WO2023229375A1 - 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
WO2023229375A1
WO2023229375A1 PCT/KR2023/007091 KR2023007091W WO2023229375A1 WO 2023229375 A1 WO2023229375 A1 WO 2023229375A1 KR 2023007091 W KR2023007091 W KR 2023007091W WO 2023229375 A1 WO2023229375 A1 WO 2023229375A1
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Prior art keywords
methyl
piperidin
dihydroquinoxaline
dione
dioxo
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PCT/KR2023/007091
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French (fr)
Korean (ko)
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윤수영
장창영
김병규
김형진
정세환
곽영신
최민호
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주식회사 엘지화학
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Publication of WO2023229375A1 publication Critical patent/WO2023229375A1/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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—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:
  • R 1 represents hydrogen, halo, cyano(-CN), alkyl or alkylcarbonyl
  • R 2 represents hydrogen, halo, cyano, amino, alkyl, alkynyl, alkylcarbonyl alkylcarbonylamino, alkoxy or cycloalkyl;
  • R 3 represents hydrogen or alkyl
  • R 4 represents alkyl
  • R 5 represents aryl, aralkyl, arylcarbonyl, unsaturated heterocyclyl or unsaturated heterocyclyl-alkyl;
  • the aryl and heterocyclyl are halo, cyano, amino, carboxy (-COOH), alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, haloalkyl, cyanoalkyl, haloalkoxy, alkoxyalkyl, alkylcarbonyl , unsubstituted or substituted with alkylcarbonyl, alkylaminoalkyl, dialkylaminoalkyl, alkylaminosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino, aminosulfonyl unsubstituted or substituted with cycloalkyl-alkyl, are may be optionally substituted with one or more substituents selected from the group consisting of alkyl, saturated heterocyclyl-alkyl unsubstituted or substituted with alkyl or halo, and unsaturated heterocyclyl;
  • the heterocyclyl 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).
  • 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.
  • 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.
  • 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.
  • heterocyclyl refers to an unsaturated, partially or fully saturated, single or fused group having one or more heteroatoms selected from N, O and S, for example 1 to 3 heteroatoms. It refers to a hydrocarbon that forms a cyclic 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.
  • heterocyclyls examples include pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, triazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, and thiazolyl.
  • R 1 represents hydrogen, halo, cyano, C 1 -C 7 alkyl or C 1 -C 7 alkylcarbonyl;
  • R 2 is hydrogen, halo, cyano, amino, C 1 -C 7 alkyl, C 2 -C 7 alkynyl, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkylcarbonylamino, C 1 -C 7 represents alkoxy or C 3 -C 10 cycloalkyl;
  • R 3 represents hydrogen or C 1 -C 7 alkyl
  • R 4 represents C 1 -C 7 alkyl
  • R 5 is 5 having 1 to 3 heteroatoms selected from C 6 -C 10 aryl, C 6 -C 10 aryl-C 1 -C 7 alkyl, C 6 -C 10 arylcarbonyl, N, O and S represents a to 12 membered unsaturated heterocyclyl, or a 5 to 12 membered unsaturated heterocyclyl-C 1 -C 7 alkyl having 1 to 3 heteroatoms selected from N, O and S;
  • aryl and heterocyclyl are unsubstituted or
  • substituted aminosulfonyl C 6 -C 10 aryl-C 1 -C 7 alkyl, unsubstituted or substituted with C 1 -C 7 alkyl or halo, having 1 to 3 heteroatoms selected from N, O and S 1 to 12 membered saturated heterocyclyl-C 1 -C 7 alkyl selected from the group consisting of 5 to 12 membered unsaturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S. It may be substituted with 4 substituents.
  • 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 Scheme 1 below.
  • R 1 , R 2 , R 3 and R 4 are as defined herein, R 6 represents aryl, and R 7 and R 8 are each independently selected from halo, cyano, amino, carboxy (-COOH ), alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, haloalkyl, cyanoalkyl, haloalkoxy, alkoxyalkyl, alkylcarbonyl, alkylaminoalkyl unsubstituted or substituted with alkylcarbonyl, dialkylaminoalkyl , alkylaminosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino, aminosulfonyl unsubstituted or substituted with cycloalkyl-alkyl, aralkyl, saturated heterocyclyl-alkyl unsubstituted or substituted with alkyl or halo, or unsaturated heterocyclyl.
  • 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
  • DIPEA N,N-diisopropylethylamine
  • PdCl 2 (PPh 3 ) 2 Bis(triphenylphosphine)palladium(II) dichloride
  • Step A Preparation of tert-butyl 4-((2-nitrophenyl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((2-aminophenyl)amino)piperidine-1-carboxylate
  • the filtered mixture was distilled under reduced pressure, dissolved in DCM, and extracted using a saturated aqueous NaHCO 3 solution. Afterwards, the organic layer was dried using anhydrous MgSO 4 and then distilled under reduced pressure to obtain the title compound (10.15 g).
  • Step C Preparation of tert-butyl 4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate
  • Step D Preparation of 1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
  • Step A Preparation of tert-butyl 4-((4-chloro-2-nitrophenyl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((2-amino-4-chlorophenyl)amino)piperidine-1-carboxylate
  • Step C of tert-butyl 4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate manufacturing
  • Step D Preparation of 6-chloro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
  • Step A Preparation of tert-butyl 4-((5-chloro-2-nitrophenyl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((2-amino-5-chlorophenyl)amino)piperidine-1-carboxylate
  • Step C of tert-butyl 4-(7-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate manufacturing
  • Step D Preparation of 6-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
  • Step A Preparation of tert-butyl 4-((4-fluoro-2-nitrophenyl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((2-amino-4-fluorophenyl)amino)piperidine-1-carboxylate
  • Step C Tert-Butyl 4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate manufacture of
  • Step D Preparation of 6-fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
  • Step A Preparation of tert-butyl 4-((4-methoxy-2-nitrophenyl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((2-amino-4-methoxyphenyl)amino)piperidine-1-carboxylate
  • Step C Tert-Butyl 4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate manufacture of
  • Step D Preparation of 6-methoxy-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
  • Step A Preparation of tert-butyl 4-((4-bromo-2-nitrophenyl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((2-amino-4-bromophenyl)amino)piperidine-1-carboxylate
  • Step C Tert-Butyl 4-(6-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate manufacture of
  • Step D Preparation of 6-bromo-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
  • Step A Preparation of tert-butyl 4-((5-bromo-2-nitrophenyl)amino)piperidine-1-carboxylate
  • Step B Preparation of tert-butyl 4-((2-amino-5-bromophenyl)amino)piperidine-1-carboxylate
  • Step C Tert-Butyl 4-(7-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate manufacture of
  • Step D Preparation of 6-bromo-1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
  • Example 1 1-Methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (1 Preparation of -methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • Example 3 1-Methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (1 Preparation of -methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • Example 5 1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2 ,3-dione (1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione) manufacturing
  • Step A 2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-car
  • valdehyde 2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-car
  • Step B 1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2, Preparation of 3-dione
  • Example 6 1-Methyl-4-(1-(5-((4-methylpiperazin-1-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-1,4- Dihydroquinoxaline-2,3-dione (1-methyl-4-(1-(5-((4-methylpiperazin-1-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-1 Manufacture of ,4-dihydroquinoxaline-2,3-dione)
  • Example 7 6-Chloro-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3- Preparation of dione (6-chloro-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • Example 8 6-Chloro-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3- Preparation of dione (6-chloro-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • Example 10 6-Chloro-1-(1-(5-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline- 2,3-dione (6-chloro-1-(1-(5-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione )
  • Example 11 6-Chloro-1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydro Quinoxaline-2,3-dione (6-chloro-1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline Preparation of -2,3-dione)
  • Step A 2-(4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine -Manufacture of 5-carbaldehyde
  • Example 5 using 1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (1.0 g, 2.73 mmol) obtained in Preparation Example 2
  • the title compound (450 mg) was obtained in a manner similar to step A of .
  • Step B 6-Chloro-1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoc Preparation of saline-2,3-dione
  • Example 12 1-Methyl-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Preparation of dione (1-methyl-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • Example 13 2-(4-(7-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri Midine-5-carbonitrile (2-(4-(7-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 Manufacture of -carbonitrile)
  • Example 14 6-Chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3- Preparation of dione (6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • Example 15 6-Chloro-4-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-1-methyl-1,4-dihydro Quinoxaline-2,3-dione (6-chloro-4-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-1-methyl-1,4-dihydroquinoxaline Preparation of -2,3-dione)
  • Step A 2-(4-(7-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine -Manufacture of 5-carbaldehyde
  • Step B 6-Chloro-4-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-1-methyl-1,4-dihydroquinoc
  • Example 16 6-Chloro-4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydroquinoxaline-2,3-dione (6- Preparation of chloro-4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 17 6-Chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3- Preparation of dione (6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • Example 18 2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Pyrimidine-5-carbonitrile (2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine- Manufacture of 5-carbonitrile)
  • Example 19 6-Fluoro-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Preparation of dione (6-fluoro-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • Example 20 6-Fluoro-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Preparation of dione (6-fluoro-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • Example 22 6-methoxy-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Preparation of dione (6-methoxy-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • Example 23 6-methoxy-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Preparation of dione (6-methoxy-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • Example 24 N-methyl-2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri Midine-5-sulfonamide (N-methyl-2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- Manufacture of sulfonamide)
  • Example 25 1-Methyl-4-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (1 Preparation of -methyl-4-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • Example 26 1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione (1 -Manufacture of (1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 27 1-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione ( Preparation of 1-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 28 1-(1-(5-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3- Preparation of dione (1-(1-(5-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 29 2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- Preparation of carboxylic acid (2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carboxylic acid)
  • Example 30 1-(1-(5-acetylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione (1 -Manufacture of (1-(5-acetylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 31 1-methyl-4-(1-(pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (1-methyl- Preparation of 4-(1-(pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • Example 32 1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione (1 -Manufacture of (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 34 2-(4-(7-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Pyrimidine-5-carbonitrile (2-(4-(7-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine- Manufacture of 5-carbonitrile)
  • Example 35 1-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-4-methyl-2,3-dioxo-1,2,3,4-tetra Hydroquinoxaline-6-carbonitrile (1-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline Preparation of -6-carbonitrile)
  • the concentrated mixture was diluted with 30% MeOH in DCM solution and extracted using saturated NaHCO 3 aqueous solution.
  • the organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure.
  • the concentrated residue was purified by MPLC to obtain the title compound (8 mg).
  • Example 36 4-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetra Hydroquinoxaline-6-carbonitrile (4-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline Preparation of -6-carbonitrile)
  • Example 37 2-(4-(6-acetyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri Midine-5-carbonitrile (2-(4-(6-acetyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 Manufacture of -carbonitrile)
  • the reaction mixture was cooled to room temperature and concentrated by distillation under reduced pressure.
  • the concentrated mixture was diluted with 30% MeOH in DCM solution, 1 N HCl aqueous solution (1 mL) was added, and stirred at room temperature for 1 hour.
  • the mixture was then extracted using saturated aqueous NaHCO 3 solution.
  • the organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure.
  • the concentrated residue was purified by MPLC to obtain the title compound (8 mg).
  • Example 38 2-(4-(7-acetyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri Midine-5-carbonitrile (2-(4-(7-acetyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 Manufacture of -carbonitrile)
  • Example 34 2-(4-(7-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1- obtained in Example 34 1)
  • the title compound (11) was prepared in a manner similar to Example 37 using pyrimidine-5-carbonitrile (50 mg, 0.11 mmol) and tributyl (1-ethoxyvinyl) stannane (61 mg, 0.17 mmol). mg) was obtained.
  • Example 39 1-(1-(5-(azetidin-1-ylmethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline- 2,3-dione (1-(1-(5-(azetidin-1-ylmethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione )
  • Example 40 1-(1-(5-((3,3-difluoroazetidin-1-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl- 1,4-dihydroquinoxaline-2,3-dione (1-(1-(5-((3,3-difluoroazetidin-1-yl)methyl)pyrimidin-2-yl)piperidin-4-yl) Preparation of -4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 41 N-methyl-N-((2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1 -yl)pyrimidin-5-yl)methyl)acetamide (N-methyl-N-((2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)- Preparation of yl)piperidin-1-yl)pyrimidin-5-yl)methyl)acetamide)
  • Step A 1-Methyl-4-(1-(5-((methylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Manufacture of dione
  • Step B N-methyl-N-((2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1- Preparation of 1) pyrimidin-5-yl) methyl) acetamide
  • Example 42 1-(1-(5-(methoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3- Preparation of dione (1-(1-(5-(methoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Step A 1-(1-(5-(chloromethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione manufacture of
  • Step B 1-(1-(5-(methoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-da Preparation of ions
  • Example 43 1-(1-(5-(ethoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3- Preparation of dione (1-(1-(5-(ethoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 45 N-(Cyclopropylmethyl)-2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1 -yl)pyrimidine-5-sulfonamide (N-(cyclopropylmethyl)-2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1- Preparation of yl)pyrimidine-5-sulfonamide)
  • Example 46 1-(1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione ( Preparation of 1-(1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 47 1-Methyl-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (1 Preparation of -methyl-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • Example 48 1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione ( Preparation of 1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 49 1-Methyl-4-(1-(5-vinylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (1 Preparation of -methyl-4-(1-(5-vinylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • reaction mixture was purged with nitrogen gas for 10 minutes using a nitrogen balloon. The mixture was stirred at 100°C for 20 hours. The reaction mixture was cooled to room temperature and concentrated by distillation under reduced pressure. The concentrated residue was diluted with DCM and extracted using brine. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The concentrated residue was purified by MPLC to obtain the title compound (26 mg).
  • Example 50 1-Methyl-4-(1-(5-(2-methylprop-1-en-1-yl)pyrimidin-2-yl)piperidin-4-yl)-1,4 -Dihydroquinoxaline-2,3-dione (1-methyl-4-(1-(5-(2-methylprop-1-en-1-yl)pyrimidin-2-yl)piperidin-4-yl) -Manufacture of 1,4-dihydroquinoxaline-2,3-dione)
  • Example 48 1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-da obtained in Example 48 ion (70 mg, 0.17 mmol) and 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxabororane (0.10
  • the title compound (55 mg) was obtained in a similar manner to Example 49 using mL, 0.50 mmol).
  • Example 51 1-(1-(5-isobutylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione ( Preparation of 1-(1-(5-isobutylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 52 1-(1-(5-((7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-6 -Chloro-4-methyl-1,4-dihydroquinoxaline-2,3-dione (1-(1-(5-((7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl )pyrimidin-2-yl)piperidin-4-yl)-6-chloro-4-methyl-1,4-dihydroquinoxaline-2,3-dione) Preparation
  • Example 53 1-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3 -Preparation of dione (1-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 54 1-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoc saline-2,3-dione (1-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3 Manufacture of -dione)
  • Example 55 1-(1-(5-ethynylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione ( Preparation of 1-(1-(5-ethynylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • the reaction mixture was purged using a nitrogen balloon for 15 minutes and then stirred at 100°C for 20 hours.
  • the reaction mixture was cooled to room temperature and concentrated by distillation under reduced pressure.
  • the residue was diluted using DCM and extracted using brine.
  • the organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure.
  • the residue was diluted with DCM (2 mL), 1.0 M TBAF in THF (0.296 mL, 0.296 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was diluted with DCM and extracted using 0.1 N NaOH aqueous solution.
  • the organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure.
  • the residue was purified by MPLC to give the title compound (11 mg).
  • Example 56 2-(4-(6-ethynyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Pyrimidine-5-carbonitrile (2-(4-(6-ethynyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine- Manufacture of 5-carbonitrile)
  • Example 57 1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2, Preparation of 3-dione (1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 58 1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3 -Preparation of dione (1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 59 5-Fluoro-6-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine -1-yl)nicotinonitrile (5-fluoro-6-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1 Preparation of -yl)nicotinitrile)
  • Example 60 6-Fluoro-4-methyl-1-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Preparation of dione (6-fluoro-4-methyl-1-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
  • Example 61 6-Fluoro-4-methyl-1-(1-(thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydro Quinoxaline-2,3-dione (6-fluoro-4-methyl-1-(1-(thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline Preparation of -2,3-dione)
  • Example 62 4-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Preparation of benzonitrile (4-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)benzonitrile)
  • 6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (30 mg, 0.11 mmol) obtained in Preparation Example 4 and 4-Fluorobenzonitrile (52 mg, 0.43 mmol) was dissolved in DMSO (1.5 mL), then DIPEA (0.057 mL, 0.33 mmol) was added at room temperature, and the reaction mixture was stirred at 70°C for 20 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed three times with brine. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The residue was purified by MPLC to give the title compound (31 mg).
  • Example 63 1-(1-(benzo[d]thiazol-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2, Preparation of 3-dione (1-(1-(benzo[d]thiazol-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 64 1-(1-(benzo[d]oxazol-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2, Preparation of 3-dione (1-(1-(benzo[d]oxazol-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 65 1-(1-(5-(1,1-difluoroethyl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4 -Dihydroquinoxaline-2,3-dione (1-(1-(5-(1,1-difluoroethyl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1 Manufacture of ,4-dihydroquinoxaline-2,3-dione)
  • Example 66 1-(1-(5-aminopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3 -Preparation of dione (1-(1-(5-aminopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Step A 6-Fluoro-4-methyl-1-(1-(5-nitropyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Manufacture of dione
  • Step B 1-(1-(5-aminopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3- Manufacturing of dione
  • Example 66 1-(1-(5-aminopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2 obtained in Example 66
  • the title compound (18 mg) was obtained in a similar manner to Step B of Example 41 using ,3-dione (30 mg, 0.081 mmol).
  • Example 68 N-(2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1 -yl)pyrimidin-5-yl)cyclopropanecarbosamide (N-(2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)- Preparation of yl)piperidin-1-yl)pyrimidin-5-yl)cyclopropanecarboxamide)
  • Example 66 1-(1-(5-aminopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2 obtained in Example 66
  • the title compound (11 mg) was obtained in a similar manner to Example 3 using ,3-dione (30 mg, 0.081 mmol) and cyclopropanecarbonyl chloride (13 mg, 0.12 mmol).
  • Example 69 5-Fluoro-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Preparation of nicotinonitrile (5-fluoro-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile)
  • Example 70 1-(1-(5-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4 -methyl-1,4-dihydroquinoxaline-2,3-dione (1-(1-(5-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-2-yl)piperidin- Preparation of 4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 71 1-(1-(5-(2,5-dihydrofuran-3-yl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl- 1,4-dihydroquinoxaline-2,3-dione (1-(1-(5-(2,5-dihydrofuran-3-yl)pyrimidin-2-yl)piperidin-4-yl)-6- Preparation of fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Example 72 5-Fluoro-6-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine -1-yl)nicotinonitrile (5-fluoro-6-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1 Preparation of -yl)nicotinitrile)
  • Example 73 2-(4-(6-cyclopropyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Pyrimidine-5-carbonitrile (2-(4-(6-cyclopropyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine- Manufacture of 5-carbonitrile)
  • Example 74 2-(4-(6-amino-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri Midine-5-carbonitrile (2-(4-(6-amino-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 Manufacture of -carbonitrile)
  • Step A 2-(4-(6-((diphenylmethylene)amino)-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine -1-day) Preparation of pyrimidine-5-carbonitrile
  • Step B 2-(4-(6-amino-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine -Manufacture of 5-carbonitrile
  • Example 75 3,5-difluoro-4-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1 -yl)benzonitrile (3,5-difluoro-4-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)benzonitrile) manufacture of
  • Example 76 3,5-difluoro-4-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl) piperidin-1-yl)benzonitrile (3,5-difluoro-4-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl )Manufacture of piperidin-1-yl)benzonitrile)
  • Example 77 3,5-difluoro-4-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl) piperidin-1-yl)benzonitrile (3,5-difluoro-4-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl )Manufacture of piperidin-1-yl)benzonitrile)
  • Example 78 N-(1-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-4-methyl-2,3-dioxo-1,2,3, 4-Tetrahydroquinoxalin-6-yl)acetamide (N-(1-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-4-methyl-2,3-dioxo-1, Preparation of 2,3,4-tetrahydroquinoxalin-6-yl)acetamide)
  • Example 79 1-(1-(5-(2,5-dihydrofuran-3-yl)-3-fluoropyridin-2-yl)piperidin-4-yl)-6-fluoro- 4-methyl-1,4-dihydroquinoxaline-2,3-dione (1-(1-(5-(2,5-dihydrofuran-3-yl)-3-fluoropyridin-2-yl)piperidin- Preparation of 4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
  • Step A 1-(1-(5-bromo-3-fluoropyridin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline Preparation of -2,3-dione
  • Step B 1-(1-(5-(2,5-dihydrofuran-3-yl)-3-fluoropyridin-2-yl)piperidin-4-yl)-6-fluoro-4 -Preparation of methyl-1,4-dihydroquinoxaline-2,3-dione
  • Example 80 1-(1-(benzo[d]thiazol-2-ylmethyl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2 ,3-dione (1-(1-(benzo[d]thiazol-2-ylmethyl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione) manufacturing
  • Example 81 2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Benzo[d]thiazole-6-carbonitrile (2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1- Preparation of yl)benzo[d]thiazole-6-carbonitrile)
  • Example 82 1-(1-((3-benzyl-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)-6-fluoro-4-methyl-1 ,4-dihydroquinoxaline-2,3-dione (1-(1-((3-benzyl-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)-6-fluoro Preparation of -4-methyl-1,4-dihydroquinoxaline-2,3-dione)

Abstract

The present invention relates to a heterocyclic compound represented by chemical formula 1, exhibiting a diacylglycerol kinase inhibitor activity, a pharmaceutical composition comprising same as an active ingredient, and 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 PCTKR2023007091-appb-img-000001
Figure PCTKR2023007091-appb-img-000001
상기 화학식 1에서,In Formula 1,
R1은 수소, 할로, 시아노(-CN), 알킬 또는 알킬카르보닐을 나타내고;R 1 represents hydrogen, halo, cyano(-CN), alkyl or alkylcarbonyl;
R2는 수소, 할로, 시아노, 아미노, 알킬, 알키닐, 알킬카르보닐 알킬카르보닐아미노, 알콕시 또는 사이클로알킬을 나타내며;R 2 represents hydrogen, halo, cyano, amino, alkyl, alkynyl, alkylcarbonyl alkylcarbonylamino, alkoxy or cycloalkyl;
R3는 수소 또는 알킬을 나타내고;R 3 represents hydrogen or alkyl;
R4는 알킬을 나타내며;R 4 represents alkyl;
R5는 아릴, 아르알킬, 아릴카르보닐, 불포화 헤테로사이클릴 또는 불포화 헤테로사이클릴-알킬을 나타내고;R 5 represents aryl, aralkyl, arylcarbonyl, unsaturated heterocyclyl or unsaturated heterocyclyl-alkyl;
상기 아릴 및 헤테로사이클릴은 할로, 시아노, 아미노, 카르복시(-COOH), 알킬, 알케닐, 알키닐, 알콕시, 하이드록시알킬, 할로알킬, 시아노알킬, 할로알콕시, 알콕시알킬, 알킬카르보닐, 비치환되거나 알킬카르보닐로 치환된 알킬아미노알킬, 다이알킬아미노알킬, 알킬아미노설포닐, 알킬카르보닐아미노, 사이클로알킬카르보닐아미노, 비치환되거나 사이클로알킬-알킬로 치환된 아미노설포닐, 아르알킬, 비치환되거나 알킬 또는 할로로 치환된 포화 헤테로사이클릴-알킬, 및 불포화 헤테로사이클릴로 이루어지는 그룹에서 선택되는 하나 이상의 치환기로 임의로 치환될 수 있으며;The aryl and heterocyclyl are halo, cyano, amino, carboxy (-COOH), alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, haloalkyl, cyanoalkyl, haloalkoxy, alkoxyalkyl, alkylcarbonyl , unsubstituted or substituted with alkylcarbonyl, alkylaminoalkyl, dialkylaminoalkyl, alkylaminosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino, aminosulfonyl unsubstituted or substituted with cycloalkyl-alkyl, are may be optionally substituted with one or more substituents selected from the group consisting of alkyl, saturated heterocyclyl-alkyl unsubstituted or substituted with alkyl or halo, and unsaturated heterocyclyl;
상기 헤테로사이클릴은 질소(N), 산소(O) 및 황(S) 원자로부터 선택되는 하나 이상의 헤테로원자를 가질 수 있다.The heterocyclyl 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 "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 “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 “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 “헤테로사이클릴”은 N, O 및 S 중에서 선택된 하나 이상의 헤테로원자, 예를 들면 1개 내지 3개의 헤테로원자를 갖는, 불포화되거나 부분적 또는 전체적으로 포화된 단일 또는 융합고리환을 이루는 탄화수소를 의미한다. 구체적으로, 상기 헤테로사이클릴은 1 내지 3개의 헤테로 원자를 갖는 5 내지 12원의 탄화수소일 수 있다. 상기 불포화 헤테로사이클릴은 헤테로아릴 등의 방향족 탄화수소를 포함할 수 있다. 헤테로사이클릴의 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, 티에노[3,2-d]피리미디닐, 벤조[d]티아졸릴, 벤조[d]옥사졸릴 등을 포함하지만, 이에 한정되는 것은 아니다.Unless otherwise stated, the term “heterocyclyl” herein refers to an unsaturated, partially or fully saturated, single or fused group having one or more heteroatoms selected from N, O and S, for example 1 to 3 heteroatoms. It refers to a hydrocarbon that forms a cyclic 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. Examples of heterocyclyls include pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, triazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, and 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, chromane, Thiochroman, 1,2,3,4-tetrahydroquinoline, 4H-benzo[1,3]dioxin, 2,3-dihydrobenzo[1,4]dioxin, 6,7-dihydro-5H-cyclo It includes, but is not limited to, penta[d]pyrimidine, thieno[3,2-d]pyrimidinyl, benzo[d]thiazolyl, benzo[d]oxazolyl, etc.
본 발명의 일 구체예에 따르면, 상기 화학식 1에서According to one embodiment of the present invention, in Formula 1
R1은 수소, 할로, 시아노, C1-C7 알킬 또는 C1-C7 알킬카르보닐을 나타내고;R 1 represents hydrogen, halo, cyano, C 1 -C 7 alkyl or C 1 -C 7 alkylcarbonyl;
R2는 수소, 할로, 시아노, 아미노, C1-C7 알킬, C2-C7 알키닐, C1-C7 알킬카르보닐, C1-C7 알킬카르보닐아미노, C1-C7 알콕시 또는 C3-C10 사이클로알킬를 나타내며;R 2 is hydrogen, halo, cyano, amino, C 1 -C 7 alkyl, C 2 -C 7 alkynyl, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkylcarbonylamino, C 1 -C 7 represents alkoxy or C 3 -C 10 cycloalkyl;
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 C6-C10 아릴, C6-C10 아릴-C1-C7 알킬, C6-C10 아릴카르보닐, N, O 및 S로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 12원의 불포화 헤테로사이클릴, 또는 N, O 및 S로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 12원의 불포화 헤테로사이클릴-C1-C7 알킬을 나타내고;R 5 is 5 having 1 to 3 heteroatoms selected from C 6 -C 10 aryl, C 6 -C 10 aryl-C 1 -C 7 alkyl, C 6 -C 10 arylcarbonyl, N, O and S represents a to 12 membered unsaturated heterocyclyl, or a 5 to 12 membered unsaturated heterocyclyl-C 1 -C 7 alkyl having 1 to 3 heteroatoms selected from N, O and S;
상기 아릴 및 헤테로사이클릴은 비치환되거나The aryl and heterocyclyl are unsubstituted or
할로, 시아노, 아미노, 카르복시(-COOH), C1-C7 알킬, C2-C7 알케닐, C2-C7 알키닐, C1-C7 알콕시, 하이드록시-C1-C7 알킬, 할로-C1-C7 알킬, 시아노-C1-C7 알킬, 할로-C1-C7 알콕시, C1-C7 알콕시-C1-C7 알킬, C1-C7 알킬카르보닐, 비치환되거나 C1-C7 알킬카르보닐로 치환된 C1-C7 알킬아미노-C1-C7 알킬, 다이(C1-C7 알킬)아미노-C1-C7 알킬, C1-C7 알킬아미노설포닐, C1-C7 알킬카르보닐아미노, C3-C10 사이클로알킬카르보닐아미노, 비치환되거나 C3-C10 사이클로알킬-C1-C7 알킬로 치환된 아미노설포닐, C6-C10 아릴-C1-C7 알킬, 비치환되거나 C1-C7 알킬 또는 할로로 치환된 N, O 및 S로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 12원의 포화 헤테로사이클릴-C1-C7 알킬, 및 N, O 및 S로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 12원의 불포화 헤테로사이클릴로 이루어지는 그룹에서 선택되는 1 내지 4개의 치환기로 치환될 수 있다.Halo, cyano, amino, carboxy (-COOH), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, hydroxy-C 1 -C 7 alkyl, halo-C 1 -C 7 alkyl, cyano-C 1 -C 7 alkyl, halo-C 1 -C 7 alkoxy, C 1 -C 7 alkoxy-C 1 -C 7 alkyl, C 1 -C 7 Alkylcarbonyl, C 1 -C 7 alkylamino-C 1 -C 7 alkyl, unsubstituted or substituted with C 1 -C 7 alkylcarbonyl, di(C 1 -C 7 alkyl ) amino -C 1 -C 7 alkyl , C 1 -C 7 alkylaminosulfonyl, C 1 -C 7 alkylcarbonylamino, C 3 -C 10 cycloalkylcarbonylamino, unsubstituted or C 3 -C 10 cycloalkyl-C 1 -C 7 alkyl. substituted aminosulfonyl, C 6 -C 10 aryl-C 1 -C 7 alkyl, unsubstituted or substituted with C 1 -C 7 alkyl or halo, having 1 to 3 heteroatoms selected from N, O and S 1 to 12 membered saturated heterocyclyl-C 1 -C 7 alkyl selected from the group consisting of 5 to 12 membered unsaturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S. It may be substituted with 4 substituents.
