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.33 (t, J = 7.8 Hz, 2H), 7.21 (d, J = 7.9 Hz, 3H), 5.46 (t, J = 11.7 Hz, 1H), 4.85 (br s, 1H), 4.25 (br s, 1H), 3.59 (s, 3H), 2.91 (br s, 1H), 2.87-2.66 (m, 2H), 2.50 (br s, 1H), 1.70 (br s, 1H), 1.44 (br s, 1H), 1.30-1.26 (m, 2H), 1.22 (brs, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.14 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.33 (t, J = 7.8 Hz, 2H), 7.21 ( d, J = 7.9 Hz, 3H), 5.46 (t, J = 11.7 Hz, 1H), 4.85 (br s, 1H), 4.25 (br s, 1H), 3.59 (s, 3H), 2.91 (br s, 1H), 2.87-2.66 (m, 2H), 2.50 (br s, 1H), 1.70 (br s, 1H), 1.44 (br s, 1H), 1.30-1.26 (m, 2H), 1.22 (brs, 2H) )
LC/MS: 439.1 (M+H)LC/MS: 439.1 (M+H)
실시예 23: 7-클로로-4-(1-(2-(2-플루오로페닐)-2-메틸프로파노일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(2-(2-fluorophenyl)-2-methylpropanoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 23: 7-Chloro-4-(1-(2-(2-fluorophenyl)-2-methylpropanoyl)piperidin-4-yl)-1-methyl-1,4-dihydro Pyrido[2,3-b]pyrazine-2,3-dione (7-chloro-4-(1-(2-(2-fluorophenyl)-2-methylpropanoyl)piperidin-4-yl)-1-methyl Preparation of -1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000186
Figure PCTKR2023007097-appb-img-000186
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (60 mg, 0.17 mmol)과 2-(2-플루오로페닐)-2-메틸프로판산 (33 mg, 0.18 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (26 mg)을 얻었다7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (60) obtained in Preparation Example 4 mg, 0.17 mmol) and 2-(2-fluorophenyl)-2-methylpropanoic acid (33 mg, 0.18 mmol) to obtain the title compound (26 mg) in a similar manner to Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.34 (td, J = 7.8, 1.2 Hz, 1H), 7.24-7.20 (m, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.14-7.10 (m, 1H), 5.41-5.36 (m, 1H), 4.96 (br s, 1H), 3.62 (d, J = 5.5 Hz, 1H), 3.60 (s, 3H), 2.81-2.65 (m, 3H), 2.31 (s, 1H), 1.74-1.65 (m, 1H), 1.61-1.57 (m, 6H), 1.27-1.22 (m, 1H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.34 (td, J = 7.8, 1.2 Hz, 1H), 7.24-7.20 (m, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.14-7.10 (m, 1H), 5.41-5.36 (m, 1H), 4.96 (br s, 1H), 3.62 (d) , J = 5.5 Hz, 1H), 3.60 (s, 3H), 2.81-2.65 (m, 3H), 2.31 (s, 1H), 1.74-1.65 (m, 1H), 1.61-1.57 (m, 6H), 1.27-1.22 (m, 1H)
LC/MS: 459.1 (M+H)LC/MS: 459.1 (M+H)
실시예 24: 7-클로로-4-(1-(4-클로로벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(4-chlorobenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 24: 7-Chloro-4-(1-(4-chlorobenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione (7-chloro-4-(1-(4-chlorobenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione )Manufacture of
Figure PCTKR2023007097-appb-img-000187
Figure PCTKR2023007097-appb-img-000187
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol)과 4-클로로벤조일 클로라이드 (20 mg, 0.11 mmol)를 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (19 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 4-chlorobenzoyl chloride (20 mg, 0.11 mmol) to obtain the title compound (19 mg) in a similar manner to Example 8.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 1.8 Hz, 1H), 7.52-7.51 (m, 1H), 7.44-7.39 (m, 4H), 5.60 (d, J = 11.3 Hz, 1H), 4.89 (br s, 1H), 3.87 (br s, 1H), 3.62 (s, 3H), 3.18 (br s, 1H), 2.91 (br s, 3H), 1.75 (d, J = 44.9 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 1.8 Hz, 1H), 7.52-7.51 (m, 1H), 7.44-7.39 (m, 4H), 5.60 (d, J = 11.3 Hz) , 1H), 4.89 (br s, 1H), 3.87 (br s, 1H), 3.62 (s, 3H), 3.18 (br s, 1H), 2.91 (br s, 3H), 1.75 (d, J = 44.9 Hz, 2H)
LC/MS: 433.1 (M+H)LC/MS: 433.1 (M+H)
실시예 25: 7-클로로-1-메틸-4-(1-(4-(트라이플루오로메틸)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 25: 7-Chloro-1-methyl-4-(1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b ]Manufacture of pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000188
Figure PCTKR2023007097-appb-img-000188
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol)과 4-(트라이플루오로메틸)벤조일 클로라이드 (21 mg, 0.11 mmol)를 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (26 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 4-(trifluoromethyl)benzoyl chloride (21 mg, 0.11 mmol) to obtain the title compound (26 mg) in a similar manner to Example 8.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 1.8 Hz, 1H), 5.63 (t, J = 11.4 Hz, 1H), 4.94 (s, 1H), 3.80-3.75 (m, 1H), 3.62 (s, 3H), 3.20 (s, 1H), 2.93 (s, 3H), 1.82 (s, 1H), 1.65 (s, 1H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.51 ( d, J = 1.8 Hz, 1H), 5.63 (t, J = 11.4 Hz, 1H), 4.94 (s, 1H), 3.80-3.75 (m, 1H), 3.62 (s, 3H), 3.20 (s, 1H) ), 2.93 (s, 3H), 1.82 (s, 1H), 1.65 (s, 1H)
LC/MS: 467.1 (M+H)LC/MS: 467.1 (M+H)
실시예 26: 4-((4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-일)설포닐)벤조나이트릴 (4-((4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1-yl)sulfonyl)benzonitrile)의 제조Example 26: 4-((4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl) piperidin-1-yl) sulfonyl) benzonitrile (4-((4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin- Preparation of 4(1H)-yl)piperidin-1-yl)sulfonyl)benzonitrile)
Figure PCTKR2023007097-appb-img-000189
Figure PCTKR2023007097-appb-img-000189
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol)과 4-시아노벤젠설포닐 클로라이드 (22.3 mg, 0.111 mmol)를 이용하여 실시예 3과 유사한 방법으로 표제 화합물 (42 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 4-cyanobenzenesulfonyl chloride (22.3 mg, 0.111 mmol) to obtain the title compound (42 mg) in a similar manner to Example 3.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.17 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 2.0 Hz, 1H), 5.30~5.25 (m, 1H), 4.06~4.04 (m, 2H), 3.62 (s, 3H), 3.11~3.04 (m, 2H), 2.61~2.56 (m, 2H), 1.75~1.73 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.17 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.5 Hz, 2H), 7.50 ( d, J = 2.0 Hz, 1H), 5.30~5.25 (m, 1H), 4.06~4.04 (m, 2H), 3.62 (s, 3H), 3.11~3.04 (m, 2H), 2.61~2.56 (m, 2H), 1.75~1.73 (m, 2H)
LC/MS: 482 (M+Na)LC/MS: 482 (M+Na)
실시예 27: 4-(4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르보닐)벤조나이트릴 (4-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carbonyl)benzonitrile)의 제조Example 27: 4-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p Peridine-1-carbonyl)benzonitrile (4-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin-4(1H) Preparation of -yl)piperidine-1-carbonyl)benzonitrile)
Figure PCTKR2023007097-appb-img-000190
Figure PCTKR2023007097-appb-img-000190
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol)과 4-(트라이플루오로메틸)벤조일 클로라이드 (18 mg, 0.11 mmol)를 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (1 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 4-(trifluoromethyl)benzoyl chloride (18 mg, 0.11 mmol) to obtain the title compound (1 mg) in a similar manner to Example 8.
LC/MS: 424.1 (M+H)LC/MS: 424.1 (M+H)
실시예 28: 4-(1-((4-(터트-부틸)페닐)설포닐)피페리딘-4-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (4-(1-((4-(tert-butyl)phenyl)sulfonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 28: 4-(1-((4-(tert-butyl)phenyl)sulfonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2 ,3-b]pyrazine-2,3-dione (4-(1-((4-(tert-butyl)phenyl)sulfonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4 Preparation of -dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000191
Figure PCTKR2023007097-appb-img-000191
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (37 mg, 0.10 mmol)과 4-(터트-부틸)벤젠설포닐 클로라이드 (26 mg, 0.111 mmol)를 이용하여 실시예 3과 유사한 방법으로 표제 화합물 (43 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (37) obtained in Preparation Example 4 mg, 0.10 mmol) and 4-(tert-butyl)benzenesulfonyl chloride (26 mg, 0.111 mmol) to obtain the title compound (43 mg) in a similar manner to Example 3.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (d, J = 1.5 Hz, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 2.0 Hz, 1H), 5.23~5.18 (m, 1H), 4.01~3.99 (m, 2H), 3.62 (s, 3H), 3.14~3.10 (m, 2H), 2.51~2.46 (m, 2H), 1.73~1.70 (m, 2H), 1.40 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (d, J = 1.5 Hz, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.49 ( d, J = 2.0 Hz, 1H), 5.23~5.18 (m, 1H), 4.01~3.99 (m, 2H), 3.62 (s, 3H), 3.14~3.10 (m, 2H), 2.51~2.46 (m, 2H), 1.73~1.70 (m, 2H), 1.40 (s, 9H)
LC/MS: 491 (M+H), 513 (M+Na)LC/MS: 491 (M+H), 513 (M+Na)
실시예 29: 7-클로로-4-(1-(2,3-다이하이드로벤조[b][1,4]다이옥신-6-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(2,3-dihydrobenzo[b][1,4]dioxine-6-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 29: 7-Chloro-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-carbonyl)piperidin-4-yl)-1-methyl-1 ,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (7-chloro-4-(1-(2,3-dihydrobenzo[b][1,4]dioxine-6- Preparation of carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000192
Figure PCTKR2023007097-appb-img-000192
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol)과 2,3-다이하이드로벤조[b][1,4]다이옥신-6-카르복시산 (32 mg, 0.11 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (35 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylic acid (32 mg, 0.11 mmol) to prepare the title compound (35 mg) in a similar manner to Example 1. got it
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 3.7 Hz, 1H), 7.51 (s, 1H), 6.95-6.80 (m, 3H), 5.59 (t, J = 11.3 Hz, 1H), 4.99 (d, J = 9.5 Hz, 1H), 4.45-4.23 (m, 4H), 3.75-3.72 (m, 1H), 3.61 (s, 3H), 2.94-2.80 (m, 3H), 1.77 (d, J = 7.9 Hz, 2H), 1.59 (d, J = 11.6 Hz, 1H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 3.7 Hz, 1H), 7.51 (s, 1H), 6.95-6.80 (m, 3H), 5.59 (t, J = 11.3 Hz, 1H) ), 4.99 (d, J = 9.5 Hz, 1H), 4.45-4.23 (m, 4H), 3.75-3.72 (m, 1H), 3.61 (s, 3H), 2.94-2.80 (m, 3H), 1.77 ( d, J = 7.9 Hz, 2H), 1.59 (d, J = 11.6 Hz, 1H)
LC/MS: 457.1 (M+H)LC/MS: 457.1 (M+H)
실시예 30: 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-(트라이플루오로메틸)페닐)피페리딘-1-카르복사마이드 (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide)의 제조Example 30: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( 4-(trifluoromethyl)phenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin Preparation of -4(1H)-yl)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide)
Figure PCTKR2023007097-appb-img-000193
Figure PCTKR2023007097-appb-img-000193
4-(트라이플루오로메틸)아닐린 (18 mg, 0.11 mol)과 제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol)을 이용하여 실시예 15와 유사한 방법으로 표제 화합물 (28 mg)을 얻었다.4-(trifluoromethyl)aniline (18 mg, 0.11 mol) and 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido obtained in Preparation Example 4 The title compound (28 mg) was obtained in a similar manner to Example 15 using [2,3-b]pyrazine-2,3-dione (30 mg, 0.10 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.50-7.42 (m, 4H), 7.11 (s, 1H), 5.60-5.55 (m, 1H), 4.30 (d, J = 13.4 Hz, 2H), 3.61 (s, 3H), 3.05 (td, J = 12.8, 1.7 Hz, 2H), 2.88 (qd, J = 12.3, 4.0 Hz, 2H), 1.75-1.72 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.50-7.42 (m, 4H), 7.11 (s, 1H) ), 5.60-5.55 (m, 1H), 4.30 (d, J = 13.4 Hz, 2H), 3.61 (s, 3H), 3.05 (td, J = 12.8, 1.7 Hz, 2H), 2.88 (qd, J = 12.3, 4.0 Hz, 2H), 1.75-1.72 (m, 2H)
LC/MS: 482.1 (M+H)LC/MS: 482.1 (M+H)
실시예 31: 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-클로로페닐)피페리딘-1-카르복사마이드 (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-chlorophenyl)piperidine-1-carboxamide)의 제조Example 31: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( 4-Chlorophenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin-4(1H) Preparation of -yl)-N-(4-chlorophenyl)piperidine-1-carboxamide)
Figure PCTKR2023007097-appb-img-000194
Figure PCTKR2023007097-appb-img-000194
4-클로로아닐린 (14 mg, 0.11 mol)과 제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol)을 이용하여 실시예 15와 유사한 방법으로 표제 화합물 (31 mg)을 얻었다.4-chloroaniline (14 mg, 0.11 mol) and 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-] obtained in Preparation Example 4 b] The title compound (31 mg) was obtained in a similar manner to Example 15 using pyrazine-2,3-dione (30 mg, 0.10 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.20 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.35-7.32 (m, 2H), 7.18 (dd, J = 11.6, 3.1 Hz, 2H), 7.06 (s, 1H), 5.58-5.53 (m, 1H), 4.29 (d, J = 13.4 Hz, 2H), 3.60 (s, 3H), 3.04-2.99 (m, 2H), 2.86 (qd, J = 12.3, 3.9 Hz, 2H), 1.83-1.71 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.20 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.35-7.32 (m, 2H), 7.18 (dd, J = 11.6, 3.1 Hz, 2H), 7.06 (s, 1H), 5.58-5.53 (m, 1H), 4.29 (d, J = 13.4 Hz, 2H), 3.60 (s, 3H), 3.04-2.99 (m, 2H), 2.86 (qd, J = 12.3, 3.9 Hz, 2H), 1.83-1.71 (m, 2H)
LC/MS: 448.0 (M+H)LC/MS: 448.0 (M+H)
실시예 32: 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-시아노페닐)피페리딘-1-카르복사마이드 (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-cyanophenyl)piperidine-1-carboxamide)의 제조Example 32: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( 4-Cyanophenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin-4(1H )-yl)-N-(4-cyanophenyl)piperidine-1-carboxamide) Preparation
Figure PCTKR2023007097-appb-img-000195
Figure PCTKR2023007097-appb-img-000195
4-아미노벤조나이트릴 (13 mg, 0.11 mol)과 제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.10 mmol)을 이용하여 실시예 15와 유사한 방법으로 표제 화합물 (19 mg)을 얻었다.4-Aminobenzonitrile (13 mg, 0.11 mol) and 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido [2, [3-b] The title compound (19 mg) was obtained in a similar manner to Example 15 using pyrazine-2,3-dione (30 mg, 0.10 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 1.8 Hz, 1H), 7.61 (s, 1H), 7.53 (dd, J = 5.5, 3.7 Hz, 3H), 7.51-7.43 (m, 2H), 5.62-5.57 (m, 1H), 4.33 (d, J = 13.7 Hz, 2H), 3.61 (d, J = 3.1 Hz, 3H), 3.02 (t, J = 12.1 Hz, 2H), 2.89-2.81 (m, 2H), 1.72 (d, J = 9.8 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 1.8 Hz, 1H), 7.61 (s, 1H), 7.53 (dd, J = 5.5, 3.7 Hz, 3H), 7.51-7.43 (m , 2H), 5.62-5.57 (m, 1H), 4.33 (d, J = 13.7 Hz, 2H), 3.61 (d, J = 3.1 Hz, 3H), 3.02 (t, J = 12.1 Hz, 2H), 2.89 -2.81 (m, 2H), 1.72 (d, J = 9.8 Hz, 2H)
LC/MS: 439.1 (M+H)LC/MS: 439.1 (M+H)
실시예 33: 7-클로로-4-(1-(사이클로헥산카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(cyclohexanecarbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 33: 7-Chloro-4-(1-(cyclohexanecarbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione (7-chloro-4-(1-(cyclohexanecarbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione) manufacturing
Figure PCTKR2023007097-appb-img-000196
Figure PCTKR2023007097-appb-img-000196
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 2 염산염 (30 mg, 0.082 mmol)과 사이클로헥산카르보닐 클로라이드 (14.36 mg, 0.098 mmol)를 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (32 mg)을 합성하였다.2 of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione obtained in Preparation Example 4 The title compound (32 mg) was synthesized in a manner similar to Example 8 using hydrochloride (30 mg, 0.082 mmol) and cyclohexanecarbonyl chloride (14.36 mg, 0.098 mmol).