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)벤질)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
1-(1-(3-클로로벤질)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(3-chlorobenzyl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbonitrile;
1-(1-(5-((다이메틸아미노)메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-da ion;
1-메틸-4-(1-(5-((4-메틸피페라진-1-일)메틸)피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(5-((4-methylpiperazin-1-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline -2,3-dione;
6-클로로-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-chloro-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
6-클로로-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤질)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-chloro-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
2-(4-(6-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- carbonitrile;
6-클로로-1-(1-(5-(하이드록시메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;6-chloro-1-(1-(5-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3- Dion;
6-클로로-1-(1-(5-((다이메틸아미노)메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;6-Chloro-1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2 ,3-dione;
1-메틸-4-(1-(5-(트라이플루오로메틸)피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
2-(4-(7-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(7-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- carbonitrile;
6-클로로-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
6-클로로-4-(1-(5-((다이메틸아미노)메틸)피리미딘-2-일)피페리딘-4-일)-1-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;6-Chloro-4-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-1-methyl-1,4-dihydroquinoxaline-2 ,3-dione;
6-클로로-4-(1-(3-클로로벤질)피페리딘-4-일)-1-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;6-chloro-4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydroquinoxaline-2,3-dione;
6-클로로-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤질)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
2-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 -carbonitrile;
6-플루오로-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-fluoro-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
6-플루오로-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤질)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-fluoro-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
2-(4-(6-메톡시-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 -carbonitrile;
6-메톡시-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-methoxy-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
6-메톡시-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤질)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-methoxy-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
N-메틸-2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-설폰아마이드;N-methyl-2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- sulfonamide;
1-메틸-4-(1-(5-메틸피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
1-(1-(5-클로로피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
1-(1-(5-메톡시피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
1-(1-(5-(하이드록시메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르복시산;2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carboxylic acid;
1-(1-(5-아세틸피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-acetylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
1-메틸-4-(1-(피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
1-(1-(5-에틸피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
2-(4-(6-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 -carbonitrile;
2-(4-(7-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(7-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 -carbonitrile;
1-(1-(5-시아노피리미딘-2-일)피페리딘-4-일)-4-메틸-2,3-다이옥소-1,2,3,4-테트라하이드로퀴녹살린-6-카르보나이트릴;1-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline- 6-carbonitrile;
4-(1-(5-시아노피리미딘-2-일)피페리딘-4-일)-1-메틸-2,3-다이옥소-1,2,3,4-테트라하이드로퀴녹살린-6-카르보나이트릴;4-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline- 6-carbonitrile;
2-(4-(6-아세틸-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-acetyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- carbonitrile;
2-(4-(7-아세틸-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(7-acetyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- carbonitrile;
1-(1-(5-(아제티딘-1-일메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(azetidin-1-ylmethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3- Dion;
1-(1-(5-((3,3-다이플루오로아제티딘-1-일)메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-((3,3-difluoroazetidin-1-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4- Dihydroquinoxaline-2,3-dione;
N-메틸-N-((2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-일)메틸)아세트아마이드;N-methyl-N-((2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri midin-5-yl)methyl)acetamide;
1-(1-(5-(메톡시메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(methoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
1-(1-(5-(에톡시메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(ethoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
2-(2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-일)아세토나이트릴;2-(2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidin-5-yl ) Acetonitrile;
N-(사이클로프로필메틸)-2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-설폰아마이드;N-(cyclopropylmethyl)-2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri Mydine-5-sulfonamide;
1-(1-(4-메톡시피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
1-메틸-4-(1-(5-프로필피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
1-(1-(5-브로모피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
1-메틸-4-(1-(5-비닐피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(5-vinylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
1-메틸-4-(1-(5-(2-메틸프로프-1-엔-1-일)피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(5-(2-methylprop-1-en-1-yl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoc saline-2,3-dione;
1-(1-(5-아이소부틸피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-isobutylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
1-(1-(5-((7-옥사-2-아자스피로[3.5]노난-2-일)메틸)피리미딘-2-일)피페리딘-4-일)-6-클로로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-((7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-6-chloro-4 -methyl-1,4-dihydroquinoxaline-2,3-dione;
1-(1-(5-(다이플루오로메톡시)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
1-(1-(5-(다이플루오로메톡시)피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2, 3-dione;
1-(1-(5-에티닐피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-ethynylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
2-(4-(6-에티닐-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-ethynyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 -carbonitrile;
1-(1-(5-브로모피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione ;
1-(1-(5-클로로피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
5-플루오로-6-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴;5-fluoro-6-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl ) Nicotinonitrile;
6-플루오로-4-메틸-1-(1-(5-프로필피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-fluoro-4-methyl-1-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
6-플루오로-4-메틸-1-(1-(티에노[3,2-d]피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-Fluoro-4-methyl-1-(1-(thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2 ,3-dione;
4-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)벤조나이트릴;4-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)benzonitrile;
1-(1-(벤조[d]티아졸-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(benzo[d]thiazol-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione ;
1-(1-(벤조[d]옥사졸-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(benzo[d]oxazol-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione ;
1-(1-(5-(1,1-다이플루오로에틸)피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(1,1-difluoroethyl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoc saline-2,3-dione;
1-(1-(5-아미노피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-aminopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
N-(2-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-일)아세트아마이드;N-(2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri midin-5-yl)acetamide;
N-(2-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-일)사이클로프로판카르보사마이드;N-(2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri midin-5-yl)cyclopropanecarbosamide;
5-플루오로-6-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴;5-fluoro-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile ;
1-(1-(5-(3,6-다이하이드로-2H-피란-4-일)피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1 ,4-dihydroquinoxaline-2,3-dione;
1-(1-(5-(2,5-다이하이드로퓨란-3-일)피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(2,5-dihydrofuran-3-yl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4- Dihydroquinoxaline-2,3-dione;
5-플루오로-6-(4-(6-메톡시-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴;5-fluoro-6-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl ) Nicotinonitrile;
2-(4-(6-사이클로프로필-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-cyclopropyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 -carbonitrile;
2-(4-(6-아미노-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-amino-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- carbonitrile;
3,5-다이플루오로-4-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)벤조나이트릴;3,5-difluoro-4-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)benzo nitrile;
3,5-다이플루오로-4-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)벤조나이트릴;3,5-difluoro-4-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine- 1-1)benzonitrile;
3,5-다이플루오로-4-(4-(6-메톡시-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)벤조나이트릴;3,5-difluoro-4-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine- 1-1)benzonitrile;
N-(1-(1-(5-시아노피리미딘-2-일)피페리딘-4-일)-4-메틸-2,3-다이옥소-1,2,3,4-테트라하이드로퀴녹살린-6-일)아세트아마이드;N-(1-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-4-methyl-2,3-dioxo-1,2,3,4-tetrahydro quinoxalin-6-yl)acetamide;
1-(1-(5-(2,5-다이하이드로퓨란-3-일)-3-플루오로피리딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(2,5-dihydrofuran-3-yl)-3-fluoropyridin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl- 1,4-dihydroquinoxaline-2,3-dione;
1-(1-(벤조[d]티아졸-2-일메틸)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(benzo[d]thiazol-2-ylmethyl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-da ion;
2-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)벤조[d]티아졸-6-카르보나이트릴;2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)benzo[d] Thiazole-6-carbonitrile;
1-(1-((3-벤질-1,2,4-옥사다이아졸-5-일)메틸)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-((3-benzyl-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-di Hydroquinoxaline-2,3-dione;
4-(4-(6-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)-3,5-다이플루오로벤조나이트릴;4-(4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)-3,5- difluorobenzonitrile;
5-메톡시-6-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴;5-methoxy-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile ;
5-클로로-6-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴; 및5-chloro-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile; and
5-브로모-6-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴.5-Bromo-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile .
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 1에 따라 제조될 수 있다.For example, the compound of Formula 1 can be prepared according to Scheme 1 below.
[반응식 1][Scheme 1]
Figure PCTKR2023007091-appb-img-000002
Figure PCTKR2023007091-appb-img-000002
상기 반응식 1에서 R1, R2, R3 및 R4는 본원에서 정의된 것과 같고, R6은 아릴을 나타내고, R7 및 R8은 각각 독립적으로 할로, 시아노, 아미노, 카르복시(-COOH), 알킬, 알케닐, 알키닐, 알콕시, 하이드록시알킬, 할로알킬, 시아노알킬, 할로알콕시, 알콕시알킬, 알킬카르보닐, 비치환되거나 알킬카르보닐로 치환된 알킬아미노알킬, 다이알킬아미노알킬, 알킬아미노설포닐, 알킬카르보닐아미노, 사이클로알킬카르보닐아미노, 비치환되거나 사이클로알킬-알킬로 치환된 아미노설포닐, 아르알킬, 비치환되거나 알킬 또는 할로로 치환된 포화 헤테로사이클릴-알킬, 또는 불포화 헤테로사이클릴을 나타낸다.In Scheme 1, R 1 , R 2 , R 3 and R 4 are as defined herein, R 6 represents aryl, and R 7 and R 8 are each independently selected from halo, cyano, amino, carboxy (-COOH ), alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, haloalkyl, cyanoalkyl, haloalkoxy, alkoxyalkyl, alkylcarbonyl, alkylaminoalkyl unsubstituted or substituted with alkylcarbonyl, dialkylaminoalkyl , alkylaminosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino, aminosulfonyl unsubstituted or substituted with cycloalkyl-alkyl, aralkyl, saturated heterocyclyl-alkyl unsubstituted or substituted with alkyl or halo, or unsaturated heterocyclyl.
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:
DAST: 다이에틸아미노설퍼 트라이플루오라이드DAST: diethylaminosulfur trifluoride
DCE: 다이클로로에탄DCE: dichloroethane
DCM: 다이클로로메탄DCM: dichloromethane
DIPEA: N,N-다이아이소프로필에틸아민DIPEA: N,N-diisopropylethylamine
DMF: N,N-다이메틸포름아미드DMF: N,N-dimethylformamide
DMSO: 다이메틸 설폭사이드DMSO: dimethyl sulfoxide
EtOAc: 에틸 아세테이트EtOAc: ethyl acetate
EtOH: 에탄올EtOH: Ethanol
IPA: 아이소프로필알코올IPA: Isopropyl Alcohol
MeOH: 메탄올MeOH: methanol
MPLC: 중압 액체 크로마토그래피(medium pressure liquid chromatography)MPLC: medium pressure liquid chromatography
PdCl2(PPh3)2: 비스(트라이페닐포스핀)팔라듐(II) 다이클로라이드PdCl 2 (PPh 3 ) 2 : Bis(triphenylphosphine)palladium(II) dichloride
(PPh4)4Pd: 테트라키스(트라이페닐포스핀)팔라듐(0)(PPh 4 ) 4 Pd: tetrakis(triphenylphosphine)palladium (0)
TEA: 트라이에틸아민TEA: triethylamine
THF: 테트라하이드로퓨란THF: tetrahydrofuran
제조예 1: 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Preparation Example 1: Preparation of 1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTKR2023007091-appb-img-000003
Figure PCTKR2023007091-appb-img-000003
단계 A: 터트-부틸 4-((2-나이트로페닐)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((2-nitrophenyl)amino)piperidine-1-carboxylate
Figure PCTKR2023007091-appb-img-000004
Figure PCTKR2023007091-appb-img-000004
1-플루오로-2-나이트로벤젠 (3.76 mL, 35.40 mmol)과 터트-부틸 4-아미노피페리딘-1-카르복실레이트 (7.45 g, 37.20 mmol)를 DMF (150 mL)에 녹인 후 포타슘 카보네이트 (7.35 g, 53.20 mmol)를 가한 뒤 80℃에서 20 시간 교반하였다. 반응액을 상온으로 식힌 후 감압증류하여 농축한 혼합물을 EtOAc에 녹인 후 brine으로 4회 세척하였다. 이후 무수 MgSO4를 이용하여 건조한 뒤 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (11.27 g)을 얻었다.1-Fluoro-2-nitrobenzene (3.76 mL, 35.40 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (7.45 g, 37.20 mmol) were dissolved in DMF (150 mL) and potassium Carbonate (7.35 g, 53.20 mmol) was added and stirred at 80°C for 20 hours. The reaction solution was cooled to room temperature, distilled under reduced pressure, and the concentrated mixture was dissolved in EtOAc and washed four times with brine. Afterwards, it was dried using anhydrous MgSO 4 and then distilled under reduced pressure. The residue was purified by MPLC to give the title compound (11.27 g).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 6.7 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.66 (t, J = 7.8 Hz, 1H), 4.04 (br s, 2H), 3.70 (d, J = 6.7 Hz, 1H), 3.07 (t, J = 11.6 Hz, 2H), 2.08 (d, J = 12.5 Hz, 2H), 1.57 (q, J = 22.7, 10.8 Hz, 2H), 1.49 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 6.7 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 6.89 ( d, J = 8.5 Hz, 1H), 6.66 (t, J = 7.8 Hz, 1H), 4.04 (br s, 2H), 3.70 (d, J = 6.7 Hz, 1H), 3.07 (t, J = 11.6 Hz) , 2H), 2.08 (d, J = 12.5 Hz, 2H), 1.57 (q, J = 22.7, 10.8 Hz, 2H), 1.49 (s, 9H)
LC/MS: 344.2 (M+Na)LC/MS: 344.2 (M+Na)
단계 B: 터트-부틸 4-((2-아미노페닐)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((2-aminophenyl)amino)piperidine-1-carboxylate
Figure PCTKR2023007091-appb-img-000005
Figure PCTKR2023007091-appb-img-000005
터트-부틸 4-((2-나이트로페닐)아미노)피페리딘-1-카르복실레이트 (11.27 g, 35.21 mmol)를 MeOH (450 mL)에 녹인 후 0℃에서 Zinc (11.49 g, 175.74 mmol)을 천천히 첨가한 뒤, NH4Cl (9.40 g, 175.74 mmol)을 천천히 첨가하였다. 이후 혼합물을 1 시간 동안 0℃에서 교반한 뒤 60℃로 가열하여 16 시간 동안 교반하였다. 이후 혼합물을 상온으로 식힌 뒤, Celite®/Silica Pad에 여과하였다. 여과된 혼합물을 감압증류한 다음 DCM으로 녹인 후, 포화 NaHCO3 수용액을 이용하여 추출하였다. 이후 유기층을 무수 MgSO4를 이용하여 건조한 뒤 감압증류하여 표제 화합물 (10.15 g)을 얻었다.Tert-butyl 4-((2-nitrophenyl)amino)piperidine-1-carboxylate (11.27 g, 35.21 mmol) was dissolved in MeOH (450 mL) and then dissolved in Zinc (11.49 g, 175.74 mmol) at 0°C. ) was slowly added, and then NH 4 Cl (9.40 g, 175.74 mmol) was slowly added. The mixture was then stirred at 0°C for 1 hour, then heated to 60°C and stirred for 16 hours. Afterwards, the mixture was cooled to room temperature and filtered through Celite ® /Silica Pad. The filtered mixture was distilled under reduced pressure, dissolved in DCM, and extracted using a saturated aqueous NaHCO 3 solution. Afterwards, the organic layer was dried using anhydrous MgSO 4 and then distilled under reduced pressure to obtain the title compound (10.15 g).
1H-NMR (500 MHz, CHLOROFORM-D) δ 6.80 (t, J = 7.5 Hz, 1H), 6.74 (d, J = 7.0 Hz, 1H), 6.71 (t, J = 9.0 Hz, 2H), 4.03 (br s, 3H), 3.44-3.34 (m, 3H), 2.95 (t, J= 12.0 Hz, 2H), 2.06 (d, J = 12.2 Hz, 2H), 1.49 (s, 9H), 1.44-1.38 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 6.80 (t, J = 7.5 Hz, 1H), 6.74 (d, J = 7.0 Hz, 1H), 6.71 (t, J = 9.0 Hz, 2H), 4.03 ( br s, 3H), 3.44-3.34 (m, 3H), 2.95 (t, J= 12.0 Hz, 2H), 2.06 (d, J = 12.2 Hz, 2H), 1.49 (s, 9H), 1.44-1.38 ( m, 2H)
LC/MS: 236.1 (M-tBu+2H)LC/MS: 236.1 (M-tBu+2H)
단계 C: 터트-부틸 4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-카르복실레이트의 제조Step C: Preparation of tert-butyl 4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate
Figure PCTKR2023007091-appb-img-000006
Figure PCTKR2023007091-appb-img-000006
터트-부틸 4-((2-아미노페닐)아미노)피페리딘-1-카르복실레이트 (10.15 g, 34.8 mmol)를 DCE (350 mL)에 녹인 뒤 TEA (19.42 mL, 139 mmol)를 넣어주었다. 이후 반응 혼합물에 에틸 2-클로로-2-옥소아세테이트 (7.78 mL, 69.7 mmol)를 0℃에서 천천히 가하였다. 혼합물을 상온에서 30분 교반한 뒤 80℃에서 20시간 교반하였다. 반응 혼합물을 상온으로 식힌 후 감압증류하였다. 농축된 혼합물을 DCM으로 묽힌 후 포화 NH4Cl 수용액으로 추출하였다. 유기층을 무수 MgSO4를 이용하여 건조한 후 감압증류하였다. 잔류물을 DMF (350 mL)에 녹인 뒤 세슘 카보네이트 (17.02 g, 52.2 mmol)와 아이오도메탄 (2.86 mL, 45.7 mmol)을 가하고 상온에서 2 시간 동안 교반하였다. 반응 혼합물을 감압 증류하여 농축된 혼합물을 EtOAc로 묽히고 brine으로 3회 세척하였다. 유기층을 무수 MgSO4를 이용하여 건조한 뒤 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (6.29 g)을 얻었다.Tert-butyl 4-((2-aminophenyl)amino)piperidine-1-carboxylate (10.15 g, 34.8 mmol) was dissolved in DCE (350 mL) and TEA (19.42 mL, 139 mmol) was added. . Afterwards, ethyl 2-chloro-2-oxoacetate (7.78 mL, 69.7 mmol) was slowly added to the reaction mixture at 0°C. The mixture was stirred at room temperature for 30 minutes and then at 80°C for 20 hours. The reaction mixture was cooled to room temperature and then distilled under reduced pressure. The concentrated mixture was diluted with DCM and extracted with saturated NH 4 Cl aqueous solution. The organic layer was dried using anhydrous MgSO 4 and then distilled under reduced pressure. The residue was dissolved in DMF (350 mL), cesium carbonate (17.02 g, 52.2 mmol) and iodomethane (2.86 mL, 45.7 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was distilled under reduced pressure, and the concentrated mixture was diluted with EtOAc and washed three times with brine. 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 (6.29 g).
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.46 (d, J = 7.3 Hz, 1H), 7.29 (br s, 3H), 4.79 (br s, 1H), 4.35 (br s, 2H), 3.67 (s, 3H), 2.90-2.77 (m, 4H), 1.78 (d, J = 11.0 Hz, 2H), 1.52 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.46 (d, J = 7.3 Hz, 1H), 7.29 (br s, 3H), 4.79 (br s, 1H), 4.35 (br s, 2H), 3.67 ( s, 3H), 2.90-2.77 (m, 4H), 1.78 (d, J = 11.0 Hz, 2H), 1.52 (s, 9H)
LC/MS: 360.2 (M+H)LC/MS: 360.2 (M+H)
단계 D: 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step D: Preparation of 1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTKR2023007091-appb-img-000007
Figure PCTKR2023007091-appb-img-000007
터트-부틸 4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-카르복실레이트 (6.29 g, 17.50 mmol)를 DCM (175 mL)에 녹인 뒤 4 M HCl in 1,4-다이옥산 (43.8 mL, 175 mmol)를 첨가한 뒤 12 시간동안 상온에서 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 (4.24 g)을 얻었다.Tert-butyl 4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate (6.29 g, 17.50 mmol) After dissolving in DCM (175 mL), 4 M HCl in 1,4-dioxane (43.8 mL, 175 mmol) was added and stirred at room temperature for 12 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 (4.24 g).
LC/MS: 260.2 (M+H)LC/MS: 260.2 (M+H)
제조예 2: 6-클로로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Preparation Example 2: Preparation of 6-chloro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTKR2023007091-appb-img-000008
Figure PCTKR2023007091-appb-img-000008
단계 A: 터트-부틸 4-((4-클로로-2-나이트로페닐)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((4-chloro-2-nitrophenyl)amino)piperidine-1-carboxylate
Figure PCTKR2023007091-appb-img-000009
Figure PCTKR2023007091-appb-img-000009
4-클로로-1-플루오로-2-나이트로벤젠 (10 g, 57.0 mmol)을 이용하여 제조예 1의 단계 A의 방법과 유사한 방법으로 표제 화합물 (19.8 g)을 얻었다.The title compound (19.8 g) was obtained in a similar manner to Step A of Preparation Example 1 using 4-chloro-1-fluoro-2-nitrobenzene (10 g, 57.0 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (s, 1H), 8.05 (d, J = 6.7 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 6.84 (d, J = 9.2 Hz, 1H), 4.02 (d, J = 8.9 Hz, 2H), 3.65 (d, J = 3.7 Hz, 1H), 3.05 (t, J = 11.7 Hz, 2H), 2.05 (d, J = 12.8 Hz, 2H), 1.51-1.56 (m, 2H), 1.48 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (s, 1H), 8.05 (d, J = 6.7 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 6.84 (d, J = 9.2 Hz, 1H), 4.02 (d, J = 8.9 Hz, 2H), 3.65 (d, J = 3.7 Hz, 1H), 3.05 (t, J = 11.7 Hz, 2H), 2.05 (d, J = 12.8 Hz, 2H), 1.51-1.56 (m, 2H), 1.48 (s, 9H)
LC/MS: 378.1 (M+Na), 300.1 (M-tbu+2H)LC/MS: 378.1 (M+Na), 300.1 (M-tbu+2H)
단계 B: 터트-부틸 4-((2-아미노-4-클로로페닐)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((2-amino-4-chlorophenyl)amino)piperidine-1-carboxylate
Figure PCTKR2023007091-appb-img-000010
Figure PCTKR2023007091-appb-img-000010
터트-부틸 4-((4-클로로-2-나이트로페닐)아미노)피페리딘-1-카르복실레이트 (19.8 g, 55.6 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (18 g, 55.2 mmol)을 얻었다.The title compound was prepared in a manner similar to Step B of Preparation Example 1 using tert-butyl 4-((4-chloro-2-nitrophenyl)amino)piperidine-1-carboxylate (19.8 g, 55.6 mmol). (18 g, 55.2 mmol) was obtained.
LC/MS: 270.1 (M-tBu+2H)LC/MS: 270.1 (M-tBu+2H)
단계 C: 터트-부틸 4-(6-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-카르복실레이트의 제조Step C: of tert-butyl 4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate manufacturing
Figure PCTKR2023007091-appb-img-000011
Figure PCTKR2023007091-appb-img-000011
터트-부틸 4-((2-아미노-4-클로로페닐)아미노)피페리딘-1-카르복실레이트 (18 g, 55.2 mmol)와 DIPEA (48.2 mL, 276 mmol)를 이용하여 제조예 1의 단계 C와 같은 방법을 이용하여 표제 화합물 (10.4 g)을 얻었다.Preparation Example 1 using tert-butyl 4-((2-amino-4-chlorophenyl)amino)piperidine-1-carboxylate (18 g, 55.2 mmol) and DIPEA (48.2 mL, 276 mmol) The title compound (10.4 g) was obtained using the same method as Step C.
1H-NMR (400 MHz, DMSO-D6) δ 7.67 (d, J = 9.1 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.25 (dd, J = 9.1, 2.3 Hz, 1H), 4.57 (br s, 1H), 4.01 (d, J = 11.0 Hz, 2H), 3.46 (s, 3H), 2.83-3.00 (m, 2H), 2.46-2.57 (m, 2H), 1.63 (d, J = 11.0 Hz, 2H), 1.39 (s, 9H)1H-NMR (400 MHz, DMSO-D6) δ 7.67 (d, J = 9.1 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.25 (dd, J = 9.1, 2.3 Hz, 1H), 4.57 (br s, 1H), 4.01 (d, J = 11.0 Hz, 2H), 3.46 (s, 3H), 2.83-3.00 (m, 2H), 2.46-2.57 (m, 2H), 1.63 (d, J = 11.0 Hz, 2H), 1.39 (s, 9H)
LC/MS: 394.2 (M+H)LC/MS: 394.2 (M+H)
단계 D: 6-클로로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step D: Preparation of 6-chloro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTKR2023007091-appb-img-000012
Figure PCTKR2023007091-appb-img-000012
터트-부틸 4-(6-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-카르복실레이트 (10.4 g, 26.4 mmol)를 이용하여 제조예 1의 단계 D와 같은 방법을 이용하여 표제 화합물 (7.58 g)을 얻었다.Tert-butyl 4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate (10.4 g, The title compound (7.58 g) was obtained using the same method as Step D of Preparation Example 1 using 26.4 mmol).
LC/MS: 294.1 (M+H)LC/MS: 294.1 (M+H)
제조예 3: 6-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Preparation Example 3: Preparation of 6-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTKR2023007091-appb-img-000013
Figure PCTKR2023007091-appb-img-000013
단계 A: 터트-부틸 4-((5-클로로-2-나이트로페닐)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((5-chloro-2-nitrophenyl)amino)piperidine-1-carboxylate
Figure PCTKR2023007091-appb-img-000014
Figure PCTKR2023007091-appb-img-000014
4-클로로-2-플루오로-1-나이트로벤젠 (3 g, 17.09 mmol)을 이용하여 제조예 1의 단계 A와 유사한 방법으로 표제 화합물 (6.00 g)을 얻었다.The title compound (6.00 g) was obtained in a similar manner to Step A of Preparation Example 1 using 4-chloro-2-fluoro-1-nitrobenzene (3 g, 17.09 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.15 (d, J = 8.9 Hz, 2H), 6.86 (s, 1H), 6.64 (d, J = 8.9 Hz, 1H), 4.04 (br s, 1H), 3.65-3.64 (m, 1H), 3.09 (t, J = 11.9 Hz, 2H), 2.08 (d, J = 11.6 Hz, 2H), 1.60-1.54 (m, 3H), 1.49 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.15 (d, J = 8.9 Hz, 2H), 6.86 (s, 1H), 6.64 (d, J = 8.9 Hz, 1H), 4.04 (br s, 1H) , 3.65-3.64 (m, 1H), 3.09 (t, J = 11.9 Hz, 2H), 2.08 (d, J = 11.6 Hz, 2H), 1.60-1.54 (m, 3H), 1.49 (s, 9H)
LC/MS: 378.1 (M+Na)LC/MS: 378.1 (M+Na)
단계 B: 터트-부틸 4-((2-아미노-5-클로로페닐)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((2-amino-5-chlorophenyl)amino)piperidine-1-carboxylate
Figure PCTKR2023007091-appb-img-000015
Figure PCTKR2023007091-appb-img-000015
터트-부틸 4-((5-클로로-2-나이트로페닐)아미노)피페리딘-1-카르복실레이트 (6 g, 16.86 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (5.44 g)을 얻었다.The title compound was prepared in a manner similar to Step B of Preparation Example 1 using tert-butyl 4-((5-chloro-2-nitrophenyl)amino)piperidine-1-carboxylate (6 g, 16.86 mmol). (5.44 g) was obtained.
LC/MS: 348.2 (M+Na)LC/MS: 348.2 (M+Na)
단계 C: 터트-부틸 4-(7-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-카르복실레이트의 제조Step C: of tert-butyl 4-(7-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate manufacturing
Figure PCTKR2023007091-appb-img-000016
Figure PCTKR2023007091-appb-img-000016
터트-부틸 4-((2-아미노-5-클로로페닐)아미노)피페리딘-1-카르복실레이트 (5.44 g, 16.70 mmol)를 이용하여 제조예 1의 단계 C와 유사한 방법으로 표제 화합물 (3.58 g)을 얻었다.The title compound ( 3.58 g) was obtained.
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.40 (s, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 4.68 (br s, 1H), 4.40 (br s, 2H), 3.65 (s, 3H), 2.90 (br s, 2H), 2.81-2.71 (m, 2H), 1.77 (d, J = 11.6 Hz, 2H), 1.53 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.40 (s, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 4.68 (br s, 1H) , 4.40 (br s, 2H), 3.65 (s, 3H), 2.90 (br s, 2H), 2.81-2.71 (m, 2H), 1.77 (d, J = 11.6 Hz, 2H), 1.53 (s, 9H) )
LC/MS: 394.2 (M+H)LC/MS: 394.2 (M+H)
단계 D: 6-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step D: Preparation of 6-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTKR2023007091-appb-img-000017
Figure PCTKR2023007091-appb-img-000017
터트-부틸 4-(7-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-카르복실레이트 (3.58 g, 9.09 mmol)를 이용하여 제조예 1의 단계 D와 유사한 방법으로 표제 화합물 (2.37 g)을 얻었다.Tert-butyl 4-(7-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate (3.58 g, The title compound (2.37 g) was obtained in a similar manner to Step D of Preparation Example 1 using 9.09 mmol).
LC/MS: 294.1 (M+H)LC/MS: 294.1 (M+H)
제조예 4: 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Preparation Example 4: Preparation of 6-fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTKR2023007091-appb-img-000018
Figure PCTKR2023007091-appb-img-000018
단계 A: 터트-부틸 4-((4-플루오로-2-나이트로페닐)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((4-fluoro-2-nitrophenyl)amino)piperidine-1-carboxylate
Figure PCTKR2023007091-appb-img-000019
Figure PCTKR2023007091-appb-img-000019
1,4-다이플루오로-2-나이트로벤젠 (3.45 mL, 31.4 mmol)을 이용하여 제조예 1의 단계 A와 유사한 방법으로 표제 화합물 (9.9 g)을 얻었다.The title compound (9.9 g) was obtained in a similar manner to Step A of Preparation Example 1 using 1,4-difluoro-2-nitrobenzene (3.45 mL, 31.4 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.00 (d, J = 6.7 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 6.88 (dd, J = 9.2, 3.1 Hz, 1H), 4.04 (br s, 2H), 3.66 (d, J = 4.3 Hz, 1H), 3.07 (t, J = 11.6 Hz, 2H), 2.07 (d, J = 10.4 Hz, 2H), 1.60-1.56 (m, 2H), 1.50 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.00 (d, J = 6.7 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 6.88 ( dd, J = 9.2, 3.1 Hz, 1H), 4.04 (br s, 2H), 3.66 (d, J = 4.3 Hz, 1H), 3.07 (t, J = 11.6 Hz, 2H), 2.07 (d, J = 10.4 Hz, 2H), 1.60-1.56 (m, 2H), 1.50 (s, 9H)
LC/MS: 362.1 (M+Na)LC/MS: 362.1 (M+Na)
단계 B: 터트-부틸 4-((2-아미노-4-플루오로페닐)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((2-amino-4-fluorophenyl)amino)piperidine-1-carboxylate
Figure PCTKR2023007091-appb-img-000020
Figure PCTKR2023007091-appb-img-000020
터트-부틸 4-((4-플루오로-2-나이트로페닐)아미노)피페리딘-1-카르복실레이트 (9.9 g, 29.2 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (8.98 g)을 얻었다.In a manner similar to Step B of Preparation Example 1 using tert-butyl 4-((4-fluoro-2-nitrophenyl)amino)piperidine-1-carboxylate (9.9 g, 29.2 mmol), the title Compound (8.98 g) was obtained.
LC/MS: 254.1 (M-tBu+H)LC/MS: 254.1 (M-tBu+H)
단계 C: 터트-부틸 4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-카르복실레이트의 제조Step C: Tert-Butyl 4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate manufacture of
Figure PCTKR2023007091-appb-img-000021
Figure PCTKR2023007091-appb-img-000021
터트-부틸 4-((2-아미노-4-플루오로페닐)아미노)피페리딘-1-카르복실레이트 (8.98 g, 29.0 mmol)를 이용하여 제조예 1의 단계 C와 유사한 방법으로 표제 화합물 (4.0 g)을 얻었다.The title compound was prepared in a manner similar to Step C of Preparation Example 1 using tert-butyl 4-((2-amino-4-fluorophenyl)amino)piperidine-1-carboxylate (8.98 g, 29.0 mmol). (4.0 g) was obtained.
1H-NMR (400 MHz, CHLOROFORM-D) d 7.36 (q, J = 4.7 Hz, 1H), 6.99-6.92 (m, 2H), 4.72 (br s, 1H), 4.47-4.31 (m, 2H), 3.60 (s, 3H), 2.83 (d, J = 12.3 Hz, 2H), 2.71 (qd, J = 12.3, 3.9 Hz, 2H), 1.74 (d, J = 11.4 Hz, 2H), 1.48 (s, 9H)1H-NMR (400 MHz, CHLOROFORM-D) d 7.36 (q, J = 4.7 Hz, 1H), 6.99-6.92 (m, 2H), 4.72 (br s, 1H), 4.47-4.31 (m, 2H), 3.60 (s, 3H), 2.83 (d, J = 12.3 Hz, 2H), 2.71 (qd, J = 12.3, 3.9 Hz, 2H), 1.74 (d, J = 11.4 Hz, 2H), 1.48 (s, 9H) )
LC/MS: 400.2 (M+Na)LC/MS: 400.2 (M+Na)
단계 D: 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step D: Preparation of 6-fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTKR2023007091-appb-img-000022
Figure PCTKR2023007091-appb-img-000022
터트-부틸 4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-카르복실레이트 (4.0 g, 10.60 mmol)를 이용하여 제조예 1의 단계 D와 유사한 방법으로 표제 화합물 (2.30 g)을 얻었다.Tert-butyl 4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate (4.0 g , 10.60 mmol) to obtain the title compound (2.30 g) in a similar manner to Step D of Preparation Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.54 (s, 1H), 7.02-6.96 (m, 2H), 4.77 (br s, 1H), 3.63 (s, 3H), 3.31 (d, J = 11.9 Hz, 2H), 2.81 (t, J = 12.2 Hz, 2H), 2.72 (q, J = 12.1 Hz, 2H), 1.79 (d, J = 11.9 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.54 (s, 1H), 7.02-6.96 (m, 2H), 4.77 (br s, 1H), 3.63 (s, 3H), 3.31 (d, J = 11.9 Hz, 2H), 2.81 (t, J = 12.2 Hz, 2H), 2.72 (q, J = 12.1 Hz, 2H), 1.79 (d, J = 11.9 Hz, 2H)
LC/MS: 278.1 (M+H)LC/MS: 278.1 (M+H)
제조예 5: 6-메톡시-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Preparation Example 5: Preparation of 6-methoxy-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTKR2023007091-appb-img-000023
Figure PCTKR2023007091-appb-img-000023
단계 A: 터트-부틸 4-((4-메톡시-2-나이트로페닐)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((4-methoxy-2-nitrophenyl)amino)piperidine-1-carboxylate
Figure PCTKR2023007091-appb-img-000024
Figure PCTKR2023007091-appb-img-000024
1-플루오로-4-메톡시-2-나이트로벤젠 (5.0 g, 29.2 mmol)을 이용하여 제조예 1의 단계 A와 유사한 방법으로 표제 화합물 (8.1 g)을 얻었다.The title compound (8.1 g) was obtained in a similar manner to Step A of Preparation Example 1 using 1-fluoro-4-methoxy-2-nitrobenzene (5.0 g, 29.2 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.05 (d, J = 7.0 Hz, 1H), 7.65 (s, 1H), 7.17 (d, J = 9.5 Hz, 1H), 6.87 (d, J = 9.5 Hz, 1H), 4.02 (s, br 2H), 3.82 (s, 3H), 3.67 (br s, 1H), 3.07 (t, J = 11.4 Hz, 2H), 2.07 (d, J = 12.2 Hz, 2H), 1.61-1.53 (m, 2H), 1.50 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.05 (d, J = 7.0 Hz, 1H), 7.65 (s, 1H), 7.17 (d, J = 9.5 Hz, 1H), 6.87 (d, J = 9.5 Hz, 1H), 4.02 (s, br 2H), 3.82 (s, 3H), 3.67 (br s, 1H), 3.07 (t, J = 11.4 Hz, 2H), 2.07 (d, J = 12.2 Hz, 2H) ), 1.61-1.53 (m, 2H), 1.50 (s, 9H)
LC/MS: 374.1 (M+Na)LC/MS: 374.1 (M+Na)
단계 B: 터트-부틸 4-((2-아미노-4-메톡시페닐)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((2-amino-4-methoxyphenyl)amino)piperidine-1-carboxylate
Figure PCTKR2023007091-appb-img-000025
Figure PCTKR2023007091-appb-img-000025
터트-부틸 4-((4-메톡시-2-나이트로페닐)아미노)피페리딘-1-카르복실레이트 (8.1 g, 23.05 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (7.3 g)을 얻었다.tert-butyl 4-((4-methoxy-2-nitrophenyl)amino)piperidine-1-carboxylate (8.1 g, 23.05 mmol) was prepared in a manner similar to Step B of Preparation Example 1. Compound (7.3 g) was obtained.
LC/MS: 322.2 (M+H)LC/MS: 322.2 (M+H)
단계 C: 터트-부틸 4-(6-메톡시-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-카르복실레이트의 제조Step C: Tert-Butyl 4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate manufacture of
Figure PCTKR2023007091-appb-img-000026
Figure PCTKR2023007091-appb-img-000026
터트-부틸 4-((2-아미노-4-메톡시페닐)아미노)피페리딘e-1-카르복실레이트 (7.3 g, 22.71 mmol)를 이용하여 제조예 1의 단계 C와 유사한 방법으로 표제 화합물 (1.8 g)을 얻었다.tert-butyl 4-((2-amino-4-methoxyphenyl)amino)piperidinee-1-carboxylate (7.3 g, 22.71 mmol) was prepared in a manner similar to Step C of Preparation Example 1. Compound (1.8 g) was obtained.
1H-NMR (400 MHz, CHLOROFORM-D) d 7.33 (d, J = 10.1 Hz, 1H), 6.76 (td, J = 4.8, 2.7 Hz, 2H), 4.76 (br s, 1H), 4.31 (br s, 2H), 3.85 (s, 3H), 3.60 (s, 3H), 2.87-2.66 (m, 4H), 1.73 (d, J = 11.0 Hz, 2H), 1.47 (s, 9H)1H-NMR (400 MHz, CHLOROFORM-D) d 7.33 (d, J = 10.1 Hz, 1H), 6.76 (td, J = 4.8, 2.7 Hz, 2H), 4.76 (br s, 1H), 4.31 (br s , 2H), 3.85 (s, 3H), 3.60 (s, 3H), 2.87-2.66 (m, 4H), 1.73 (d, J = 11.0 Hz, 2H), 1.47 (s, 9H)
LC/MS: 412.2 (M+Na)LC/MS: 412.2 (M+Na)
단계 D: 6-메톡시-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step D: Preparation of 6-methoxy-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTKR2023007091-appb-img-000027
Figure PCTKR2023007091-appb-img-000027
터트-부틸 4-(6-메톡시-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-카르복실레이트 (1.8 g, 4.62 mmol)를 이용하여 제조예 1의 단계 D와 유사한 방법으로 표제 화합물 (1.2 g)을 얻었다.Tert-Butyl 4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate (1.8 g , 4.62 mmol) to obtain the title compound (1.2 g) in a similar manner to Step D of Preparation Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.54 (d, J = 8.9 Hz, 1H), 6.82-6.78 (m, 2H), 4.80 (br s, 1H), 3.89 (s, 3H), 3.64 (s, 3H), 3.32 (d, J = 11.3 Hz, 2H), 2.85-2.72 (m, 4H), 1.96 (br s, 1H), 1.79 (d, J = 12.5 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.54 (d, J = 8.9 Hz, 1H), 6.82-6.78 (m, 2H), 4.80 (br s, 1H), 3.89 (s, 3H), 3.64 ( s, 3H), 3.32 (d, J = 11.3 Hz, 2H), 2.85-2.72 (m, 4H), 1.96 (br s, 1H), 1.79 (d, J = 12.5 Hz, 2H)
LC/MS: 290.1 (M+H)LC/MS: 290.1 (M+H)
제조예 6: 6-브로모-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Preparation Example 6: Preparation of 6-bromo-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTKR2023007091-appb-img-000028
Figure PCTKR2023007091-appb-img-000028
단계 A: 터트-부틸 4-((4-브로모-2-나이트로페닐)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((4-bromo-2-nitrophenyl)amino)piperidine-1-carboxylate
Figure PCTKR2023007091-appb-img-000029
Figure PCTKR2023007091-appb-img-000029
4-브로모-1-플루오로-2-나이트로벤젠 (5.53 mL, 45.5 mmol)을 이용하여 제조예 1의 단계 A와 유사한 방법으로 표제 화합물 (14.3 g)을 얻었다.The title compound (14.3 g) was obtained in a similar manner to Step A of Preparation Example 1 using 4-bromo-1-fluoro-2-nitrobenzene (5.53 mL, 45.5 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.33 (s, 1H), 8.07 (d, J = 7.0 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H), 6.79 (d, J = 9.2 Hz, 1H), 4.03 (br s, 2H), 3.64 (d, J = 8.2 Hz, 1H), 3.04 (t, J = 11.6 Hz, 2H), 2.05 (d, J = 12.8 Hz, 2H), 1.55 (br s, 2H), 1.48 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.33 (s, 1H), 8.07 (d, J = 7.0 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H), 6.79 (d, J = 9.2 Hz, 1H), 4.03 (br s, 2H), 3.64 (d, J = 8.2 Hz, 1H), 3.04 (t, J = 11.6 Hz, 2H), 2.05 (d, J = 12.8 Hz, 2H), 1.55 (br s, 2H), 1.48 (s, 9H)
LC/MS: 422.1 (M+Na)LC/MS: 422.1 (M+Na)
단계 B: 터트-부틸 4-((2-아미노-4-브로모페닐)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((2-amino-4-bromophenyl)amino)piperidine-1-carboxylate
Figure PCTKR2023007091-appb-img-000030
Figure PCTKR2023007091-appb-img-000030
터트-부틸 4-((4-브로모-2-나이트로페닐)아미노)피페리딘-1-카르복실레이트 (14.3 g, 35.7 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (11.3 g)을 얻었다.The title product was prepared in a manner similar to Step B of Preparation Example 1 using tert-butyl 4-((4-bromo-2-nitrophenyl)amino)piperidine-1-carboxylate (14.3 g, 35.7 mmol). Compound (11.3 g) was obtained.
1H-NMR (500 MHz, CHLOROFORM-D) δ 6.88 (d, J = 8.2 Hz, 1H), 6.85 (s, 1H), 6.52 (d, J = 8.2 Hz, 1H), 4.03 (br s, 2H), 3.40-3.32 (m, 4H), 2.94 (t, J = 11.7 Hz, 2H), 2.00 (d, J = 12.5 Hz, 2H), 1.47 (s, 9H), 1.40-1.34 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 6.88 (d, J = 8.2 Hz, 1H), 6.85 (s, 1H), 6.52 (d, J = 8.2 Hz, 1H), 4.03 (br s, 2H) , 3.40-3.32 (m, 4H), 2.94 (t, J = 11.7 Hz, 2H), 2.00 (d, J = 12.5 Hz, 2H), 1.47 (s, 9H), 1.40-1.34 (m, 2H)
LC/MS: 314.0 (M-tBu+H)LC/MS: 314.0 (M-tBu+H)
단계 C: 터트-부틸 4-(6-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-카르복실레이트의 제조Step C: Tert-Butyl 4-(6-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate manufacture of
Figure PCTKR2023007091-appb-img-000031
Figure PCTKR2023007091-appb-img-000031
터트-부틸 4-((2-아미노-4-브로모페닐)아미노)피페리딘-1-카르복실레이트 (11.3 g, 30.5 mmol)를 이용하여 제조예 1의 단계 C와 유사한 방법으로 표제 화합물 (10.4 g)을 얻었다.The title compound was prepared in a manner similar to Step C of Preparation Example 1 using tert-butyl 4-((2-amino-4-bromophenyl)amino)piperidine-1-carboxylate (11.3 g, 30.5 mmol). (10.4 g) was obtained.
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.39 (s, 1H), 7.35 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 4.71 (br s, 1H), 4.33 (br s, 2H), 3.63 (s, 3H), 2.86 (br s, 2H), 2.71 (d, J = 10.7 Hz, 2H), 1.75 (d, J = 11.3 Hz, 2H), 1.50 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.39 (s, 1H), 7.35 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 4.71 (br s, 1H) , 4.33 (br s, 2H), 3.63 (s, 3H), 2.86 (br s, 2H), 2.71 (d, J = 10.7 Hz, 2H), 1.75 (d, J = 11.3 Hz, 2H), 1.50 ( s, 9H)
LC/MS: 460.1 (M+Na)LC/MS: 460.1 (M+Na)
단계 D: 6-브로모-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step D: Preparation of 6-bromo-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTKR2023007091-appb-img-000032
Figure PCTKR2023007091-appb-img-000032
터트-부틸 4-(6-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-카르복실레이트 (1.0 g, 2.28 mmol)를 이용하여 제조예 1의 단계 D와 유사한 방법으로 표제 화합물 (630 mg)을 얻었다.Tert-Butyl 4-(6-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate (1.0 g , 2.28 mmol) to obtain the title compound (630 mg) in a similar manner to Step D of Preparation Example 1.
LC/MS: 338.1 (M+H)LC/MS: 338.1 (M+H)
제조예 7: 6-브로모-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Preparation Example 7: Preparation of 6-bromo-1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTKR2023007091-appb-img-000033
Figure PCTKR2023007091-appb-img-000033
단계 A: 터트-부틸 4-((5-브로모-2-나이트로페닐)아미노)피페리딘-1-카르복실레이트의 제조Step A: Preparation of tert-butyl 4-((5-bromo-2-nitrophenyl)amino)piperidine-1-carboxylate
Figure PCTKR2023007091-appb-img-000034
Figure PCTKR2023007091-appb-img-000034
4-브로모-2-플루오로-1-나이트로벤젠 (10 g, 45.5 mmol)을 이용하여 제조예 1의 단계 A와 유사한 방법으로 표제 화합물 (17.7 g)을 얻었다.The title compound (17.7 g) was obtained in a similar manner to Step A of Preparation Example 1 using 4-bromo-2-fluoro-1-nitrobenzene (10 g, 45.5 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.10 (d, J = 6.7 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.02 (s, 1H), 6.77 (d, J = 9.2 Hz, 1H), 4.02 (br s, 2H), 3.64-3.63 (m, 1H), 3.07 (t, J = 11.4 Hz, 2H), 2.06 (d, J = 9.8 Hz, 2H), 1.58 (br s, 2H), 1.48 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.10 (d, J = 6.7 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.02 (s, 1H), 6.77 (d, J = 9.2 Hz, 1H), 4.02 (br s, 2H), 3.64-3.63 (m, 1H), 3.07 (t, J = 11.4 Hz, 2H), 2.06 (d, J = 9.8 Hz, 2H), 1.58 (br s) , 2H), 1.48 (s, 9H)
LC/MS: 422.1 (M+Na)LC/MS: 422.1 (M+Na)
단계 B: 터트-부틸 4-((2-아미노-5-브로모페닐)아미노)피페리딘-1-카르복실레이트의 제조Step B: Preparation of tert-butyl 4-((2-amino-5-bromophenyl)amino)piperidine-1-carboxylate
Figure PCTKR2023007091-appb-img-000035
Figure PCTKR2023007091-appb-img-000035
터트-부틸 4-((5-브로모-2-나이트로페닐)아미노)피페리딘-1-카르복실레이트 (17.7 g, 44.2 mmol)를 이용하여 제조예 1의 단계 B와 유사한 방법으로 표제 화합물 (12.9 g)을 얻었다.tert-butyl 4-((5-bromo-2-nitrophenyl)amino)piperidine-1-carboxylate (17.7 g, 44.2 mmol) was used in a similar manner to Step B of Preparation Example 1. Compound (12.9 g) was obtained.
1H-NMR (500 MHz, CHLOROFORM-D) δ 6.76 (d, J = 8.2 Hz, 1H), 6.74 (s, 1H), 6.59 (d, J = 8.2 Hz, 1H), 4.05 (br s, 2H), 3.34 (d, J = 19.8 Hz, 2H), 3.25 (br s, 2H), 2.96 (t, J = 13.0 Hz, 2H), 2.03 (d, J = 14.3 Hz, 2H), 1.47 (s, 9H), 1.38 (d, J = 11.6 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 6.76 (d, J = 8.2 Hz, 1H), 6.74 (s, 1H), 6.59 (d, J = 8.2 Hz, 1H), 4.05 (br s, 2H) , 3.34 (d, J = 19.8 Hz, 2H), 3.25 (br s, 2H), 2.96 (t, J = 13.0 Hz, 2H), 2.03 (d, J = 14.3 Hz, 2H), 1.47 (s, 9H) ), 1.38 (d, J = 11.6 Hz, 2H)
LC/MS: 314.0 (M-tBu+H)LC/MS: 314.0 (M-tBu+H)
단계 C: 터트-부틸 4-(7-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-카르복실레이트의 제조Step C: Tert-Butyl 4-(7-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate manufacture of
Figure PCTKR2023007091-appb-img-000036
Figure PCTKR2023007091-appb-img-000036
터트-부틸 4-((2-아미노-5-브로모페닐)아미노)피페리딘-1-카르복실레이트 (12.9 g, 34.8 mmol)를 이용하여 제조예 1의 단계 C와 유사한 방법으로 표제 화합물 (10.4 g)을 얻었다.The title compound was prepared in a manner similar to Step C of Preparation Example 1 using tert-butyl 4-((2-amino-5-bromophenyl)amino)piperidine-1-carboxylate (12.9 g, 34.8 mmol). (10.4 g) was obtained.
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.51 (s, 1H), 7.38 (d, J = 8.9 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 4.63 (br s, 1H), 4.35 (br s, 2H), 3.62 (s, 3H), 2.88 (br s, 2H), 2.73 (d, J = 11.3 Hz, 2H), 1.74 (d, J = 10.1 Hz, 2H), 1.51 (s, 9H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.51 (s, 1H), 7.38 (d, J = 8.9 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 4.63 (br s, 1H) , 4.35 (br s, 2H), 3.62 (s, 3H), 2.88 (br s, 2H), 2.73 (d, J = 11.3 Hz, 2H), 1.74 (d, J = 10.1 Hz, 2H), 1.51 ( s, 9H)
LC/MS: 460.1 (M+Na)LC/MS: 460.1 (M+Na)
단계 D: 6-브로모-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step D: Preparation of 6-bromo-1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTKR2023007091-appb-img-000037
Figure PCTKR2023007091-appb-img-000037
터트-부틸 4-(7-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-카르복실레이트 (1.0 g, 2.28 mmol)를 이용하여 제조예 1의 단계 D와 유사한 방법으로 표제 화합물 (691 mg)을 얻었다.Tert-Butyl 4-(7-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1-carboxylate (1.0 g , 2.28 mmol) to obtain the title compound (691 mg) in a similar manner to Step D of Preparation Example 1.
LC/MS: 338.1 (M+H)LC/MS: 338.1 (M+H)
제조예 8: 2-클로로-5-(1,1-다이플루오로에틸)피리미딘의 제조Preparation Example 8: Preparation of 2-chloro-5-(1,1-difluoroethyl)pyrimidine
Figure PCTKR2023007091-appb-img-000038
Figure PCTKR2023007091-appb-img-000038
1-(2-클로로피리미딘-5-일)에탄-1-온 (100 mg, 0.64 mmol)을 DCM (7 mL)에 녹인 후 -78℃에서 DAST (0.42 mL, 3.19 mmol)를 가하였다. 이후 반응 혼합물의 온도를 천천히 상온까지 올려주며 20 시간 교반하였다. 이후 DCM으로 혼합물을 묽힌 뒤 포화 NaHCO3 수용액을 이용하여 추출한 다음 유기층을 무수 MgSO4로 건조하고 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (40 mg)을 얻었다.1-(2-Chloropyrimidin-5-yl)ethan-1-one (100 mg, 0.64 mmol) was dissolved in DCM (7 mL), and then DAST (0.42 mL, 3.19 mmol) was added at -78°C. Afterwards, the temperature of the reaction mixture was slowly raised to room temperature and stirred for 20 hours. Afterwards, the mixture was diluted with DCM and extracted using a saturated aqueous NaHCO 3 solution. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The residue was purified by MPLC to give the title compound (40 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.78 (s, 2H), 2.01 (t, J = 18.3 Hz, 3H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.78 (s, 2H), 2.01 (t, J = 18.3 Hz, 3H)
제조예 9: 2-클로로-N-메틸피리미딘-5-설폰아마이드의 제조Preparation Example 9: Preparation of 2-chloro-N-methylpyrimidine-5-sulfonamide
Figure PCTKR2023007091-appb-img-000039
Figure PCTKR2023007091-appb-img-000039
2-클로로피리미딘-5-설포닐 클로라이드 (250 mg, 1.174 mmol)를 THF에 녹인 후 -78℃에서 DIPEA (0.615 ml, 3.52 mmol)와 메탄아민 (0.880 mL, 1.760 mmol)을 서서히 가하였다. 같은 온도에서 1시간 교반 해준 후 물을 넣어 주어 반응을 종결시켰다. 반응 혼합물을 EtOAc로 추출해 준 후 유기층을 무수 MgSO4로 건조하고 감압증류한 뒤 잔류물을 MPLC로 정제하여 표제 화합물 (126 mg)을 얻었다.2-Chloropyrimidine-5-sulfonyl chloride (250 mg, 1.174 mmol) was dissolved in THF, and then DIPEA (0.615 ml, 3.52 mmol) and methanamine (0.880 mL, 1.760 mmol) were slowly added at -78°C. After stirring at the same temperature for 1 hour, water was added to terminate the reaction. The reaction mixture was extracted with EtOAc, the organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure, and the residue was purified by MPLC to obtain the title compound (126 mg).
1H-NMR (400 MHz, CHLOROFORM-D) δ 9.01 (s, 2H), 4.51-4.74 (1H), 2.79 (d, J = 5.0 Hz, 3H)1H-NMR (400 MHz, CHLOROFORM-D) δ 9.01 (s, 2H), 4.51-4.74 (1H), 2.79 (d, J = 5.0 Hz, 3H)
제조예 10: 2-클로로-N-(사이클로프로필메틸)피리미딘-5-설폰아마이드의 제조Preparation Example 10: Preparation of 2-chloro-N-(cyclopropylmethyl)pyrimidine-5-sulfonamide
Figure PCTKR2023007091-appb-img-000040
Figure PCTKR2023007091-appb-img-000040
2-클로로피리미딘-5-설포닐 클로라이드 (250 mg, 1.174 mmol)와 사이클로프로필메탄아민 (125 mg, 1.760 mmol)을 이용하여 제조예 9와 유사한 방법으로 표제 화합물 (140 mg)을 얻었다.The title compound (140 mg) was obtained in a similar manner to Preparation Example 9 using 2-chloropyrimidine-5-sulfonyl chloride (250 mg, 1.174 mmol) and cyclopropylmethanamine (125 mg, 1.760 mmol).
1H-NMR (400 MHz, CHLOROFORM-D) δ 9.01 (d, J = 4.1 Hz, 2H), 4.80 (s, 1H), 2.96 (dd, J = 6.9, 5.0 Hz, 2H), 0.94-0.89 (m, 1H), 0.56-0.51 (m, 2H), 0.17 (q, J = 5.2 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 9.01 (d, J = 4.1 Hz, 2H), 4.80 (s, 1H), 2.96 (dd, J = 6.9, 5.0 Hz, 2H), 0.94-0.89 (m , 1H), 0.56-0.51 (m, 2H), 0.17 (q, J = 5.2 Hz, 2H)
실시예 1: 1-메틸-4-(1-(4-(트라이플루오로메톡시)벤질)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 1: 1-Methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (1 Preparation of -methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000041
Figure PCTKR2023007091-appb-img-000041
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (20 mg, 0.08 mmol)을 DCM (0.5 mL)에 녹인 후 4-(트라이플루오로메톡시)벤즈알데하이드 (17.17 mg, 0.090 mmol)와 아세트산(5.17 μl, 0.090 mmol)을 첨가한 뒤 30 분 동안 상온에서 교반하였다. 이후 소듐 트라이아세톡시보로하이드라이드 (57 mg, 0.27 mmol)를 가한 뒤 상온에서 16 시간 교반하였다. 반응혼합물을 DCM으로 묽힌 뒤 포화 NaHCO3 수용액을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조한 뒤 감압증류하여 농축하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (5 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (20 mg, 0.08 mmol) obtained in Preparation Example 1 was dissolved in DCM (0.5 mL). After dissolving in 4-(trifluoromethoxy)benzaldehyde (17.17 mg, 0.090 mmol) and acetic acid (5.17 μl, 0.090 mmol) were added and stirred at room temperature for 30 minutes. Afterwards, sodium triacetoxyborohydride (57 mg, 0.27 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM and extracted using a saturated aqueous NaHCO 3 solution. The organic layer was dried over anhydrous MgSO 4 and concentrated by distillation under reduced pressure. The residue was purified by MPLC to give the title compound (5 mg).
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.55 (t, J = 3.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2H), 7.26-7.36 (m, 3H), 7.18 (d, J = 7.8 Hz, 2H), 4.73 (br s, 1H), 3.65 (s, 3H), 3.58 (s, 2H), 3.05 (d, J = 11.9 Hz, 2H), 2.89 (qd, J = 12.3, 3.7 Hz, 2H), 2.21 (t, J = 10.7 Hz, 2H), 1.75-1.72 (m, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 7.55 (t, J = 3.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2H), 7.26-7.36 (m, 3H), 7.18 (d, J = 7.8 Hz, 2H), 4.73 (br s, 1H), 3.65 (s, 3H), 3.58 (s, 2H), 3.05 (d, J = 11.9 Hz, 2H), 2.89 (qd, J = 12.3, 3.7 Hz, 2H), 2.21 (t, J = 10.7 Hz, 2H), 1.75-1.72 (m, 2H)
LC/MS: 434.1 (M+H)LC/MS: 434.1 (M+H)
실시예 2: 1-(1-(3-클로로벤질)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(3-chlorobenzyl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 2: 1-(1-(3-chlorobenzyl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione (1-(1-( Preparation of 3-chlorobenzyl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000042
Figure PCTKR2023007091-appb-img-000042
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (20 mg, 0.08 mmol)과 3-클로로벤즈알데하이드 (12.69 mg, 0.09 mmol)를 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (7 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (20 mg, 0.08 mmol) and 3-chlorobenzaldehyde obtained in Preparation Example 1 The title compound (7 mg) was obtained in a similar manner to Example 1 using (12.69 mg, 0.09 mmol).
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.57 (br s, 1H), 7.38 (br s, 1H), 7.25-7.29 (m, 6H), 4.74 (br s, 1H), 3.65 (s, 3H), 3.56 (s, 2H), 3.05 (d, J = 11.4 Hz, 2H), 2.93-2.85 (m, 2H), 2.22 (t, J = 11.4 Hz, 2H), 1.73 (d, J = 11.9 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 7.57 (br s, 1H), 7.38 (br s, 1H), 7.25-7.29 (m, 6H), 4.74 (br s, 1H), 3.65 (s, 3H) ), 3.56 (s, 2H), 3.05 (d, J = 11.4 Hz, 2H), 2.93-2.85 (m, 2H), 2.22 (t, J = 11.4 Hz, 2H), 1.73 (d, J = 11.9 Hz) , 2H)
LC/MS: 384.2 (M+H)LC/MS: 384.2 (M+H)
실시예 3: 1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 3: 1-Methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (1 Preparation of -methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000043
Figure PCTKR2023007091-appb-img-000043
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (30 mg, 0.11 mmol)과 DIPEA (0.035 mL, 0.199 mmol)을 DCM (1 mL)에 녹인 후 4-(트라이플루오로메톡시)벤조일 클로라이드 (20 mg, 0.09 mmol)를 상온에서 가한 뒤 반응 혼합물을 1 시간 동안 상온에서 교반하였다. 혼합물을 DCM으로 묽힌 뒤 brine을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조한 뒤 감압 증류하여 농축하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (29 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (30 mg, 0.11 mmol) obtained in Preparation Example 1 and DIPEA (0.035 mL, 0.199 mmol) was dissolved in DCM (1 mL), 4-(trifluoromethoxy)benzoyl chloride (20 mg, 0.09 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with DCM and extracted using brine. The organic layer was dried over anhydrous MgSO 4 and concentrated by distillation under reduced pressure. The residue was purified by MPLC to give the title compound (29 mg).
1H-NMR (400 MHz, DMSO-D6) δ 7.86 (d, J = 7.8 Hz, 2H), 7.78-7.76 (m, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.43 (q, J = 3.2 Hz, 1H), 7.29 (q, J = 3.2 Hz, 2H), 4.84 (br s, 1H), 4.64 (d, J = 11.0 Hz, 2H), 3.58 (d, J = 9.1 Hz, 1H), 3.52 (s, 3H), 3.01 (d, J = 12.8 Hz, 1H), 2.64 (t, J = 11.0 Hz, 2H), 1.85-1.69 (m, 2H)1H-NMR (400 MHz, DMSO-D6) δ 7.86 (d, J = 7.8 Hz, 2H), 7.78-7.76 (m, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.43 (q, J = 3.2 Hz, 1H), 7.29 (q, J = 3.2 Hz, 2H), 4.84 (br s, 1H), 4.64 (d, J = 11.0 Hz, 2H), 3.58 (d, J = 9.1 Hz, 1H) , 3.52 (s, 3H), 3.01 (d, J = 12.8 Hz, 1H), 2.64 (t, J = 11.0 Hz, 2H), 1.85-1.69 (m, 2H)
LC/MS: 448.1 (M+H)LC/MS: 448.1 (M+H)
실시예 4: 2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbonitrile)의 제조Example 4: 2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- Preparation of carbonitrile (2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbonitrile)
Figure PCTKR2023007091-appb-img-000044
Figure PCTKR2023007091-appb-img-000044
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (30 mg, 0.11 mmol)과 DIPEA (0.035 mL, 0.199 mmol)을 IPA (1 mL)에 녹인 후 2-클로로피리미딘-5-카르보나이트릴 (48 mg, 0.35 mmol)을 상온에서 가하였다. 반응 혼합물을 70℃로 가열한 뒤 6시간동안 교반하였다. 반응 혼합물을 상온으로 식히고 EtOAc로 묽혔다. 이후 혼합물을 30 분 동안 교반한 뒤 여과하여 표제 화합물 (35 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (30 mg, 0.11 mmol) obtained in Preparation Example 1 and DIPEA (0.035 mL, 0.199 mmol) was dissolved in IPA (1 mL), and then 2-chloropyrimidine-5-carbonitrile (48 mg, 0.35 mmol) was added at room temperature. The reaction mixture was heated to 70°C and stirred for 6 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The mixture was then stirred for 30 minutes and then filtered to obtain the title compound (35 mg).
1H-NMR (500 MHz, DMSO-D6) δ 8.79 (s, 2H), 7.78 (d, J = 7.3 Hz, 1H), 7.43 (d, J = 6.7 Hz, 1H), 7.30 (d, J = 6.1 Hz, 2H), 4.88 (d, J = 12.8 Hz, 3H), 3.52 (s, 3H), 3.26 (t, J = 12.7 Hz, 2H), 2.60 (q, J = 11.4 Hz, 2H), 1.85 (d, J = 12.2 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.79 (s, 2H), 7.78 (d, J = 7.3 Hz, 1H), 7.43 (d, J = 6.7 Hz, 1H), 7.30 (d, J = 6.1 Hz, 2H), 4.88 (d, J = 12.8 Hz, 3H), 3.52 (s, 3H), 3.26 (t, J = 12.7 Hz, 2H), 2.60 (q, J = 11.4 Hz, 2H), 1.85 ( d, J = 12.2 Hz, 2H)
LC/MS: 363.1 (M+H)LC/MS: 363.1 (M+H)
실시예 5: 1-(1-(5-((다이메틸아미노)메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 5: 1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2 ,3-dione (1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione) manufacturing
Figure PCTKR2023007091-appb-img-000045
Figure PCTKR2023007091-appb-img-000045
단계 A: 2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르발데히드의 제조Step A: 2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-car Preparation of valdehyde
Figure PCTKR2023007091-appb-img-000046
Figure PCTKR2023007091-appb-img-000046
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (100 mg, 0.39 mmol)과 2-클로로피리미딘-5-카르발데히드 (86 mg, 0.602 mmol)를 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (90 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (100 mg, 0.39 mmol) and 2-chloropyrimidine obtained in Preparation Example 1 The title compound (90 mg) was obtained in a similar manner to Example 4 using -5-carbaldehyde (86 mg, 0.602 mmol).