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.16 (d, J = 1.8 Hz, 1H), 7.51-7.47 (m, 1H), 5.57-5.53 (m, 1H), 4.84 (d, J = 10.5 Hz, 1H), 4.08 (d, J = 15.1 Hz, 1H), 3.60 (s, 3H), 3.16 (t, J = 13.3 Hz, 1H), 2.89-2.75 (m, 2H), 2.67-2.49 (m, 2H), 1.81 (s, 2H), 1.72 (d, J = 16.9 Hz, 3H), 1.26 (d, J = 9.1 Hz, 4H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.16 (d, J = 1.8 Hz, 1H), 7.51-7.47 (m, 1H), 5.57-5.53 (m, 1H), 4.84 (d, J = 10.5 Hz) , 1H), 4.08 (d, J = 15.1 Hz, 1H), 3.60 (s, 3H), 3.16 (t, J = 13.3 Hz, 1H), 2.89-2.75 (m, 2H), 2.67-2.49 (m, 2H), 1.81 (s, 2H), 1.72 (d, J = 16.9 Hz, 3H), 1.26 (d, J = 9.1 Hz, 4H)
LC/MS: 405 (M+H)LC/MS: 405 (M+H)
실시예 34: 7-클로로-1-메틸-4-(1-(2-옥소-2-페닐에틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(1-(2-oxo-2-phenylethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 34: 7-Chloro-1-methyl-4-(1-(2-oxo-2-phenylethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(2-oxo-2-phenylethyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b ]Manufacture of pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000197
Figure PCTKR2023007097-appb-img-000197
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 2 염산염 (30 mg, 0.082 mmol)를 ACN (5 ml)에 녹이고 2-브로모-1-페닐에탄-1-온 (19.49 mg, 0.098 mmol)과 K2CO3 (33.8 mg, 0.245 mmol)를 넣어준 후 상온에서 2시간 동안 교반해 주었다. NaHCO3를 넣어준 후 DCM으로 추출하였다. 유기층을 무수 MgSO4를 이용하여 건조한 뒤 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (19 mg)을 얻었다.2 of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione obtained in Preparation Example 4 Dissolve hydrochloride (30 mg, 0.082 mmol) in ACN (5 ml) and add 2-bromo-1-phenylethan-1-one (19.49 mg, 0.098 mmol) and K 2 CO 3 (33.8 mg, 0.245 mmol). After adding it, it was stirred at room temperature for 2 hours. NaHCO 3 was added and extracted with DCM. The organic layer was dried using anhydrous MgSO4 and then distilled under reduced pressure. The residue was purified by MPLC to give the title compound (19 mg).
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.20 (d, J = 1.8 Hz, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 7.57 (t, J = 7.3 Hz, 1H), 7.51-7.45 (m, 4H), 5.35 (s, 1H), 3.92 (s, 2H), 3.60 (s, 4H), 3.18-3.09 (m, 4H), 2.49 (d, J = 12.8 Hz, 2H), 1.24 (s, 1H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.20 (d, J = 1.8 Hz, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 7.57 (t, J = 7.3 Hz, 1H), 7.51-7.45 (m, 4H), 5.35 (s, 1H), 3.92 (s, 2H), 3.60 (s, 4H), 3.18-3.09 (m, 4H), 2.49 (d, J = 12.8 Hz, 2H) , 1.24 (s, 1H)
LC/MS: 413 (M+H)LC/MS: 413 (M+H)
실시예 35: 7-클로로-1-메틸-4-((1s,4s)-4-(4-(트라이플루오로메톡시)페녹시)사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-((1s,4s)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 35: 7-Chloro-1-methyl-4-((1s,4s)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)-1,4-dihydropyrido[2, 3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-((1s,4s)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)-1,4-dihydropyrid[2 ,3-b]pyrazine-2,3-dione) production
Figure PCTKR2023007097-appb-img-000198
Figure PCTKR2023007097-appb-img-000198
제조예 20에서 얻은 7-클로로-1-메틸-4-((1r,4r)-4-하이드록시사이클로헥실)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (20 mg, 0.065 mmol), 4-(트라이플루오로메톡시)페놀 (17.3 mg, 0.097 mmol)과 트라이페닐포스핀 (33.9 mg, 0.129)을 THF (6 mL)에 녹인 후 DIAD (0.025 ml, 0.129 mmol)을 첨가하였다. 반응액을 상온에서 16 시간 동안 교반 후 H2O과 EtOAc로 희석하고 추출한 유기층을 무수 Na2CO3로 건조 후 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (15 mg)을 얻었다.7-Chloro-1-methyl-4-((1r,4r)-4-hydroxycyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine obtained in Preparation Example 20 -2,3-Dione (20 mg, 0.065 mmol), 4-(trifluoromethoxy)phenol (17.3 mg, 0.097 mmol) and triphenylphosphine (33.9 mg, 0.129) were dissolved in THF (6 mL). Then DIAD (0.025 ml, 0.129 mmol) was added. The reaction solution was stirred at room temperature for 16 hours, diluted with H 2 O and EtOAc, and the extracted organic layer was dried over anhydrous Na 2 CO 3 and distilled under reduced pressure. The residue was purified by MPLC to give the title compound (15 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.24 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 5.47-5.42 (m, 1H), 4.63 (s, 1H), 3.64 (s, 3H), 3.17~3.09 (m, 2H), 2.25~2.22 (m, 2H), 1.76~1.71 (m, 2H), 1.55~1.52 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.24 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 9.0 Hz, 2H), 7.04 ( d, J = 9.0 Hz, 2H), 5.47-5.42 (m, 1H), 4.63 (s, 1H), 3.64 (s, 3H), 3.17-3.09 (m, 2H), 2.25-2.22 (m, 2H) , 1.76~1.71 (m, 2H), 1.55~1.52 (m, 2H)
LC/MS: 470 (M+H)LC/MS: 470 (M+H)
실시예 36: 7-클로로-4-(1-((4-클로로페닐)설포닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 36: 7-Chloro-4-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione (7-chloro-4-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b] Preparation of pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000199
Figure PCTKR2023007097-appb-img-000199
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 2 염산염 (30 mg, 0.082 mmol)과 4-클로로벤젠설포닐 클로라이드 (17.22 mg, 0.082 mmol)를 이용하여 실시예 3과 유사한 방법으로 표제 화합물 (32 mg)을 수득하였다.2 of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione obtained in Preparation Example 4 The title compound (32 mg) was obtained in a similar manner to Example 3 using hydrochloride (30 mg, 0.082 mmol) and 4-chlorobenzenesulfonyl chloride (17.22 mg, 0.082 mmol).
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.13 (d, J = 2.3 Hz, 1H), 7.73 (dt, J = 8.8, 2.3 Hz, 2H), 7.53 (dt, J = 8.8, 2.1 Hz, 2H), 7.46 (d, J = 1.8 Hz, 1H), 5.20 (qd, J = 8.1, 4.0 Hz, 1H), 3.97 (dd, J = 9.8, 2.1 Hz, 2H), 3.58 (s, 3H), 3.04 (qd, J = 12.5, 4.1 Hz, 2H), 2.48 (td, J = 12.3, 2.3 Hz, 2H), 1.69 (d, J = 11.9 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.13 (d, J = 2.3 Hz, 1H), 7.73 (dt, J = 8.8, 2.3 Hz, 2H), 7.53 (dt, J = 8.8, 2.1 Hz, 2H) ), 7.46 (d, J = 1.8 Hz, 1H), 5.20 (qd, J = 8.1, 4.0 Hz, 1H), 3.97 (dd, J = 9.8, 2.1 Hz, 2H), 3.58 (s, 3H), 3.04 (qd, J = 12.5, 4.1 Hz, 2H), 2.48 (td, J = 12.3, 2.3 Hz, 2H), 1.69 (d, J = 11.9 Hz, 2H)
LC/MS: 470 (M+H)LC/MS: 470 (M+H)
실시예 37: 7-클로로-4-(1-(2-(4-클로로페닐)-2-옥소에틸)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 37: 7-Chloro-4-(1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[ 2,3-b] pyrazine-2,3-dione (7-chloro-4-(1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)-1-methyl-1, Preparation of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000200
Figure PCTKR2023007097-appb-img-000200
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 2 염산염 (30 mg, 0.082 mmol)과 2-브로모-1-(4-클로로페닐)에탄-1-온 (22.86 mg, 0.098 mmol)을 이용하여 실시예 34와 유사한 방법으로 표제 화합물 (21 mg)을 수득하였다.2 of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione obtained in Preparation Example 4 The title compound (21 mg) was prepared in a manner similar to Example 34 using hydrochloride (30 mg, 0.082 mmol) and 2-bromo-1-(4-chlorophenyl)ethan-1-one (22.86 mg, 0.098 mmol). was obtained.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.21-8.19 (m, 1H), 8.01 (d, J = 8.2 Hz, 2H), 7.46-7.41 (m, 3H), 5.36 (t, J = 12.6 Hz, 1H), 3.88 (s, 2H), 3.60 (s, 3H), 3.15-3.04 (m, 4H), 2.50 (d, J = 11.4 Hz, 2H), 1.62 (d, J = 11.0 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.21-8.19 (m, 1H), 8.01 (d, J = 8.2 Hz, 2H), 7.46-7.41 (m, 3H), 5.36 (t, J = 12.6 Hz) , 1H), 3.88 (s, 2H), 3.60 (s, 3H), 3.15-3.04 (m, 4H), 2.50 (d, J = 11.4 Hz, 2H), 1.62 (d, J = 11.0 Hz, 2H)
LC/MS: 448 (M+H)LC/MS: 448 (M+H)
실시예 38: 4-(2-(4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-일)아세틸)벤조나이트릴 (4-(2-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1-yl)acetyl)benzonitrile)의 제조Example 38: 4-(2-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)- 1) piperidin-1-yl) acetyl) benzonitrile (4-(2-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b ]Preparation of pyrazin-4(1H)-yl)piperidin-1-yl)acetyl)benzonitrile)
Figure PCTKR2023007097-appb-img-000201
Figure PCTKR2023007097-appb-img-000201
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 2 염산염 (30 mg, 0.082 mmol)과 4-(2-브로모아세틸)벤조나이트릴 (21.94 mg, 0.098 mmol)를 이용하여 실시예 34와 유사한 방법으로 표제화합물 (10 mg)을 수득하였다.2 of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione obtained in Preparation Example 4 The title compound (10 mg) was obtained in a similar manner to Example 34 using hydrochloride (30 mg, 0.082 mmol) and 4-(2-bromoacetyl)benzonitrile (21.94 mg, 0.098 mmol).
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.19 (d, J = 2.3 Hz, 1H), 8.16 (t, J = 4.1 Hz, 2H), 7.81-7.76 (m, 2H), 7.46 (d, J = 1.8 Hz, 1H), 5.39-5.33 (m, 1H), 3.88 (s, 2H), 3.59 (d, J = 5.0 Hz, 3H), 3.12-3.01 (m, 4H), 2.50-2.44 (m, 2H), 1.62 (d, J = 13.3 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.19 (d, J = 2.3 Hz, 1H), 8.16 (t, J = 4.1 Hz, 2H), 7.81-7.76 (m, 2H), 7.46 (d, J = 1.8 Hz, 1H), 5.39-5.33 (m, 1H), 3.88 (s, 2H), 3.59 (d, J = 5.0 Hz, 3H), 3.12-3.01 (m, 4H), 2.50-2.44 (m, 2H), 1.62 (d, J = 13.3 Hz, 2H)
LC/MS: 438 (M+H)LC/MS: 438 (M+H)
실시예 39: 7-클로로-1-메틸-4-(1-(2-옥소-2-(4-(트라이플루오로메틸)페닐)에틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 39: 7-Chloro-1-methyl-4-(1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)piperidin-4-yl)-1,4- Dihydropyrido[2,3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) Preparation of piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000202
Figure PCTKR2023007097-appb-img-000202
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온의 2 염산염 (30 mg, 0.082 mmol)과 2-브로모-1-(4-(트라이플루오로메틸)페닐)ethan-1-one (26.1 mg, 0.098 mmol)를 이용하여 실시예 34와 유사한 방법으로 표제 화합물 (5 mg)을 수득하였다.2 of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione obtained in Preparation Example 4 The title was prepared in a similar manner to Example 34 using hydrochloride (30 mg, 0.082 mmol) and 2-bromo-1-(4-(trifluoromethyl)phenyl)ethan-1-one (26.1 mg, 0.098 mmol). Compound (5 mg) was obtained.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.20 (d, J = 1.8 Hz, 1H), 8.17 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 1.8 Hz, 1H), 5.21-5.44 (1H), 3.88 (s, 2H), 3.60 (s, 3H), 3.09 (dd, J = 19.9, 11.7 Hz, 4H), 2.45 (t, J = 11.2 Hz, 2H), 1.64 (s, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.20 (d, J = 1.8 Hz, 1H), 8.17 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.46 ( d, J = 1.8 Hz, 1H), 5.21-5.44 (1H), 3.88 (s, 2H), 3.60 (s, 3H), 3.09 (dd, J = 19.9, 11.7 Hz, 4H), 2.45 (t, J = 11.2 Hz, 2H), 1.64 (s, 2H)
LC/MS: 481 (M+H)LC/MS: 481 (M+H)
실시예 40: 7-클로로-1-메틸-4-(4-((4-(트라이플루오로메톡시)페닐)아미노)사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(4-((4-(trifluoromethoxy)phenyl)amino)cyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 40: 7-Chloro-1-methyl-4-(4-((4-(trifluoromethoxy)phenyl)amino)cyclohexyl)-1,4-dihydropyrido[2,3-b] Pyrazine-2,3-dione (7-chloro-1-methyl-4-(4-((4-(trifluoromethoxy)phenyl)amino)cyclohexyl)-1,4-dihydropyrid[2,3-b]pyrazine- Preparation of 2,3-dione)
Figure PCTKR2023007097-appb-img-000203
Figure PCTKR2023007097-appb-img-000203
제조예 14에서 얻은 7-클로로-1-메틸-4-(4-옥소사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (50 mg, 0.16 mmol)과 4-(트라이플루오로메톡시)아닐린 (86 mg, 0.487 mmol), 소듐 트라이아세톡시보로하이드라이드 (172 mg, 0.812 mmol)를 DCE (1.7 mL)에 녹인 후 아세트산(14 μL, 0.244 mmol)을 상온에서 가하였다. 반응 혼합물을 60℃에서 25 시간 동안 교반하였다. 반응 혼합물을 식힌 뒤 감압증류하고, DCM으로 묽혔다. 혼합물을 포화 NaHCO3 수용액을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조 후 감압증류한 뒤, MPLC로 정제하여 표제 화합물 (13 mg)을 얻었다.7-Chloro-1-methyl-4-(4-oxocyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (50 mg, 0.16 mmol), 4-(trifluoromethoxy)aniline (86 mg, 0.487 mmol), and sodium triacetoxyborohydride (172 mg, 0.812 mmol) were dissolved in DCE (1.7 mL) and then added to acetic acid (14 μL, 0.244 mmol) was added at room temperature. The reaction mixture was stirred at 60° C. for 25 hours. The reaction mixture was cooled, distilled under reduced pressure, and diluted with DCM. The mixture was extracted using saturated aqueous NaHCO 3 solution. The organic layer was dried over anhydrous MgSO 4 , distilled under reduced pressure, and purified by MPLC to obtain the title compound (13 mg).