LC/MS: 366.1 (M+H)LC/MS: 366.1 (M+H)
단계 B: 1-(1-(5-((다이메틸아미노)메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step B: 1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2, Preparation of 3-dione
Figure PCTKR2023007091-appb-img-000047
Figure PCTKR2023007091-appb-img-000047
2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르발데히드 (35 mg, 0.10 mmol)와 2 M 다이메틸아민 용액 in THF (0.239 mL, 0.479 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (28 mg)을 얻었다.2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbaldehyde ( The title compound (28 mg) was obtained in a similar manner to Example 1 using 35 mg, 0.10 mmol) and 2 M dimethylamine solution in THF (0.239 mL, 0.479 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.28 (d, J = 12.5 Hz, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.22-7.29 (m, 3H), 5.02 (d, J = 13.1 Hz, 2H), 4.93 (br s, 1H), 3.65 (s, 3H), 3.30 (s, 2H), 3.03 (t, J = 12.8 Hz, 2H), 2.83 (q, J = 11.4 Hz, 2H), 2.26 (s, 6H), 1.87 (d, J = 12.8 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.28 (d, J = 12.5 Hz, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.22-7.29 (m, 3H), 5.02 (d, J = 13.1 Hz, 2H), 4.93 (br s, 1H), 3.65 (s, 3H), 3.30 (s, 2H), 3.03 (t, J = 12.8 Hz, 2H), 2.83 (q, J = 11.4 Hz, 2H), 2.26 (s, 6H), 1.87 (d, J = 12.8 Hz, 2H)
LC/MS: 395.2 (M+H)LC/MS: 395.2 (M+H)
실시예 6: 1-메틸-4-(1-(5-((4-메틸피페라진-1-일)메틸)피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-methyl-4-(1-(5-((4-methylpiperazin-1-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 6: 1-Methyl-4-(1-(5-((4-methylpiperazin-1-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-1,4- Dihydroquinoxaline-2,3-dione (1-methyl-4-(1-(5-((4-methylpiperazin-1-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-1 Manufacture of ,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000048
Figure PCTKR2023007091-appb-img-000048
실시예 5의 단계 A에서 수득한 2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르발데히드 (40 mg, 0.11 mmol)와 1-메틸피페라진 (43.9 mg, 0.44 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (35 mg)을 얻었다.2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) obtained in Step A of Example 5 The title compound (35 mg) was obtained in a similar manner to Example 1 using pyrimidine-5-carbaldehyde (40 mg, 0.11 mmol) and 1-methylpiperazine (43.9 mg, 0.44 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.27 (s, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.26-7.34 (m, 3H), 5.02 (d, J = 13.1 Hz, 2H), 4.91 (br s, 1H), 3.65 (s, 3H), 3.36 (s, 2H), 3.02 (t, J = 12.8 Hz, 2H), 2.83 (dd, J = 22.3, 11.9 Hz, 2H), 2.50 (br s, 7H), 2.31 (s, 3H), 1.69-2.00 (m, 3H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.27 (s, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.26-7.34 (m, 3H), 5.02 (d, J = 13.1 Hz, 2H) ), 4.91 (br s, 1H), 3.65 (s, 3H), 3.36 (s, 2H), 3.02 (t, J = 12.8 Hz, 2H), 2.83 (dd, J = 22.3, 11.9 Hz, 2H), 2.50 (br s, 7H), 2.31 (s, 3H), 1.69-2.00 (m, 3H)
LC/MS: 450.3 (M+H)LC/MS: 450.3 (M+H)
실시예 7: 6-클로로-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (6-chloro-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 7: 6-Chloro-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3- Preparation of dione (6-chloro-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000049
Figure PCTKR2023007091-appb-img-000049
제조예 2에서 수득한 6-클로로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (40 mg, 0.14 mmol)을 이용하여 실시예 3과 유사한 방법으로 표제 화합물 (48 mg)을 얻었다.Using 6-chloro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (40 mg, 0.14 mmol) obtained in Preparation Example 2 The title compound (48 mg) was obtained in a similar manner to Example 3.
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.53 (d, J = 7.6 Hz, 2H), 7.33 (d, J = 8.9 Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.16-7.25 (m, 2H), 4.97 (br s, 1H), 4.73 (br s, 2H), 4.00 (br s, 1H), 3.66 (d, J = 25.3 Hz, 3H), 3.17-3.12 (m, 1H), 2.87 (d, J = 10.7 Hz, 2H), 1.89 (d, J = 25.0 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.53 (d, J = 7.6 Hz, 2H), 7.33 (d, J = 8.9 Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.16- 7.25 (m, 2H), 4.97 (br s, 1H), 4.73 (br s, 2H), 4.00 (br s, 1H), 3.66 (d, J = 25.3 Hz, 3H), 3.17-3.12 (m, 1H) ), 2.87 (d, J = 10.7 Hz, 2H), 1.89 (d, J = 25.0 Hz, 2H)
LC/MS: 482.1 (M+H), 504.1 (M+Na)LC/MS: 482.1 (M+H), 504.1 (M+Na)
실시예 8: 6-클로로-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤질)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (6-chloro-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 8: 6-Chloro-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3- Preparation of dione (6-chloro-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000050
Figure PCTKR2023007091-appb-img-000050
제조예 2에서 수득한 6-클로로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (40 mg, 0.14 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (48 mg)을 얻었다.Using 6-chloro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (40 mg, 0.14 mmol) obtained in Preparation Example 2 The title compound (48 mg) was obtained in a similar manner to Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.47 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.22-7.16 (m, 4H), 4.70 (br s, 1H), 3.62 (s, 3H), 3.57 (s, 2H), 3.04 (d, J = 11.0 Hz, 2H), 2.82 (q, J = 12.2 Hz, 2H), 2.20 (t, J = 11.6 Hz, 2H), 1.72 (d, J = 12.5 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.47 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.22-7.16 (m, 4H), 4.70 (br s, 1H), 3.62 (s, 3H), 3.57 (s, 2H), 3.04 (d, J = 11.0 Hz, 2H), 2.82 (q, J = 12.2 Hz, 2H), 2.20 (t, J = 11.6 Hz, 2H), 1.72 (d, J = 12.5 Hz, 2H)
LC/MS: 468.1 (M+H)LC/MS: 468.1 (M+H)
실시예 9: 2-(4-(6-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (2-(4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbonitrile)의 제조Example 9: 2-(4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri Midine-5-carbonitrile (2-(4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 Manufacture of -carbonitrile)
Figure PCTKR2023007091-appb-img-000051
Figure PCTKR2023007091-appb-img-000051
제조예 2에서 수득한 6-클로로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (100 mg, 0.14 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (81 mg)을 얻었다.Using 6-chloro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (100 mg, 0.14 mmol) obtained in Preparation Example 2 The title compound (81 mg) was obtained in a similar manner to Example 4.
1H-NMR (500 MHz, DMSO-D6) δ 8.79 (d, J = 4.9 Hz, 3H), 7.78 (d, J = 9.2 Hz, 1H), 7.48 (s, 1H), 7.31 (d, J = 8.9 Hz, 1H), 4.75-4.94 (m, 3H), 3.50 (s, 3H), 3.24 (t, J = 13.0 Hz, 2H), 2.53-2.66 (m, 2H), 1.84 (d, J = 11.9 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.79 (d, J = 4.9 Hz, 3H), 7.78 (d, J = 9.2 Hz, 1H), 7.48 (s, 1H), 7.31 (d, J = 8.9 Hz, 1H), 4.75-4.94 (m, 3H), 3.50 (s, 3H), 3.24 (t, J = 13.0 Hz, 2H), 2.53-2.66 (m, 2H), 1.84 (d, J = 11.9 Hz) , 2H)
LC/MS: 397.1 (M+H), 419.1 (M+Na)LC/MS: 397.1 (M+H), 419.1 (M+Na)
실시예 10: 6-클로로-1-(1-(5-(하이드록시메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (6-chloro-1-(1-(5-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 10: 6-Chloro-1-(1-(5-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline- 2,3-dione (6-chloro-1-(1-(5-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione )Manufacture of
Figure PCTKR2023007091-appb-img-000052
Figure PCTKR2023007091-appb-img-000052
제조예 2에서 수득한 6-클로로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (1.0 g, 2.73 mmol)과 (2-클로로피리미딘-5-일)메탄올 (1.97 g, 13.64 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (905 mg)을 얻었다.6-Chloro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (1.0 g, 2.73 mmol) obtained in Preparation Example 2 and ( The title compound (905 mg) was obtained in a similar manner to Example 4 using 2-chloropyrimidin-5-yl)methanol (1.97 g, 13.64 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.34 (s, 2H), 7.76 (d, J = 8.9 Hz, 1H), 7.48 (s, 1H), 7.31 (d, J = 8.9 Hz, 1H), 5.09 (t, J = 5.0 Hz, 1H), 4.80 (t, J = 13.7 Hz, 3H), 4.35 (d, J = 4.9 Hz, 2H), 3.50 (s, 3H), 3.09 (t, J = 12.8 Hz, 2H), 2.53-2.59 (m, 2H), 1.75 (d, J = 11.9 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.34 (s, 2H), 7.76 (d, J = 8.9 Hz, 1H), 7.48 (s, 1H), 7.31 (d, J = 8.9 Hz, 1H), 5.09 (t, J = 5.0 Hz, 1H), 4.80 (t, J = 13.7 Hz, 3H), 4.35 (d, J = 4.9 Hz, 2H), 3.50 (s, 3H), 3.09 (t, J = 12.8 Hz, 2H), 2.53-2.59 (m, 2H), 1.75 (d, J = 11.9 Hz, 2H)
LC/MS: 402.1 (M+H)LC/MS: 402.1 (M+H)
실시예 11: 6-클로로-1-(1-(5-((다이메틸아미노)메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (6-chloro-1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 11: 6-Chloro-1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydro Quinoxaline-2,3-dione (6-chloro-1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline Preparation of -2,3-dione)
Figure PCTKR2023007091-appb-img-000053
Figure PCTKR2023007091-appb-img-000053
단계 A: 2-(4-(6-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르발데히드의 제조Step A: 2-(4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine -Manufacture of 5-carbaldehyde
Figure PCTKR2023007091-appb-img-000054
Figure PCTKR2023007091-appb-img-000054
제조예 2에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (1.0 g, 2.73 mmol)을 이용하여 실시예 5의 단계 A와 유사한 방법으로 표제 화합물 (450 mg)을 얻었다.Example 5 using 1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (1.0 g, 2.73 mmol) obtained in Preparation Example 2 The title compound (450 mg) was obtained in a manner similar to step A of .
LC/MS: 400.1 (M+H), 422.1 (M+Na)LC/MS: 400.1 (M+H), 422.1 (M+Na)
단계 B: 6-클로로-1-(1-(5-((다이메틸아미노)메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step B: 6-Chloro-1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoc Preparation of saline-2,3-dione
Figure PCTKR2023007091-appb-img-000055
Figure PCTKR2023007091-appb-img-000055
단계 A에서 수득한 2-(4-(6-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르발데히드 (50 mg, 0.13 mmol)을 이용하여 실시예 5의 단계 B와 같은 방법을 이용하여 표제 화합물 (28 mg)을 얻었다.2-(4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) obtained in Step A The title compound (28 mg) was obtained using the same method as Step B of Example 5 using pyrimidine-5-carbaldehyde (50 mg, 0.13 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.26 (d, J = 5.2 Hz, 2H), 7.38 (d, J = 9.2 Hz, 1H), 7.24 (s, 1H), 7.18 (d, J = 8.9 Hz, 1H), 5.02 (d, J = 13.1 Hz, 2H), 4.89 (s, 1H), 3.62 (s, 3H), 3.29 (s, 2H), 3.02 (t, J = 12.7 Hz, 2H), 2.77 (q, J = 12.2 Hz, 2H), 2.25 (s, 6H), 1.85 (d, J = 12.2 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.26 (d, J = 5.2 Hz, 2H), 7.38 (d, J = 9.2 Hz, 1H), 7.24 (s, 1H), 7.18 (d, J = 8.9 Hz, 1H), 5.02 (d, J = 13.1 Hz, 2H), 4.89 (s, 1H), 3.62 (s, 3H), 3.29 (s, 2H), 3.02 (t, J = 12.7 Hz, 2H), 2.77 (q, J = 12.2 Hz, 2H), 2.25 (s, 6H), 1.85 (d, J = 12.2 Hz, 2H)
LC/MS: 429.2 (M+H), 451.2 (M+Na)LC/MS: 429.2 (M+H), 451.2 (M+Na)
실시예 12: 1-메틸-4-(1-(5-(트라이플루오로메틸)피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-methyl-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 12: 1-Methyl-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Preparation of dione (1-methyl-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000056
Figure PCTKR2023007091-appb-img-000056
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.192 mmol)과 2-클로로-5-(트라이플루오로메틸)피리미딘 (165 mg, 0.90 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (41 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.192 mmol) and 2-chloro-5 obtained in Preparation Example 1 The title compound (41 mg) was obtained in a similar manner to Example 4 using -(trifluoromethyl)pyrimidine (165 mg, 0.90 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.74 (s, 2H), 7.78 (d, J = 6.1 Hz, 1H), 7.43 (d, J = 6.1 Hz, 1H), 7.30 (d, J = 6.4 Hz, 2H), 4.89 (d, J = 11.9 Hz, 3H), 3.52 (s, 3H), 3.24 (t, J = 12.8 Hz, 2H), 2.64-2.57 (m, 2H), 1.83 (d, J = 12.2 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.74 (s, 2H), 7.78 (d, J = 6.1 Hz, 1H), 7.43 (d, J = 6.1 Hz, 1H), 7.30 (d, J = 6.4) Hz, 2H), 4.89 (d, J = 11.9 Hz, 3H), 3.52 (s, 3H), 3.24 (t, J = 12.8 Hz, 2H), 2.64-2.57 (m, 2H), 1.83 (d, J) = 12.2 Hz, 2H)
LC/MS: 406.1 (M+H), 428.1 (M+Na)LC/MS: 406.1 (M+H), 428.1 (M+Na)
실시예 13: 2-(4-(7-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (2-(4-(7-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbonitrile)의 제조Example 13: 2-(4-(7-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri Midine-5-carbonitrile (2-(4-(7-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 Manufacture of -carbonitrile)
Figure PCTKR2023007091-appb-img-000057
Figure PCTKR2023007091-appb-img-000057
제조예 3에서 수득한 6-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (500 mg, 1.70 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (476 mg)을 얻었다.Using 6-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (500 mg, 1.70 mmol) obtained in Preparation Example 3 The title compound (476 mg) was obtained in a similar manner to Example 4.
1H-NMR (500 MHz, DMSO-D6) δ 8.79 (s, 2H), 7.87 (s, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 4.86 (br s, 1H), 4.83 (br s, 2H), 3.49 (s, 3H), 3.33-3.22 (m, 2H), 2.61-2.54 (m, 2H), 1.84 (d, J = 12.5 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.79 (s, 2H), 7.87 (s, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 4.86 (br s, 1H), 4.83 (br s, 2H), 3.49 (s, 3H), 3.33-3.22 (m, 2H), 2.61-2.54 (m, 2H), 1.84 (d, J = 12.5 Hz, 2H)
LC/MS: 397.1 (M+H), 419.1 (M+Na)LC/MS: 397.1 (M+H), 419.1 (M+Na)
실시예 14: 6-클로로-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 14: 6-Chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3- Preparation of dione (6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000058
Figure PCTKR2023007091-appb-img-000058
제조예 3에서 수득한 6-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (100 mg, 0.34 mmol)을 이용하여 실시예 3과 유사한 방법으로 표제 화합물 (122 mg)을 얻었다.Using 6-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (100 mg, 0.34 mmol) obtained in Preparation Example 3 The title compound (122 mg) was obtained in a similar manner to Example 3.
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.56 (d, J = 7.9 Hz, 2H), 7.39 (s, 1H), 7.31-7.27 (m, 3H), 7.22 (d, J = 8.5 Hz, 1H), 5.00 (br s, 1H), 4.64 (br s, 1H), 4.00 (br s, 1H), 3.66 (s, 3H), 3.19 (br s, 2H), 2.92 (d, J = 11.9 Hz, 2H), 1.93-1.83 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.56 (d, J = 7.9 Hz, 2H), 7.39 (s, 1H), 7.31-7.27 (m, 3H), 7.22 (d, J = 8.5 Hz, 1H ), 5.00 (br s, 1H), 4.64 (br s, 1H), 4.00 (br s, 1H), 3.66 (s, 3H), 3.19 (br s, 2H), 2.92 (d, J = 11.9 Hz, 2H), 1.93-1.83 (m, 2H)
LC/MS: 482.1 (M+H)LC/MS: 482.1 (M+H)
실시예 15: 6-클로로-4-(1-(5-((다이메틸아미노)메틸)피리미딘-2-일)피페리딘-4-일)-1-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (6-chloro-4-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-1-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 15: 6-Chloro-4-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-1-methyl-1,4-dihydro Quinoxaline-2,3-dione (6-chloro-4-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-1-methyl-1,4-dihydroquinoxaline Preparation of -2,3-dione)
Figure PCTKR2023007091-appb-img-000059
Figure PCTKR2023007091-appb-img-000059
단계 A: 2-(4-(7-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르발데히드의 제조Step A: 2-(4-(7-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine -Manufacture of 5-carbaldehyde
Figure PCTKR2023007091-appb-img-000060
Figure PCTKR2023007091-appb-img-000060
제조예 3에서 수득한 6-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (500 mg, 1.70 mmol)을 이용하여 실시예 5의 단계 A와 유사한 방법으로 표제 화합물 (290 mg)을 얻었다.Using 6-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (500 mg, 1.70 mmol) obtained in Preparation Example 3 The title compound (290 mg) was obtained in a similar manner to Step A of Example 5.
1H-NMR (500 MHz, DMSO-D6) δ 9.79 (s, 1H), 8.83 (s, 2H), 7.88 (s, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 4.94 (d, J = 11.9 Hz, 2H), 4.85 (br s, 1H), 3.49 (s, 3H), 3.31-3.22 (m, 2H), 2.59 (d, J = 11.3 Hz, 2H), 1.85 (d, J = 11.9 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 9.79 (s, 1H), 8.83 (s, 2H), 7.88 (s, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 4.94 (d, J = 11.9 Hz, 2H), 4.85 (br s, 1H), 3.49 (s, 3H), 3.31-3.22 (m, 2H), 2.59 (d, J = 11.3 Hz, 2H), 1.85 (d, J = 11.9 Hz, 2H)
LC/MS: 400.1 (M+H)LC/MS: 400.1 (M+H)
단계 B: 6-클로로-4-(1-(5-((다이메틸아미노)메틸)피리미딘-2-일)피페리딘-4-일)-1-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step B: 6-Chloro-4-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-1-methyl-1,4-dihydroquinoc Preparation of saline-2,3-dione
Figure PCTKR2023007091-appb-img-000061
Figure PCTKR2023007091-appb-img-000061
단계 A에서 수득한 2-(4-(7-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르발데히드 (50 mg, 0.13 mmol)를 이용하여 실시예 5의 단계 B와 유사한 방법으로 표제 화합물 (18 mg)을 얻었다.2-(4-(7-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) obtained in Step A The title compound (18 mg) was obtained in a similar manner to Step B of Example 5 using pyrimidine-5-carbaldehyde (50 mg, 0.13 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.30 (d, J = 4.9 Hz, 2H), 7.41 (s, 1H), 7.25 (d, J = 8.9 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 5.04 (d, J = 13.1 Hz, 2H), 4.80 (br s, 1H), 3.64 (s, 3H), 3.32 (s, 2H), 3.06 (t, J = 12.8 Hz, 2H), 2.83 (q, J = 11.3 Hz, 2H), 2.27 (s, 6H), 1.87 (d, J = 12.5 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.30 (d, J = 4.9 Hz, 2H), 7.41 (s, 1H), 7.25 (d, J = 8.9 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 5.04 (d, J = 13.1 Hz, 2H), 4.80 (br s, 1H), 3.64 (s, 3H), 3.32 (s, 2H), 3.06 (t, J = 12.8 Hz, 2H) , 2.83 (q, J = 11.3 Hz, 2H), 2.27 (s, 6H), 1.87 (d, J = 12.5 Hz, 2H)
LC/MS: 429.1 (M+H)LC/MS: 429.1 (M+H)
실시예 16: 6-클로로-4-(1-(3-클로로벤질)피페리딘-4-일)-1-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (6-chloro-4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 16: 6-Chloro-4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydroquinoxaline-2,3-dione (6- Preparation of chloro-4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000062
Figure PCTKR2023007091-appb-img-000062
제조예 3에서 수득한 6-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.17 mmol)과 3-클로로벤즈알데하이드 (0.046 mL, 0.409 mmol)를 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (48 mg)을 얻었다.6-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.17 mmol) obtained in Preparation Example 3 and 3 -The title compound (48 mg) was obtained in a similar manner to Example 1 using chlorobenzaldehyde (0.046 mL, 0.409 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.52 (s, 1H), 7.40 (s, 1H), 7.25 (d, J = 9.2 Hz, 2H), 7.31-7.23 (d, J = 8.5 Hz, 1H), 4.59 (s, 1H), 3.65 (s, 3H), 3.59 (s, 2H), 3.07 (d, J = 11.3 Hz, 2H), 2.93-2.86 (m, 2H), 2.25 (t, J = 11.6 Hz, 2H), 1.75 (d, J = 11.6 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.52 (s, 1H), 7.40 (s, 1H), 7.25 (d, J = 9.2 Hz, 2H), 7.31-7.23 (d, J = 8.5 Hz, 1H ), 4.59 (s, 1H), 3.65 (s, 3H), 3.59 (s, 2H), 3.07 (d, J = 11.3 Hz, 2H), 2.93-2.86 (m, 2H), 2.25 (t, J = 11.6 Hz, 2H), 1.75 (d, J = 11.6 Hz, 2H)
LC/MS: 418.1 (M+H)LC/MS: 418.1 (M+H)
실시예 17: 6-클로로-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤질)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 17: 6-Chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3- Preparation of dione (6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000063
Figure PCTKR2023007091-appb-img-000063
제조예 3에서 수득한 6-클로로-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.17 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (47 mg)을 얻었다.Using 6-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.17 mmol) obtained in Preparation Example 3 The title compound (47 mg) was obtained in a similar manner to Example 1.
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.51 (s, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.22-7.18 (m, 3H), 4.59 (s, 1H), 3.65 (s, 3H), 3.60 (s, 2H), 3.07 (d, J = 11.3 Hz, 2H), 2.92-2.85 (m, 2H), 2.24 (t, J = 11.7 Hz, 2H), 1.74 (d, J = 12.2 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.51 (s, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.22-7.18 (m, 3H), 4.59 (s, 1H), 3.65 (s) , 3H), 3.60 (s, 2H), 3.07 (d, J = 11.3 Hz, 2H), 2.92-2.85 (m, 2H), 2.24 (t, J = 11.7 Hz, 2H), 1.74 (d, J = 12.2 Hz, 2H)
LC/MS: 468.1 (M+H)LC/MS: 468.1 (M+H)
실시예 18: 2-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbonitrile)의 제조Example 18: 2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Pyrimidine-5-carbonitrile (2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine- Manufacture of 5-carbonitrile)
Figure PCTKR2023007091-appb-img-000064
Figure PCTKR2023007091-appb-img-000064
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.18 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (33 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.18 mmol) obtained in Preparation Example 4 The title compound (33 mg) was obtained in a similar manner to Example 4.
1H-NMR (500 MHz, DMSO-D6) δ 8.79 (d, J = 1.1 Hz, 2H), 7.81-7.78 (m, 1H), 7.35 (d, J = 10.7 Hz, 1H), 7.13 (t, J = 8.4 Hz, 1H), 4.87 (d, J = 12.5 Hz, 3H), 3.49 (s, 3H), 3.24 (t, J = 13.0 Hz, 2H), 2.57 (q, J = 11.5 Hz, 2H), 1.84 (d, J = 12.2 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.79 (d, J = 1.1 Hz, 2H), 7.81-7.78 (m, 1H), 7.35 (d, J = 10.7 Hz, 1H), 7.13 (t, J = 8.4 Hz, 1H), 4.87 (d, J = 12.5 Hz, 3H), 3.49 (s, 3H), 3.24 (t, J = 13.0 Hz, 2H), 2.57 (q, J = 11.5 Hz, 2H), 1.84 (d, J = 12.2 Hz, 2H)
LC/MS: 381.1 (M+H), 403.1 (M+Na)LC/MS: 381.1 (M+H), 403.1 (M+Na)
실시예 19: 6-플루오로-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (6-fluoro-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 19: 6-Fluoro-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Preparation of dione (6-fluoro-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000065
Figure PCTKR2023007091-appb-img-000065
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.18 mmol)을 이용하여 실시예 3과 유사한 방법으로 표제 화합물 (72 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.18 mmol) obtained in Preparation Example 4 The title compound (72 mg) was obtained in a similar manner to Example 3.
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.54-7.46 (m, 2H), 7.34 (q, J = 4.7 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.00-6.96 (m, 2H), 4.97 (br s, 2H), 4.68 (br s, 1H), 3.61 (s, 3H), 3.15 (br s, 2H), 2.91-2.85 (m, 2H), 1.85 (br s, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 7.54-7.46 (m, 2H), 7.34 (q, J = 4.7 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.00-6.96 (m , 2H), 4.97 (br s, 2H), 4.68 (br s, 1H), 3.61 (s, 3H), 3.15 (br s, 2H), 2.91-2.85 (m, 2H), 1.85 (br s, 2H) )
LC/MS: 466.1 (M+H)LC/MS: 466.1 (M+H)
실시예 20: 6-플루오로-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤질)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (6-fluoro-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 20: 6-Fluoro-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Preparation of dione (6-fluoro-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000066
Figure PCTKR2023007091-appb-img-000066
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.18 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (60 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.18 mmol) obtained in Preparation Example 4 The title compound (60 mg) was obtained in a similar manner to Example 1.
1H-NMR (400 MHz, CHLOROFORM-D) d 7.49 (q, J = 5.0 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 6.98-6.93 (m, 2H), 4.70 (br s, 1H), 3.60 (s, 3H), 3.56 (s, 2H), 3.03 (d, J = 11.9 Hz, 2H), 2.82 (dd, J = 12.3, 3.7 Hz, 2H), 2.22-2.16 (m, 2H), 1.72 (d, J = 9.6 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) d 7.49 (q, J = 5.0 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 6.98- 6.93 (m, 2H), 4.70 (br s, 1H), 3.60 (s, 3H), 3.56 (s, 2H), 3.03 (d, J = 11.9 Hz, 2H), 2.82 (dd, J = 12.3, 3.7 Hz, 2H), 2.22-2.16 (m, 2H), 1.72 (d, J = 9.6 Hz, 2H)
LC/MS: 452.1 (M+H)LC/MS: 452.1 (M+H)
실시예 21: 2-(4-(6-메톡시-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (2-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbonitrile)의 제조Example 21: 2-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Pyrimidine-5-carbonitrile (2-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine- Manufacture of 5-carbonitrile)
Figure PCTKR2023007091-appb-img-000067
Figure PCTKR2023007091-appb-img-000067
제조예 5에서 수득한 6-메톡시-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.17 mmol)를 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (38 mg)을 얻었다.6-methoxy-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.17 mmol) obtained in Preparation Example 5 The title compound (38 mg) was obtained in a similar manner to Example 4.
1H-NMR (500 MHz, DMSO-D6) δ 8.79 (s, 2H), 7.70 (d, J = 9.2 Hz, 1H), 6.93 (s, 1H), 6.87 (d, J = 9.2 Hz, 1H), 4.87 (d, J = 12.5 Hz, 3H), 3.84 (s, 3H), 3.51 (s, 3H), 3.24 (t, J = 12.7 Hz, 2H), 2.59 (d, J = 11.6 Hz, 2H), 1.82 (d, J = 12.2 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.79 (s, 2H), 7.70 (d, J = 9.2 Hz, 1H), 6.93 (s, 1H), 6.87 (d, J = 9.2 Hz, 1H), 4.87 (d, J = 12.5 Hz, 3H), 3.84 (s, 3H), 3.51 (s, 3H), 3.24 (t, J = 12.7 Hz, 2H), 2.59 (d, J = 11.6 Hz, 2H), 1.82 (d, J = 12.2 Hz, 2H)
LC/MS: 393.1 (M+H), 415.1 (M+Na)LC/MS: 393.1 (M+H), 415.1 (M+Na)
실시예 22: 6-메톡시-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (6-methoxy-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 22: 6-methoxy-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Preparation of dione (6-methoxy-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000068
Figure PCTKR2023007091-appb-img-000068
제조예 5에서 수득한 6-메톡시-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.17 mmol)을 이용하여 실시예 3과 유사한 방법으로 표제 화합물 (65 mg)을 얻었다.6-methoxy-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.17 mmol) obtained in Preparation Example 5 The title compound (65 mg) was obtained in a similar manner to Example 3.
1H-NMR (400 MHz, CHLOROFORM-D) d 7.53-7.51 (m, 2H), 7.31 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 10.5 Hz, 2H), 6.79 (dd, J = 11.9, 2.7 Hz, 2H), 4.96 (br s, 2H), 4.72 (br s, 1H), 3.86 (s, 3H), 3.61 (s, 3H), 3.20 (br s, 2H), 2.88 (d, J = 8.7 Hz, 2H), 1.87 (br s, 2H)1H-NMR (400 MHz, CHLOROFORM-D) d 7.53-7.51 (m, 2H), 7.31 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 10.5 Hz, 2H), 6.79 (dd, J = 11.9, 2.7 Hz, 2H), 4.96 (br s, 2H), 4.72 (br s, 1H), 3.86 (s, 3H), 3.61 (s, 3H), 3.20 (br s, 2H), 2.88 (d , J = 8.7 Hz, 2H), 1.87 (br s, 2H)
LC/MS: 478.1 (M+H)LC/MS: 478.1 (M+H)
실시예 23: 6-메톡시-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤질)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (6-methoxy-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 23: 6-methoxy-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Preparation of dione (6-methoxy-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000069
Figure PCTKR2023007091-appb-img-000069
제조예 5에서 수득한 6-메톡시-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.17 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (62 mg)을 얻었다.6-methoxy-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.17 mmol) obtained in Preparation Example 5 The title compound (62 mg) was obtained in a similar manner to Example 1.
1H-NMR (400 MHz, CHLOROFORM-D) d 7.47 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H),7.17 (d, J = 8.2 Hz, 2H), 6.77 (td, J = 9.1, 2.7 Hz, 2H), 4.72 (br s, 1H), 3.85 (s, 3H), 3.60 (s, 3H), 3.56 (s, 2H), 3.02 (d, J = 11.9 Hz, 2H), 2.83 (td, J = 12.3, 8.7 Hz, 2H), 2.19 (t, J = 11.7 Hz, 2H), 1.71 (d, J = 9.6 Hz, 2H) 1H-NMR (400 MHz, CHLOROFORM-D) d 7.47 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 6.77 ( td, J = 9.1, 2.7 Hz, 2H), 4.72 (br s, 1H), 3.85 (s, 3H), 3.60 (s, 3H), 3.56 (s, 2H), 3.02 (d, J = 11.9 Hz, 2H), 2.83 (td, J = 12.3, 8.7 Hz, 2H), 2.19 (t, J = 11.7 Hz, 2H), 1.71 (d, J = 9.6 Hz, 2H)
LC/MS: 486.2 (M+Na)LC/MS: 486.2 (M+Na)
실시예 24: N-메틸-2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-설폰아마이드 (N-methyl-2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-sulfonamide)의 제조Example 24: N-methyl-2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri Midine-5-sulfonamide (N-methyl-2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- Manufacture of sulfonamide)
Figure PCTKR2023007091-appb-img-000070
Figure PCTKR2023007091-appb-img-000070
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (70 mg, 0.237 mmol)과 제조예 8에서 수득한 2-클로로-5-(1,1-다이플루오로에틸)피리미딘 (59.2 mg, 0.285 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (53 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (70 mg, 0.237 mmol) obtained in Preparation Example 1 and Preparation Example 8 The title compound (53 mg) was obtained in a similar manner to Example 4 using 2-chloro-5-(1,1-difluoroethyl)pyrimidine (59.2 mg, 0.285 mmol).
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.66 (s, 2H), 8.18 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 5.67 (s, 1H), 5.08 (d, J = 13.3 Hz, 2H), 4.32 (d, J = 5.5 Hz, 1H), 3.60 (s, 3H), 3.10 (dd, J = 13.0, 10.7 Hz, 2H), 2.86 (dd, J = 12.3, 4.1 Hz, 2H), 2.72 (d, J = 5.0 Hz, 3H), 1.79 (d, J = 10.1 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.66 (s, 2H), 8.18 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 5.67 (s, 1H), 5.08 (d, J = 13.3 Hz, 2H), 4.32 (d, J = 5.5 Hz, 1H), 3.60 (s, 3H), 3.10 (dd, J = 13.0, 10.7 Hz, 2H), 2.86 (dd, J = 12.3, 4.1 Hz, 2H), 2.72 (d, J = 5.0 Hz, 3H), 1.79 (d, J = 10.1 Hz, 2H)
LC/MS: 466 (M+Na)LC/MS: 466 (M+Na)
실시예 25: 1-메틸-4-(1-(5-메틸피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-methyl-4-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 25: 1-Methyl-4-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (1 Preparation of -methyl-4-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000071
Figure PCTKR2023007091-appb-img-000071
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.19 mmol)과 2-클로로-5-메틸피리미딘 (74 mg, 0.58 mmol)을 2-프로판올 (2 mL)에 녹인 뒤 DIPEA (0.10 mL, 0.58 mmol)를 상온에서 가하였다. 반응 혼합물을 70℃로 가열한 뒤 18 시간 동안 교반하였다. 반응 혼합물을 상온에서 식힌 후 감압 증류하여 농축한 다음 15% MeOH in DCM 용액과 brine을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조하고 감압증류하였다. 농축된 잔류물을 MPLC로 정제하여 표제 화합물 (48 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.19 mmol) and 2-chloro-5 obtained in Preparation Example 1 -Methylpyrimidine (74 mg, 0.58 mmol) was dissolved in 2-propanol (2 mL), and then DIPEA (0.10 mL, 0.58 mmol) was added at room temperature. The reaction mixture was heated to 70°C and stirred for 18 hours. The reaction mixture was cooled to room temperature, concentrated by distillation under reduced pressure, and then extracted using a 15% MeOH in DCM solution and brine. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The concentrated residue was purified by MPLC to obtain the title compound (48 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (s, 2H), 7.49 (d, J = 7.9 Hz, 1H), 7.26-7.24 (m, 3H), 4.98 (d, J = 12.8 Hz, 3H), 3.67 (s, 3H), 3.03 (t, J = 12.8 Hz, 2H), 2.88-2.81 (m, 2H), 2.17 (s, 3H), 1.87 (d, J = 12.5 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (s, 2H), 7.49 (d, J = 7.9 Hz, 1H), 7.26-7.24 (m, 3H), 4.98 (d, J = 12.8 Hz, 3H) ), 3.67 (s, 3H), 3.03 (t, J = 12.8 Hz, 2H), 2.88-2.81 (m, 2H), 2.17 (s, 3H), 1.87 (d, J = 12.5 Hz, 2H)
LC/MS: 352.2 (M+H), 374.1 (M+Na)LC/MS: 352.2 (M+H), 374.1 (M+Na)
실시예 26: 1-(1-(5-클로로피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 26: 1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione (1 -Manufacture of (1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000072
Figure PCTKR2023007091-appb-img-000072
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.19 mmol)과 2,5-다이클로로피리미딘 (86 mg, 0.58 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (67 mg)을 얻었다.1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.19 mmol) and 2,5-dione obtained in Preparation Example 1 The title compound (67 mg) was obtained in a similar manner to Example 4 using chloropyrimidine (86 mg, 0.58 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.28 (s, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.28-7.24 (m, 3H), 4.98 (d, J = 12.8 Hz, 2H), 4.91 (br s, 1H), 3.68 (s, 3H), 3.06 (t, J = 12.8 Hz, 2H), 2.84 (dd, J = 22.3, 12.2 Hz, 2H), 1.89 (d, J = 12.5 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.28 (s, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.28-7.24 (m, 3H), 4.98 (d, J = 12.8 Hz, 2H) ), 4.91 (br s, 1H), 3.68 (s, 3H), 3.06 (t, J = 12.8 Hz, 2H), 2.84 (dd, J = 22.3, 12.2 Hz, 2H), 1.89 (d, J = 12.5 Hz, 2H)
LC/MS: 372.1 (M+H)LC/MS: 372.1 (M+H)
실시예 27: 1-(1-(5-메톡시피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 27: 1-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione ( Preparation of 1-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000073
Figure PCTKR2023007091-appb-img-000073
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.19 mmol)과 2-클로로-5-메톡시피리미딘 (84 mg, 0.58 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (6 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.19 mmol) and 2-chloro-5 obtained in Preparation Example 1 The title compound (6 mg) was obtained in a similar manner to Example 4 using -methoxypyrimidine (84 mg, 0.58 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.12 (s, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.16-7.26 (m, 3H), 4.89 (d, J = 12.8 Hz, 3H), 3.83 (s, 3H), 3.65 (s, 3H), 3.01 (t, J = 12.7 Hz, 2H), 2.83 (d, J = 12.2 Hz, 2H), 1.84 (d, J = 12.2 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.12 (s, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.16-7.26 (m, 3H), 4.89 (d, J = 12.8 Hz, 3H) ), 3.83 (s, 3H), 3.65 (s, 3H), 3.01 (t, J = 12.7 Hz, 2H), 2.83 (d, J = 12.2 Hz, 2H), 1.84 (d, J = 12.2 Hz, 2H) )
LC/MS: 368.1 (M+H)LC/MS: 368.1 (M+H)
실시예 28: 1-(1-(5-(하이드록시메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 28: 1-(1-(5-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3- Preparation of dione (1-(1-(5-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000074
Figure PCTKR2023007091-appb-img-000074
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.19 mmol)과 (2-클로로피리미딘-5-일)메탄올 (502 mg, 3.47 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (349 mg)을 얻었다.1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.19 mmol) obtained in Preparation Example 1 and (2-chloropyri) The title compound (349 mg) was obtained in a similar manner to Example 4 using midin-5-yl)methanol (502 mg, 3.47 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.35 (s, 2H), 7.76 (d, J = 7.0 Hz, 1H), 7.43 (d, J = 4.6 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 5.09 (t, J = 5.5 Hz, 1H), 4.82 (d, J = 12.2 Hz, 3H), 4.35 (d, J = 5.5 Hz, 2H), 3.52 (s, 3H), 3.11 (t, J = 12.7 Hz, 2H), 2.58 (d, J = 9.8 Hz, 2H), 1.75 (d, J = 11.9 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.35 (s, 2H), 7.76 (d, J = 7.0 Hz, 1H), 7.43 (d, J = 4.6 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 5.09 (t, J = 5.5 Hz, 1H), 4.82 (d, J = 12.2 Hz, 3H), 4.35 (d, J = 5.5 Hz, 2H), 3.52 (s, 3H), 3.11 ( t, J = 12.7 Hz, 2H), 2.58 (d, J = 9.8 Hz, 2H), 1.75 (d, J = 11.9 Hz, 2H)
LC/MS: 390.1 (M+Na)LC/MS: 390.1 (M+Na)
실시예 29: 2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르복시산 (2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carboxylic acid)의 제조Example 29: 2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- Preparation of carboxylic acid (2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carboxylic acid)
Figure PCTKR2023007091-appb-img-000075
Figure PCTKR2023007091-appb-img-000075
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (300 mg, 1.16 mmol)과 2-클로로피리미딘-5-카르복시산 (550 mg, 3.47 mmol)을 2-프로판올 (12 mL)에 녹인 후 DIPEA (0.61 mL)를 상온에서 가한 뒤 반응 혼합물을 70℃로 가열하여 18 시간 동안 교반하였다. 반응 혼합물을 상온에서 식힌 후 감압 증류하여 농축한 다음 30% MeOH in DCM (v/v) 용액으로 묽혔다. 묽힌 혼합물에 1 N HCl 수용액을 가하여 pH 1~2까지 산성으로 만든 뒤 brine을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조하고 감압증류하였다. 농축된 잔류물을 MPLC로 정제하여 표제 화합물 (51 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (300 mg, 1.16 mmol) and 2-chloropyrimidine obtained in Preparation Example 1 -5-Carboxylic acid (550 mg, 3.47 mmol) was dissolved in 2-propanol (12 mL), then DIPEA (0.61 mL) was added at room temperature, and the reaction mixture was heated to 70°C and stirred for 18 hours. The reaction mixture was cooled at room temperature, concentrated by distillation under reduced pressure, and then diluted with 30% MeOH in DCM (v/v) solution. A 1 N HCl aqueous solution was added to the diluted mixture to make it acidic to pH 1-2 and then extracted using brine. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The concentrated residue was purified by MPLC to obtain the title compound (51 mg).
1H-NMR (500 MHz, DMSO-D6) δ 12.83 (br s, 1H), 8.80 (s, 2H), 7.77 (s, 1H), 7.43 (d, J = 4.6 Hz, 1H), 7.29 (d, J = 7.3 Hz, 2H), 4.92 (d, J = 12.5 Hz, 3H), 3.51 (s, 3H), 3.22 (t, J = 12.7 Hz, 2H), 2.60 (q, J = 22.4, 12.1 Hz, 2H), 1.82 (d, J = 11.6 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 12.83 (br s, 1H), 8.80 (s, 2H), 7.77 (s, 1H), 7.43 (d, J = 4.6 Hz, 1H), 7.29 (d, J = 7.3 Hz, 2H), 4.92 (d, J = 12.5 Hz, 3H), 3.51 (s, 3H), 3.22 (t, J = 12.7 Hz, 2H), 2.60 (q, J = 22.4, 12.1 Hz, 2H), 1.82 (d, J = 11.6 Hz, 2H)
LC/MS: 382.0 (M+H)LC/MS: 382.0 (M+H)
실시예 30: 1-(1-(5-아세틸피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-acetylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 30: 1-(1-(5-acetylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione (1 -Manufacture of (1-(5-acetylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000076
Figure PCTKR2023007091-appb-img-000076
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.19 mmol)과 1-(2-클로로피리미딘-5-일)에탄-1-온 (91 mg, 0.58 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (59 mg)을 얻었다.1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.19 mmol) obtained in Preparation Example 1 and 1-(2- The title compound (59 mg) was obtained in a similar manner to Example 4 using chloropyrimidin-5-yl)ethan-1-one (91 mg, 0.58 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.87 (s, 2H), 7.44 (d, J = 7.9 Hz, 1H), 7.18-7.27 (m, 3H), 5.18 (d, J = 13.1 Hz, 2H), 4.91 (br s, 1H), 3.66 (s, 3H), 3.12 (t, J = 13.0 Hz, 2H), 2.85 (d, J = 11.6 Hz, 2H), 2.50 (s, 3H), 1.92 (d, J = 13.1 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.87 (s, 2H), 7.44 (d, J = 7.9 Hz, 1H), 7.18-7.27 (m, 3H), 5.18 (d, J = 13.1 Hz, 2H) ), 4.91 (br s, 1H), 3.66 (s, 3H), 3.12 (t, J = 13.0 Hz, 2H), 2.85 (d, J = 11.6 Hz, 2H), 2.50 (s, 3H), 1.92 ( d, J = 13.1 Hz, 2H)
LC/MS: 380.2 (M+H), 402.1 (M+Na)LC/MS: 380.2 (M+H), 402.1 (M+Na)
실시예 31: 1-메틸-4-(1-(피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-methyl-4-(1-(pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 31: 1-methyl-4-(1-(pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (1-methyl- Preparation of 4-(1-(pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000077
Figure PCTKR2023007091-appb-img-000077
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.19 mmol)과 2-클로로피리미딘 (66.3 mg, 0.578 mmol)을 이용하여 실시예 25와 유사한 방법으로 표제 화합물 (60 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.19 mmol) and 2-chloropyrimidine obtained in Preparation Example 1 The title compound (60 mg) was obtained in a similar manner to Example 25 using (66.3 mg, 0.578 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.34 (d, J = 4.9 Hz, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.24-7.19 (m, 3H), 6.53 (t, J = 4.7 Hz, 1H), 5.03 (d, J = 12.8 Hz, 2H), 4.95 (br s, 1H), 3.65 (s, 3H), 3.03 (t, J = 12.7 Hz, 2H), 2.86-2.79 (m, 2H), 1.87 (d, J = 12.2 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.34 (d, J = 4.9 Hz, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.24-7.19 (m, 3H), 6.53 (t, J = 4.7 Hz, 1H), 5.03 (d, J = 12.8 Hz, 2H), 4.95 (br s, 1H), 3.65 (s, 3H), 3.03 (t, J = 12.7 Hz, 2H), 2.86-2.79 ( m, 2H), 1.87 (d, J = 12.2 Hz, 2H)
LC/MS: 338.1 (M+H), 360.1 (M+Na)LC/MS: 338.1 (M+H), 360.1 (M+Na)
실시예 32: 1-(1-(5-에틸피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 32: 1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione (1 -Manufacture of (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000078
Figure PCTKR2023007091-appb-img-000078
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.19 mmol)과 2-클로로-5-에틸피리미딘 (0.07 mL, 0.58 mmol)을 이용하여 실시예 25와 유사한 방법으로 표제 화합물 (68 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.19 mmol) and 2-chloro-5 obtained in Preparation Example 1 The title compound (68 mg) was obtained in a similar manner to Example 25 using -ethylpyrimidine (0.07 mL, 0.58 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (s, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.28-7.21 (m, 3H), 4.99-4.93 (m, 3H), 3.65 (s, 3H), 3.02 (t, J = 12.8 Hz, 2H), 2.86-2.81 (m, 2H), 2.50 (q, J = 7.3 Hz, 2H), 1.86 (d, J = 13.4 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (s, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.28-7.21 (m, 3H), 4.99-4.93 (m, 3H), 3.65 (s, 3H), 3.02 (t, J = 12.8 Hz, 2H), 2.86-2.81 (m, 2H), 2.50 (q, J = 7.3 Hz, 2H), 1.86 (d, J = 13.4 Hz, 2H) , 1.22 (t, J = 7.6 Hz, 3H)
LC/MS: 366.2 (M+H), 388.1 (M+Na)LC/MS: 366.2 (M+H), 388.1 (M+Na)
실시예 33: 2-(4-(6-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (2-(4-(6-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbonitrile)의 제조Example 33: 2-(4-(6-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Pyrimidine-5-carbonitrile (2-(4-(6-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine- Manufacture of 5-carbonitrile)
Figure PCTKR2023007091-appb-img-000079
Figure PCTKR2023007091-appb-img-000079
제조예 5에서 수득한 6-브로모-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (200 mg, 0.59 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (210 mg)을 얻었다.6-Bromo-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (200 mg, 0.59 mmol) obtained in Preparation Example 5 The title compound (210 mg) was obtained in a similar manner to Example 4.
1H-NMR (500 MHz, DMSO-D6) δ 8.79 (s, 2H), 7.73 (d, J = 9.2 Hz, 1H), 7.58 (s, 1H), 7.43 (d, J = 8.9 Hz, 1H), 4.87 (d, J = 12.5 Hz, 3H), 3.50 (s, 3H), 3.24 (t, J = 12.7 Hz, 2H), 2.56 (d, J = 11.6 Hz, 2H), 1.83 (d, J = 12.5 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.79 (s, 2H), 7.73 (d, J = 9.2 Hz, 1H), 7.58 (s, 1H), 7.43 (d, J = 8.9 Hz, 1H), 4.87 (d, J = 12.5 Hz, 3H), 3.50 (s, 3H), 3.24 (t, J = 12.7 Hz, 2H), 2.56 (d, J = 11.6 Hz, 2H), 1.83 (d, J = 12.5 Hz, 2H)
LC/MS: 441.1 (M+H)LC/MS: 441.1 (M+H)
실시예 34: 2-(4-(7-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (2-(4-(7-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbonitrile)의 제조Example 34: 2-(4-(7-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Pyrimidine-5-carbonitrile (2-(4-(7-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine- Manufacture of 5-carbonitrile)
Figure PCTKR2023007091-appb-img-000080
Figure PCTKR2023007091-appb-img-000080
제조예 6에서 수득한 6-브로모-1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (200 mg, 0.59 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (240 mg)을 얻었다.6-Bromo-1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (200 mg, 0.59 mmol) obtained in Preparation Example 6 The title compound (240 mg) was obtained in a similar manner to Example 4.
1H-NMR (500 MHz, DMSO-D6) δ 8.79 (s, 2H), 7.96 (s, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 4.84 (d, J = 11.9 Hz, 3H), 3.48 (s, 3H), 3.29 (d, J = 12.5 Hz, 2H), 2.56 (d, J = 12.5 Hz, 2H), 1.83 (d, J = 11.9 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.79 (s, 2H), 7.96 (s, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 4.84 (d, J = 11.9 Hz, 3H), 3.48 (s, 3H), 3.29 (d, J = 12.5 Hz, 2H), 2.56 (d, J = 12.5 Hz, 2H), 1.83 (d, J = 11.9 Hz, 2H)
LC/MS: 441.1 (M+H)LC/MS: 441.1 (M+H)
실시예 35: 1-(1-(5-시아노피리미딘-2-일)피페리딘-4-일)-4-메틸-2,3-다이옥소-1,2,3,4-테트라하이드로퀴녹살린-6-카르보나이트릴 (1-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile)의 제조Example 35: 1-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-4-methyl-2,3-dioxo-1,2,3,4-tetra Hydroquinoxaline-6-carbonitrile (1-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline Preparation of -6-carbonitrile)
Figure PCTKR2023007091-appb-img-000081
Figure PCTKR2023007091-appb-img-000081
실시예 33에서 수득한 2-(4-(6-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (50 mg, 0.11 mmol), 징크 다이시아나이드(zinc dicyanide) (14 mg, 0.12 mmol)와 테트라키스(트라이페닐포스핀)팔라듐(0) (39.3 mg, 0.034 mmol)을 무수 DMF (1 mL)에 녹인 후 질소 풍선을 이용하여 반응 혼합물을 질소 기체로 15 분 동안 퍼징시켜 주었다. 이후 반응 혼합물을 100℃로 18 시간 동안 교반하였다. 반응 혼합물을 상온으로 식힌 뒤 감압 증류하여 농축하였다. 농축된 혼합물을 30% MeOH in DCM 용액으로 묽힌 뒤 포화 NaHCO3 수용액을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조하고 감압증류하였다. 농축된 잔류물을 MPLC로 정제하여 표제 화합물 (8 mg)을 얻었다.2-(4-(6-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1- obtained in Example 33 1) pyrimidine-5-carbonitrile (50 mg, 0.11 mmol), zinc dicyanide (14 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (0) (39.3 mg, 0.034 mmol) was dissolved in anhydrous DMF (1 mL), and the reaction mixture was purged with nitrogen gas for 15 minutes using a nitrogen balloon. The reaction mixture was then stirred at 100°C for 18 hours. The reaction mixture was cooled to room temperature and concentrated by distillation under reduced pressure. The concentrated mixture was diluted with 30% MeOH in DCM solution and extracted using saturated NaHCO 3 aqueous solution. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The concentrated residue was purified by MPLC to obtain the title compound (8 mg).
1H-NMR (500 MHz, DMSO-D6) δ 8.78 (s, 2H), 7.83-7.99 (m, 2H), 7.72 (d, J = 8.5 Hz, 1H), 4.86 (d, J = 11.6 Hz, 3H), 3.50 (d, J = 10.4 Hz, 3H), 3.24 (t, J = 12.5 Hz, 2H), 2.53-2.64 (m, 2H), 1.84 (d, J = 11.3 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.78 (s, 2H), 7.83-7.99 (m, 2H), 7.72 (d, J = 8.5 Hz, 1H), 4.86 (d, J = 11.6 Hz, 3H) ), 3.50 (d, J = 10.4 Hz, 3H), 3.24 (t, J = 12.5 Hz, 2H), 2.53-2.64 (m, 2H), 1.84 (d, J = 11.3 Hz, 2H)
LC/MS: 410.1 (M+Na)LC/MS: 410.1 (M+Na)
실시예 36: 4-(1-(5-시아노피리미딘-2-일)피페리딘-4-일)-1-메틸-2,3-다이옥소-1,2,3,4-테트라하이드로퀴녹살린-6-카르보나이트릴 (4-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile)의 제조Example 36: 4-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetra Hydroquinoxaline-6-carbonitrile (4-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline Preparation of -6-carbonitrile)
Figure PCTKR2023007091-appb-img-000082
Figure PCTKR2023007091-appb-img-000082
실시예 34에서 수득한 2-(4-(7-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (50 mg, 0.11 mmol)을 이용하여 실시예 35와 유사한 방법으로 표제 화합물 (26 mg)을 얻었다.2-(4-(7-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1- obtained in Example 34 1) The title compound (26 mg) was obtained in a similar manner to Example 35 using pyrimidine-5-carbonitrile (50 mg, 0.11 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.79 (s, 2H), 8.31 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 4.86 (d, J = 12.2 Hz, 3H), 3.52 (s, 3H), 3.31-3.26 (m, 2H), 2.52-2.63 (m, 2H), 1.86 (d, J = 11.3 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.79 (s, 2H), 8.31 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 4.86 (d, J = 12.2 Hz, 3H), 3.52 (s, 3H), 3.31-3.26 (m, 2H), 2.52-2.63 (m, 2H), 1.86 (d, J = 11.3 Hz, 2H)
LC/MS: 410.1 (M+Na)LC/MS: 410.1 (M+Na)
실시예 37: 2-(4-(6-아세틸-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (2-(4-(6-acetyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbonitrile)의 제조Example 37: 2-(4-(6-acetyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri Midine-5-carbonitrile (2-(4-(6-acetyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 Manufacture of -carbonitrile)
Figure PCTKR2023007091-appb-img-000083
Figure PCTKR2023007091-appb-img-000083
실시예 33에서 수득한 2-(4-(6-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (50 mg, 0.11 mmol)과 트라이부틸(1-에톡시비닐)스탄난(tributyl(1-ethoxyvinyl)stannane) (61 mg, 0.17 mmol)과 테트라키스(트라이페닐포스핀)팔라듐(0) (39.3 mg, 0.034 mmol)을 무수 DMF (1 mL)에 녹인 후 질소 풍선을 이용하여 반응 혼합물을 질소 기체로 15 분 동안 퍼징시켜 주었다. 이후 반응 혼합물을 100℃로 18 시간 동안 교반하였다. 반응 혼합물을 상온으로 식힌 뒤 감압 증류하여 농축하였다. 농축된 혼합물을 30% MeOH in DCM 용액으로 묽히고 1 N HCl 수용액 (1 mL)을 가한 뒤 1 시간 동안 상온에서 교반하였다. 이후 혼합물을 포화 NaHCO3 수용액을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조하고 감압증류하였다. 농축된 잔류물을 MPLC로 정제하여 표제 화합물 (8 mg)을 얻었다.2-(4-(6-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1- obtained in Example 33 1) pyrimidine-5-carbonitrile (50 mg, 0.11 mmol) and tributyl (1-ethoxyvinyl) stannane (61 mg, 0.17 mmol) and tetrakis (tri Phenylphosphine)palladium(0) (39.3 mg, 0.034 mmol) was dissolved in anhydrous DMF (1 mL), and the reaction mixture was purged with nitrogen gas for 15 minutes using a nitrogen balloon. The reaction mixture was then stirred at 100°C for 18 hours. The reaction mixture was cooled to room temperature and concentrated by distillation under reduced pressure. The concentrated mixture was diluted with 30% MeOH in DCM solution, 1 N HCl aqueous solution (1 mL) was added, and stirred at room temperature for 1 hour. The mixture was then extracted using saturated aqueous NaHCO 3 solution. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The concentrated residue was purified by MPLC to obtain the title compound (8 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.54 (s, 2H), 7.90 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 5.13 (d, J = 13.1 Hz, 2H), 4.90 (br s, 1H), 3.72 (s, 3H), 3.12 (t, J = 12.5 Hz, 2H), 2.84 (t, J = 10.8 Hz, 2H), 2.65 (s, 3H), 1.94 (d, J = 11.6 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.54 (s, 2H), 7.90 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 5.13 (d, J = 13.1 Hz, 2H), 4.90 (br s, 1H), 3.72 (s, 3H), 3.12 (t, J = 12.5 Hz, 2H), 2.84 (t, J = 10.8 Hz, 2H) , 2.65 (s, 3H), 1.94 (d, J = 11.6 Hz, 2H)
LC/MS: 405. 2 (M+H), 427.2 (M+Na)LC/MS: 405.2 (M+H), 427.2 (M+Na)
실시예 38: 2-(4-(7-아세틸-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (2-(4-(7-acetyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbonitrile)의 제조Example 38: 2-(4-(7-acetyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri Midine-5-carbonitrile (2-(4-(7-acetyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 Manufacture of -carbonitrile)
Figure PCTKR2023007091-appb-img-000084
Figure PCTKR2023007091-appb-img-000084
실시예 34에서 수득한 2-(4-(7-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (50 mg, 0.11 mmol)과 트라이부틸(1-에톡시비닐)스탄난 (61 mg, 0.17 mmol)을 이용하여 실시예 37과 유사한 방법으로 표제 화합물 (11 mg)을 얻었다.2-(4-(7-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1- obtained in Example 34 1) The title compound (11) was prepared in a manner similar to Example 37 using pyrimidine-5-carbonitrile (50 mg, 0.11 mmol) and tributyl (1-ethoxyvinyl) stannane (61 mg, 0.17 mmol). mg) was obtained.
1H-NMR (500 MHz, DMSO-D6) δ 8.80 (s, 2H), 8.03 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 4.98 (br s, 1H), 4.87 (d, J = 12.8 Hz, 2H), 3.54 (s, 3H), 3.35-3.43 (m, 2H), 2.63 (s, 3H), 2.53-2.61 (m, 2H), 1.88 (d, J = 11.9 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.80 (s, 2H), 8.03 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 4.98 (br s, 1H), 4.87 (d, J = 12.8 Hz, 2H), 3.54 (s, 3H), 3.35-3.43 (m, 2H), 2.63 (s, 3H), 2.53-2.61 (m, 2H) ), 1.88 (d, J = 11.9 Hz, 2H)
LC/MS: 405. 2 (M+H), 427.2 (M+Na)LC/MS: 405.2 (M+H), 427.2 (M+Na)
실시예 39: 1-(1-(5-(아제티딘-1-일메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-(azetidin-1-ylmethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 39: 1-(1-(5-(azetidin-1-ylmethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline- 2,3-dione (1-(1-(5-(azetidin-1-ylmethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione )Manufacture of
Figure PCTKR2023007091-appb-img-000085
Figure PCTKR2023007091-appb-img-000085
실시예 5의 단계 A에서 수득한 2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르발데히드 (50 mg, 0.14 mmol)와 아제티딘 (20 mg, 0.35 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (21 mg)을 얻었다.2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) obtained in Step A of Example 5 The title compound (21 mg) was obtained in a similar manner to Example 1 using pyrimidine-5-carbaldehyde (50 mg, 0.14 mmol) and azetidine (20 mg, 0.35 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.27 (d, J = 7.6 Hz, 2H), 7.46 (d, J = 7.9 Hz, 1H), 7.15-7.32 (m, 3H), 5.01 (d, J = 12.8 Hz, 2H), 4.93 (br s, 1H), 3.65 (s, 3H), 3.42 (s, 2H), 3.23 (t, J = 6.7 Hz, 4H), 3.02 (t, J = 12.8 Hz, 2H), 2.81 (q, J = 11.2 Hz, 2H), 2.13-2.07 (m, 2H), 1.86 (d, J = 12.5 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.27 (d, J = 7.6 Hz, 2H), 7.46 (d, J = 7.9 Hz, 1H), 7.15-7.32 (m, 3H), 5.01 (d, J = 12.8 Hz, 2H), 4.93 (br s, 1H), 3.65 (s, 3H), 3.42 (s, 2H), 3.23 (t, J = 6.7 Hz, 4H), 3.02 (t, J = 12.8 Hz, 2H), 2.81 (q, J = 11.2 Hz, 2H), 2.13-2.07 (m, 2H), 1.86 (d, J = 12.5 Hz, 2H)
LC/MS: 407.2 (M+H), 408.2 (M+2H)LC/MS: 407.2 (M+H), 408.2 (M+2H)
실시예 40: 1-(1-(5-((3,3-다이플루오로아제티딘-1-일)메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-((3,3-difluoroazetidin-1-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 40: 1-(1-(5-((3,3-difluoroazetidin-1-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl- 1,4-dihydroquinoxaline-2,3-dione (1-(1-(5-((3,3-difluoroazetidin-1-yl)methyl)pyrimidin-2-yl)piperidin-4-yl) Preparation of -4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000086
Figure PCTKR2023007091-appb-img-000086
실시예 5의 단계 A에서 수득한 2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르발데히드 (50 mg, 0.14 mmol)와 3,3-다이플루오로아제티딘 (35 mg, 0.38 mmol)을 이용하여 실시예 1과 유사한 방법으로 표제 화합물 (7 mg)을 얻었다.2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) obtained in Step A of Example 5 The title compound (7 mg) was obtained in a similar manner to Example 1 using pyrimidine-5-carbaldehyde (50 mg, 0.14 mmol) and 3,3-difluoroazetidine (35 mg, 0.38 mmol). .
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.27 (d, J = 4.9 Hz, 2H), 7.46 (d, J = 7.9 Hz, 1H), 7.14-7.27 (m, 3H), 5.02 (d, J = 12.8 Hz, 2H), 4.90 (br s, 1H), 3.65 (s, 3H), 3.60-3.56 (m, 6H), 3.03 (t, J = 13.0 Hz, 2H), 2.86-2.79 (m, 2H), 1.87 (d, J = 11.9 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.27 (d, J = 4.9 Hz, 2H), 7.46 (d, J = 7.9 Hz, 1H), 7.14-7.27 (m, 3H), 5.02 (d, J = 12.8 Hz, 2H), 4.90 (br s, 1H), 3.65 (s, 3H), 3.60-3.56 (m, 6H), 3.03 (t, J = 13.0 Hz, 2H), 2.86-2.79 (m, 2H) ), 1.87 (d, J = 11.9 Hz, 2H)
LC/MS: 443.2 (M+H)LC/MS: 443.2 (M+H)
실시예 41: N-메틸-N-((2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-일)메틸)아세트아마이드 (N-methyl-N-((2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidin-5-yl)methyl)acetamide)의 제조Example 41: N-methyl-N-((2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1 -yl)pyrimidin-5-yl)methyl)acetamide (N-methyl-N-((2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)- Preparation of yl)piperidin-1-yl)pyrimidin-5-yl)methyl)acetamide)
Figure PCTKR2023007091-appb-img-000087
Figure PCTKR2023007091-appb-img-000087
단계 A: 1-메틸-4-(1-(5-((메틸아미노)메틸)피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step A: 1-Methyl-4-(1-(5-((methylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Manufacture of dione
Figure PCTKR2023007091-appb-img-000088
Figure PCTKR2023007091-appb-img-000088
실시예 5의 단계 A에서 수득한 2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르발데히드 (50 mg, 0.14 mmol)와 아세트산(0.024 mL, 0.411 mmol)울 DCM (2 mL)에 녹인 뒤 2 M 메탄아민 in THF (0.342 mL, 0.684 mmol)을 상온에서 가하였다. 반응 혼합물을 30 분 동안 상온에서 교반한 뒤 소듐 트라이아세톡시보로하이드라이드 (87 mg, 0.411 mmol)를 가하였다. 이후 반응 혼합물을 6 시간 동안 교반하였다. 반응 종결 후 혼합물을 DCM을 이용하여 묽힌 후 포화 NaHCO3 수용액을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조하고 감압증류하여 농축된 잔류물을 추가 정제없이 다음 반응에 이용하였다.2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) obtained in Step A of Example 5 Pyrimidine-5-carbaldehyde (50 mg, 0.14 mmol) and acetic acid (0.024 mL, 0.411 mmol) were dissolved in DCM (2 mL) and then 2 M methanamine in THF (0.342 mL, 0.684 mmol) was added at room temperature. did. The reaction mixture was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (87 mg, 0.411 mmol) was added. The reaction mixture was then stirred for 6 hours. After completion of the reaction, the mixture was diluted with DCM and extracted with a saturated aqueous NaHCO 3 solution. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure, and the concentrated residue was used in the next reaction without further purification.