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.22 (t, J = 1.8 Hz, 1H), 7.49 (dd, J = 5.9, 1.8 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 6.69-6.56 (m, 2H), 5.51-5.37 (m, 1H), 4.34 (br s, 1H), 3.78 (br s, 1H), 3.62 (d, J = 3.7 Hz, 3H), 2.87-2.74 (m, 2H), 2.07 (d, J = 16.0 Hz, 2H), 1.77-1.67 (m, 2H), 1.57 (t, J = 6.2 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.22 (t, J = 1.8 Hz, 1H), 7.49 (dd, J = 5.9, 1.8 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 6.69-6.56 (m, 2H), 5.51-5.37 (m, 1H), 4.34 (br s, 1H), 3.78 (br s, 1H), 3.62 (d, J = 3.7 Hz, 3H), 2.87-2.74 ( m, 2H), 2.07 (d, J = 16.0 Hz, 2H), 1.77-1.67 (m, 2H), 1.57 (t, J = 6.2 Hz, 2H)
LCMS: 469.1 (M+H), 470.1 (M+2H) 471.1 (M+3H)LCMS: 469.1 (M+H), 470.1 (M+2H) 471.1 (M+3H)
실시예 41: 7-클로로-1-메틸-4-((1r,4r)-4-((5-메틸피리미딘-2-일)옥시)사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-((1r,4r)-4-((5-methylpyrimidin-2-yl)oxy)cyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 41: 7-Chloro-1-methyl-4-((1r,4r)-4-((5-methylpyrimidin-2-yl)oxy)cyclohexyl)-1,4-dihydropyrido[ 2,3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-((1r,4r)-4-((5-methylpyrimidin-2-yl)oxy)cyclohexyl)-1 ,Manufacture of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000204
Figure PCTKR2023007097-appb-img-000204
제조예 20에서 얻은 7-클로로-1-메틸-4-((1r,4r)-4-하이드록시사이클로헥실)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (45 mg, 0.145 mmol), 2-클로로-5-메틸피리미딘, Cs2CO3 (142 mg, 0.436 mmol), xantphos (8.4 mg, 0.015 mmol), Pd2(dba)3 (6.7 mg, 0.0073 mmol)을 1,4-다이옥산 (6 mL) 용매하에서 110℃에서 6시간 동안 교반하였다. 반응액을 상온으로 식힌 다음 Celite로 필터하고 여과액을 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (11 mg)을 얻었다.7-Chloro-1-methyl-4-((1r,4r)-4-hydroxycyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine obtained in Preparation Example 20 -2,3-dione (45 mg, 0.145 mmol), 2-chloro-5-methylpyrimidine, Cs 2 CO 3 (142 mg, 0.436 mmol), xantphos (8.4 mg, 0.015 mmol), Pd 2 (dba ) 3 (6.7 mg, 0.0073 mmol) was stirred at 110°C for 6 hours in 1,4-dioxane (6 mL) solvent. The reaction solution was cooled to room temperature, filtered through Celite, and the filtrate was distilled under reduced pressure. The residue was purified by MPLC to give the title compound (11 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.34 (s, 2H), 8.23 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 5.47~5.43 (m, 1H), 5.14~5.09 (m, 1H), 3.64 (s, 3H), 2.94~2.87 (m, 2H), 2.38~2.36 (m, 2H), 2.25 (s, 3H), 1.80~1.72 (m, 4H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.34 (s, 2H), 8.23 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 5.47~5.43 (m, 1H) ), 5.14~5.09 (m, 1H), 3.64 (s, 3H), 2.94~2.87 (m, 2H), 2.38~2.36 (m, 2H), 2.25 (s, 3H), 1.80~1.72 (m, 4H) )
LC/MS: 424 (M+Na)LC/MS: 424 (M+Na)
실시예 42: 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-메틸-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드 (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-methyl-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)의 제조Example 42: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-methyl -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3 -b] Preparation of pyrazin-4(1H)-yl)-N-methyl-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)
Figure PCTKR2023007097-appb-img-000205
Figure PCTKR2023007097-appb-img-000205
실시예 15에서 얻은 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드 (25 mg, 0.05 mmol)를 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (20 mg)을 얻었다.4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N- obtained in Example 15 The title compound (20 mg) was obtained in a similar manner to Step E of Preparation Example 1 using (4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (25 mg, 0.05 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.9 Hz, 2H), 5.41 (t, J = 12.1 Hz, 1H), 4.01 (d, J = 12.8 Hz, 2H), 3.61 (s, 3H), 3.27 (s, 3H), 2.80-2.75 (m, 2H), 2.67 (qd, J = 12.2, 3.4 Hz, 2H), 1.51 (d, J = 11.6 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 8.5 Hz, 2H), 7.20 ( d, J = 8.9 Hz, 2H), 5.41 (t, J = 12.1 Hz, 1H), 4.01 (d, J = 12.8 Hz, 2H), 3.61 (s, 3H), 3.27 (s, 3H), 2.80- 2.75 (m, 2H), 2.67 (qd, J = 12.2, 3.4 Hz, 2H), 1.51 (d, J = 11.6 Hz, 2H)
LC/MS: 512.1 (M+H), 534.1 (M+Na)LC/MS: 512.1 (M+H), 534.1 (M+Na)
실시예 43: 7-클로로-4-((2R,5S)-2,5-다이메틸-1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-((2R,5S)-2,5-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 43: 7-Chloro-4-((2R,5S)-2,5-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1-methyl- 1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (7-chloro-4-((2R,5S)-2,5-dimethyl-1-(4-(trifluoromethoxy )benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione) Preparation
Figure PCTKR2023007097-appb-img-000206
Figure PCTKR2023007097-appb-img-000206
제조예 21에서 얻은 7-클로로-4-((2R,5S)-2,5-다이메틸피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (34 mg, 0.095 mmol)과 4-(트라이플루오로메톡시)벤조일 클로라이드 (0.018 ml, 0.114 mmol)를 이용하여 실시예 1과 같은 방법으로 표제 화합물 (39 mg)을 얻었다7-Chloro-4-((2R,5S)-2,5-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido [2,3- obtained in Preparation Example 21 b] The title compound (39 mg) was prepared in the same manner as in Example 1 using pyrazine-2,3-dione (34 mg, 0.095 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.018 ml, 0.114 mmol). ) got
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.25 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H), 5.48~5.43 (m, 1H), 4.40 (br s, 1H), 3.68~3.65 (m, 1H), 3.63 (s, 3H), 3.32~3.27 (m, 1H), 3.17~3.10 (m, 1H), 2.74~2.70 (m, 1H), 2.03~1.99 (m, 1H), 1.38 (d, J = 6.5 Hz, 3H), 0.79 (d, J = 7.0 Hz, 3H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.25 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 2.0 Hz, 1H), 7.30 ( d, J = 8.5 Hz, 2H), 5.48~5.43 (m, 1H), 4.40 (br s, 1H), 3.68~3.65 (m, 1H), 3.63 (s, 3H), 3.32~3.27 (m, 1H) ), 3.17~3.10 (m, 1H), 2.74~2.70 (m, 1H), 2.03~1.99 (m, 1H), 1.38 (d, J = 6.5 Hz, 3H), 0.79 (d, J = 7.0 Hz, 3H)
LC/MS: 511 (M+H)LC/MS: 511 (M+H)
실시예 44: 7-클로로-4-(1-(4-플루오로-3-(트라이플루오로메틸)벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(4-fluoro-3-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 44: 7-Chloro-4-(1-(4-fluoro-3-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione (7-chloro-4-(1-(4-fluoro-3-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1, Preparation of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000207
Figure PCTKR2023007097-appb-img-000207
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (50 mg, 0.170 mmol)을 DMF (3 mL)에 녹이고 4-플루오로-3-(트라이플루오로메틸)벤조산(35.3 mg, 0.170 mmol), DIPEA (74.1 μl, 0.424 mmol)와 HATU (77 mg, 0.204 mmol)를 넣어준 후 상온에서 12시간동안 교반하엿다. EtOAc로 묽힌 후 brine으로 여러 번 씻어주었다. 유기층을 무수 MgSO4로 건조 후 감압증류한 뒤, MPLC로 정제하여 표제 화합물 (55 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (50) obtained in Preparation Example 4 mg, 0.170 mmol) was dissolved in DMF (3 mL) and 4-fluoro-3-(trifluoromethyl)benzoic acid (35.3 mg, 0.170 mmol), DIPEA (74.1 μl, 0.424 mmol) and HATU (77 mg, 0.204 mmol) were dissolved in DMF (3 mL). mmol) was added and stirred at room temperature for 12 hours. It was diluted with EtOAc and washed several times with brine. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure, and then purified by MPLC to obtain the title compound (55 mg).
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.19 (d, J = 2.3 Hz, 1H), 7.74 (d, J = 6.4 Hz, 1H), 7.70-7.66 (m, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.27 (d, J = 9.1 Hz, 1H), 7.24 (s, 0H), 5.61 (d, J = 11.4 Hz, 1H), 4.66-5.07 (1H), 3.65-3.97 (1H), 3.61 (s, 3H), 3.04-3.34 (1H), 2.91 (s, 3H), 1.79-1.59 (m, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.19 (d, J = 2.3 Hz, 1H), 7.74 (d, J = 6.4 Hz, 1H), 7.70-7.66 (m, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.27 (d, J = 9.1 Hz, 1H), 7.24 (s, 0H), 5.61 (d, J = 11.4 Hz, 1H), 4.66-5.07 (1H), 3.65-3.97 (1H) ), 3.61 (s, 3H), 3.04-3.34 (1H), 2.91 (s, 3H), 1.79-1.59 (m, 2H)
LC/MS: 485 (M+H)LC/MS: 485 (M+H)
실시예 45: 7-클로로-1-메틸-4-(1-(4-(트라이플루오로메틸)사이클로헥산-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(1-(4-(trifluoromethyl)cyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 45: 7-Chloro-1-methyl-4-(1-(4-(trifluoromethyl)cyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyri [2,3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(4-(trifluoromethyl)cyclohexane-1-carbonyl)piperidin-4-yl)-1 ,Manufacture of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000208
Figure PCTKR2023007097-appb-img-000208
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (40 mg, 0.13 mmol)과 4-(트라이플루오로메틸)사이클로헥산-1-카르복시산 (31 mg, 0.16 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (51 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.13 mmol) and 4-(trifluoromethyl)cyclohexane-1-carboxylic acid (31 mg, 0.16 mmol) to obtain the title compound (51 mg) in a similar manner to Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 1.8 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 5.61-5.56 (m, 1H), 4.84 (d, J = 12.2 Hz, 1H), 4.01 (d, J = 12.8 Hz, 1H), 3.62 (s, 3H), 3.21 (t, J = 12.1 Hz, 1H), 2.90-2.56 (m, 4H), 2.13-1.91 (m, 5H), 1.74-1.68 (m, 4H), 1.64-1.59 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 1.8 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 5.61-5.56 (m, 1H), 4.84 (d, J = 12.2 Hz, 1H), 4.01 (d, J = 12.8 Hz, 1H), 3.62 (s, 3H), 3.21 (t, J = 12.1 Hz, 1H), 2.90-2.56 (m, 4H), 2.13-1.91 (m, 5H), 1.74-1.68 (m, 4H), 1.64-1.59 (m, 2H)
LC/MS: 473.1 (M+H), 495.1 (M+Na)LC/MS: 473.1 (M+H), 495.1 (M+Na)
실시예 46: 7-클로로-4-(1-(5-플루오로-2-(트라이플루오로메틸)벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(5-fluoro-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 46: 7-Chloro-4-(1-(5-fluoro-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione (7-chloro-4-(1-(5-fluoro-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1, Preparation of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000209
Figure PCTKR2023007097-appb-img-000209
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (40 mg, 0.136 mmol)과 5-플루오로-2-(트라이플루오로메틸)벤조산(28.2 mg, 0.136 mmol)을 이용하여 실시예 45와 유사한 방법으로 표제 화합물 (35 mg)을 수득하였다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.136 mmol) and 5-fluoro-2-(trifluoromethyl)benzoic acid (28.2 mg, 0.136 mmol) to obtain the title compound (35 mg) in a similar manner to Example 45.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.18 (dd, J = 6.9, 1.8 Hz, 1H), 7.75-7.69 (m, 1H), 7.48 (dd, J = 7.3, 2.3 Hz, 1H), 7.21-7.03 (m, 2H), 5.62-5.50 (m, 1H), 4.98-4.91 (m, 1H), 3.60 (d, J = 3.7 Hz, 3H), 3.49 (dd, J = 35.0, 13.5 Hz, 1H), 3.26-3.13 (m, 1H), 3.02-2.80 (m, 3H), 1.82-1.77 (m, 1H), 1.61-1.54 (m, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.18 (dd, J = 6.9, 1.8 Hz, 1H), 7.75-7.69 (m, 1H), 7.48 (dd, J = 7.3, 2.3 Hz, 1H), 7.21 -7.03 (m, 2H), 5.62-5.50 (m, 1H), 4.98-4.91 (m, 1H), 3.60 (d, J = 3.7 Hz, 3H), 3.49 (dd, J = 35.0, 13.5 Hz, 1H) ), 3.26-3.13 (m, 1H), 3.02-2.80 (m, 3H), 1.82-1.77 (m, 1H), 1.61-1.54 (m, 2H)
LC/MS: 485 (M+H)LC/MS: 485 (M+H)
실시예 47: 4-(1-(4-브로모-2-(트라이플루오로메틸)벤조일)피페리딘-4-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (4-(1-(4-bromo-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 47: 4-(1-(4-bromo-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione (4-(1-(4-bromo-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-7-chloro-1-methyl-1, Preparation of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000210
Figure PCTKR2023007097-appb-img-000210
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (40 mg, 0.136 mmol)과 4-브로모-2-(트라이플루오로메틸)벤조산(36.5 mg, 0.136 mmol)을 이용하여 실시예 45와 유사한 방법으로 표제 화합물 (35 mg)을 수득하였다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.136 mmol) and 4-bromo-2-(trifluoromethyl)benzoic acid (36.5 mg, 0.136 mmol) to obtain the title compound (35 mg) in a similar manner to Example 45.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.18 (dd, J = 6.6, 2.1 Hz, 1H), 7.85 (d, J = 13.7 Hz, 1H), 7.77-7.71 (m, 1H), 7.51-7.47 (m, 1H), 7.39 (d, J = 8.2 Hz, 1H), 5.67-5.49 (m, 1H), 4.98-4.91 (m, 1H), 3.60 (d, J = 3.7 Hz, 3H), 3.53-3.41 (m, 1H), 3.23-3.09 (m, 1H), 3.02-2.81 (m, 3H), 1.81-1.76 (m, 1H), 1.58 (s, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.18 (dd, J = 6.6, 2.1 Hz, 1H), 7.85 (d, J = 13.7 Hz, 1H), 7.77-7.71 (m, 1H), 7.51-7.47 (m, 1H), 7.39 (d, J = 8.2 Hz, 1H), 5.67-5.49 (m, 1H), 4.98-4.91 (m, 1H), 3.60 (d, J = 3.7 Hz, 3H), 3.53- 3.41 (m, 1H), 3.23-3.09 (m, 1H), 3.02-2.81 (m, 3H), 1.81-1.76 (m, 1H), 1.58 (s, 2H)
LC/MS:456 (M+H)LC/MS:456 (M+H)
실시예 48: 7-클로로-4-(1-(5-플루오로-2-메틸벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(5-fluoro-2-methylbenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 48: 7-Chloro-4-(1-(5-fluoro-2-methylbenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione (7-chloro-4-(1-(5-fluoro-2-methylbenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3- b]Manufacture of pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000211
Figure PCTKR2023007097-appb-img-000211