LC/MS: 381.2 (M+H)LC/MS: 381.2 (M+H)
단계 B: N-메틸-N-((2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-일)메틸)아세트아마이드의 제조Step B: N-methyl-N-((2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1- Preparation of 1) pyrimidin-5-yl) methyl) acetamide
Figure PCTKR2023007091-appb-img-000089
Figure PCTKR2023007091-appb-img-000089
단계 A에서 수득한 1-메틸-4-(1-(5-((메틸아미노)메틸)피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온이 포함된 혼합물과 아세트산 무수물 (0.026 mL, 0.27 mmol)을 이용하여 실시예 3과 유사한 방법으로 표제 화합물 (8 mg)을 얻었다.1-Methyl-4-(1-(5-((methylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2 obtained in Step A The title compound (8 mg) was obtained in a similar manner to Example 3 using a mixture containing ,3-dione and acetic anhydride (0.026 mL, 0.27 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.29 and 8.21 (s and s, 2H), 7.46 (d, J = 7.3 Hz, 1H), 7.15-7.33 (m, 3H), 5.02 (d, J = 11.9 Hz, 2H), 4.88 (br s, 1H), 4.41 and 4.37 (s and s, 2H), 3.65 and 3.49 (s and s, 3H), 3.02 (t, J = 12.1 Hz, 2H), 2.96 and 2.92 (s and s, 3H) 2.86-2.79 (m, 2H), 2.23 and 2.13 (s and s, 1H), 2.13 (s, 2H), 1.86 (d, J = 11.6 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.29 and 8.21 (s and s, 2H), 7.46 (d, J = 7.3 Hz, 1H), 7.15-7.33 (m, 3H), 5.02 (d, J = 11.9 Hz, 2H), 4.88 (br s, 1H), 4.41 and 4.37 (s and s, 2H), 3.65 and 3.49 (s and s, 3H), 3.02 (t, J = 12.1 Hz, 2H), 2.96 and 2.92 (s and s, 3H) 2.86-2.79 (m, 2H), 2.23 and 2.13 (s and s, 1H), 2.13 (s, 2H), 1.86 (d, J = 11.6 Hz, 2H)
LC/MS: 445.2 (M+Na)LC/MS: 445.2 (M+Na)
실시예 42: 1-(1-(5-(메톡시메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-(methoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 42: 1-(1-(5-(methoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3- Preparation of dione (1-(1-(5-(methoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000090
Figure PCTKR2023007091-appb-img-000090
단계 A: 1-(1-(5-(클로로메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step A: 1-(1-(5-(chloromethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione manufacture of
Figure PCTKR2023007091-appb-img-000091
Figure PCTKR2023007091-appb-img-000091
실시예 28에서 수득한 1-(1-(5-(하이드록시메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (300 mg, 0.82 mmol)을 1,2-다이클로로에탄 (10 mL)에 녹인 후 0℃에서 티오닐 클로라이드 (0.18 mL, 2.45 mmol)를 가하였다. 반응 혼합물을 80℃에서 20시간 교반하였다. 이후 혼합물을 상온으로 식힌 뒤 감압 증류하였다. 농축된 잔류물을 EtOAc로 묽힌 후 15 분간 교반한 다음 여과하여 표제 화합물 (299 mg)을 얻었다.1-(1-(5-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2, obtained in Example 28, 3-Dione (300 mg, 0.82 mmol) was dissolved in 1,2-dichloroethane (10 mL), and then thionyl chloride (0.18 mL, 2.45 mmol) was added at 0°C. The reaction mixture was stirred at 80°C for 20 hours. Afterwards, the mixture was cooled to room temperature and then distilled under reduced pressure. The concentrated residue was diluted with EtOAc, stirred for 15 minutes, and then filtered to obtain the title compound (299 mg).
1H-NMR (400 MHz, DMSO-D6) d 8.44 (s, 2H), 7.73-7.71 (m, 1H), 7.40-7.37 (m, 1H), 7.26-7.23 (m, 2H), 4.78 (d, J = 13.3 Hz, 3H), 4.68 (s, 2H), 3.47 (s, 3H), 3.14-3.08 (m, 2H), 2.54 (dd, J = 12.3, 4.1 Hz, 2H), 1.73 (d, J = 10.1 Hz, 2H)1H-NMR (400 MHz, DMSO-D6) d 8.44 (s, 2H), 7.73-7.71 (m, 1H), 7.40-7.37 (m, 1H), 7.26-7.23 (m, 2H), 4.78 (d, J = 13.3 Hz, 3H), 4.68 (s, 2H), 3.47 (s, 3H), 3.14-3.08 (m, 2H), 2.54 (dd, J = 12.3, 4.1 Hz, 2H), 1.73 (d, J = 10.1 Hz, 2H)
LC/MS: 351.1 (M-Cl+H)LC/MS: 351.1 (M-Cl+H)
단계 B: 1-(1-(5-(메톡시메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step B: 1-(1-(5-(methoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-da Preparation of ions
Figure PCTKR2023007091-appb-img-000092
Figure PCTKR2023007091-appb-img-000092
단계 A에서 수득한 1-(1-(5-(클로로메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.13 mmol)을 MeOH (1 mL)에 녹인 후 25% 소듐 메톡사이드 in MeOH (0.037 mL, 0.14 mmol)을 상온에서 가한 뒤 2 시간 동안 상온에서 교반하였다. 반응 혼합물을 농축한 뒤, EtOAc로 묽힌 후 brine을 이용하여 세척하였다. 유기층을 무수 MgSO4로 건조하고 감압증류하였다. 농축된 잔류물을 MPLC로 정제하여 표제 화합물 (35 mg)을 얻었다.1-(1-(5-(chloromethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3- obtained in Step A Dione (50 mg, 0.13 mmol) was dissolved in MeOH (1 mL), 25% sodium methoxide in MeOH (0.037 mL, 0.14 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, diluted with EtOAc, and washed with brine. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The concentrated residue was purified by MPLC to obtain the title compound (35 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.34 (s, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.18-7.35 (m, 3H), 5.05 (d, J = 13.1 Hz, 2H), 4.97 (br s, 1H), 4.32 (s, 2H), 3.67 (s, 3H), 3.39 (s, 3H), 3.06 (t, J = 12.8 Hz, 2H), 2.87-2.80 (m, 2H), 1.89 (d, J = 12.5 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.34 (s, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.18-7.35 (m, 3H), 5.05 (d, J = 13.1 Hz, 2H) ), 4.97 (br s, 1H), 4.32 (s, 2H), 3.67 (s, 3H), 3.39 (s, 3H), 3.06 (t, J = 12.8 Hz, 2H), 2.87-2.80 (m, 2H) ), 1.89 (d, J = 12.5 Hz, 2H)
LC/MS: 404.2 (M+Na), 405.1 (M+H+Na)LC/MS: 404.2 (M+Na), 405.1 (M+H+Na)
실시예 43: 1-(1-(5-(에톡시메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-(ethoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 43: 1-(1-(5-(ethoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3- Preparation of dione (1-(1-(5-(ethoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000093
Figure PCTKR2023007091-appb-img-000093
실시예 42의 단계 A에서 수득한 1-(1-(5-(클로로메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.13 mmol)과 25% 소듐 에톡사이드 in ethanol (0.047 mL, 0.14 mmol)을 실시예 42의 단계 B와 유사한 방법으로 표제 화합물 (30 mg)을 얻었다.1-(1-(5-(chloromethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline- obtained in Step A of Example 42 The title compound (30 mg) was obtained in a similar manner to Step B of Example 42 by adding 2,3-dione (50 mg, 0.13 mmol) and 25% sodium ethoxide in ethanol (0.047 mL, 0.14 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.32 (s, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.13-7.38 (m, 3H), 5.04-4.96 (m, 3H), 4.35 (s, 2H), 3.65 (s, 3H), 3.53 (q, J = 7.1 Hz, 2H), 3.04 (t, J = 12.8 Hz, 2H), 2.80 (q, J = 11.5 Hz, 2H), 1.87 (d, J = 12.5 Hz, 2H), 1.24 (t, J = 6.9 Hz, 3H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.32 (s, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.13-7.38 (m, 3H), 5.04-4.96 (m, 3H), 4.35 (s, 2H), 3.65 (s, 3H), 3.53 (q, J = 7.1 Hz, 2H), 3.04 (t, J = 12.8 Hz, 2H), 2.80 (q, J = 11.5 Hz, 2H), 1.87 (d, J = 12.5 Hz, 2H), 1.24 (t, J = 6.9 Hz, 3H)
LC/MS: 418.2 (M+Na), 419.2 (M+Na+H)LC/MS: 418.2 (M+Na), 419.2 (M+Na+H)
실시예 44: 2-(2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-일)아세토나이트릴 (2-(2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidin-5-yl)acetonitrile)의 제조Example 44: 2-(2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine -5-yl)acetonitrile (2-(2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidin-5 Preparation of -yl)acetonitrile)
Figure PCTKR2023007091-appb-img-000094
Figure PCTKR2023007091-appb-img-000094
실시예 42의 단계 A에서 수득한 1-(1-(5-(클로로메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.13 mmol)을 DMSO (1 mL)에 녹인 후 상온에서 소듐 시아나이드 (25 mg, 0.52 mmol)를 가하였다. 반응 혼합물을 70℃에서 2 시간 교반 후 상온으로 식혔다. 혼합물을 EtOAc로 묽힌 후 포화 NaHCO3 수용액을 이용하여 3회 세척하였다. 유기층을 무수 MgSO4로 건조하고 감압증류하였다. 농축된 잔류물을 MPLC로 정제하여 표제 화합물 (24 mg)을 얻었다.1-(1-(5-(chloromethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline- obtained in Step A of Example 42 2,3-Dione (50 mg, 0.13 mmol) was dissolved in DMSO (1 mL), and then sodium cyanide (25 mg, 0.52 mmol) was added at room temperature. The reaction mixture was stirred at 70°C for 2 hours and then cooled to room temperature. The mixture was diluted with EtOAc and washed three times using saturated aqueous NaHCO 3 solution. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The concentrated residue was purified by MPLC to obtain the title compound (24 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.33 (s, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.20-7.36 (m, 3H), 5.04 (d, J = 13.1 Hz, 2H), 4.94 (s, 1H), 3.68 (s, 3H), 3.61 (s, 2H), 3.07 (t, J = 12.8 Hz, 2H), 2.85 (q, J = 22.1, 11.4 Hz, 2H), 1.90 (d, J = 12.5 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.33 (s, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.20-7.36 (m, 3H), 5.04 (d, J = 13.1 Hz, 2H) ), 4.94 (s, 1H), 3.68 (s, 3H), 3.61 (s, 2H), 3.07 (t, J = 12.8 Hz, 2H), 2.85 (q, J = 22.1, 11.4 Hz, 2H), 1.90 (d, J = 12.5 Hz, 2H)
LC/MS: 377.2 (M+H), 399.1 (M+Na)LC/MS: 377.2 (M+H), 399.1 (M+Na)
실시예 45: N-(사이클로프로필메틸)-2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-설폰아마이드 (N-(cyclopropylmethyl)-2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-sulfonamide)의 제조Example 45: N-(Cyclopropylmethyl)-2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1 -yl)pyrimidine-5-sulfonamide (N-(cyclopropylmethyl)-2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1- Preparation of yl)pyrimidine-5-sulfonamide)
Figure PCTKR2023007091-appb-img-000095
Figure PCTKR2023007091-appb-img-000095
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (40 mg, 0.136 mmol)과 제조예 10에서 수득한 2-클로로-N-(사이클로프로필메틸)피리미딘-5-설폰아마이드 (40.3 mg, 0.163 mmol)를 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (28 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (40 mg, 0.136 mmol) obtained in Preparation Example 1 and Preparation Example 10 The title compound (28 mg) was obtained in a similar manner to Example 4 using 2-chloro-N-(cyclopropylmethyl)pyrimidine-5-sulfonamide (40.3 mg, 0.163 mmol).
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.66 (s, 2H), 8.17 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 5.54-5.80 (1H), 5.08 (d, J = 13.3 Hz, 2H), 4.48 (s, 1H), 3.60 (s, 3H), 3.09 (s, 2H), 2.90-2.85 (m, 4H), 1.78 (d, J = 9.1 Hz, 2H), 0.91-1.03 (1H), 0.54-0.51 (m, 2H), 0.17 (d, J = 5.5 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) δ 8.66 (s, 2H), 8.17 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 5.54-5.80 (1H), 5.08 (d, J = 13.3 Hz, 2H), 4.48 (s, 1H), 3.60 (s, 3H), 3.09 (s, 2H), 2.90-2.85 (m, 4H), 1.78 (d, J = 9.1 Hz) , 2H), 0.91-1.03 (1H), 0.54-0.51 (m, 2H), 0.17 (d, J = 5.5 Hz, 2H)
LC/MS: 506 (M+H)LC/MS: 506 (M+H)
실시예 46: 1-(1-(4-메톡시피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 46: 1-(1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione ( Preparation of 1-(1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000096
Figure PCTKR2023007091-appb-img-000096
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (80 mg, 0.19 mmol)과 2-클로로-4-메톡시피리미딘 (44.6 mg, 0.309 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (86 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (80 mg, 0.19 mmol) and 2-chloro-4 obtained in Preparation Example 1 The title compound (86 mg) was obtained in a similar manner to Example 4 using -methoxypyrimidine (44.6 mg, 0.309 mmol).
1H-NMR (400 MHz, CHLOROFORM-D) 8.10 (d, J = 6.0 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.28 (m, 1H), 7.24 (m, 2H), 6.04 (d, J = 6.0 Hz, 1H), 5.04 (m, 1H), 4.98 (m, 2H), 3.92 (s, 3H), 3.68 (s, 3H), 3.03 (m, 2H), 2.83 (m, 2H), 1.88 (m, 2H)1H-NMR (400 MHz, CHLOROFORM-D) 8.10 (d, J = 6.0 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.28 (m, 1H), 7.24 (m, 2H), 6.04 (d, J = 6.0 Hz, 1H), 5.04 (m, 1H), 4.98 (m, 2H), 3.92 (s, 3H), 3.68 (s, 3H), 3.03 (m, 2H), 2.83 (m, 2H), 1.88 (m, 2H)
실시예 47: 1-메틸-4-(1-(5-프로필피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-methyl-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 47: 1-Methyl-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (1 Preparation of -methyl-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000097
Figure PCTKR2023007091-appb-img-000097
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.19 mmol)과 2-클로로-5-프로필피리미딘 (91 mg, 0.58 mmol)을 이용하여 실시예 25와 유사한 방법으로 표제 화합물 (38 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.19 mmol) and 2-chloro-5 obtained in Preparation Example 1 The title compound (38 mg) was obtained in a similar manner to Example 25 using -propylpyrimidine (91 mg, 0.58 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (s, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.24-7.22 (m, 3H), 4.99-4.93 (m, 3H), 3.65 (s, 3H), 3.02 (t, J = 12.8 Hz, 2H), 2.83 (dd, J = 22.1, 12.1 Hz, 2H), 2.43 (t, J = 7.5 Hz, 2H), 1.86 (d, J = 12.2 Hz, 2H), 1.63-1.56 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (s, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.24-7.22 (m, 3H), 4.99-4.93 (m, 3H), 3.65 (s, 3H), 3.02 (t, J = 12.8 Hz, 2H), 2.83 (dd, J = 22.1, 12.1 Hz, 2H), 2.43 (t, J = 7.5 Hz, 2H), 1.86 (d, J = 12.2 Hz, 2H), 1.63-1.56 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H)
LC/MS: 380.2 (M+H), 381.2 (M+2H)LC/MS: 380.2 (M+H), 381.2 (M+2H)
실시예 48: 1-(1-(5-브로모피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 48: 1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione ( Preparation of 1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000098
Figure PCTKR2023007091-appb-img-000098
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (500 mg, 0.193 mmol)과 5-브로모-2-클로로피리미딘 (746 mg, 3.86 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (630 mg)을 얻었다.1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (500 mg, 0.193 mmol) obtained in Preparation Example 1 and 5-bromo- The title compound (630 mg) was obtained in a similar manner to Example 4 using 2-chloropyrimidine (746 mg, 3.86 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.49 (s, 2H), 7.76 (t, J = 3.8 Hz, 1H), 7.44-7.42 (m, 1H), 7.30-7.28 (m, 2H), 4.83 (br s, 1H), 4.74 (d, J = 13.1 Hz, 2H), 3.52 (s, 3H), 3.15 (t, J = 12.8 Hz, 2H), 2.58 (dd, J = 21.7, 11.9 Hz, 2H), 1.77 (d, J = 12.2 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.49 (s, 2H), 7.76 (t, J = 3.8 Hz, 1H), 7.44-7.42 (m, 1H), 7.30-7.28 (m, 2H), 4.83 (br s, 1H), 4.74 (d, J = 13.1 Hz, 2H), 3.52 (s, 3H), 3.15 (t, J = 12.8 Hz, 2H), 2.58 (dd, J = 21.7, 11.9 Hz, 2H) ), 1.77 (d, J = 12.2 Hz, 2H)
LC/MS: 416.1 (M+H)LC/MS: 416.1 (M+H)
실시예 49: 1-메틸-4-(1-(5-비닐피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-methyl-4-(1-(5-vinylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 49: 1-Methyl-4-(1-(5-vinylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (1 Preparation of -methyl-4-(1-(5-vinylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000099
Figure PCTKR2023007091-appb-img-000099
실시예 48에서 수득한 1-(1-(5-브로모피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.12 mmol), 포타슘 카보네이트 (49.8 mg, 0.36 mmol), 4,4,5,5-테트라메틸-2-비닐-1,3,2-다이옥사보로란 (0.11 mL, 0.60 mmol)을 1,4-다이옥산 (1.5 mL), water (1.5 mL) cosolvent에 녹인 뒤 테트라키스(트라이페닐포스핀)팔라듐(0) (13 mg, 0.012 mmol)을 가하였다. 이후 질소 풍선을 이용하여 반응 혼합물을 10 분간 질소 기체로 퍼징하였다. 혼합물을 100℃에서 20 시간 교반하였다. 반응 혼합물을 상온으로 식힌 뒤 감압 증류하여 농축하였다. 농축된 잔류물을 DCM으로 묽힌 후 brine을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조하고 감압증류하였다. 농축된 잔류물을 MPLC로 정제하여 표제 화합물 (26 mg)을 얻었다.1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-da obtained in Example 48 ion (50 mg, 0.12 mmol), potassium carbonate (49.8 mg, 0.36 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxabororane (0.11 mL, 0.60 mmol) ) was dissolved in 1,4-dioxane (1.5 mL) and water (1.5 mL) cosolvent, and then tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.012 mmol) was added. Afterwards, the reaction mixture was purged with nitrogen gas for 10 minutes using a nitrogen balloon. The mixture was stirred at 100°C for 20 hours. The reaction mixture was cooled to room temperature and concentrated by distillation under reduced pressure. The concentrated residue was diluted with DCM and extracted using brine. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The concentrated residue was purified by MPLC to obtain the title compound (26 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.42 (s, 2H), 7.48 (d, J = 7.9 Hz, 1H), 7.30-7.22 (m, 3H), 6.55 (dd, J = 17.7, 11.3 Hz, 1H), 5.65 (d, J = 17.7 Hz, 1H), 5.19 (d, J = 11.3 Hz, 1H), 5.06 (d, J = 12.8 Hz, 2H), 4.97 (br s, 1H), 3.68 (s, 3H), 3.07 (t, J = 12.7 Hz, 2H), 2.85 (q, J = 11.1 Hz, 2H), 1.90 (d, J = 12.5 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.42 (s, 2H), 7.48 (d, J = 7.9 Hz, 1H), 7.30-7.22 (m, 3H), 6.55 (dd, J = 17.7, 11.3 Hz) , 1H), 5.65 (d, J = 17.7 Hz, 1H), 5.19 (d, J = 11.3 Hz, 1H), 5.06 (d, J = 12.8 Hz, 2H), 4.97 (br s, 1H), 3.68 ( s, 3H), 3.07 (t, J = 12.7 Hz, 2H), 2.85 (q, J = 11.1 Hz, 2H), 1.90 (d, J = 12.5 Hz, 2H)
LC/MS: 364.2 (M+H)LC/MS: 364.2 (M+H)
실시예 50: 1-메틸-4-(1-(5-(2-메틸프로프-1-엔-1-일)피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-methyl-4-(1-(5-(2-methylprop-1-en-1-yl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 50: 1-Methyl-4-(1-(5-(2-methylprop-1-en-1-yl)pyrimidin-2-yl)piperidin-4-yl)-1,4 -Dihydroquinoxaline-2,3-dione (1-methyl-4-(1-(5-(2-methylprop-1-en-1-yl)pyrimidin-2-yl)piperidin-4-yl) -Manufacture of 1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000100
Figure PCTKR2023007091-appb-img-000100
실시예 48에서 수득한 1-(1-(5-브로모피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (70 mg, 0.17 mmol)과 4,4,5,5-테트라메틸-2-(2-메틸프로프-1-엔-1-일)-1,3,2-다이옥사보로란 (0.10 mL, 0.50 mmol)을 이용하여 실시예 49와 유사한 방법으로 표제 화합물 (55 mg)을 얻었다.1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-da obtained in Example 48 ion (70 mg, 0.17 mmol) and 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxabororane (0.10 The title compound (55 mg) was obtained in a similar manner to Example 49 using mL, 0.50 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.25 (s, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.27-7.22 (m, 3H), 6.01 (s, 1H), 5.01 (d, J = 13.4 Hz, 2H), 4.94 (br s, 1H), 3.65 (s, 3H), 3.04 (t, J = 12.8 Hz, 2H), 2.87-2.79 (m, 2H), 1.91 (s, 3H), 1.85 (s, 3H), 1.30-1.26 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.25 (s, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.27-7.22 (m, 3H), 6.01 (s, 1H), 5.01 (d) , J = 13.4 Hz, 2H), 4.94 (br s, 1H), 3.65 (s, 3H), 3.04 (t, J = 12.8 Hz, 2H), 2.87-2.79 (m, 2H), 1.91 (s, 3H) ), 1.85 (s, 3H), 1.30-1.26 (m, 2H)
LC/MS: 392.2 (M+H)LC/MS: 392.2 (M+H)
실시예 51: 1-(1-(5-아이소부틸피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-isobutylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 51: 1-(1-(5-isobutylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione ( Preparation of 1-(1-(5-isobutylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000101
Figure PCTKR2023007091-appb-img-000101
실시예 50에서 수득한 1-메틸-4-(1-(5-(2-메틸프로프-1-엔-1-일)피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (30 mg, 0.077 mmol)을 DCM (1 mL), MeOH (1 mL)에 녹인 후 20% 팔라듐 하이드록사이드 on carbon (5.4 mg, 7.66 μmol)을 상온에서 가하였다. 수소 풍선을 이용하여 반응 혼합물을 수소 기체로 3회 채운 뒤 상온에서 2 시간동안 교반하였다. Celite®를 이용하여 혼합물을 여과한 뒤, 감압 농축하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (11 mg)을 얻었다.1-Methyl-4-(1-(5-(2-methylprop-1-en-1-yl)pyrimidin-2-yl)piperidin-4-yl)-1 obtained in Example 50 ,4-dihydroquinoxaline-2,3-dione (30 mg, 0.077 mmol) was dissolved in DCM (1 mL) and MeOH (1 mL) and then dissolved in 20% palladium hydroxide on carbon (5.4 mg, 7.66 μmol). ) was added at room temperature. The reaction mixture was filled with hydrogen gas three times using a hydrogen balloon and stirred at room temperature for 2 hours. The mixture was filtered using Celite ® and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (11 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.16 (s, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.26-7.15 (m, 3H), 4.98 (d, J = 13.1 Hz, 2H), 4.93 (br s, 1H), 3.65 (s, 3H), 3.02 (t, J = 12.7 Hz, 2H), 2.83 (d, J = 11.6 Hz, 2H), 2.32 (d, J = 7.0 Hz, 2H), 1.87 (d, J = 12.2 Hz, 2H), 1.83-1.71 (m, 1H), 0.93 (d, J = 6.4 Hz, 6H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.16 (s, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.26-7.15 (m, 3H), 4.98 (d, J = 13.1 Hz, 2H) ), 4.93 (br s, 1H), 3.65 (s, 3H), 3.02 (t, J = 12.7 Hz, 2H), 2.83 (d, J = 11.6 Hz, 2H), 2.32 (d, J = 7.0 Hz, 2H), 1.87 (d, J = 12.2 Hz, 2H), 1.83-1.71 (m, 1H), 0.93 (d, J = 6.4 Hz, 6H)
LC/MS: 394.2 (M+H)LC/MS: 394.2 (M+H)
실시예 52: 1-(1-(5-((7-옥사-2-아자스피로[3.5]노난-2-일)메틸)피리미딘-2-일)피페리딘-4-일)-6-클로로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-((7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-6-chloro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 52: 1-(1-(5-((7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-6 -Chloro-4-methyl-1,4-dihydroquinoxaline-2,3-dione (1-(1-(5-((7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl )pyrimidin-2-yl)piperidin-4-yl)-6-chloro-4-methyl-1,4-dihydroquinoxaline-2,3-dione) Preparation
Figure PCTKR2023007091-appb-img-000102
Figure PCTKR2023007091-appb-img-000102
2-(4-(6-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르발데히드 (80 mg, 0.20 mmol)와 7-옥사-2-아자스피로[3.5]노난 하이드로클로라이드 (36 mg, 0.22 mmol)를 이용하여 실시예 5의 단계 B와 같은 방법을 이용하여 표제 화합물 (60 mg)을 얻었다.2-(4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- The title compound ( 60 mg) was obtained.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.36 (s, 1H), 8.02 (s, 1H), 7.26 (s, 1H), 7.18 (d, J = 8.9 Hz, 1H), 6.97 (d, J = 8.9 Hz, 1H), 5.56 (m, 1H), 4.89 (m, 2H), 3.66 (m, 2H), 3.62 (m, 2H), 3.56 (s, 3H), 3.23 (m, 4H), 3.00 (m, 2H), 2.76 (m, 2H), 1.62 (m, 8H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.36 (s, 1H), 8.02 (s, 1H), 7.26 (s, 1H), 7.18 (d, J = 8.9 Hz, 1H), 6.97 (d, J = 8.9 Hz, 1H), 5.56 (m, 1H), 4.89 (m, 2H), 3.66 (m, 2H), 3.62 (m, 2H), 3.56 (s, 3H), 3.23 (m, 4H), 3.00 (m, 2H), 2.76 (m, 2H), 1.62 (m, 8H)
실시예 53: 1-(1-(5-(다이플루오로메톡시)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 53: 1-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3 -Preparation of dione (1-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000103
Figure PCTKR2023007091-appb-img-000103
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.19 mmol)과 2-클로로-5-(다이플루오로메톡시)피리미딘 (0.047 mL, 0.386 mmol)을 이용하여 실시예 25와 유사한 방법으로 표제 화합물 (46 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.19 mmol) and 2-chloro-5 obtained in Preparation Example 1 The title compound (46 mg) was obtained in a similar manner to Example 25 using -(difluoromethoxy)pyrimidine (0.047 mL, 0.386 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.23 (d, J = 4.9 Hz, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.20-7.27 (m, 3H), 6.43 (t, J = 72.9 Hz, 1H), 4.99-4.90 (m, 3H), 3.66 (s, 3H), 3.05 (t, J = 12.8 Hz, 2H), 2.86-2.80 (m, 2H), 1.87 (d, J = 12.8 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.23 (d, J = 4.9 Hz, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.20-7.27 (m, 3H), 6.43 (t, J = 72.9 Hz, 1H), 4.99-4.90 (m, 3H), 3.66 (s, 3H), 3.05 (t, J = 12.8 Hz, 2H), 2.86-2.80 (m, 2H), 1.87 (d, J = 12.8 Hz, 2H)
LC/MS: 404.1 (M+H), 426.1 (M+Na)LC/MS: 404.1 (M+H), 426.1 (M+Na)
실시예 54: 1-(1-(5-(다이플루오로메톡시)피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 54: 1-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoc saline-2,3-dione (1-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3 Manufacture of -dione)
Figure PCTKR2023007091-appb-img-000104
Figure PCTKR2023007091-appb-img-000104
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.18 mmol)과 2-클로로-5-(다이플루오로메톡시)피리미딘 (0.044 mL, 0.36 mmol)을 이용하여 실시예 25와 유사한 방법으로 표제 화합물 (51 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.18 mmol) obtained in Preparation Example 4 and The title compound (51 mg) was obtained in a similar manner to Example 25 using 2-chloro-5-(difluoromethoxy)pyrimidine (0.044 mL, 0.36 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.23 (d, J = 4.0 Hz, 2H), 7.40 (q, J = 4.7 Hz, 1H), 6.97 (dd, J = 21.2, 9.3 Hz, 2H), 6.43 (t, J = 72.8 Hz, 1H), 4.98 (d, J = 12.5 Hz, 2H), 4.88 (br s, 1H), 3.62 (s, 3H), 3.04 (t, J = 12.8 Hz, 2H), 2.82-2.75 (m, 2H), 1.86 (d, J = 12.5 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.23 (d, J = 4.0 Hz, 2H), 7.40 (q, J = 4.7 Hz, 1H), 6.97 (dd, J = 21.2, 9.3 Hz, 2H), 6.43 (t, J = 72.8 Hz, 1H), 4.98 (d, J = 12.5 Hz, 2H), 4.88 (br s, 1H), 3.62 (s, 3H), 3.04 (t, J = 12.8 Hz, 2H) , 2.82-2.75 (m, 2H), 1.86 (d, J = 12.5 Hz, 2H)
LC/MS: 422.1 (M+H), 444.1 (M+Na)LC/MS: 422.1 (M+H), 444.1 (M+Na)
실시예 55: 1-(1-(5-에티닐피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-ethynylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 55: 1-(1-(5-ethynylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione ( Preparation of 1-(1-(5-ethynylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000105
Figure PCTKR2023007091-appb-img-000105
실시예 48에서 수득한 1-(1-(5-브로모피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (70 mg, 0.17 mmol), 쿠퍼(I) 아이오다이드 (8.24 mg, 0.043 mmol), PdCl2(PPh3)2 (15.18 mg, 0.022 mmol)를 무수 DMF (2 mL)에 녹인 후 TEA (0.030 mL, 0.22 mmol), 에티닐트라이메틸실란 (0.080 mL, 0.58 mmol)을 상온에서 가하였다. 반응 혼합물을 질소 풍선을 이용해 15 분 동안 퍼징한 뒤 100℃에서 20 시간 교반하였다. 반응 혼합물을 상온으로 식힌 뒤 감압 증류하여 농축하였다. 잔류물을 DCM을 이용하여 묽힌 후 brine을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조하고 감압증류하였다. 잔류물을 DCM (2 mL)으로 묽힌 후 상온에서 1.0 M TBAF in THF (0.296 mL, 0.296 mmol)를 가한 뒤, 상온에서 1 시간 동안 교반하였다. 반응 혼합물을 DCM으로 묽힌 뒤 0.1 N NaOH 수용액을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조하고 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (11 mg)을 얻었다.1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-da obtained in Example 48 ion (70 mg, 0.17 mmol), Cooper(I) iodide (8.24 mg, 0.043 mmol), and PdCl 2 (PPh 3 ) 2 (15.18 mg, 0.022 mmol) were dissolved in anhydrous DMF (2 mL) and then dissolved in TEA ( 0.030 mL, 0.22 mmol) and ethynyltrimethylsilane (0.080 mL, 0.58 mmol) were added at room temperature. The reaction mixture was purged using a nitrogen balloon for 15 minutes and then stirred at 100°C for 20 hours. The reaction mixture was cooled to room temperature and concentrated by distillation under reduced pressure. The residue was diluted using DCM and extracted using brine. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The residue was diluted with DCM (2 mL), 1.0 M TBAF in THF (0.296 mL, 0.296 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM and extracted using 0.1 N NaOH aqueous solution. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The residue was purified by MPLC to give the title compound (11 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.45 (s, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.18-7.28 (m, 3H), 5.07 (d, J = 13.1 Hz, 2H), 4.95 (br s, 1H), 3.68 (s, 3H), 3.22 (s, 1H), 3.08 (t, J = 12.8 Hz, 2H), 2.87-2.81 (m, 2H), 1.91 (d, J = 12.2 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.45 (s, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.18-7.28 (m, 3H), 5.07 (d, J = 13.1 Hz, 2H) ), 4.95 (br s, 1H), 3.68 (s, 3H), 3.22 (s, 1H), 3.08 (t, J = 12.8 Hz, 2H), 2.87-2.81 (m, 2H), 1.91 (d, J = 12.2 Hz, 2H)