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (40 mg, 0.136 mmol)과 5-플루오로-2-메틸벤조산(20.92 mg, 0.136 mmol)을 이용하여 실시예 45와 유사한 방법으로 표제화합물 (30 mg)을 수득하였다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.136 mmol) and 5-fluoro-2-methylbenzoic acid (20.92 mg, 0.136 mmol) to obtain the title compound (30 mg) in a similar manner to Example 45.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.17 (d, J = 19.2 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.19 (dd, J = 13.0, 7.5 Hz, 1H), 7.04-6.86 (m, 2H), 5.59 (s, 1H), 4.98 (s, 1H), 3.60 (t, J = 16.7 Hz, 4H), 3.18-3.12 (m, 1H), 2.96-2.82 (m, 3H), 2.34 (d, J = 77.8 Hz, 3H), 1.80 (d, J = 11.4 Hz, 1H), 1.58 (d, J = 14.6 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.17 (d, J = 19.2 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.19 (dd, J = 13.0, 7.5 Hz, 1H), 7.04-6.86 (m, 2H), 5.59 (s, 1H), 4.98 (s, 1H), 3.60 (t, J = 16.7 Hz, 4H), 3.18-3.12 (m, 1H), 2.96-2.82 (m, 3H), 2.34 (d, J = 77.8 Hz, 3H), 1.80 (d, J = 11.4 Hz, 1H), 1.58 (d, J = 14.6 Hz, 2H)
LC/MS:431 (M+H)LC/MS:431 (M+H)
실시예 49: 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-에틸-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드 (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-ethyl-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)의 제조Example 49: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-ethyl -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3 -b] Preparation of pyrazin-4(1H)-yl)-N-ethyl-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)
Figure PCTKR2023007097-appb-img-000212
Figure PCTKR2023007097-appb-img-000212
실시예 15에서 얻은 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드 (40 mg, 0.08 mmol)과 브로모에탄 (7.80 μL, 0.10 mmol)을 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (15 mg)을 얻었다.4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N- obtained in Example 15 A method similar to Step E of Preparation Example 1 using (4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (40 mg, 0.08 mmol) and bromoethane (7.80 μL, 0.10 mmol) The title compound (15 mg) was obtained.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.16 (d, J = 1.8 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.19-7.16 (m, 2H), 5.38 (t, J = 11.9 Hz, 1H), 3.96 (d, J = 13.1 Hz, 2H), 3.71 (q, J = 7.0 Hz, 2H), 3.60 (s, 3H), 2.73 (dd, J = 13.0, 11.4 Hz, 2H), 2.62 (qd, J = 12.3, 3.4 Hz, 2H), 1.46 (dd, J = 11.6, 2.1 Hz, 2H), 1.17 (t, J = 7.0 Hz, 3H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.16 (d, J = 1.8 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.19- 7.16 (m, 2H), 5.38 (t, J = 11.9 Hz, 1H), 3.96 (d, J = 13.1 Hz, 2H), 3.71 (q, J = 7.0 Hz, 2H), 3.60 (s, 3H), 2.73 (dd, J = 13.0, 11.4 Hz, 2H), 2.62 (qd, J = 12.3, 3.4 Hz, 2H), 1.46 (dd, J = 11.6, 2.1 Hz, 2H), 1.17 (t, J = 7.0 Hz) , 3H)
LC/MS:526.1 (M+H), 548.1 (M+Na)LC/MS:526.1 (M+H), 548.1 (M+Na)
실시예 50: 7-클로로-1,6-다이메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 50: 7-Chloro-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2 ,3-b]pyrazine-2,3-dione (7-chloro-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[ Preparation of 2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000213
Figure PCTKR2023007097-appb-img-000213
제조예 21에서 얻은 7-클로로-1,6-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (47 mg, 0.136 mmol)과 4-(트라이플루오로메톡시)벤조일 클로라이드 (0.026 ml, 0.163 mmol)를 이용하여 실시예 8과 같은 방법으로 표제 화합물 (43 mg)을 얻었다7-Chloro-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da obtained in Preparation Example 21 The title compound (43 mg) was obtained in the same manner as in Example 8 using ion (47 mg, 0.136 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.026 ml, 0.163 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.54 (d, J = 9.0 Hz, 2H), 7.49 (s, 1H), 7.29 (d, J = 8.5 Hz, 2H), 5.66 (br s, 1H), 4.93 (br s, 1H), 3.88 (br s, 1H), 3.62 (s, 3H), 3.23 (br s, 1H), 2.96 (br s, 3H), 2.65 (s, 3H), 1.83~1.67 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.54 (d, J = 9.0 Hz, 2H), 7.49 (s, 1H), 7.29 (d, J = 8.5 Hz, 2H), 5.66 (br s, 1H) , 4.93 (br s, 1H), 3.88 (br s, 1H), 3.62 (s, 3H), 3.23 (br s, 1H), 2.96 (br s, 3H), 2.65 (s, 3H), 1.83~1.67 (m, 2H)
LC/MS: 497 (M+H)LC/MS: 497 (M+H)
실시예 51: 7-브로모-1,6-다이메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-bromo-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 51: 7-Bromo-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[ 2,3-b]pyrazine-2,3-dione (7-bromo-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid Preparation of [2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000214
Figure PCTKR2023007097-appb-img-000214
제조예 23에서 얻은 7-브로모-1,6-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (49 mg, 0.126 mmol)과 4-(트라이플루오로메톡시)벤조일 클로라이드 (0.024 ml, 0.151 mmol)를 이용하여 실시예 8과 같은 방법으로 표제 화합물 (59 mg)을 얻었다7-Bromo-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3- obtained in Preparation Example 23 The title compound (59 mg) was obtained in the same manner as in Example 8 using dione (49 mg, 0.126 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.024 ml, 0.151 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.64 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 5.65 (br s, 1H), 4.93 (br s, 1H), 3.89 (br s, 1H), 3.62 (s, 3H), 3.22 (br s, 1H), 2.96 (br s, 3H), 2.68 (s, 3H), 1.82~1.67 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.64 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 5.65 (br s, 1H) , 4.93 (br s, 1H), 3.89 (br s, 1H), 3.62 (s, 3H), 3.22 (br s, 1H), 2.96 (br s, 3H), 2.68 (s, 3H), 1.82~1.67 (m, 2H)
LC/MS: 541, 543 (M+H)LC/MS: 541, 543 (M+H)
실시예 52: 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(사이클로프로필메틸)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드 (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(cyclopropylmethyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)의 제조Example 52: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( Cyclopropylmethyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid Preparation of [2,3-b]pyrazin-4(1H)-yl)-N-(cyclopropylmethyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)
Figure PCTKR2023007097-appb-img-000215
Figure PCTKR2023007097-appb-img-000215
실시예 15에서 얻은 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드 (50 mg, 0.10 mmol)와 (브로모메틸)사이클로프로판 (15 mg, 0.11 mmol)을 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (31 mg)을 얻었다.4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N- obtained in Example 15 Preparation Example 1 using (4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (50 mg, 0.10 mmol) and (bromomethyl)cyclopropane (15 mg, 0.11 mmol) The title compound (31 mg) was obtained in a similar manner to E.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.16 (s, 1H), 7.48 (s, 1H), 7.28-7.19 (m, 4H), 5.39 (s, 1H), 4.00 (d, J = 12.5 Hz, 2H), 3.60 (s, 3H), 3.54 (d, J = 6.4 Hz, 2H), 2.74 (t, J = 12.5 Hz, 2H), 2.64 (t, J = 10.7 Hz, 2H), 1.48 (d, J = 11.0 Hz, 2H), 1.13 (s, 1H), 0.45 (d, J = 7.3 Hz, 2H), 0.15 (d, J = 4.0 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.16 (s, 1H), 7.48 (s, 1H), 7.28-7.19 (m, 4H), 5.39 (s, 1H), 4.00 (d, J = 12.5 Hz , 2H), 3.60 (s, 3H), 3.54 (d, J = 6.4 Hz, 2H), 2.74 (t, J = 12.5 Hz, 2H), 2.64 (t, J = 10.7 Hz, 2H), 1.48 (d , J = 11.0 Hz, 2H), 1.13 (s, 1H), 0.45 (d, J = 7.3 Hz, 2H), 0.15 (d, J = 4.0 Hz, 2H)
LC/MS: 552.2 (M+H), 574.2 (M+Na)LC/MS: 552.2 (M+H), 574.2 (M+Na)
실시예 53: 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(사이클로헥실메틸)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드 (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(cyclohexylmethyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)의 제조Example 53: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( Cyclohexylmethyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid Preparation of [2,3-b]pyrazin-4(1H)-yl)-N-(cyclohexylmethyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)
Figure PCTKR2023007097-appb-img-000216
Figure PCTKR2023007097-appb-img-000216
실시예 15에서 얻은 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드 (50 mg, 0.10 mmol)와 (브로모메틸)사이클로헥산 (20 mg, 0.11 mmol)을 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (11 mg)을 얻었다.4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N- obtained in Example 15 Preparation Example 1 using (4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (50 mg, 0.10 mmol) and (bromomethyl)cyclohexane (20 mg, 0.11 mmol) The title compound (11 mg) was obtained in a similar manner to E.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.16 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.9 Hz, 2H), 5.40 (s, 1H), 4.02 (d, J = 13.1 Hz, 2H), 3.61 (s, 3H), 3.51 (d, J = 7.0 Hz, 2H), 2.76 (t, J = 12.2 Hz, 2H), 2.65 (dd, J = 12.1, 9.3 Hz, 2H), 1.81-1.69 (m, 6H), 1.49 (d, J = 10.1 Hz, 2H), 1.28-1.18 (m, 3H), 1.04-0.97 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.16 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.16 ( d, J = 8.9 Hz, 2H), 5.40 (s, 1H), 4.02 (d, J = 13.1 Hz, 2H), 3.61 (s, 3H), 3.51 (d, J = 7.0 Hz, 2H), 2.76 ( t, J = 12.2 Hz, 2H), 2.65 (dd, J = 12.1, 9.3 Hz, 2H), 1.81-1.69 (m, 6H), 1.49 (d, J = 10.1 Hz, 2H), 1.28-1.18 (m , 3H), 1.04-0.97 (m, 2H)
LC/MS: 594.2 (M+H), 595.2 (M+2H)LC/MS: 594.2 (M+H), 595.2 (M+2H)
실시예 54: 7-클로로-1-메틸-4-(1-(5-메틸-1-페닐-1H-피라졸-4-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(1-(5-methyl-1-phenyl-1H-pyrazole-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 54: 7-Chloro-1-methyl-4-(1-(5-methyl-1-phenyl-1H-pyrazole-4-carbonyl)piperidin-4-yl)-1,4-di Hydropyrido[2,3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(5-methyl-1-phenyl-1H-pyrazole-4-carbonyl)piperidin Preparation of -4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000217
Figure PCTKR2023007097-appb-img-000217
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (40 mg, 0.136 mmol)과 5-메틸-1-페닐-1H-피라졸-4-카르복시산 (29.3 mg, 0.145 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (22 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.136 mmol) and 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (29.3 mg, 0.145 mmol) to obtain the title compound (22 mg) in a similar manner to Example 1.
LC/MS: 480.0 (M+H)LC/MS: 480.0 (M+H)
실시예 55: 7-클로로-4-(1-(1-(5-클로로피리딘-2-일)-5-(트라이플루오로메틸)-1H-피라졸-4-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(1-(5-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 55: 7-Chloro-4-(1-(1-(5-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl)piperidine- 4-yl)-1-methyl-1,4-dihydropyrido [2,3-b] pyrazine-2,3-dione (7-chloro-4-(1-(1-(5-chloropyridin- 2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione) manufacture of
Figure PCTKR2023007097-appb-img-000218
Figure PCTKR2023007097-appb-img-000218
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (40 mg, 0.136 mmol)과 1-(5-클로로피리딘-2-일)-5-(트라이플루오로메틸)-1H-피라졸-4-카르복시산 (42.3 mg, 0.145 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (39 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.136 mmol) and 1-(5-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (42.3 mg, 0.145 mmol). The title compound (39 mg) was obtained in a similar manner.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.48 (s, 1H), 8.19 (s, 1H), 7.87 (dd, J = 2.3, 8.7 Hz, 1H), 7.82 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.49 (s, 1H), 5.64-5.56 (m, 1H), 4.96 (d, J = 10.4 Hz, 1H), 3.88 (d, J = 14.2 Hz, 1H), 3.62 (s, 3H), 3.33-3.24 (m, 1H), 3.00-2.88 (m, 3H), 1.81 (d, J = 11.6 Hz, 1H), 1.67 (d, J = 11.9 Hz, 1H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.48 (s, 1H), 8.19 (s, 1H), 7.87 (dd, J = 2.3, 8.7 Hz, 1H), 7.82 (s, 1H), 7.75 (d) , J = 8.7 Hz, 1H), 7.49 (s, 1H), 5.64-5.56 (m, 1H), 4.96 (d, J = 10.4 Hz, 1H), 3.88 (d, J = 14.2 Hz, 1H), 3.62 (s, 3H), 3.33-3.24 (m, 1H), 3.00-2.88 (m, 3H), 1.81 (d, J = 11.6 Hz, 1H), 1.67 (d, J = 11.9 Hz, 1H)
LC/MS: 569.4 (M+H)LC/MS: 569.4 (M+H)
실시예 56: 7-클로로-1-메틸-4-(1-(피페리딘-4-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 염산염 (7-chloro-1-methyl-4-(1-(piperidine-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride)의 제조Example 56: 7-Chloro-1-methyl-4-(1-(piperidine-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione hydrochloride (7-chloro-1-methyl-4-(1-(piperidine-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b] Preparation of pyrazine-2,3-dione hydrochloride)
Figure PCTKR2023007097-appb-img-000219
Figure PCTKR2023007097-appb-img-000219
제조예 4의 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (300 mg, 0.906 mmol)과 1-(터트-부톡시카르보닐)피페리딘-4-카르복시산 (208 mg, 0.906 mmol)을 이용하여 실시예 1과 유사한 방법으로 혼합물 (257 mg)을 수득하였고 이후 정제하지 않고 제조예 1의 단계 F와 유사한 방법으로 표제 화합물 (224 mg)을 합성하였다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione of Preparation Example 4 (300 mg , 0.906 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (208 mg, 0.906 mmol) were used to obtain a mixture (257 mg) in a similar manner to Example 1 and then purified. The title compound (224 mg) was synthesized in a manner similar to Step F of Preparation Example 1.
1H-NMR (500 MHz, METHANOL-D4) δ 8.24 (s, 1H), 7.90 (s, 1H), 5.72 (br. s., 1H), 4.71 (d, J = 13.0 Hz, 1H), 4.24 (d, J = 13.3 Hz, 1H), 3.63-3.57 (m, 3H), 3.45 (t, J = 13.6 Hz, 2H), 3.19-3.04 (m, 3H), 2.85-2.63 (m, 4H), 2.06-1.88 (m, 4H), 1.85 (d, J = 12.8 Hz, 1H), 1.78 (d, J = 11.1 Hz, 1H)1H-NMR (500 MHz, METHANOL-D4) δ 8.24 (s, 1H), 7.90 (s, 1H), 5.72 (br. s., 1H), 4.71 (d, J = 13.0 Hz, 1H), 4.24 ( d, J = 13.3 Hz, 1H), 3.63-3.57 (m, 3H), 3.45 (t, J = 13.6 Hz, 2H), 3.19-3.04 (m, 3H), 2.85-2.63 (m, 4H), 2.06 -1.88 (m, 4H), 1.85 (d, J = 12.8 Hz, 1H), 1.78 (d, J = 11.1 Hz, 1H)
LC/MS: 443.4 (M+H)LC/MS: 443.4 (M+H)
실시예 57: N-((1r,4r)-4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)사이클로헥실)-4-(트라이플루오로메톡시)벤즈아마이드 (N-((1r,4r)-4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)cyclohexyl)-4-(trifluoromethoxy)benzamide)의 제조Example 57: N-((1r,4r)-4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4( 1H)-yl)cyclohexyl)-4-(trifluoromethoxy)benzamide (N-((1r,4r)-4-(7-chloro-1-methyl-2,3-dioxo-2,3- Preparation of dihydropyrido[2,3-b]pyrazin-4(1H)-yl)cyclohexyl)-4-(trifluoromethoxy)benzamide)
Figure PCTKR2023007097-appb-img-000220
Figure PCTKR2023007097-appb-img-000220
제조예 17의 4-(4-아미노사이클로헥실)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (50 mg, 0.162 mmol)과 4-(트라이플루오로메톡시)벤조일 클로라이드 (43.6 mg, 0.194 mmol)를 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (25 mg)을 얻었다.4-(4-aminocyclohexyl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione of Preparation Example 17 (50 mg, 0.162 mmol) and 4-(trifluoromethoxy)benzoyl chloride (43.6 mg, 0.194 mmol) to obtain the title compound (25 mg) in a similar manner to Example 8.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.12-8.26 (1H), 7.72-7.88 (2H), 7.39-7.49 (1H), 7.26-7.36 (2H), 5.81-5.97 (1H), 5.25-5.41 (1H), 4.11-4.23 (1H), 3.52-3.68 (3H), 2.83-3.02 (2H), 2.18-2.35 (2H), 1.71-1.86 (2H), 1.45-1.51 (2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.12-8.26 (1H), 7.72-7.88 (2H), 7.39-7.49 (1H), 7.26-7.36 (2H), 5.81-5.97 (1H), 5.25-5.41 (1H), 4.11-4.23 (1H), 3.52-3.68 (3H), 2.83-3.02 (2H), 2.18-2.35 (2H), 1.71-1.86 (2H), 1.45-1.51 (2H)
LC/MS: 497 (M+H)LC/MS: 497 (M+H)
실시예 58: 7-클로로-4-(1-(5-클로로피리미딘e-2-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(5-chloropyrimidine-2-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 58: 7-Chloro-4-(1-(5-chloropyrimidinee-2-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2, 3-b] pyrazine-2,3-dione (7-chloro-4-(1-(5-chloropyrimidine-2-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2, Preparation of 3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000221
Figure PCTKR2023007097-appb-img-000221
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (40 mg, 0.136 mmol)과 5-클로로피리미딘-2-카르복시산 (23.67 mg, 0.149 mmol)을 이용하여 실시예 44와 유사한 방법으로 표제 화합물 (44 mg)을 수득하였다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.136 mmol) and 5-chloropyrimidine-2-carboxylic acid (23.67 mg, 0.149 mmol) to obtain the title compound (44 mg) in a similar manner to Example 44.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.78 (s, 2H), 8.21 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 5.56 (d, J = 11.4 Hz, 1H), 4.95 (d, J = 9.1 Hz, 1H), 3.72 (d, J = 13.3 Hz, 1H), 3.60 (s, 3H), 3.26 (td, J = 13.2, 2.9 Hz, 1H), 3.04-2.95 (m, 3H), 1.82 (d, J = 8.7 Hz, 1H), 1.64 (d, J = 11.0 Hz, 1H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.78 (s, 2H), 8.21 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 5.56 (d, J = 11.4 Hz, 1H), 4.95 (d, J = 9.1 Hz, 1H), 3.72 (d, J = 13.3 Hz, 1H), 3.60 (s, 3H), 3.26 (td, J = 13.2, 2.9 Hz, 1H), 3.04-2.95 (m, 3H), 1.82 (d, J = 8.7 Hz, 1H), 1.64 (d, J = 11.0 Hz, 1H)
LC/MS: 436 (M+H)LC/MS: 436 (M+H)
실시예 59: 7-클로로-4-(1-(6-클로로니코티노일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(6-chloronicotinoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 59: 7-Chloro-4-(1-(6-chloronicotinoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione (7-chloro-4-(1-(6-chloronicotinoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3 Manufacture of -dione)
Figure PCTKR2023007097-appb-img-000222
Figure PCTKR2023007097-appb-img-000222
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (40 mg, 0.136 mmol)과 6-클로로니코틴산 (23.52 mg, 0.149 mmol)을 이용하여 실시예 44와 유사한 방법으로 표제 화합물 (53 mg)을 수득하였다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.136 mmol) and 6-chloronicotinic acid (23.52 mg, 0.149 mmol) to obtain the title compound (53 mg) in a similar manner to Example 44.
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.50 (d, J = 1.8 Hz, 1H), 8.19 (d, J = 1.8 Hz, 1H), 7.79 (dd, J = 8.2, 2.3 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 5.61 (d, J = 11.4 Hz, 1H), 4.89 (s, 1H), 3.82 (d, J = 27.0 Hz, 1H), 3.61 (s, 3H), 3.26 (s, 1H), 2.96-2.83 (m, 3H), 1.75 (d, J = 38.9 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.50 (d, J = 1.8 Hz, 1H), 8.19 (d, J = 1.8 Hz, 1H), 7.79 (dd, J = 8.2, 2.3 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 5.61 (d, J = 11.4 Hz, 1H), 4.89 (s, 1H), 3.82 (d, J = 27.0 Hz, 1H), 3.61 (s, 3H), 3.26 (s, 1H), 2.96-2.83 (m, 3H), 1.75 (d, J = 38.9 Hz, 2H)
LC/MS: 435 (M+H)LC/MS: 435 (M+H)
실시예 60: 7-클로로-4-(1-(1-아이소부틸피페리딘-4-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(1-isobutylpiperidine-4-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 60: 7-Chloro-4-(1-(1-isobutylpiperidine-4-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2 ,3-b]pyrazine-2,3-dione (7-chloro-4-(1-(1-isobutylpiperidine-4-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2 ,3-b]pyrazine-2,3-dione) production
Figure PCTKR2023007097-appb-img-000223
Figure PCTKR2023007097-appb-img-000223
실시예 56에서 얻은 7-클로로-1-메틸-4-(1-(피페리딘-4-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 염산염 (30 mg, 0.068 mmol)과 1-브로모-2-메틸프로판 (9 mg, 0.081 mmol)을 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (7.7 mg)을 얻었다.7-Chloro-1-methyl-4-(1-(piperidine-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-obtained in Example 56 b] The title compound was prepared in a manner similar to Step E of Preparation Example 1 using pyrazine-2,3-dione hydrochloride (30 mg, 0.068 mmol) and 1-bromo-2-methylpropane (9 mg, 0.081 mmol). (7.7 mg) was obtained.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.17 (s, 1H), 7.49 (s, 1H), 5.57 (br. s., 1H), 4.84 (d, J = 12.7 Hz, 1H), 4.21 (br. s., 2H), 4.08 (d, J = 12.8 Hz, 1H), 3.87 (d, J = 5.0 Hz, 2H), 3.61 (s, 3H), 3.22 (t, J = 12.4 Hz, 1H), 2.91-2.66 (m, 6H), 1.94 (tt, J = 6.8, 13.3 Hz, 1H), 1.82-1.67 (m, 6H), 0.94 (d, J = 6.7 Hz, 6H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.17 (s, 1H), 7.49 (s, 1H), 5.57 (br. s., 1H), 4.84 (d, J = 12.7 Hz, 1H), 4.21 ( br. s., 2H), 4.08 (d, J = 12.8 Hz, 1H), 3.87 (d, J = 5.0 Hz, 2H), 3.61 (s, 3H), 3.22 (t, J = 12.4 Hz, 1H) , 2.91-2.66 (m, 6H), 1.94 (tt, J = 6.8, 13.3 Hz, 1H), 1.82-1.67 (m, 6H), 0.94 (d, J = 6.7 Hz, 6H)
LC/MS: 463.0 (M+H),LC/MS: 463.0 (M+H),
실시예 61: 4-(1-(1-아세틸피페리딘-4-카르보닐)피페리딘-4-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (4-(1-(1-acetylpiperidine-4-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 61: 4-(1-(1-acetylpiperidin-4-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2, 3-b] pyrazine-2,3-dione (4-(1-(1-acetylpiperidine-4-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrid[2, Preparation of 3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000224
Figure PCTKR2023007097-appb-img-000224
실시예 56에서 얻은 7-클로로-1-메틸-4-(1-(피페리딘-4-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 염산염 (30 mg, 0.068 mmol)과 아세틸 클로라이드 (0.015 ml, 0.203 mmol)를 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (17.6 mg)을 얻었다.7-Chloro-1-methyl-4-(1-(piperidine-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-obtained in Example 56 b] The title compound (17.6 mg) was obtained in a similar manner to Example 8 using pyrazine-2,3-dione hydrochloride (30 mg, 0.068 mmol) and acetyl chloride (0.015 ml, 0.203 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (br. s., 1H), 7.49 (s, 1H), 5.60 (br. s., 1H), 4.84 (d, J = 11.7 Hz, 1H), 4.61 (t, J = 14.3 Hz, 1H), 4.08 (d, J = 11.9 Hz, 1H), 3.90 (br. s., 1H), 3.61 (s, 3H), 3.23 (t, J = 13.0 Hz, 1H), 3.18-3.07 (m, 1H), 2.89 (br. s., 1H), 2.83- 2.74 (m, 2H), 2.74-2.65 (m, 2H), 2.11 (s, 3H), 1.90-1.71 (m, 6H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (br. s., 1H), 7.49 (s, 1H), 5.60 (br. s., 1H), 4.84 (d, J = 11.7 Hz, 1H) , 4.61 (t, J = 14.3 Hz, 1H), 4.08 (d, J = 11.9 Hz, 1H), 3.90 (br. s., 1H), 3.61 (s, 3H), 3.23 (t, J = 13.0 Hz) , 1H), 3.18-3.07 (m, 1H), 2.89 (br. s., 1H), 2.83- 2.74 (m, 2H), 2.74-2.65 (m, 2H), 2.11 (s, 3H), 1.90- 1.71 (m, 6H)
LC/MS: 449.0 (M+H),LC/MS: 449.0 (M+H),
실시예 62: 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(사이클로부틸메틸)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드 (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(cyclobutylmethyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)의 제조Example 62: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( Cyclobutylmethyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid Preparation of [2,3-b]pyrazin-4(1H)-yl)-N-(cyclobutylmethyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)
Figure PCTKR2023007097-appb-img-000225
Figure PCTKR2023007097-appb-img-000225
실시예 15에서 얻은 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드 (50 mg, 0.10 mmol)와 (브로모메틸)사이클로부탄 (17 mg, 0.11 mmol)을 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (10 mg)을 얻었다.4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N- obtained in Example 15 Preparation Example 1 using (4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (50 mg, 0.10 mmol) and (bromomethyl)cyclobutane (17 mg, 0.11 mmol) The title compound (10 mg) was obtained in a similar manner to E.
LC/MS:526.1 (M+H), 548.1 (M+Na)LC/MS:526.1 (M+H), 548.1 (M+Na)
실시예 63: 6-메톡시-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (6-methoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 63: 6-methoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (6-methoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3- b]Manufacture of pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000226
Figure PCTKR2023007097-appb-img-000226
제조예 7의 6-메톡시-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.103 mmol)을 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (35 mg)을 얻었다.6-methoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione of Preparation Example 7 (30 mg, 0.103 mmol) to obtain the title compound (35 mg) in a similar manner to Example 8.
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.50 (t, J = 7.5 Hz, 3H), 7.28 (d, J = 7.0 Hz, 2H), 6.70 (d, J = 8.9 Hz, 1H), 5.59 (t, J = 11.4 Hz, 1H), 4.92 (s, 1H), 3.98 (br s, 4H), 3.62 (br s, 3H), 3.21 (s, 1H), 3.02-2.90 (m, 3H), 1.80 (d, J = 53.1 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.50 (t, J = 7.5 Hz, 3H), 7.28 (d, J = 7.0 Hz, 2H), 6.70 (d, J = 8.9 Hz, 1H), 5.59 ( t, J = 11.4 Hz, 1H), 4.92 (s, 1H), 3.98 (br s, 4H), 3.62 (br s, 3H), 3.21 (s, 1H), 3.02-2.90 (m, 3H), 1.80 (d, J = 53.1 Hz, 2H)
LC/MS: 479.1 (M+H), 480.2 (M+2H)LC/MS: 479.1 (M+H), 480.2 (M+2H)
실시예 64: 6-클로로-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 64: 6-Chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione (6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b ]Manufacture of pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000227
Figure PCTKR2023007097-appb-img-000227
제조예 15에서 얻은 6-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.102 mmol)을 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (30 mg)을 얻었다.6-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 15 mg, 0.102 mmol) to obtain the title compound (30 mg) in a similar manner to Example 8.
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.54 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 7.3 Hz, 2H), 7.25 (d, J = 8.5 Hz, 1H), 5.57 (br s, 1H), 4.91 (br s, 1H), 3.86 (br s, 1H), 3.63 (s, 3H), 3.22 (br s, 1H) 3.01-2.83 (m, 3H), 1.82 (br s, 1H), 1.68 (br s, 1H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.54 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 7.3 Hz, 2H), 7.25 ( d, J = 8.5 Hz, 1H), 5.57 (br s, 1H), 4.91 (br s, 1H), 3.86 (br s, 1H), 3.63 (s, 3H), 3.22 (br s, 1H) 3.01- 2.83 (m, 3H), 1.82 (br s, 1H), 1.68 (br s, 1H)
LC/MS: 483.1 (M+H), 505.1 (M+Na)LC/MS: 483.1 (M+H), 505.1 (M+Na)
실시예 65: 7-클로로-1-메틸-4-(1-(피페라진-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(1-(piperazine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 65: 7-Chloro-1-methyl-4-(1-(piperazine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b] Pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(piperazine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine- Preparation of 2,3-dione)
Figure PCTKR2023007097-appb-img-000228
Figure PCTKR2023007097-appb-img-000228
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (150 mg, 0.453 mmol)과 4-(터트-부톡시카르보닐)피페라진-1-카르복시산 (104 mg, 0.r453 mmol)을 이용하여 실시예 57과 유사한 방법으로 표제 화합물 (38 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (150 mg, 0.453 mmol) and 4-(tert-butoxycarbonyl)piperazine-1-carboxylic acid (104 mg, 0.r453 mmol) to obtain the title compound (38 mg) in a similar manner to Example 57.