LC/MS: 362.1 (M+H)LC/MS: 362.1 (M+H)
실시예 56: 2-(4-(6-에티닐-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (2-(4-(6-ethynyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbonitrile)의 제조Example 56: 2-(4-(6-ethynyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Pyrimidine-5-carbonitrile (2-(4-(6-ethynyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine- Manufacture of 5-carbonitrile)
Figure PCTKR2023007091-appb-img-000106
Figure PCTKR2023007091-appb-img-000106
실시예 33에서 수득한 2-(4-(6-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (50 mg, 0.11 mmol)을 이용하여 실시예 55와 유사한 방법으로 표제 화합물 (20 mg)을 얻었다.2-(4-(6-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1- obtained in Example 33 1) The title compound (20 mg) was obtained in a similar manner to Example 55 using pyrimidine-5-carbonitrile (50 mg, 0.11 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.53 (s, 2H), 7.33-7.43 (m, 3H), 5.11 (d, J = 13.4 Hz, 2H), 4.82 (br s, 1H), 3.64 (s, 3H), 3.17 (s, 1H), 3.10 (t, J = 13.0 Hz, 2H), 2.82 (q, J = 10.8 Hz, 2H), 1.91 (d, J = 12.5 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.53 (s, 2H), 7.33-7.43 (m, 3H), 5.11 (d, J = 13.4 Hz, 2H), 4.82 (br s, 1H), 3.64 ( s, 3H), 3.17 (s, 1H), 3.10 (t, J = 13.0 Hz, 2H), 2.82 (q, J = 10.8 Hz, 2H), 1.91 (d, J = 12.5 Hz, 2H)
LC/MS: 387.1 (M+H)LC/MS: 387.1 (M+H)
실시예 57: 1-(1-(5-브로모피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 57: 1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2, Preparation of 3-dione (1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000107
Figure PCTKR2023007091-appb-img-000107
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (800 mg, 2.88 mmol)과 5-브로모-2-클로로피리미딘 (1.12 g, 5.77 mmol)를 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (1.21 g)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (800 mg, 2.88 mmol) obtained in Preparation Example 4 and The title compound (1.21 g) was obtained in a similar manner to Example 4 using 5-bromo-2-chloropyrimidine (1.12 g, 5.77 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.48 (s, 2H), 7.78 (dd, J = 8.4, 5.3 Hz, 1H), 7.35 (d, J = 10.4 Hz, 1H), 7.12 (t, J = 8.1 Hz, 1H), 4.79 (br s, 1H), 4.73 (d, J = 12.8 Hz, 2H), 3.49 (s, 3H), 3.13 (t, J = 12.7 Hz, 2H), 2.60-2.55 (m, 2H), 1.77 (d, J = 12.2 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.48 (s, 2H), 7.78 (dd, J = 8.4, 5.3 Hz, 1H), 7.35 (d, J = 10.4 Hz, 1H), 7.12 (t, J = 8.1 Hz, 1H), 4.79 (br s, 1H), 4.73 (d, J = 12.8 Hz, 2H), 3.49 (s, 3H), 3.13 (t, J = 12.7 Hz, 2H), 2.60-2.55 ( m, 2H), 1.77 (d, J = 12.2 Hz, 2H)
LC/MS: 434.0 (M+H)LC/MS: 434.0 (M+H)
실시예 58: 1-(1-(5-클로로피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 58: 1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3 -Preparation of dione (1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000108
Figure PCTKR2023007091-appb-img-000108
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.18 mmol)과 2,5-다이클로로피리미딘 (53 mg, 0.36 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (38 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.18 mmol) obtained in Preparation Example 4 and The title compound (38 mg) was obtained in a similar manner to Example 4 using 2,5-dichloropyrimidine (53 mg, 0.36 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.45 (s, 2H), 7.78 (dd, J = 9.0, 5.3 Hz, 1H), 7.35 (d, J = 10.4 Hz, 1H), 7.13 (t, J = 8.4 Hz, 1H), 4.79 (br s, 1H), 4.74 (d, J = 13.4 Hz, 2H), 3.49 (s, 3H), 3.14 (t, J = 12.5 Hz, 2H), 2.56 (dd, J = 21.2, 12.1 Hz, 2H), 1.77 (d, J = 11.9 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.45 (s, 2H), 7.78 (dd, J = 9.0, 5.3 Hz, 1H), 7.35 (d, J = 10.4 Hz, 1H), 7.13 (t, J = 8.4 Hz, 1H), 4.79 (br s, 1H), 4.74 (d, J = 13.4 Hz, 2H), 3.49 (s, 3H), 3.14 (t, J = 12.5 Hz, 2H), 2.56 (dd, J = 21.2, 12.1 Hz, 2H), 1.77 (d, J = 11.9 Hz, 2H)
LC/MS: 390.1 (M+H)LC/MS: 390.1 (M+H)
실시예 59: 5-플루오로-6-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴 (5-fluoro-6-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile)의 제조Example 59: 5-Fluoro-6-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine -1-yl)nicotinonitrile (5-fluoro-6-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1 Preparation of -yl)nicotinitrile)
Figure PCTKR2023007091-appb-img-000109
Figure PCTKR2023007091-appb-img-000109
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.18 mmol)과 6-클로로-5-플루오로니코티노나이트릴 (56.5 mg, 0.361 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제화합물 (33 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.18 mmol) obtained in Preparation Example 4 and The title compound (33 mg) was obtained in a similar manner to Example 4 using 6-chloro-5-fluoronicotinonitrile (56.5 mg, 0.361 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.45 (s, 1H), 8.03 (d, J = 14.6 Hz, 1H), 7.78 (dd, J = 8.5, 5.5 Hz, 1H), 7.36 (d, J = 10.4 Hz, 1H), 7.13 (t, J = 8.5 Hz, 1H), 4.82 (br s, 1H), 4.48 (d, J = 13.1 Hz, 2H), 3.49 (s, 3H), 3.28 (t, J = 12.8 Hz, 2H), 2.72-2.64 (m, 2H), 1.81 (d, J = 11.6 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.45 (s, 1H), 8.03 (d, J = 14.6 Hz, 1H), 7.78 (dd, J = 8.5, 5.5 Hz, 1H), 7.36 (d, J = 10.4 Hz, 1H), 7.13 (t, J = 8.5 Hz, 1H), 4.82 (br s, 1H), 4.48 (d, J = 13.1 Hz, 2H), 3.49 (s, 3H), 3.28 (t, J = 12.8 Hz, 2H), 2.72-2.64 (m, 2H), 1.81 (d, J = 11.6 Hz, 2H)
LC/MS: 398.1 (M+H)LC/MS: 398.1 (M+H)
실시예 60: 6-플루오로-4-메틸-1-(1-(5-프로필피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (6-fluoro-4-methyl-1-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 60: 6-Fluoro-4-methyl-1-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Preparation of dione (6-fluoro-4-methyl-1-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000110
Figure PCTKR2023007091-appb-img-000110
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.18 mmol)과 2-클로로-5-프로필피리미딘 (57 mg, 0.36 mmol)을 이용하여 실시예 25와 유사한 방법으로 표제 화합물 (32 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.18 mmol) obtained in Preparation Example 4 and The title compound (32 mg) was obtained in a similar manner to Example 25 using 2-chloro-5-propylpyrimidine (57 mg, 0.36 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (s, 2H), 7.41 (dd,J = 5.0 Hz, 9 0H, 1H), 6.98 (d,J = 10.0 Hz,1H), 6.93 (t, J = 8.3 Hz, 1H), 5.05-4.92 (m, 3H), 3.62 (s, 3H), 3.01 (t, J = 13.0 Hz, 2H), 2.82-2.74 (m, 2H), 2.43 (t, J = 7.5 Hz, 2H), 1.86 (d, J = 12.5 Hz, 2H), 1.63-1.59 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (s, 2H), 7.41 (dd,J = 5.0 Hz, 9 0H, 1H), 6.98 (d,J = 10.0 Hz,1H), 6.93 (t, J = 8.3 Hz, 1H), 5.05-4.92 (m, 3H), 3.62 (s, 3H), 3.01 (t, J = 13.0 Hz, 2H), 2.82-2.74 (m, 2H), 2.43 (t, J = 7.5 Hz, 2H), 1.86 (d, J = 12.5 Hz, 2H), 1.63-1.59 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H)
LC/MS: 398.2 (M+H)LC/MS: 398.2 (M+H)
실시예 61: 6-플루오로-4-메틸-1-(1-(티에노[3,2-d]피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (6-fluoro-4-methyl-1-(1-(thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 61: 6-Fluoro-4-methyl-1-(1-(thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydro Quinoxaline-2,3-dione (6-fluoro-4-methyl-1-(1-(thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline Preparation of -2,3-dione)
Figure PCTKR2023007091-appb-img-000111
Figure PCTKR2023007091-appb-img-000111
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (60 mg, 0.216 mmol)과 2-클로로티에노[3,2-d]피리미딘 (36.8 mg, 0.216 mmol)을 이용하여 제조예 4와 유사한 방법으로 표제 화합물 (30 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (60 mg, 0.216 mmol) obtained in Preparation Example 4 and The title compound (30 mg) was obtained in a similar manner to Preparation Example 4 using 2-chlorothieno[3,2-d]pyrimidine (36.8 mg, 0.216 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.78 (s, 1H), 7.85 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.24 (s, 1H), 7.15 (d, J = 8.5 Hz, 1H), 5.60 (m, 1H), 4.98 (m, 2H), 3.52 (s, 3H), 2.98 (m, 2H), 2.62 (m, 2H), 1.73 (m, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.78 (s, 1H), 7.85 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.24 (s, 1H), 7.15 (d, J = 8.5 Hz, 1H), 5.60 (m, 1H), 4.98 (m, 2H), 3.52 (s, 3H), 2.98 (m, 2H), 2.62 (m, 2H), 1.73 (m, 2H)
실시예 62: 4-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)벤조나이트릴 (4-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)benzonitrile)의 제조Example 62: 4-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Preparation of benzonitrile (4-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)benzonitrile)
Figure PCTKR2023007091-appb-img-000112
Figure PCTKR2023007091-appb-img-000112
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (30 mg, 0.11 mmol)과 4-플루오로벤조나이트릴 (52 mg, 0.43 mmol)을 DMSO (1.5 mL)에 녹인 후 DIPEA (0.057 mL, 0.33 mmol)을 상온에서 가한 뒤 반응 혼합물을 70℃에서 20 시간 동안 교반하였다. 반응 혼합물을 상온으로 식힌 뒤 EtOAc로 묽힌 후 brine으로 3회 세척하였다. 유기층을 무수 MgSO4로 건조하고 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (31 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (30 mg, 0.11 mmol) obtained in Preparation Example 4 and 4-Fluorobenzonitrile (52 mg, 0.43 mmol) was dissolved in DMSO (1.5 mL), then DIPEA (0.057 mL, 0.33 mmol) was added at room temperature, and the reaction mixture was stirred at 70°C for 20 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed three times with brine. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The residue was purified by MPLC to give the title compound (31 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 7.53 (d, J = 8.5 Hz, 2H), 7.36 (q, J = 4.7 Hz, 1H), 7.00 (d, J = 9.8 Hz, 1H), 6.97-6.91 (m, 3H), 4.80 (br s, 1H), 4.05 (d, J = 12.8 Hz, 2H), 3.62 (s, 3H), 3.08 (t, J = 12.5 Hz, 2H), 2.95-2.88 (m, 2H), 1.89 (d, J = 12.2 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 7.53 (d, J = 8.5 Hz, 2H), 7.36 (q, J = 4.7 Hz, 1H), 7.00 (d, J = 9.8 Hz, 1H), 6.97- 6.91 (m, 3H), 4.80 (br s, 1H), 4.05 (d, J = 12.8 Hz, 2H), 3.62 (s, 3H), 3.08 (t, J = 12.5 Hz, 2H), 2.95-2.88 ( m, 2H), 1.89 (d, J = 12.2 Hz, 2H)
LC/MS: 379.1 (M+H)LC/MS: 379.1 (M+H)
실시예 63: 1-(1-(벤조[d]티아졸-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(benzo[d]thiazol-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 63: 1-(1-(benzo[d]thiazol-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2, Preparation of 3-dione (1-(1-(benzo[d]thiazol-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000113
Figure PCTKR2023007091-appb-img-000113
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (25 mg, 0.090 mmol)과 2-클로로벤조[d]티아졸 (31 mg, 0.18 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (21 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (25 mg, 0.090 mmol) obtained in Preparation Example 4 and The title compound (21 mg) was obtained in a similar manner to Example 4 using 2-chlorobenzo[d]thiazole (31 mg, 0.18 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 7.72-7.87 (m, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 10.7 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 8.2 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 4.80 (br s, 1H), 4.18 (d, J = 12.8 Hz, 2H), 3.49 (s, 3H), 3.42 (t, J = 12.7 Hz, 2H), 2.77-2.70 (m, 2H), 1.84 (d, J = 12.2 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 7.72-7.87 (m, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 10.7 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 8.2 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 4.80 (br s, 1H), 4.18 (d, J = 12.8 Hz, 2H) , 3.49 (s, 3H), 3.42 (t, J = 12.7 Hz, 2H), 2.77-2.70 (m, 2H), 1.84 (d, J = 12.2 Hz, 2H)
LC/MS: 411.1 (M+H)LC/MS: 411.1 (M+H)
실시예 64: 1-(1-(벤조[d]옥사졸-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(benzo[d]oxazol-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 64: 1-(1-(benzo[d]oxazol-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2, Preparation of 3-dione (1-(1-(benzo[d]oxazol-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000114
Figure PCTKR2023007091-appb-img-000114
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (25 mg, 0.090 mmol)과 2-클로로벤조[d]옥사졸 (28 mg, 0.18 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (18 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (25 mg, 0.090 mmol) obtained in Preparation Example 4 and The title compound (18 mg) was obtained in a similar manner to Example 4 using 2-chlorobenzo[d]oxazole (28 mg, 0.18 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 7.74-7.87 (m, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 10.7 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.19-7.12 (m, 2H), 7.04 (t, J = 7.5 Hz, 1H), 4.79 (br s, 1H), 4.29 (d, J = 12.5 Hz, 2H), 3.49 (s, 3H), 3.35-3.45 (m, 2H), 2.72 (dd, J = 21.8, 12.4 Hz, 2H), 1.83 (d, J = 13.1 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 7.74-7.87 (m, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 10.7 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.19-7.12 (m, 2H), 7.04 (t, J = 7.5 Hz, 1H), 4.79 (br s, 1H), 4.29 (d, J = 12.5 Hz, 2H), 3.49 ( s, 3H), 3.35-3.45 (m, 2H), 2.72 (dd, J = 21.8, 12.4 Hz, 2H), 1.83 (d, J = 13.1 Hz, 2H)
LC/MS: 395.1 (M+H)LC/MS: 395.1 (M+H)
실시예 65: 1-(1-(5-(1,1-다이플루오로에틸)피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-(1,1-difluoroethyl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 65: 1-(1-(5-(1,1-difluoroethyl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4 -Dihydroquinoxaline-2,3-dione (1-(1-(5-(1,1-difluoroethyl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1 Manufacture of ,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000115
Figure PCTKR2023007091-appb-img-000115
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (25 mg, 0.090 mmol)과 제조예 8에서 수득한 2-클로로-5-(1,1-다이플루오로에틸)피리미딘 (29 mg, 0.162 mmol)을 이용하여 실시예 25와 유사한 방법으로 표제 화합물 (35 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (25 mg, 0.090 mmol) obtained in Preparation Example 4 and The title compound (35 mg) was obtained in a similar manner to Example 25 using 2-chloro-5-(1,1-difluoroethyl)pyrimidine (29 mg, 0.162 mmol) obtained in Preparation Example 8.
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.45 (s, 2H), 7.40 (dd, J = 8.9, 4.9 Hz, 1H), 6.88-7.06 (m, 2H), 5.08 (d, J = 13.4 Hz, 2H), 4.88 (br s, 1H), 3.62 (s, 3H), 3.06 (t, J = 13.0 Hz, 2H), 2.78 (q, J = 11.2 Hz, 2H), 1.94 (t, J = 18.2 Hz, 3H), 1.88 (d, J = 13.4 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.45 (s, 2H), 7.40 (dd, J = 8.9, 4.9 Hz, 1H), 6.88-7.06 (m, 2H), 5.08 (d, J = 13.4 Hz) , 2H), 4.88 (br s, 1H), 3.62 (s, 3H), 3.06 (t, J = 13.0 Hz, 2H), 2.78 (q, J = 11.2 Hz, 2H), 1.94 (t, J = 18.2 Hz, 3H), 1.88 (d, J = 13.4 Hz, 2H)
LC/MS: 420.2 (M+H)LC/MS: 420.2 (M+H)
실시예 66: 1-(1-(5-아미노피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-aminopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 66: 1-(1-(5-aminopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3 -Preparation of dione (1-(1-(5-aminopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000116
Figure PCTKR2023007091-appb-img-000116
단계 A: 6-플루오로-4-메틸-1-(1-(5-니트로피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step A: 6-Fluoro-4-methyl-1-(1-(5-nitropyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3 -Manufacture of dione
Figure PCTKR2023007091-appb-img-000117
Figure PCTKR2023007091-appb-img-000117
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (800 mg, 2.88 mmol)과 2-클로로-5-니트로피리미딘 (920 mg, 5.77 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (1.06 g)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (800 mg, 2.88 mmol) obtained in Preparation Example 4 and The title compound (1.06 g) was obtained in a similar manner to Example 4 using 2-chloro-5-nitropyrimidine (920 mg, 5.77 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 9.15 (s, 2H), 7.82-7.80 (m, 1H), 7.36 (d, J = 10.7 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 4.95 (d, J = 12.8 Hz, 2H), 4.89 (br s, 1H), 3.49 (s, 3H), 2.61 (dd, J = 22.4, 10.5 Hz, 2H), 1.88 (d, J = 12.2 Hz, 2H), 1.24-1.16 (m, 2H)1H-NMR (500 MHz, DMSO-D6) δ 9.15 (s, 2H), 7.82-7.80 (m, 1H), 7.36 (d, J = 10.7 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H) ), 4.95 (d, J = 12.8 Hz, 2H), 4.89 (br s, 1H), 3.49 (s, 3H), 2.61 (dd, J = 22.4, 10.5 Hz, 2H), 1.88 (d, J = 12.2 Hz, 2H), 1.24-1.16 (m, 2H)
LC/MS: 401.1 (M+H)LC/MS: 401.1 (M+H)
단계 B: 1-(1-(5-아미노피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step B: 1-(1-(5-aminopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3- Manufacturing of dione
Figure PCTKR2023007091-appb-img-000118
Figure PCTKR2023007091-appb-img-000118
단계 A에서 수득한 6-플루오로-4-메틸-1-(1-(5-nitro피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (840 mg, 2.10 mmol)을 50% MeOH in DCM (v/v) 용액에 녹인 뒤 0℃에서 아연 (686 mg, 10.49 mmol), 암모늄 클로라이드 (561 mg, 10.49 mmol)를 천천히 가하였다. 이후 혼합물을 60℃에서 20 시간 동안 교반하였다. 반응 혼합물을 상온으로 식히고 Celite®를 이용하여 여과한 뒤 잔류물을 감압증류하였다. 농축된 혼합물을 DCM으로 묽히고 0.3 N NaOH 수용액을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조하고 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (71 mg)을 얻었다.6-fluoro-4-methyl-1-(1-(5-nitropyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2, obtained in Step A, Dissolve 3-dione (840 mg, 2.10 mmol) in 50% MeOH in DCM (v/v) solution, then slowly add zinc (686 mg, 10.49 mmol) and ammonium chloride (561 mg, 10.49 mmol) at 0°C. did. The mixture was then stirred at 60°C for 20 hours. The reaction mixture was cooled to room temperature, filtered using Celite ® , and the residue was distilled under reduced pressure. The concentrated mixture was diluted with DCM and extracted using 0.3 N NaOH aqueous solution. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The residue was purified by MPLC to give the title compound (71 mg).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.01 (d, J = 4.0 Hz, 2H), 7.41 (q, J = 4.8 Hz, 1H), 6.98 (d, J = 9.8 Hz, 1H), 6.93 (t, J = 8.7 Hz, 1H), 4.92 (br s, 1H), 4.83 (d, J = 13.1 Hz, 2H), 3.61 (s, 3H), 3.19 (br s, 2H), 2.97 (t, J = 13.0 Hz, 2H), 2.81-2.77 (m, 2H), 1.87-1.81 (m, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.01 (d, J = 4.0 Hz, 2H), 7.41 (q, J = 4.8 Hz, 1H), 6.98 (d, J = 9.8 Hz, 1H), 6.93 ( t, J = 8.7 Hz, 1H), 4.92 (br s, 1H), 4.83 (d, J = 13.1 Hz, 2H), 3.61 (s, 3H), 3.19 (br s, 2H), 2.97 (t, J = 13.0 Hz, 2H), 2.81-2.77 (m, 2H), 1.87-1.81 (m, 2H)
LC/MS: 371.1 (M+H)LC/MS: 371.1 (M+H)
실시예 67: N-(2-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-일)아세트아마이드 (N-(2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidin-5-yl)acetamide)의 제조Example 67: N-(2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1 -yl)pyrimidin-5-yl)acetamide (N-(2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin Preparation of -1-yl)pyrimidin-5-yl)acetamide)
Figure PCTKR2023007091-appb-img-000119
Figure PCTKR2023007091-appb-img-000119
실시예 66에서 수득한 1-(1-(5-아미노피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (30 mg, 0.081 mmol)을 이용하여 실시예 41의 단계 B와 유사한 방법으로 표제 화합물 (18 mg)을 얻었다.1-(1-(5-aminopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2 obtained in Example 66 The title compound (18 mg) was obtained in a similar manner to Step B of Example 41 using ,3-dione (30 mg, 0.081 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 9.86 (s, 1H), 8.53 (s, 2H), 7.77 (dd, J = 8.5, 5.2 Hz, 1H), 7.35 (d, J = 10.4 Hz, 1H), 7.12 (t, J = 8.4 Hz, 1H), 4.79 (br s, 1H), 4.75 (d, J = 12.8 Hz, 2H), 3.49 (s, 3H), 3.08 (t, J = 12.5 Hz, 2H), 2.56 (dd, J = 20.8, 11.3 Hz, 2H), 2.03 (s, 3H), 1.74 (d, J = 12.2 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 9.86 (s, 1H), 8.53 (s, 2H), 7.77 (dd, J = 8.5, 5.2 Hz, 1H), 7.35 (d, J = 10.4 Hz, 1H) ), 7.12 (t, J = 8.4 Hz, 1H), 4.79 (br s, 1H), 4.75 (d, J = 12.8 Hz, 2H), 3.49 (s, 3H), 3.08 (t, J = 12.5 Hz, 2H), 2.56 (dd, J = 20.8, 11.3 Hz, 2H), 2.03 (s, 3H), 1.74 (d, J = 12.2 Hz, 2H)
LC/MS: 413.1 (M+H)LC/MS: 413.1 (M+H)
실시예 68: N-(2-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-일)사이클로프로판카르보사마이드 (N-(2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidin-5-yl)cyclopropanecarboxamide)의 제조Example 68: N-(2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1 -yl)pyrimidin-5-yl)cyclopropanecarbosamide (N-(2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)- Preparation of yl)piperidin-1-yl)pyrimidin-5-yl)cyclopropanecarboxamide)
Figure PCTKR2023007091-appb-img-000120
Figure PCTKR2023007091-appb-img-000120
실시예 66에서 수득한 1-(1-(5-아미노피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (30 mg, 0.081 mmol)과 사이클로프로판카르보닐 클로라이드 (13 mg, 0.12 mmol)를 이용하여 실시예 3과 유사한 방법으로 표제 화합물 (11 mg)을 얻었다.1-(1-(5-aminopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2 obtained in Example 66 The title compound (11 mg) was obtained in a similar manner to Example 3 using ,3-dione (30 mg, 0.081 mmol) and cyclopropanecarbonyl chloride (13 mg, 0.12 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 10.11 (s, 1H), 8.55 (s, 2H), 7.78-7.75 (m, 1H), 7.35 (d, J = 10.7 Hz, 1H), 7.14-7.10 (m, 1H), 4.67-4.84 (m, 3H), 3.49 (s, 3H), 3.08 (t, J = 12.5 Hz, 2H), 2.52-2.66 (m, 2H), 1.74 (d, J = 11.6 Hz, 3H), 0.81 (s, 4H)1H-NMR (500 MHz, DMSO-D6) δ 10.11 (s, 1H), 8.55 (s, 2H), 7.78-7.75 (m, 1H), 7.35 (d, J = 10.7 Hz, 1H), 7.14-7.10 (m, 1H), 4.67-4.84 (m, 3H), 3.49 (s, 3H), 3.08 (t, J = 12.5 Hz, 2H), 2.52-2.66 (m, 2H), 1.74 (d, J = 11.6) Hz, 3H), 0.81 (s, 4H)
LC/MS: 439.1 (M+H)LC/MS: 439.1 (M+H)
실시예 69: 5-플루오로-6-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴 (5-fluoro-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile)의 제조Example 69: 5-Fluoro-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Preparation of nicotinonitrile (5-fluoro-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile)
Figure PCTKR2023007091-appb-img-000121
Figure PCTKR2023007091-appb-img-000121
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.19 mmol)과 6-클로로-5-플루오로니코티노나이트릴 (60 mg, 0.39 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (33 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.19 mmol) obtained in Preparation Example 1 and 6-chloro-5 -The title compound (33 mg) was obtained in a similar manner to Example 4 using fluoronicotinonitrile (60 mg, 0.39 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.45 (s, 1H), 8.03 (d, J = 14.3 Hz, 1H), 7.78-7.76 (m, 1H), 7.43 (d, J = 4.9 Hz, 1H), 7.22-7.37 (m, 2H), 4.86 (br s, 1H), 4.49 (d, J = 12.8 Hz, 2H), 3.52 (s, 3H), 3.21-3.31 (m, 2H), 2.74-2.67 (m, 2H), 1.82 (d, J = 11.6 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.45 (s, 1H), 8.03 (d, J = 14.3 Hz, 1H), 7.78-7.76 (m, 1H), 7.43 (d, J = 4.9 Hz, 1H) ), 7.22-7.37 (m, 2H), 4.86 (br s, 1H), 4.49 (d, J = 12.8 Hz, 2H), 3.52 (s, 3H), 3.21-3.31 (m, 2H), 2.74-2.67 (m, 2H), 1.82 (d, J = 11.6 Hz, 2H)
LC/MS: 380.1 (M+H)LC/MS: 380.1 (M+H)
실시예 70: 1-(1-(5-(3,6-다이하이드로-2H-피란-4-일)피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 70: 1-(1-(5-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4 -methyl-1,4-dihydroquinoxaline-2,3-dione (1-(1-(5-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-2-yl)piperidin- Preparation of 4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000122
Figure PCTKR2023007091-appb-img-000122
실시예 57에서 수득한 1-(1-(5-브로모피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (80 mg, 0.184 mmol), 2-(3,6-다이하이드로-2H-피란-4-일)-4,4,5,5-테트라메틸-1,3,2-다이옥사보로레인 (42.6 mg, 0.203 mmol), 테트라키스(트라이페닐포스핀)팔라듐(0) (21.29 mg, 0.018 mmol)와 2.0 M Na2CO3 (0.276 mL, 0.553 mmol)를 1,4-다이옥산 (1 mL)에 녹인 후 80℃에서 6시간 교반하였다. 반응 혼합물을 상온으로 식히고 Celite®를 이용하여 여과한 뒤 잔류물을 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (45 mg)을 얻었다.1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline- obtained in Example 57 2,3-dione (80 mg, 0.184 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- Dioxaborolein (42.6 mg, 0.203 mmol), tetrakis(triphenylphosphine)palladium(0) (21.29 mg, 0.018 mmol) and 2.0 M Na 2 CO 3 (0.276 mL, 0.553 mmol) were mixed with 1,4-dioxane. It was dissolved in (1 mL) and stirred at 80°C for 6 hours. The reaction mixture was cooled to room temperature, filtered using Celite ® , and the residue was distilled under reduced pressure. The residue was purified by MPLC to give the title compound (45 mg).
1H-NMR (500 MHz, DMSO-D6) δ 8.78 (s, 1H), 7.80 (m, 1H), 7.72 (m, 1H), 7.36 (dd, J = 8.0, 4.0 Hz, 1H), 7.23 (m, 1H), 6.20 (m, 1H), 4.87 (m, 1H), 4.82 (m, 2H), 4.20 (m, 2H), 3.82 (m, 1H), 3.71 (m, 1H), 3.49 (s, 3H), 3.14 (m, 2H), 2.58 (m, 2H), 2.41 (m, 1H), 2.10 (m, 1H), 1.76 (m, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.78 (s, 1H), 7.80 (m, 1H), 7.72 (m, 1H), 7.36 (dd, J = 8.0, 4.0 Hz, 1H), 7.23 (m , 1H), 6.20 (m, 1H), 4.87 (m, 1H), 4.82 (m, 2H), 4.20 (m, 2H), 3.82 (m, 1H), 3.71 (m, 1H), 3.49 (s, 3H), 3.14 (m, 2H), 2.58 (m, 2H), 2.41 (m, 1H), 2.10 (m, 1H), 1.76 (m, 2H)
실시예 71: 1-(1-(5-(2,5-다이하이드로퓨란-3-일)피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-(2,5-dihydrofuran-3-yl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 71: 1-(1-(5-(2,5-dihydrofuran-3-yl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl- 1,4-dihydroquinoxaline-2,3-dione (1-(1-(5-(2,5-dihydrofuran-3-yl)pyrimidin-2-yl)piperidin-4-yl)-6- Preparation of fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000123
Figure PCTKR2023007091-appb-img-000123
실시예 57에서 수득한 1-(1-(5-브로모피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (80 mg, 0.184 mmol), 2-(2,5-다이하이드로퓨란-3-일)-4,4,5,5-테트라메틸-1,3,2-다이옥사보로레인 (39.7 mg, 0.203 mmol), 테트라키스(트라이페닐포스핀)팔라듐(0) (21.29 mg, 0.018 mmol)와 2.0M Na2CO3 (0.276 mL, 0.553 mmol)를 1,4-다이옥산 (1 mL)에 녹인 후 80℃에서 6시간 교반하였다. 반응 혼합물을 상온으로 식히고 Celite®를 이용하여 여과한 뒤 잔류물을 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (41 mg)을 얻었다.1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline- obtained in Example 57 2,3-dione (80 mg, 0.184 mmol), 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (39.7 mg, 0.203 mmol), tetrakis(triphenylphosphine)palladium(0) (21.29 mg, 0.018 mmol) and 2.0M Na 2 CO 3 (0.276 mL, 0.553 mmol) in 1,4-dioxane (1 mL). ) and stirred at 80°C for 6 hours. The reaction mixture was cooled to room temperature, filtered using Celite ® , and the residue was distilled under reduced pressure. The residue was purified by MPLC to give the title compound (41 mg).