1H-NMR (500 MHz, METHANOL-D4) δ 8.24 (s, 1H), 7.90 (s, 1H), 5.62 (br. s., 1H), 3.92 (d, J = 13.0 Hz, 2H), 3.61 (s, 3H), 3.47 (br. s., 4H), 3.21 (br. s., 4H), 3.03 (t, J = 12.7 Hz, 2H), 2.88-2.78 (m, 2H), 1.74 (d, J = 11.0 Hz, 2H)1H-NMR (500 MHz, METHANOL-D4) δ 8.24 (s, 1H), 7.90 (s, 1H), 5.62 (br. s., 1H), 3.92 (d, J = 13.0 Hz, 2H), 3.61 ( s, 3H), 3.47 (br. s., 4H), 3.21 (br. s., 4H), 3.03 (t, J = 12.7 Hz, 2H), 2.88-2.78 (m, 2H), 1.74 (d, J = 11.0 Hz, 2H)
LC/MS: 444.4 (M+H)LC/MS: 444.4 (M+H)
실시예 66: 4-(1-(1H-인돌-3-카르보닐)피페리딘-4-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (4-(1-(1H-indole-3-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 66: 4-(1-(1H-indole-3-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione (4-(1-(1H-indole-3-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrid[2,3-b ]Manufacture of pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000229
Figure PCTKR2023007097-appb-img-000229
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.091 mmol)과 1H-인돌-3-카르복시산 (17.52 mg, 0.109 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (3.4 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.091 mmol) and 1H-indole-3-carboxylic acid (17.52 mg, 0.109 mmol) to obtain the title compound (3.4 mg) in a similar manner to Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.40 (s, 1H), 8.21 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.48 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 5.61 (br. s., 1H), 4.61 (br. s., 1H), 3.74 (br. s., 1H), 3.61 (s, 3H), 3.49 (d, J = 5.6 Hz, 1H), 3.09 (d, J = 11.1 Hz, 2H), 2.98 (d, J = 8.4 Hz, 2H), 1.72 (d, J = 12.2 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.40 (s, 1H), 8.21 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.48 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 5.61 (br. s., 1H), 4.61 (br. s., 1H), 3.74 (br. s., 1H), 3.61 (s, 3H), 3.49 (d, J = 5.6 Hz, 1H), 3.09 (d, J = 11.1 Hz, 2H), 2.98 (d, J = 8.4 Hz, 2H), 1.72 (d, J = 12.2 Hz) , 2H)
LC/MS: 438.9 (M+H)LC/MS: 438.9 (M+H)
실시예 67: 6-클로로-1-메틸-4-(1-(4-옥소사이클로헥산-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (6-chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 67: 6-Chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (6-chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrid[2,3 Preparation of -b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000230
Figure PCTKR2023007097-appb-img-000230
제조예 15에서 얻은 6-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (200 mg, 0.604 mmol)과 4-옥소사이클로헥산-1-카르복시산 (86 mg, 0.604 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (53 mg)을 얻었다.6-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (200) obtained in Preparation Example 15 mg, 0.604 mmol) and 4-oxocyclohexane-1-carboxylic acid (86 mg, 0.604 mmol) to obtain the title compound (53 mg) in a similar manner to Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.47 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 5.58-5.50 (m, 1H), 4.87 (d, J = 11.0 Hz, 1H), 4.14 (d, J = 12.8 Hz, 1H), 3.62 (s, 3H), 3.30 (t, J = 13.0 Hz, 1H), 3.05-2.95 (m, 2H), 2.81-2.69 (m, 2H), 2.61 (t, J = 4.3 Hz, 1H), 2.58 (t, J = 4.0 Hz, 1H), 2.41-2.34 (m, 2H), 2.22-2.12 (m, 2 H), 2.09 (br. s., 2H), 1.82 (d, J = 11.6 Hz, 1H), 1.75 (d, J = 11.9 Hz, 1H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.47 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 5.58-5.50 (m, 1H), 4.87 (d, J = 11.0 Hz, 1H), 4.14 (d, J = 12.8 Hz, 1H), 3.62 (s, 3H), 3.30 (t, J = 13.0 Hz, 1H), 3.05-2.95 (m, 2H), 2.81-2.69 (m, 2H), 2.61 (t, J = 4.3 Hz, 1H), 2.58 (t, J = 4.0 Hz, 1H), 2.41-2.34 (m, 2H), 2.22-2.12 (m, 2H), 2.09 (br. s., 2H), 1.82 (d, J = 11.6 Hz, 1H), 1.75 (d, J = 11.9 Hz, 1H)
LC/MS: 419.9 (M+H)LC/MS: 419.9 (M+H)
실시예 68: 7-클로로-1-메틸-4-(1-(4-옥소사이클로헥산-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 68: 7-Chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrid[2,3 Preparation of -b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000231
Figure PCTKR2023007097-appb-img-000231
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (200 mg, 0.604 mmol)과 4-옥소사이클로헥산-1-카르복시산 (86 mg, 0.604 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (112 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (200 mg, 0.604 mmol) and 4-oxocyclohexane-1-carboxylic acid (86 mg, 0.604 mmol) to obtain the title compound (112 mg) in a similar manner to Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (s, 1H), 7.49 (s, 1H), 5.60 (t, J = 11.9 Hz, 1H), 4.85 (d, J = 12.8 Hz, 1H), 4.13 (d, J = 11.7 Hz, 1H), 3.61 (s, 3H), 3.27 (t, J = 12.9 Hz, 1H), 2.99 (dt, J = 4.7, 9.2 Hz, 1H), 2.96-2.87 (m, 1H), 2.78 (d, J = 9.6 Hz, 1H), 2.74-2.65 (m, 1H), 2.56 (d, J = 13.1 Hz, 2H), 2.38 (d, J = 7.9 Hz, 2H), 2.14 (d, J = 8.7 Hz, 2H), 2.11-2.01 (m, 2H), 1.79 (d, J = 11.3 Hz, 1H), 1.73 (d, J = 11.3 Hz, 1H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (s, 1H), 7.49 (s, 1H), 5.60 (t, J = 11.9 Hz, 1H), 4.85 (d, J = 12.8 Hz, 1H), 4.13 (d, J = 11.7 Hz, 1H), 3.61 (s, 3H), 3.27 (t, J = 12.9 Hz, 1H), 2.99 (dt, J = 4.7, 9.2 Hz, 1H), 2.96-2.87 (m , 1H), 2.78 (d, J = 9.6 Hz, 1H), 2.74-2.65 (m, 1H), 2.56 (d, J = 13.1 Hz, 2H), 2.38 (d, J = 7.9 Hz, 2H), 2.14 (d, J = 8.7 Hz, 2H), 2.11-2.01 (m, 2H), 1.79 (d, J = 11.3 Hz, 1H), 1.73 (d, J = 11.3 Hz, 1H)
LC/MS: 419.9 (M+H)LC/MS: 419.9 (M+H)
실시예 69: 6-클로로-4-(1-(4-(다이메틸아미노)사이클로헥산-1-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (6-chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 69: 6-Chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione (6-chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1, Preparation of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000232
Figure PCTKR2023007097-appb-img-000232
실시예 67에서 얻은 6-클로로-1-메틸-4-(1-(4-옥소사이클로헥산e-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (20 mg, 0.048 mmol)과 다이메틸아민 (3.23 mg, 0.072 mmol)을 이용하여 실시예 41과 유사한 방법으로 표제 화합물 (4.5 mg)을 얻었다.6-Chloro-1-methyl-4-(1-(4-oxocyclohexanee-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido [2 ,3-b]pyrazine-2,3-dione (20 mg, 0.048 mmol) and dimethylamine (3.23 mg, 0.072 mmol) were used to obtain the title compound (4.5 mg) in a similar manner to Example 41.
LC/MS: 449.0 (M+H)LC/MS: 449.0 (M+H)
실시예 70: 7-클로로-4-(1-(4-(다이메틸아미노)사이클로헥산-1-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 70: 7-Chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione (7-chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1, Preparation of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000233
Figure PCTKR2023007097-appb-img-000233
실시예 68에서 얻은 7-클로로-1-메틸-4-(1-(4-옥소사이클로헥산-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (20 mg, 0.048 mmol)과 다이메틸아민 (3.23 mg, 0.072 mmol)을 이용하여 실시예 41과 유사한 방법으로 표제 화합물 (3.4 mg)을 얻었다.7-Chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido [2, [3-b] The title compound (3.4 mg) was obtained in a similar manner to Example 41 using pyrazine-2,3-dione (20 mg, 0.048 mmol) and dimethylamine (3.23 mg, 0.072 mmol).
LC/MS: 449.0 (M+H)LC/MS: 449.0 (M+H)
실시예 71: 7-클로로-4-(1-(4-아이소부틸피페라진-1-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-4-(1-(4-isobutylpiperazine-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 71: 7-Chloro-4-(1-(4-isobutylpiperazine-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2, 3-b] pyrazine-2,3-dione (7-chloro-4-(1-(4-isobutylpiperazine-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2, Preparation of 3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000234
Figure PCTKR2023007097-appb-img-000234
실시예 66에서 얻은 7-클로로-1-메틸-4-(1-(피페라진-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (20 mg, 0.045 mmol)과 1-브로모-2-메틸프로판 (7 mg, 0.054 mmol)을 이용하여 제조예 1의 단계 E와 유사한 방법으로 표제 화합물 (9.6 mg)을 얻었다.7-Chloro-1-methyl-4-(1-(piperazine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b] obtained in Example 66 ] The title compound (9.6) was prepared in a manner similar to Step E of Preparation Example 1 using pyrazine-2,3-dione (20 mg, 0.045 mmol) and 1-bromo-2-methylpropane (7 mg, 0.054 mmol). mg) was obtained.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.20 (s, 1H), 7.48 (s, 1H), 5.53-5.43 (m, 1H), 3.90-3.81 (m, 3H), 3.61 (s, 3H), 3.53-3.50 (m, 2H), 3.33-3.30 (m, 1H), 3.29-3.26 (m, 2H), 2.97-2.85 (m, 4H), 2.39 (br. s., 1H), 2.09 (d, J = 7.3 Hz, 1H), 1.94 (td, J = 6.7, 13.4 Hz, 1H), 1.68 (d, J = 13.3 Hz, 2H), 1.31-1.23 (m, 3H), 0.94 (d, J = 6.7 Hz, 4H), 0.90 (d, J = 6.6 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.20 (s, 1H), 7.48 (s, 1H), 5.53-5.43 (m, 1H), 3.90-3.81 (m, 3H), 3.61 (s, 3H) , 3.53-3.50 (m, 2H), 3.33-3.30 (m, 1H), 3.29-3.26 (m, 2H), 2.97-2.85 (m, 4H), 2.39 (br. s., 1H), 2.09 (d) , J = 7.3 Hz, 1H), 1.94 (td, J = 6.7, 13.4 Hz, 1H), 1.68 (d, J = 13.3 Hz, 2H), 1.31-1.23 (m, 3H), 0.94 (d, J = 6.7 Hz, 4H), 0.90 (d, J = 6.6 Hz, 2H)
LC/MS: 464.0 (M+H)LC/MS: 464.0 (M+H)
실시예 72: 7-클로로-1-메틸-4-(1-(피롤리딘-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-(1-(pyrrolidine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 72: 7-Chloro-1-methyl-4-(1-(pyrrolidine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(pyrrolidine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine Preparation of -2,3-dione)
Figure PCTKR2023007097-appb-img-000235
Figure PCTKR2023007097-appb-img-000235
제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (25 mg, 0.075 mmol)과 피롤리딘-1-카르보닐 클로라이드 (58.1 mg, 0.435 mmol)를 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (20.2 mg)을 얻었다.7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (25) obtained in Preparation Example 4 mg, 0.075 mmol) and pyrrolidine-1-carbonyl chloride (58.1 mg, 0.435 mmol) to obtain the title compound (20.2 mg) in a similar manner to Example 8.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.20 (s, 1H), 7.47 (s, 1H), 5.52-5.44 (m, 1H), 3.93 (d, J = 8.4 Hz, 2H), 3.61 (s, 3H), 3.41 (t, J = 6.4 Hz, 4H), 2.94-2.82 (m, 5H), 1.87-1.82 (m, 4H), 1.67 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.20 (s, 1H), 7.47 (s, 1H), 5.52-5.44 (m, 1H), 3.93 (d, J = 8.4 Hz, 2H), 3.61 (s , 3H), 3.41 (t, J = 6.4 Hz, 4H), 2.94-2.82 (m, 5H), 1.87-1.82 (m, 4H), 1.67 (m, 2H)
LC/MS: 392.9 (M+H)LC/MS: 392.9 (M+H)
실시예 73: 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(3-클로로페닐)피페리딘-1-카르복사마이드 (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(3-chlorophenyl)piperidine-1-carboxamide)의 제조Example 73: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( 3-Chlorophenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin-4(1H) Preparation of -yl)-N-(3-chlorophenyl)piperidine-1-carboxamide)
Figure PCTKR2023007097-appb-img-000236
Figure PCTKR2023007097-appb-img-000236
3-클로로아닐린 (0.016 ml, 0.149 mmol)과 제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (0.04 g, 0.136 mmol)을 이용하여 실시예 15와 유사한 방법으로 표제 화합물 (35 mg)을 얻었다.3-chloroaniline (0.016 ml, 0.149 mmol) and 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido [2,3- obtained in Preparation Example 4 b] The title compound (35 mg) was obtained in a similar manner to Example 15 using pyrazine-2,3-dione (0.04 g, 0.136 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.47 (s, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.88 (s, 1H), 5.57-5.52 (m, 1H), 4.26 (d, J = 13.1 Hz, 2H), 3.60 (s, 3H), 3.03 (t, J = 12.1 Hz, 2H), 2.88 (qd, J = 12.3, 3.9 Hz, 2H), 1.73 (d, J = 9.8 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.47 (s, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.88 (s, 1H), 5.57-5.52 (m, 1H), 4.26 (d, J = 13.1 Hz, 2H), 3.60 (s, 3H), 3.03 (t, J = 12.1 Hz, 2H), 2.88 (qd, J = 12.3, 3.9 Hz, 2H), 1.73 (d, J = 9.8 Hz, 2H) )
LC/MS: 448.1 (M+H)LC/MS: 448.1 (M+H)
실시예 74: 4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-클로로벤질)피페리딘-1-카르복사마이드 (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-chlorobenzyl)piperidine-1-carboxamide)의 제조Example 74: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( 4-Chlorobenzyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin-4(1H) Preparation of -yl)-N-(4-chlorobenzyl)piperidine-1-carboxamide)
Figure PCTKR2023007097-appb-img-000237
Figure PCTKR2023007097-appb-img-000237
(4-클로로페닐)메탄아민 (0.019 ml, 0.149 mmol) 제조예 4에서 얻은 7-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (0.04 g, 0.136 mmol)을 이용하여 실시예 15와 유사한 방법으로 표제 화합물 (28 mg)을 얻었다.(4-Chlorophenyl)methanamine (0.019 ml, 0.149 mmol) 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido [2 ,3-b]pyrazine-2,3-dione (0.04 g, 0.136 mmol) was used to obtain the title compound (28 mg) in a similar manner to Example 15.
1H-NMR (500 MHz, DMSO-D6) δ 8.26 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 7.19 (t, J = 5.6 Hz, 1H), 5.41 (br s, 1H), 4.25 (d, J = 5.8 Hz, 2H), 4.15 (d, J = 13.7 Hz, 2H), 3.49 (s, 3H), 2.81 (t, J = 12.7 Hz, 2H), 2.59-2.56 (m, 2H), 1.59 (d, J = 9.8 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.26 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.32 ( d, J = 8.5 Hz, 2H), 7.19 (t, J = 5.6 Hz, 1H), 5.41 (br s, 1H), 4.25 (d, J = 5.8 Hz, 2H), 4.15 (d, J = 13.7 Hz) , 2H), 3.49 (s, 3H), 2.81 (t, J = 12.7 Hz, 2H), 2.59-2.56 (m, 2H), 1.59 (d, J = 9.8 Hz, 2H)
LC/MS: 462.1 (M+H) 484.1 (M+Na)LC/MS: 462.1 (M+H) 484.1 (M+Na)
실시예 75: 1,8-다이메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (1,8-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 75: 1,8-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione (1,8-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine- Preparation of 2,3-dione)
Figure PCTKR2023007097-appb-img-000238
Figure PCTKR2023007097-appb-img-000238
제조예 24에서 얻은 1,8-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (14 mg, 0.045 mmol)과 4-(트라이플루오로메톡시)벤조일 클로라이드 (0.015 mg, 0.068 mmol)를 이용하여 실시예 8과 같은 방법으로 표제 화합물 (19 mg)을 얻었다1,8-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (14 mg) obtained in Preparation Example 24 , 0.045 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.015 mg, 0.068 mmol) to obtain the title compound (19 mg) in the same manner as in Example 8.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.28 (d, J = 4.5 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 4.5 Hz, 1H), 5.90 (br s, 1H), 4.94 (br s, 1H), 4.13 (s, 3H), 3.89 (br s, 1H), 3.24~2.99 (m, 4H), 2.63 (s, 3H), 1.81~1.67 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.28 (d, J = 4.5 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.16 ( d, J = 4.5 Hz, 1H), 5.90 (br s, 1H), 4.94 (br s, 1H), 4.13 (s, 3H), 3.89 (br s, 1H), 3.24~2.99 (m, 4H), 2.63 (s, 3H), 1.81~1.67 (m, 2H)
LC/MS: 463 (M+H), 485 (M+Na)LC/MS: 463 (M+H), 485 (M+Na)
실시예 76: 7-클로로-1-메틸-4-((1R,3r,5S)-8-(4-(트라이플루오로메톡시)벤조일)-8-아자바이사이클로[3.2.1]옥탄-3-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-chloro-1-methyl-4-((1R,3r,5S)-8-(4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 76: 7-Chloro-1-methyl-4-((1R,3r,5S)-8-(4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octane-3 -1)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-((1R,3r,5S)-8-( Preparation of 4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000239
Figure PCTKR2023007097-appb-img-000239
제조예 16에서 얻은 4-((1R,3r,5S)-8-아자바이사이클로[3.2.1]옥탄-3-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온(30 mg, 0.094 mmol)을 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (38 mg)을 얻었다.4-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[ The title compound (38 mg) was obtained in a similar manner to Example 8 using 2,3-b]pyrazine-2,3-dione (30 mg, 0.094 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.22 (d, J = 1.8 Hz, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 1.8 Hz, 1H), 7.27 (d, J = 7.9 Hz, 2H), 56.08-5;94 (m, 1H), 4.99 (br s, 1H), 4.21-4.06 (m, 1H), 3.61 (s, 3H), 3.12 (br s, 1H), 3.00 (br s, 1H), 2.15 (br s, 2H), 1.97 (br s, 1H), 1.71 (br s, 1H), 1.57 (br s, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.22 (d, J = 1.8 Hz, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 1.8 Hz, 1H), 7.27 ( d, J = 7.9 Hz, 2H), 56.08-5;94 (m, 1H), 4.99 (br s, 1H), 4.21-4.06 (m, 1H), 3.61 (s, 3H), 3.12 (br s, 1H), 3.00 (br s, 1H), 2.15 (br s, 2H), 1.97 (br s, 1H), 1.71 (br s, 1H), 1.57 (br s, 2H)
LC/MS: 509.1 (M+H), 522.1 (M+Na)LC/MS: 509.1 (M+H), 522.1 (M+Na)
실시예 77: 6-아이소프로폭시-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (6-isopropoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 77: 6-isopropoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2, 3-b]pyrazine-2,3-dione (6-isopropoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3 Preparation of -b]pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000240
Figure PCTKR2023007097-appb-img-000240
제조예 9에서 얻은 6-아이소프로폭시-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.094 mmol)과 4-(트라이플루오로메톡시)벤조일 클로라이드 (23.28 mg, 0.104 mmol)를 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (38 mg)을 얻었다.6-Isopropoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione obtained in Preparation Example 9 The title compound (38 mg) was obtained in a similar manner to Example 8 using (30 mg, 0.094 mmol) and 4-(trifluoromethoxy)benzoyl chloride (23.28 mg, 0.104 mmol).
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.49 (dd, J = 6.9, 1.8 Hz, 2H), 7.46 (d, J = 8.7 Hz, 1H), 7.27 (s, 2H), 6.62 (d, J = 8.7 Hz, 1H), 5.54 (s, 1H), 5.15 (t, J = 6.2 Hz, 1H), 4.53-5.04 (1H), 3.64-4.23 (1H), 3.60 (s, 3H), 2.94 (s, 4H), 1.61-1.99 (2H), 1.39 (d, J = 6.4 Hz, 6H)1H-NMR (400 MHz, CHLOROFORM-D) δ 7.49 (dd, J = 6.9, 1.8 Hz, 2H), 7.46 (d, J = 8.7 Hz, 1H), 7.27 (s, 2H), 6.62 (d, J = 8.7 Hz, 1H), 5.54 (s, 1H), 5.15 (t, J = 6.2 Hz, 1H), 4.53-5.04 (1H), 3.64-4.23 (1H), 3.60 (s, 3H), 2.94 (s) , 4H), 1.61-1.99 (2H), 1.39 (d, J = 6.4 Hz, 6H)
LC/MS: 507 (M+H)LC/MS: 507 (M+H)
실시예 78: 7-플루오로-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-fluoro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 78: 7-Fluoro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (7-fluoro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3- b]Manufacture of pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000241
Figure PCTKR2023007097-appb-img-000241
제조예 10에서 얻은 7-플루오로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (30 mg, 0.108 mmol)와 4-(트라이플루오로메톡시)벤조일 클로라이드 (26.6 mg, 0.119 mmol)를 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (23 mg)을 얻었다.7-Fluoro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (obtained in Preparation Example 10) The title compound (23 mg) was obtained in a similar manner to Example 8 using 30 mg, 0.108 mmol) and 4-(trifluoromethoxy)benzoyl chloride (26.6 mg, 0.119 mmol).
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.12 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 7.8 Hz, 2H), 7.28 (dd, J = 8.7, 2.3 Hz, 1H), 5.62 (t, J = 11.4 Hz, 1H), 4.93 (s, 1H), 3.78 (s, 1H), 3.62 (d, J = 15.1 Hz, 3H), 3.17 (d, J = 11.4 Hz, 1H), 2.92 (s, 3H), 1.80-1.59 (m, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.12 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 7.8 Hz, 2H), 7.28 ( dd, J = 8.7, 2.3 Hz, 1H), 5.62 (t, J = 11.4 Hz, 1H), 4.93 (s, 1H), 3.78 (s, 1H), 3.62 (d, J = 15.1 Hz, 3H), 3.17 (d, J = 11.4 Hz, 1H), 2.92 (s, 3H), 1.80-1.59 (m, 2H)
LC/MS: 467 (M+H)LC/MS: 467 (M+H)
실시예 79: 메틸 1-메틸-2,3-다이옥소-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-7-카르복시레이트 (methyl 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate)의 제조Example 79: Methyl 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetra Hydropyrido [2,3-b] pyrazine-7-carboxylate (methyl 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1, Preparation of 2,3,4-tetrahydropyrid[2,3-b]pyrazine-7-carboxylate)
Figure PCTKR2023007097-appb-img-000242
Figure PCTKR2023007097-appb-img-000242
제조예 11에서 얻은 메틸 1-메틸-2,3-다이옥소-4-(피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-7-카르복시레이트 2 염산염 (200 mg, 0.511 mmol)을 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (159 mg)을 얻었다.Methyl 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine- obtained in Preparation Example 11 The title compound (159 mg) was obtained in a similar manner to Example 8 using 7-carboxylate 2 hydrochloride (200 mg, 0.511 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.78 (s, 1H), 8.08 (s, 1H), 7.58 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 7.9 Hz, 2H), 5.61 (br s, 1H), 4.66 (br s, 1H), 3.93 (s, 3H), 3.67 (br s, 1H), 3.55 (s, 3H), 3.28 (br s, 1H), 2.94 (br s, 1H), 2.78-2.56 (m, 2H), 1.80 (br s, 1H), 1.67 (br s, 1H)1H-NMR (500 MHz, DMSO-D6) δ 8.78 (s, 1H), 8.08 (s, 1H), 7.58 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 7.9 Hz, 2H), 5.61 (br s, 1H), 4.66 (br s, 1H), 3.93 (s, 3H), 3.67 (br s, 1H), 3.55 (s, 3H), 3.28 (br s, 1H), 2.94 (br s , 1H), 2.78-2.56 (m, 2H), 1.80 (br s, 1H), 1.67 (br s, 1H)
LC/MS: 507.2 (M+H), 529.1 (M+Na)LC/MS: 507.2 (M+H), 529.1 (M+Na)
실시예 80: 1,7-다이메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (1,7-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 80: 1,7-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione (1,7-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine- Preparation of 2,3-dione)
Figure PCTKR2023007097-appb-img-000243
Figure PCTKR2023007097-appb-img-000243
제조예 12에서 얻은 1,7-다이메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (100 mg, 0.365 mmol)을 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (119 mg)을 얻었다.1,7-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (100 mg) obtained in Preparation Example 12 , 0.365 mmol) to obtain the title compound (119 mg) in a similar manner to Example 8.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.10 (s, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.34 (s, 1H), 7.32-7.27 (m, 2H), 5.70 (br s, 1H), 4.94 (br s, 1H), 3.89 (br s, 1H), 3.64 (s, 3H), 3.22 (br s, 1H), 2.99 (s, 3H), 2.46 (s, 3H), 1.91-1.63 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.10 (s, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.34 (s, 1H), 7.32-7.27 (m, 2H), 5.70 (br s, 1H), 4.94 (br s, 1H), 3.89 (br s, 1H), 3.64 (s, 3H), 3.22 (br s, 1H), 2.99 (s, 3H), 2.46 (s, 3H), 1.91-1.63 (m, 2H)
LC/MS: 463.1 (M+H)LC/MS: 463.1 (M+H)
실시예 81: 7-브로모-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (7-bromo-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)의 제조Example 81: 7-Bromo-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (7-bromo-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3- b]Manufacture of pyrazine-2,3-dione)
Figure PCTKR2023007097-appb-img-000244
Figure PCTKR2023007097-appb-img-000244
제조예 13에서 얻은 7-브로모-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 (250 mg, 0.737 mmol)을 이용하여 실시예 8과 유사한 방법으로 표제 화합물 (165 mg)을 얻었다.7-Bromo-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (obtained in Preparation Example 13) The title compound (165 mg) was obtained in a similar manner to Example 8 using 250 mg, 0.737 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.30 (s, 1H), 7.63 (s, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 5.62 (br s, 1H), 4.92 (br s, 1H), 3.79-3.96 (m, 1H), 3.62 (s, 3H), 3.20 (br s, 1H), 2.92 (br s, 3H), 1.60-1.90 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.30 (s, 1H), 7.63 (s, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 5.62 (br s, 1H), 4.92 (br s, 1H), 3.79-3.96 (m, 1H), 3.62 (s, 3H), 3.20 (br s, 1H), 2.92 (br s, 3H), 1.60- 1.90 (m, 2H)
LC/MS: 529.1 (M+Na)LC/MS: 529.1 (M+Na)
실험예: DGKα 효소 저해 효과 측정Experimental example: Measurement of DGKα enzyme inhibition effect
먼저, 1X 기질 분석 버퍼 (40 mM MOPS (pH 7.2), 20 mM MgCl2, 1 mM DTT, 0.4 mM CaCl2, 3 mM 나트륨 데옥시콜레이트, 100 mM NaCl, 0.1 mg/mL BSA, 0.12% NP-40)에서 3X OAG (3 mM)/ATP (0.45 mM) 기질 용액을 만들고, 3분 동안 완전히 vortex하여 detergent-lipid 미셀 형성을 유도하였다. 그 다음 2X 효소 분석 버퍼 (80 mM MOPS (pH 7.2), 2 mM DTT, 200 mM NaCl, 0.2 mg/mL BSA)에서 3X DGKα (7.5 nM) 효소 용액을 만들고 나서 짧게 vortex하였다. First , 1 40), a 3X OAG (3mM)/ATP (0.45mM) substrate solution was prepared and thoroughly vortexed for 3 minutes to induce the formation of detergent-lipid micelles. Then, a 3X DGKα (7.5 nM) enzyme solution was prepared in 2X enzyme assay buffer (80 mM MOPS (pH 7.2), 2 mM DTT, 200 mM NaCl, 0.2 mg/mL BSA) and vortexed briefly.
상기 두 가지 용액을 제조 후 half-area opaque 96웰 분석 플레이트를 준비하고, 각 웰에 3X 희석된 화합물 용액(30 μM 내지 0 μM) 10 μL을 옮겼다. 다음으로 3X DGKα 효소 용액 10 μL을 동일한 플레이트에 옮기고, pipetting으로 혼합하고 나서 3X OAG/ATP 기질 용액 10 μL을 분석 플레이트에 넣고 잘 섞었다. 효소 반응을 위해 실온에서 20분 동안 플레이트를 배양하였다. 다음으로, 15 μL의 ADP-Glo 시약을 각 웰에 추가하고 pipetting으로 혼합한 다음 실온에서 40분 동안 플레이트를 배양하여 나머지 ATPs를 고갈시켰다. 이 단계 후, 30 μL의 키나아제 검출 시약을 추가한 다음 혼합하고, 실온에서 추가로 20분 동안 배양하고 Envision에서 발광을 측정하여 각 화합물의 IC50 값을 계산하였다.After preparing the two solutions, a half-area opaque 96-well assay plate was prepared, and 10 μL of 3X diluted compound solution (30 μM to 0 μM) was transferred to each well. Next, 10 μL of 3X DGKα enzyme solution was transferred to the same plate, mixed by pipetting, and then 10 μL of 3X OAG/ATP substrate solution was added to the assay plate and mixed well. The plate was incubated for 20 minutes at room temperature for the enzyme reaction. Next, 15 μL of ADP-Glo reagent was added to each well, mixed by pipetting, and then incubated the plate for 40 min at room temperature to deplete the remaining ATPs. After this step, 30 μL of Kinase Detection Reagent was added, mixed, incubated for an additional 20 minutes at room temperature, and luminescence was measured in Envision to calculate the IC 50 value for each compound.
측정 결과를 표 1에 나타내었다 (+: IC50 >1 μM, ++: 1 μM> IC50 >300 nM, +++: IC50 <300 nM).The measurement results are shown in Table 1 (+: IC 50 >1 μM, ++: 1 μM> IC 50 >300 nM, +++: IC 50 <300 nM).
[표 1][Table 1]
Figure PCTKR2023007097-appb-img-000245
Figure PCTKR2023007097-appb-img-000245
Figure PCTKR2023007097-appb-img-000246
Figure PCTKR2023007097-appb-img-000246

Claims (6)

  1. 하기 화학식 1의 화합물, 또는 이의 약제학적으로 허용되는 염 또는 입체이성질체:A compound of formula 1 below, or a pharmaceutically acceptable salt or stereoisomer thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2023007097-appb-img-000247
    Figure PCTKR2023007097-appb-img-000247
    상기 화학식 1에서,In Formula 1,
    m은 0, 1 또는 2를 나타내고;m represents 0, 1 or 2;
    X는 N 또는 CH를 나타내며;X represents N or CH;
    R1은 수소, 할로, 시아노(-CN), 알킬, 알콕시 또는 비치환되거나 할로로 치환된 아릴을 나타내고;R 1 represents hydrogen, halo, cyano(-CN), alkyl, alkoxy or aryl unsubstituted or substituted with halo;
    R2는 수소, 할로, 알킬, 알킬카르보닐 또는 알콕시카르보닐을 나타내며;R 2 represents hydrogen, halo, alkyl, alkylcarbonyl or alkoxycarbonyl;
    R3는 수소 또는 알킬을 나타내고;R 3 represents hydrogen or alkyl;
    R4는 알킬을 나타내며;R 4 represents alkyl;
    R5는 알킬을 나타내고, m이 2일 경우 서로 결합하여 고리를 형성할 수 있으며;R 5 represents alkyl, and when m is 2, they can combine with each other to form a ring;
    R6는 -C(=O)-R7, -S(=O)2-R7, -C(=O)-알킬렌-R7, -O-R7,
    Figure PCTKR2023007097-appb-img-000248
    , -C(=O)-사이클로알킬렌-R7, -알킬렌-C(=O)-R7,
    Figure PCTKR2023007097-appb-img-000249
    또는 -NH-C(=O)-R7이고; 여기에서 R7은 사이클로알킬, 아릴, 아르알킬, 헤테로사이클로알킬 또는 헤테로사이클릴을 나타내며; R8은 수소, 알킬, 사이클로알킬 또는 사이클로알킬-알킬을 나타내고;    R 6 is -C(=O)-R 7 , -S(=O) 2 -R 7 , -C(=O)-alkylene-R 7 , -OR 7 ,
    Figure PCTKR2023007097-appb-img-000248
    , -C(=O)-cycloalkylene-R 7 , -alkylene-C(=O)-R 7 ,
    Figure PCTKR2023007097-appb-img-000249
    or -NH-C(=O)-R 7 ; where R 7 represents cycloalkyl, aryl, aralkyl, heterocycloalkyl or heterocyclyl; R 8 represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl;
    상기 사이클로알킬, 아릴, 헤테로사이클로알킬 및 헤테로사이클릴은 할로, 시아노, 옥소(=O), 알킬, 알콕시, 할로알킬, 할로알콕시, 알킬카르보닐, 다이알킬아미노, 아릴, 아릴옥시 및 비치환되거나 할로로 치환된 헤테로아릴로 이루어지는 그룹에서 선택되는 하나 이상의 치환기로 임의로 치환될 수 있으며;The cycloalkyl, aryl, heterocycloalkyl and heterocyclyl include halo, cyano, oxo (=O), alkyl, alkoxy, haloalkyl, haloalkoxy, alkylcarbonyl, dialkylamino, aryl, aryloxy and unsubstituted. or may be optionally substituted with one or more substituents selected from the group consisting of heteroaryl substituted with halo;
    상기 헤테로사이클로알킬, 헤테로사이클릴 및 헤테로아릴은 질소(N), 산소(O) 및 황(S) 원자로부터 선택되는 하나 이상의 헤테로원자를 가진다.The heterocycloalkyl, heterocyclyl and heteroaryl have one or more heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms.
  2. 제1항에 있어서,According to paragraph 1,
    m은 0, 1 또는 2를 나타내고;m represents 0, 1 or 2;
    X는 N 또는 CH를 나타내며;X represents N or CH;
    R1은 수소, 할로, 시아노, C1-C7 알킬, C1-C7 알콕시 또는 비치환되거나 할로로 치환된 C6-C10 아릴을 나타내고;R 1 represents hydrogen, halo, cyano, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or C 6 -C 10 aryl unsubstituted or substituted with halo;
    R2는 수소, 할로, C1-C7 알킬, C1-C7 알킬카르보닐 또는 C1-C7 알콕시카르보닐을 나타내며;R 2 represents hydrogen, halo, C 1 -C 7 alkyl, C 1 -C 7 alkylcarbonyl or C 1 -C 7 alkoxycarbonyl;
    R3는 수소 또는 C1-C7 알킬을 나타내고;R 3 represents hydrogen or C 1 -C 7 alkyl;
    R4는 C1-C7 알킬을 나타내며;R 4 represents C 1 -C 7 alkyl;
    R5는 C1-C7 알킬을 나타내고, m이 2일 경우 서로 결합하여 C2-C4 고리를 형성할 수 있으며;R 5 represents C 1 -C 7 alkyl, and when m is 2, they may combine with each other to form a C 2 -C 4 ring;
    R6는 -C(=O)-R7, -S(=O)2-R7, -C(=O)-C1-C5 알킬렌-R7, -O-R7,
    Figure PCTKR2023007097-appb-img-000250
    , -C(=O)-C3-C6 사이클로알킬렌-R7, -C1-C5 알킬렌-C(=O)-R7,
    Figure PCTKR2023007097-appb-img-000251
    또는 -NH-C(=O)-R7이고; 여기에서 R7은 C3-C7 사이클로알킬, C6-C10 아릴, C6-C10 아릴-C1-C7 알킬, N 및 O로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 10원 헤테로사이클로알킬, 또는 N, O 및 S로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 12원 헤테로사이클릴을 나타내며; R8은 수소, C1-C7 알킬, C3-C7 사이클로알킬 또는 C3-C7 사이클로알킬-C1-C7 알킬을 나타내고;    R 6 is -C(=O)-R 7 , -S(=O) 2 -R 7 , -C(=O)-C 1 -C 5 alkylene-R 7 , -OR 7 ,
    Figure PCTKR2023007097-appb-img-000250
    , -C(=O)-C 3 -C 6 cycloalkylene-R 7 , -C 1 -C 5 alkylene-C(=O)-R 7 ,
    Figure PCTKR2023007097-appb-img-000251
    or -NH-C(=O)-R 7 ; Here, R 7 is 5 to 3 heteroatoms selected from C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryl-C 1 -C 7 alkyl, N and O. represents a 10-membered heterocycloalkyl, or a 5- to 12-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S; R 8 represents hydrogen, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl-C 1 -C 7 alkyl;
    상기 사이클로알킬, 아릴, 헤테로사이클로알킬 및 헤테로사이클릴은 비치환되거나 할로, 시아노, 옥소, C1-C7 알킬, C1-C7 알콕시, 할로-C1-C7 알킬, 할로-C1-C7 알콕시, C1-C7 알킬카르보닐, 다이(C1-C7 알킬)아미노, C6-C10 아릴, C6-C10 아릴옥시 및 비치환되거나 할로로 치환된 N 및 O로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 10원 헤테로아릴로 이루어지는 그룹에서 선택되는 1 내지 3개의 치환기로 치환되는 것을 특징으로 하는 화합물, 또는 이의 약제학적으로 허용되는 염 또는 입체이성질체.The cycloalkyl, aryl, heterocycloalkyl and heterocyclyl are unsubstituted or halo, cyano, oxo, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, halo-C 1 -C 7 alkyl, halo-C 1 -C 7 alkoxy, C 1 -C 7 alkylcarbonyl, di(C 1 -C 7 alkyl)amino, C 6 -C 10 aryl, C 6 -C 10 aryloxy and unsubstituted or halo substituted N and A compound characterized by being substituted with 1 to 3 substituents selected from the group consisting of 5 to 10 membered heteroaryl having 1 to 3 heteroatoms selected from O, or a pharmaceutically acceptable salt or stereoisomer thereof.
  3. 제1항에 있어서, 상기 화학식 1의 화합물이 다음의 그룹으로부터 선택되는 것을 특징으로 하는 화합물, 또는 이의 약제학적으로 허용되는 염 또는 입체이성질체:The compound according to claim 1, wherein the compound of formula 1 is selected from the following group, or a pharmaceutically acceptable salt or stereoisomer thereof:
    1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3- Dion;
    1,6-다이메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
    1,6-다이메틸-4-(1-토실피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;1,6-dimethyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
    4-(1-((3-클로로페닐)설포닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;4-(1-((3-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;
    4-(1-((3,4-다이클로로페닐)설포닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;4-(1-((3,4-dichlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2, 3-dione;
    1-메틸-4-(1-((4-페녹시페닐)설포닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;1-methyl-4-(1-((4-phenoxyphenyl)sulfonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3- Dion;
    1-메틸-2,3-다이옥소-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-6-카르보나이트릴;1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2 ,3-b]pyrazine-6-carbonitrile;
    7-클로로-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;
    7-클로로-1-메틸-4-(1-토실피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
    7-클로로-4-(3,3-다이메틸-1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(3,3-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2 ,3-b]pyrazine-2,3-dione;
    7-클로로-1-메틸-4-((1R,3s,5S)-8-(4-(트라이플루오로메톡시)벤조일)-8-아자바이사이클로[3.2.1]옥탄-3-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-((1R,3s,5S)-8-(4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl)- 1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
    7-브로모-1-메틸-2,3-다이옥소-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-6-카르보나이트릴;7-Bromo-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetra Hydropyrido[2,3-b]pyrazine-6-carbonitrile;
    7-클로로-1-메틸-4-(1-(2-(4-(트라이플루오로메톡시)페닐)아세틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
    7-클로로-4-(4-(3-클로로페녹시)사이클로헥실)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(4-(3-chlorophenoxy)cyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
    4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-(tri fluoromethoxy)phenyl)piperidine-1-carboxamide;
    7-클로로-1-메틸-4-(1-(2-(피리딘-2-일)아세틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Chloro-1-methyl-4-(1-(2-(pyridin-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
    7-클로로-1-메틸-4-(1-(2-(티오펜-2-일)아세틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(2-(thiophen-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
    7-클로로-4-(1-(2-(2-플루오로페닐)아세틸)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(2-(2-fluorophenyl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
    7-클로로-4-(1-(2-(퓨란-2-일)아세틸)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(2-(furan-2-yl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
    7-클로로-6-(2-플루오로페닐)-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Chloro-6-(2-fluorophenyl)-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyri do[2,3-b]pyrazine-2,3-dione;
    7-클로로-1-메틸-4-(1-(2-페닐아세틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(2-phenylacetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;
    7-클로로-1-메틸-4-(1-(1-페닐사이클로프로판-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Chloro-1-methyl-4-(1-(1-phenylcyclopropane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
    7-클로로-4-(1-(2-(2-플루오로페닐)-2-메틸프로파노일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(2-(2-fluorophenyl)-2-methylpropanoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2 ,3-b]pyrazine-2,3-dione;
    7-클로로-4-(1-(4-클로로벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(4-chlorobenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;
    7-클로로-1-메틸-4-(1-(4-(트라이플루오로메틸)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;
    4-((4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-일)설포닐)벤조나이트릴;4-((4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- 1-yl)sulfonyl)benzonitrile;
    4-(4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-카르보닐)벤조나이트릴;4-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 -carbonyl)benzonitrile;
    4-(1-((4-(터트-부틸)페닐)설포닐)피페리딘-4-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;4-(1-((4-(tert-butyl)phenyl)sulfonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione;
    7-클로로-4-(1-(2,3-다이하이드로벤조[b][1,4]다이옥신-6-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-carbonyl)piperidin-4-yl)-1-methyl-1,4-di hydropyrido[2,3-b]pyrazine-2,3-dione;
    4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-(트라이플루오로메틸)페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-(tri fluoromethyl)phenyl)piperidine-1-carboxamide;
    4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-클로로페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-chlorophenyl ) piperidine-1-carboxamide;
    4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-시아노페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-cyano phenyl)piperidine-1-carboxamide;
    7-클로로-4-(1-(사이클로헥산카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(cyclohexanecarbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;
    7-클로로-1-메틸-4-(1-(2-옥소-2-페닐에틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Chloro-1-methyl-4-(1-(2-oxo-2-phenylethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
    7-클로로-1-메틸-4-((1s,4s)-4-(4-(트라이플루오로메톡시)페녹시)사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-((1s,4s)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
    7-클로로-4-(1-((4-클로로페닐)설포닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Chloro-4-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
    7-클로로-4-(1-(2-(4-클로로페닐)-2-옥소에틸)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione;
    4-(2-(4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)피페리딘-1-일)아세틸)벤조나이트릴;4-(2-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi din-1-yl)acetyl)benzonitrile;
    7-클로로-1-메틸-4-(1-(2-옥소-2-(4-(트라이플루오로메틸)페닐)에틸)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)piperidin-4-yl)-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione;
    7-클로로-1-메틸-4-(4-((4-(트라이플루오로메톡시)페닐)아미노)사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(4-((4-(trifluoromethoxy)phenyl)amino)cyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2, 3-dione;
    7-클로로-1-메틸-4-((1r,4r)-4-((5-메틸피리미딘-2-일)옥시)사이클로헥실)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-((1r,4r)-4-((5-methylpyrimidin-2-yl)oxy)cyclohexyl)-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione;
    4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-메틸-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-methyl-N-( 4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;
    7-클로로-4-((2R,5S)-2,5-다이메틸-1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-((2R,5S)-2,5-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1-methyl-1,4- Dihydropyrido[2,3-b]pyrazine-2,3-dione;
    7-클로로-4-(1-(4-플루오로-3-(트라이플루오로메틸)벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(4-fluoro-3-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
    7-클로로-1-메틸-4-(1-(4-(트라이플루오로메틸)사이클로헥산-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(4-(trifluoromethyl)cyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido [2, 3-b]pyrazine-2,3-dione;
    7-클로로-4-(1-(5-플루오로-2-(트라이플루오로메틸)벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(5-fluoro-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
    4-(1-(4-브로모-2-(트라이플루오로메틸)벤조일)피페리딘-4-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;4-(1-(4-bromo-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
    7-클로로-4-(1-(5-플루오로-2-메틸벤조일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(5-fluoro-2-methylbenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;
    4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-에틸-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-ethyl-N-( 4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;
    7-클로로-1,6-다이메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione;
    7-브로모-1,6-다이메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Bromo-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione;
    4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(사이클로프로필메틸)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(cyclopropylmethyl) -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;
    4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(사이클로헥실메틸)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(cyclohexylmethyl) -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;
    7-클로로-1-메틸-4-(1-(5-메틸-1-페닐-1H-피라졸-4-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(5-methyl-1-phenyl-1H-pyrazole-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[ 2,3-b]pyrazine-2,3-dione;
    7-클로로-4-(1-(1-(5-클로로피리딘-2-일)-5-(트라이플루오로메틸)-1H-피라졸-4-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(1-(5-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl)piperidin-4-yl) -1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
    7-클로로-1-메틸-4-(1-(피페리딘-4-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온 염산염;7-chloro-1-methyl-4-(1-(piperidine-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione hydrochloride;
    N-((1r,4r)-4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)사이클로헥실)-4-(트라이플루오로메톡시)벤즈아마이드;N-((1r,4r)-4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl )Cyclohexyl)-4-(trifluoromethoxy)benzamide;
    7-클로로-4-(1-(5-클로로피리미딘e-2-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Chloro-4-(1-(5-chloropyrimidinee-2-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
    7-클로로-4-(1-(6-클로로니코티노일)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(6-chloronicotinoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3 -Dion;
    7-클로로-4-(1-(1-아이소부틸피페리딘-4-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(1-isobutylpiperidine-4-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione;
    4-(1-(1-아세틸피페리딘-4-카르보닐)피페리딘-4-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;4-(1-(1-acetylpiperidine-4-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
    4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(사이클로부틸메틸)-N-(4-(트라이플루오로메톡시)페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(cyclobutylmethyl) -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;
    6-메톡시-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;6-methoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
    6-클로로-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;
    7-클로로-1-메틸-4-(1-(피페라진-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(piperazine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2, 3-dione;
    4-(1-(1H-인돌-3-카르보닐)피페리딘-4-일)-7-클로로-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;4-(1-(1H-indole-3-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
    6-클로로-1-메틸-4-(1-(4-옥소사이클로헥산-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;6-chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
    7-클로로-1-메틸-4-(1-(4-옥소사이클로헥산-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
    6-클로로-4-(1-(4-(다이메틸아미노)사이클로헥산-1-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;6-chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
    7-클로로-4-(1-(4-(다이메틸아미노)사이클로헥산-1-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
    7-클로로-4-(1-(4-아이소부틸피페라진-1-카르보닐)피페리딘-4-일)-1-메틸-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-4-(1-(4-isobutylpiperazine-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
    7-클로로-1-메틸-4-(1-(피롤리딘-1-카르보닐)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-(1-(pyrrolidine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
    4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(3-클로로페닐)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(3-chlorophenyl ) piperidine-1-carboxamide;
    4-(7-클로로-1-메틸-2,3-다이옥소-2,3-다이하이드로피리도[2,3-b]피라진-4(1H)-일)-N-(4-클로로벤질)피페리딘-1-카르복사마이드;4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-chlorobenzyl ) piperidine-1-carboxamide;
    1,8-다이메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;1,8-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
    7-클로로-1-메틸-4-((1R,3r,5S)-8-(4-(트라이플루오로메톡시)벤조일)-8-아자바이사이클로[3.2.1]옥탄-3-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-chloro-1-methyl-4-((1R,3r,5S)-8-(4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl)- 1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
    6-아이소프로폭시-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;6-isopropoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
    7-플루오로-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온;7-Fluoro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
    메틸 1-메틸-2,3-다이옥소-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,2,3,4-테트라하이드로피리도[2,3-b]피라진-7-카르복시레이트;Methyl 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[ 2,3-b]pyrazine-7-carboxylate;
    1,7-다이메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온; 및1,7-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione; and
    7-브로모-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로피리도[2,3-b]피라진-2,3-다이온.7-Bromo-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione.
  4. 활성성분으로 제1항 내지 제3항 중 어느 한 항에 정의된 화학식 1의 화합물, 또는 이의 약제학적으로 허용되는 염 또는 입체이성질체를, 약제학적으로 허용되는 담체와 함께 포함하는, 다이아실글리세롤 키나아제(DGKs)와 관련된 질환의 예방 또는 치료용 약제학적 조성물.Diacylglycerol kinase comprising the compound of formula 1 as defined in any one of claims 1 to 3 as an active ingredient, or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable carrier. Pharmaceutical composition for preventing or treating diseases related to (DGKs).
  5. 제4항에 있어서, 상기 다이아실글리세롤 키나아제(DGKs)와 관련된 질환이 암인 것을 특징으로 하는 약제학적 조성물.The pharmaceutical composition according to claim 4, wherein the disease related to diacylglycerol kinases (DGKs) is cancer.
  6. 제5항에 있어서, 상기 암이 위장관암, 췌장암, 유방암, 결장암, 망막모세포종, 간암, 폐암, 난소암, 자궁경부암, 자궁내막암, 뇌종양, 고환암, 후두암, 전립선암, 신경모세포종, 신장암, 갑상선암, 식도암, 피부암, 골육종 및 방광암으로 이루어지는 그룹으로부터 선택되는 것을 특징으로 하는 약제학적 조성물.The method of claim 5, wherein the cancer is gastrointestinal cancer, pancreatic cancer, breast cancer, colon cancer, retinoblastoma, liver cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, brain tumor, testicular cancer, laryngeal cancer, prostate cancer, neuroblastoma, kidney cancer, A pharmaceutical composition selected from the group consisting of thyroid cancer, esophageal cancer, skin cancer, osteosarcoma, and bladder cancer.
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