1H-NMR (500 MHz, DMSO-D6) δ 8.50 (s, 1H), 7.77 (m, 1H), 7.45 (m, 1H), 7.36 (m, 1H), 7.12 (m, 1H), 6.40 (m, 1H), 4.85 (m, 3H), 4.82 (m, 2H), 4.70 (m, 2H), 3.60 (m, 1H), 3.49 (s, 3H), 3.13 (m, 2H), 2.56 (m, 1H), 1.78 (m, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.50 (s, 1H), 7.77 (m, 1H), 7.45 (m, 1H), 7.36 (m, 1H), 7.12 (m, 1H), 6.40 (m , 1H), 4.85 (m, 3H), 4.82 (m, 2H), 4.70 (m, 2H), 3.60 (m, 1H), 3.49 (s, 3H), 3.13 (m, 2H), 2.56 (m, 1H), 1.78 (m, 2H)
LC/MS: 424.2 (M+H)LC/MS: 424.2 (M+H)
실시예 72: 5-플루오로-6-(4-(6-메톡시-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴 (5-fluoro-6-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile)의 제조Example 72: 5-Fluoro-6-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine -1-yl)nicotinonitrile (5-fluoro-6-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1 Preparation of -yl)nicotinitrile)
Figure PCTKR2023007091-appb-img-000124
Figure PCTKR2023007091-appb-img-000124
제조예 5에서 수득한 6-메톡시-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.173 mmol)과 6-클로로-5-플루오로니코티노나이트릴 (41 mg, 0.259 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (48 mg)을 얻었다.6-methoxy-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.173 mmol) obtained in Preparation Example 5 and The title compound (48 mg) was obtained in a similar manner to Example 4 using 6-chloro-5-fluoronicotinonitrile (41 mg, 0.259 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.45 (s, 1H), 8.03 (d, J = 14.3 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 6.93 (s, 1H), 6.87 (d, J = 9.2 Hz, 1H), 4.81 (br s, 1H), 4.48 (d, J = 13.4 Hz, 2H), 3.84 (s, 3H), 3.51 (s, 3H), 3.28 (t, J = 13.0 Hz, 2H), 2.70 (q, J = 11.3 Hz, 2H), 1.80 (d, J = 11.6 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.45 (s, 1H), 8.03 (d, J = 14.3 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 6.93 (s, 1H), 6.87 (d, J = 9.2 Hz, 1H), 4.81 (br s, 1H), 4.48 (d, J = 13.4 Hz, 2H), 3.84 (s, 3H), 3.51 (s, 3H), 3.28 (t, J = 13.0 Hz, 2H), 2.70 (q, J = 11.3 Hz, 2H), 1.80 (d, J = 11.6 Hz, 2H)
LC/MS: 410.1 (M+H)LC/MS: 410.1 (M+H)
실시예 73: 2-(4-(6-사이클로프로필-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (2-(4-(6-cyclopropyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbonitrile)의 제조Example 73: 2-(4-(6-cyclopropyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Pyrimidine-5-carbonitrile (2-(4-(6-cyclopropyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine- Manufacture of 5-carbonitrile)
Figure PCTKR2023007091-appb-img-000125
Figure PCTKR2023007091-appb-img-000125
실시예 33에서 수득한 2-(4-(6-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (50 mg, 0.113 mmol), 포타슘 카보네이트 (47.0 mg, 0.340 mmol), 사이클로프로필보론산 (38.9 mg, 0.453 mmol)을 무수 DMF에 녹인 후 PdCl2(dppf)-CH2Cl2 adduct (27.8 mg, 0.034 mmol)를 상온에서 가하였다. 반응 혼합물을 질소로 30 분 동안 퍼징시켜준 뒤, 100℃에서 16 시간동안 교반하였다. 혼합물을 식힌 뒤 감압증류하였다. 농축된 혼합물을 10% MeOH in DCM 용액으로 묽힌 뒤, brine을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조한 뒤 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (11 mg)을 얻었다.2-(4-(6-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1- obtained in Example 33 1) Pyrimidine-5-carbonitrile (50 mg, 0.113 mmol), potassium carbonate (47.0 mg, 0.340 mmol), and cyclopropylboronic acid (38.9 mg, 0.453 mmol) were dissolved in anhydrous DMF and then dissolved in PdCl 2 (dppf). -CH 2 Cl 2 adduct (27.8 mg, 0.034 mmol) was added at room temperature. The reaction mixture was purged with nitrogen for 30 minutes and then stirred at 100°C for 16 hours. The mixture was cooled and distilled under reduced pressure. The concentrated mixture was diluted with 10% MeOH in DCM solution 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 (11 mg).
1H-NMR (400 MHz, CHLOROFORM-D) d 8.52 (s, 2H), 7.29 (d, J = 8.7 Hz, 1H), 7.00 (s, 1H), 6.91 (d, J = 8.7 Hz, 1H), 5.09 (d, J = 13.7 Hz, 2H), 4.85 (br s, 1H), 3.64 (s, 3H), 3.10 (t, J = 11.9 Hz, 2H), 2.82 (td, J = 12.2, 8.2 Hz, 2H), 1.97 (td, J = 8.8, 4.4 Hz, 1H), 1.90 (d, J = 11.9 Hz, 2H), 1.04 (q, J = 6.4 Hz, 2H), 0.71 (q, J = 5.3 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) d 8.52 (s, 2H), 7.29 (d, J = 8.7 Hz, 1H), 7.00 (s, 1H), 6.91 (d, J = 8.7 Hz, 1H), 5.09 (d, J = 13.7 Hz, 2H), 4.85 (br s, 1H), 3.64 (s, 3H), 3.10 (t, J = 11.9 Hz, 2H), 2.82 (td, J = 12.2, 8.2 Hz, 2H), 1.97 (td, J = 8.8, 4.4 Hz, 1H), 1.90 (d, J = 11.9 Hz, 2H), 1.04 (q, J = 6.4 Hz, 2H), 0.71 (q, J = 5.3 Hz, 2H)
LC/MS: 403.2 (M+H), 425.2 (M+H)LC/MS: 403.2 (M+H), 425.2 (M+H)
실시예 74: 2-(4-(6-아미노-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (2-(4-(6-amino-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbonitrile)의 제조Example 74: 2-(4-(6-amino-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri Midine-5-carbonitrile (2-(4-(6-amino-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 Manufacture of -carbonitrile)
Figure PCTKR2023007091-appb-img-000126
Figure PCTKR2023007091-appb-img-000126
단계 A: 2-(4-(6-((다이페닐메틸렌)아미노)-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴의 제조Step A: 2-(4-(6-((diphenylmethylene)amino)-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine -1-day) Preparation of pyrimidine-5-carbonitrile
Figure PCTKR2023007091-appb-img-000127
Figure PCTKR2023007091-appb-img-000127
실시예 33에서 수득한 2-(4-(6-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (180 mg, 0.408 mmol), xantphos (142 mg, 0.245 mmol), 세슘 카보네이트 (266 mg, 0.816 mmol), Pd2(dba)3 (112 mg, 0.122 mmol)를 무수 DMF에 녹인 후 상온에서 다이페닐메탄아민 (135 μl, 0.816 mmol)을 가하였다. 반응 혼합물을 질소 기체로 30분 동안 퍼징시켜준 뒤, 100℃에서 6시간 동안 교반하였다. 혼합물을 식힌 뒤, 감압증류하여 농축하였다. 농축된 혼합물을 DCM으로 묽히고 brine을 이용하여 추출하였다. 잔류물을 추가 정제없이 다음 반응에 이용하였다.2-(4-(6-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1- obtained in Example 33 1) Pyrimidine-5-carbonitrile (180 mg, 0.408 mmol), xantphos (142 mg, 0.245 mmol), cesium carbonate (266 mg, 0.816 mmol), Pd 2 (dba) 3 (112 mg, 0.122 mmol) was dissolved in anhydrous DMF, and then diphenylmethanamine (135 μl, 0.816 mmol) was added at room temperature. The reaction mixture was purged with nitrogen gas for 30 minutes and then stirred at 100°C for 6 hours. After cooling the mixture, it was concentrated by distillation under reduced pressure. The concentrated mixture was diluted with DCM and extracted using brine. The residue was used in the next reaction without further purification.
LC/MS: 542.2 (M+H)LC/MS: 542.2 (M+H)
단계 B: 2-(4-(6-아미노-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴의 제조Step B: 2-(4-(6-amino-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine -Manufacture of 5-carbonitrile
Figure PCTKR2023007091-appb-img-000128
Figure PCTKR2023007091-appb-img-000128
단계 A에서 얻은 2-(4-(6-((다이페닐메틸렌)아미노)-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴이 포함된 혼합물을 30% MeOH in DCM 용액에 녹인 후 1 N HCl 수용액 (2.86 ml, 2.86 mmol)을 상온에서 가하였다. 혼합물을 상온에서 2 시간 동안 교반한 뒤, 0.3 N NaOH 수용액을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조한 뒤 감압증류하였다. 농축된 혼합물을 MPLC를 이용하여 표제 화합물 (56 mg)을 얻었다.2-(4-(6-((diphenylmethylene)amino)-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperi obtained in Step A The mixture containing din-1-yl)pyrimidine-5-carbonitrile was dissolved in 30% MeOH in DCM solution, and then 1 N HCl aqueous solution (2.86 ml, 2.86 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours and then extracted using 0.3 N NaOH aqueous solution. The organic layer was dried with anhydrous MgSO 4 and then distilled under reduced pressure. The concentrated mixture was subjected to MPLC to obtain the title compound (56 mg).
1H-NMR (400 MHz, CHLOROFORM-D) d 8.52 (s, 2H), 7.19 (d, J = 9.1 Hz, 1H), 6.60-6.52 (m, 2H), 5.08 (d, J = 13.7 Hz, 2H), 4.81 (br s, 1H), 3.82 (br s, 2H), 3.58 (s, 3H), 3.12-3.06 (m, 2H), 2.82 (dd, J = 25.2, 16.0 Hz, 2H), 1.89 (d, J = 12.3 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) d 8.52 (s, 2H), 7.19 (d, J = 9.1 Hz, 1H), 6.60-6.52 (m, 2H), 5.08 (d, J = 13.7 Hz, 2H) ), 4.81 (br s, 1H), 3.82 (br s, 2H), 3.58 (s, 3H), 3.12-3.06 (m, 2H), 2.82 (dd, J = 25.2, 16.0 Hz, 2H), 1.89 ( d, J = 12.3 Hz, 2H)
LC/MS: 378.2 (M+H)LC/MS: 378.2 (M+H)
실시예 75: 3,5-다이플루오로-4-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)벤조나이트릴 (3,5-difluoro-4-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)benzonitrile)의 제조Example 75: 3,5-difluoro-4-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine-1 -yl)benzonitrile (3,5-difluoro-4-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)benzonitrile) manufacture of
Figure PCTKR2023007091-appb-img-000129
Figure PCTKR2023007091-appb-img-000129
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.193 mmol)과 3,4,5-트라이플루오로벤조나이트릴 (44.2 μl, 0.386 mmol)을 DMSO (2 ml)에 녹인 뒤, DIPEA (0.1 ml, 0.58 mmol)를 가하였다. 반응 혼합물을 100℃에서 16 시간 동안 교반하였다. 혼합물을 상온으로 식힌 뒤, EA로 묽히고, 포화 NaHCO3 수용액으로 3회 세척하였다. 유기층을 무수 MgSO4로 건조하고 감압증류하였다. 잔류물을 MPLC를 이용해 정제하여 표제 화합물 (44 mg)을 얻었다.1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.193 mmol) obtained in Preparation Example 1 and 3,4,5 -Trifluorobenzonitrile (44.2 μl, 0.386 mmol) was dissolved in DMSO (2 ml), and then DIPEA (0.1 ml, 0.58 mmol) was added. The reaction mixture was stirred at 100°C for 16 hours. The mixture was cooled to room temperature, diluted with EA, and washed three times with saturated aqueous NaHCO 3 solution. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The residue was purified using MPLC to obtain the title compound (44 mg).
1H-NMR (400 MHz, CHLOROFORM-D) d 7.55-7.53 (m, 1H), 7.32-7.27 (m, 3H), 7.17 (dd, J = 7.8, 1.4 Hz, 2H), 4.85 (br s, 1H), 3.66 (s, 3H), 3.61 (d, J = 11.4 Hz, 2H), 3.36 (t, J = 11.9 Hz, 2H), 3.07-2.97 (m, 2H), 1.85 (d, J = 12.3 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) d 7.55-7.53 (m, 1H), 7.32-7.27 (m, 3H), 7.17 (dd, J = 7.8, 1.4 Hz, 2H), 4.85 (br s, 1H) ), 3.66 (s, 3H), 3.61 (d, J = 11.4 Hz, 2H), 3.36 (t, J = 11.9 Hz, 2H), 3.07-2.97 (m, 2H), 1.85 (d, J = 12.3 Hz) , 2H)
LC/MS: 397.2 (M+H), 419.1 (M+Na)LC/MS: 397.2 (M+H), 419.1 (M+Na)
실시예 76: 3,5-다이플루오로-4-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)벤조나이트릴 (3,5-difluoro-4-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)benzonitrile)의 제조Example 76: 3,5-difluoro-4-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl) piperidin-1-yl)benzonitrile (3,5-difluoro-4-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl )Manufacture of piperidin-1-yl)benzonitrile)
Figure PCTKR2023007091-appb-img-000130
Figure PCTKR2023007091-appb-img-000130
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.180 mmol)을 이용하여 실시예 75와 유사한 방법으로 표제 화합물 (17 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.180 mmol) obtained in Preparation Example 4 The title compound (17 mg) was obtained in a manner similar to Example 75.
1H-NMR (400 MHz, CHLOROFORM-D) 7.49 (q, J = 4.9 Hz, 1H), 7.17 (dd, J = 7.8, 1.8 Hz, 2H), 7.01-6.97 (m, 2H), 4.82 (br s, 1H), 3.63 (s, 3H), 3.59 (br s, 2H), 3.35 (t, J = 12.1 Hz, 2H), 3.01-2.92 (m, 2H), 1.84 (d, J = 10.1 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) 7.49 (q, J = 4.9 Hz, 1H), 7.17 (dd, J = 7.8, 1.8 Hz, 2H), 7.01-6.97 (m, 2H), 4.82 (br s , 1H), 3.63 (s, 3H), 3.59 (br s, 2H), 3.35 (t, J = 12.1 Hz, 2H), 3.01-2.92 (m, 2H), 1.84 (d, J = 10.1 Hz, 2H) )
LC/MS: 415.2 (M+H)LC/MS: 415.2 (M+H)
실시예 77: 3,5-다이플루오로-4-(4-(6-메톡시-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)벤조나이트릴 (3,5-difluoro-4-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)benzonitrile)의 제조Example 77: 3,5-difluoro-4-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl) piperidin-1-yl)benzonitrile (3,5-difluoro-4-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl )Manufacture of piperidin-1-yl)benzonitrile)
Figure PCTKR2023007091-appb-img-000131
Figure PCTKR2023007091-appb-img-000131
제조예 5에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.180 mmol)을 이용하여 실시예 75와 유사한 방법으로 표제 화합물 (61 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.180 mmol) obtained in Preparation Example 5 The title compound (61 mg) was obtained in a similar manner to Example 75.
1H-NMR (400 MHz, CHLOROFORM-D) 7.49 (q, J = 4.9 Hz, 1H), 7.17 (dd, J = 7.8, 1.8 Hz, 2H), 7.01-6.97 (m, 2H), 4.82 (br s, 1H), 3.63 (s, 3H), 3.59 (br s, 2H), 3.35 (t, J = 12.1 Hz, 2H), 3.01-2.92 (m, 2H), 1.84 (d, J = 10.1 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) 7.49 (q, J = 4.9 Hz, 1H), 7.17 (dd, J = 7.8, 1.8 Hz, 2H), 7.01-6.97 (m, 2H), 4.82 (br s , 1H), 3.63 (s, 3H), 3.59 (br s, 2H), 3.35 (t, J = 12.1 Hz, 2H), 3.01-2.92 (m, 2H), 1.84 (d, J = 10.1 Hz, 2H) )
LC/MS: 415.2 (M+H)LC/MS: 415.2 (M+H)
실시예 78: N-(1-(1-(5-시아노피리미딘-2-일)피페리딘-4-일)-4-메틸-2,3-다이옥소-1,2,3,4-테트라하이드로퀴녹살린-6-일)아세트아마이드 (N-(1-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-6-yl)acetamide)의 제조Example 78: N-(1-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-4-methyl-2,3-dioxo-1,2,3, 4-Tetrahydroquinoxalin-6-yl)acetamide (N-(1-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-4-methyl-2,3-dioxo-1, Preparation of 2,3,4-tetrahydroquinoxalin-6-yl)acetamide)
Figure PCTKR2023007091-appb-img-000132
Figure PCTKR2023007091-appb-img-000132
실시예 74에서 수득한 2-(4-(6-아미노-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴 (50 mg, 0.132 mmol)와 TEA (0.055 ml, 0.397 mmol)를 DMF (1 ml)에 녹인 후 아세트산 무수물 (0.019 ml, 0.199 mmol)을 상온에서 가하였다. 반응 혼합물을 상온에서 4 시간 동안 교반하였다. 반응 혼합물을 감압증류한 뒤, 10% MeOH in DCM 용액으로 묽히고 brine을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조한 뒤 감압증류하였다. 잔류물을 MPLC로 정제하여 표제 화합물 (21 mg)을 얻었다.2-(4-(6-amino-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl obtained in Example 74 ) Pyrimidine-5-carbonitrile (50 mg, 0.132 mmol) and TEA (0.055 ml, 0.397 mmol) were dissolved in DMF (1 ml), and then acetic anhydride (0.019 ml, 0.199 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was distilled under reduced pressure, diluted with 10% MeOH in DCM solution, 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 (21 mg).
1H-NMR (500 MHz, DMSO-D6) δ 10.51 (d, J = 6.7 Hz, 1H), 8.79 (s, 2H), 7.85 (s, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 4.86 (d, J = 12.2 Hz, 3H), 3.46 (s, 3H), 3.25 (t, J = 12.7 Hz, 2H), 2.58 (q, J = 11.7 Hz, 2H), 2.08 (s, 3H), 1.82 (d, J = 11.9 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 10.51 (d, J = 6.7 Hz, 1H), 8.79 (s, 2H), 7.85 (s, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 4.86 (d, J = 12.2 Hz, 3H), 3.46 (s, 3H), 3.25 (t, J = 12.7 Hz, 2H), 2.58 (q, J = 11.7) Hz, 2H), 2.08 (s, 3H), 1.82 (d, J = 11.9 Hz, 2H)
LC/MS: 420.1 (M+H), 442.1 (M+Na)LC/MS: 420.1 (M+H), 442.1 (M+Na)
실시예 79: 1-(1-(5-(2,5-다이하이드로퓨란-3-일)-3-플루오로피리딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(5-(2,5-dihydrofuran-3-yl)-3-fluoropyridin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 79: 1-(1-(5-(2,5-dihydrofuran-3-yl)-3-fluoropyridin-2-yl)piperidin-4-yl)-6-fluoro- 4-methyl-1,4-dihydroquinoxaline-2,3-dione (1-(1-(5-(2,5-dihydrofuran-3-yl)-3-fluoropyridin-2-yl)piperidin- Preparation of 4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000133
Figure PCTKR2023007091-appb-img-000133
단계 A: 1-(1-(5-브로모-3-플루오로피리딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온의 제조Step A: 1-(1-(5-bromo-3-fluoropyridin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline Preparation of -2,3-dione
Figure PCTKR2023007091-appb-img-000134
Figure PCTKR2023007091-appb-img-000134
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (200 mg, 0.721 mmol)과 5-브로모-2-클로로-3-플루오로피리딘 (152 mg, 0.721 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (200 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (200 mg, 0.721 mmol) obtained in Preparation Example 4 and The title compound (200 mg) was obtained in a similar manner to Example 4 using 5-bromo-2-chloro-3-fluoropyridine (152 mg, 0.721 mmol).
LC/MS: 425.1 (M+H)LC/MS: 425.1 (M+H)
단계 B: 1-(1-(5-(2,5-다이하이드로퓨란-3-일)-3-플루오로피리딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이원의 제조Step B: 1-(1-(5-(2,5-dihydrofuran-3-yl)-3-fluoropyridin-2-yl)piperidin-4-yl)-6-fluoro-4 -Preparation of methyl-1,4-dihydroquinoxaline-2,3-dione
Figure PCTKR2023007091-appb-img-000135
Figure PCTKR2023007091-appb-img-000135
단계 A에서 수득한 1-(1-(5-브로모-3-플루오로피리딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (70 mg, 0.155 mmol)과 2-(2,5-다이하이드로퓨란-3-일)-4,4,5,5-테트라메틸-1,3,2-다이옥사보로란 (33.5 mg, 0.171 mmol)을 이용하여 실시예 70과 유사한 방법으로 표제 화합물 (58 mg)을 얻었다.1-(1-(5-bromo-3-fluoropyridin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydro obtained in Step A Quinoxaline-2,3-dione (70 mg, 0.155 mmol) and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2- The title compound (58 mg) was obtained in a similar manner to Example 70 using dioxabororane (33.5 mg, 0.171 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.46 (s, 1H), 7.71 (m, 1H), 7.40 (m, 1H), 7.31 (m, 1H), 7.08 (m, 1H), 6.35 (m, 1H), 4.60 (m, 3H), 4.54 (m, 2H), 4.40 (m, 2H), 3.61 (m, 1H), 3.49 (s, 3H), 3.16 (m, 2H), 2.55 (m, 1H), 1.72 (m, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.46 (s, 1H), 7.71 (m, 1H), 7.40 (m, 1H), 7.31 (m, 1H), 7.08 (m, 1H), 6.35 (m , 1H), 4.60 (m, 3H), 4.54 (m, 2H), 4.40 (m, 2H), 3.61 (m, 1H), 3.49 (s, 3H), 3.16 (m, 2H), 2.55 (m, 1H), 1.72 (m, 2H)
LC/MS: 441.2 (M+H)LC/MS: 441.2 (M+H)
실시예 80: 1-(1-(벤조[d]티아졸-2-일메틸)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-(benzo[d]thiazol-2-ylmethyl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 80: 1-(1-(benzo[d]thiazol-2-ylmethyl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2 ,3-dione (1-(1-(benzo[d]thiazol-2-ylmethyl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione) manufacturing
Figure PCTKR2023007091-appb-img-000136
Figure PCTKR2023007091-appb-img-000136
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (100 mg, 0.361 mmol)과 벤조[d]티아졸-2-카르발데하이드 (58.9 mg, 0.361 mmol)를 이용하여 실시예 1와 유사한 방법으로 표제 화합물 (76 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (100 mg, 0.361 mmol) obtained in Preparation Example 4 and The title compound (76 mg) was obtained in a similar manner to Example 1 using benzo[d]thiazole-2-carbaldehyde (58.9 mg, 0.361 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.09 (d, J = 7.5 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 7.5, 5.0 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 10.5 Hz, 1H), 7.12 (t, J = 8.5 Hz, 1H), 4.48 (m, 1H), 4.02 (s, 2H), 3.50 (s, 3H), 3.07 (m, 2H), 2.77 (m, 2H), 2.46 (m, 2H), 1.69 (m, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.09 (d, J = 7.5 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 7.5, 5.0 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 10.5 Hz, 1H), 7.12 (t, J = 8.5 Hz, 1H), 4.48 ( m, 1H), 4.02 (s, 2H), 3.50 (s, 3H), 3.07 (m, 2H), 2.77 (m, 2H), 2.46 (m, 2H), 1.69 (m, 2H)
LC/MS: 452.2LC/MS: 452.2
실시예 81: 2-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)벤조[d]티아졸-6-카르보나이트릴 (2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)benzo[d]thiazole-6-carbonitrile)의 제조Example 81: 2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Benzo[d]thiazole-6-carbonitrile (2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1- Preparation of yl)benzo[d]thiazole-6-carbonitrile)
Figure PCTKR2023007091-appb-img-000137
Figure PCTKR2023007091-appb-img-000137
제조예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (60 mg, 0.216 mmol)과 2-브로모벤조[d]티아졸-6-카르보나이트릴 (51.7 mg, 0.216 mmol)을 이용하여 실시예 4와 유사한 방법으로 표제 화합물 (37 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (60 mg, 0.216 mmol) obtained in Preparation Example 4 and The title compound (37 mg) was obtained in a similar manner to Example 4 using 2-bromobenzo[d]thiazole-6-carbonitrile (51.7 mg, 0.216 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.33 (s, 1H), 7.80 (dd, J = 8.5, 5.0 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 10.5 Hz, 1H), 7.14 (t, J = 8.5 Hz, 1H), 4.83 (m, 1H), 4.22 (m, 2H), 3.50 (m, 5H), 2.71 (m, 2H), 1.87 (m, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.33 (s, 1H), 7.80 (dd, J = 8.5, 5.0 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 10.5 Hz, 1H), 7.14 (t, J = 8.5 Hz, 1H), 4.83 (m, 1H), 4.22 (m, 2H), 3.50 (m, 5H) ), 2.71 (m, 2H), 1.87 (m, 2H)
LC/MS: 436.2LC/MS: 436.2
실시예 82: 1-(1-((3-벤질-1,2,4-옥사다이아졸-5-일)메틸)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온 (1-(1-((3-benzyl-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione)의 제조Example 82: 1-(1-((3-benzyl-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)-6-fluoro-4-methyl-1 ,4-dihydroquinoxaline-2,3-dione (1-(1-((3-benzyl-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)-6-fluoro Preparation of -4-methyl-1,4-dihydroquinoxaline-2,3-dione)
Figure PCTKR2023007091-appb-img-000138
Figure PCTKR2023007091-appb-img-000138
실시예 4에서 수득한 6-플루오로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (100 mg, 0.361 mmol), Cs2CO3 (352 mg, 1.082 mmol)와 3-벤질-5-(클로로메틸)-1,2,4-옥사다이아졸 (75 mg, 0.361 mmol)을 DMF (1 mL)에 녹인 후 60℃에서 40시간 교반하였다. 반응 혼합물을 상온에서 식힌 후 감압 증류하여 농축한 다음 DCM 용액과 brine을 이용하여 추출하였다. 유기층을 무수 MgSO4로 건조하고 감압 증류하였다. 농축된 잔류물을 MPLC로 정제하여 표제 화합물 (75 mg)을 얻었다.6-Fluoro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (100 mg, 0.361 mmol) obtained in Example 4, Cs 2 CO 3 (352 mg, 1.082 mmol) and 3-benzyl-5-(chloromethyl)-1,2,4-oxadiazole (75 mg, 0.361 mmol) were dissolved in DMF (1 mL) and incubated at 60°C. It was stirred for 40 hours. The reaction mixture was cooled to room temperature, concentrated by distillation under reduced pressure, and then extracted using DCM solution and brine. The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The concentrated residue was purified by MPLC to obtain the title compound (75 mg).
1H-NMR (500 MHz, DMSO-D6) δ 7.67 (m, 1H), 7.34 (m, 5H), 7.27 (m, 1H), 7.08 (m, 1H), 4.41 (m, 1H), 4.13 (s, 2H), 3.91 (s, 2H), 3.48 (s, 3H), 2.95 (m, 2H), 2.56 (m, 2H), 2.39 (m, 2H), 1.65 (m, 2H)1H-NMR (500 MHz, DMSO-D6) δ 7.67 (m, 1H), 7.34 (m, 5H), 7.27 (m, 1H), 7.08 (m, 1H), 4.41 (m, 1H), 4.13 (s) , 2H), 3.91 (s, 2H), 3.48 (s, 3H), 2.95 (m, 2H), 2.56 (m, 2H), 2.39 (m, 2H), 1.65 (m, 2H)
LC/MS: 450.2LC/MS: 450.2
실시예 83: 4-(4-(6-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)-3,5-다이플루오로벤조나이트릴 (4-(4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)-3,5-difluorobenzonitrile)의 제조Example 83: 4-(4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)- 3,5-difluorobenzonitrile (4-(4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Preparation of -3,5-difluorobenzonitrile)
Figure PCTKR2023007091-appb-img-000139
Figure PCTKR2023007091-appb-img-000139
제조예 2에서 수득한 6-클로로-4-메틸-1-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.170 mmol)을 이용하여 실시예 75와 유사한 방법으로 표제 화합물 (17 mg)을 얻었다.Using 6-chloro-4-methyl-1-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.170 mmol) obtained in Preparation Example 2 The title compound (17 mg) was obtained in a similar manner to Example 75.
1H-NMR (400 MHz, CHLOROFORM-D) d 7.46 (d, J = 8.7 Hz, 1H), 7.25-7.23 (m, 2H), 7.17 (dd, J = 7.8, 1.8 Hz, 2H), 4.81 (br s, 1H), 3.64 (s, 3H), 3.63-3.57 (m, 2H), 3.35 (t, J = 12.3 Hz, 2H), 3.01-2.91 (m, 2H), 1.84 (d, J = 10.1 Hz, 2H)1H-NMR (400 MHz, CHLOROFORM-D) d 7.46 (d, J = 8.7 Hz, 1H), 7.25-7.23 (m, 2H), 7.17 (dd, J = 7.8, 1.8 Hz, 2H), 4.81 (br s, 1H), 3.64 (s, 3H), 3.63-3.57 (m, 2H), 3.35 (t, J = 12.3 Hz, 2H), 3.01-2.91 (m, 2H), 1.84 (d, J = 10.1 Hz) , 2H)
LC/MS: 431.1 (M+H)LC/MS: 431.1 (M+H)
실시예 84: 5-메톡시-6-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴 (5-methoxy-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile)의 제조Example 84: 5-methoxy-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Preparation of nicotinonitrile (5-methoxy-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile)
Figure PCTKR2023007091-appb-img-000140
Figure PCTKR2023007091-appb-img-000140
제조예 1에서 수득한 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.193 mmol)과 6-클로로-5-메톡시니코티노나이트릴 (65.0 mg, 0.386 mmol)을 이용하여 실시예 75와 유사한 방법으로 표제 화합물 (61 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.193 mmol) obtained in Preparation Example 1 and 6-chloro-5 The title compound (61 mg) was obtained in a similar manner to Example 75 using -methoxynicotinonitrile (65.0 mg, 0.386 mmol).
1H-NMR (500 MHz, CHLOROFORM-D) δ 8.14 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.26-7.17 (m, 3H), 7.11 (s, 1H), 4,91 (br s, 1H), 4.59 (d, J = 12.2 Hz, 2H), 3.88 (s, 3H), 3.66 (s, 3H), 3.07-2.94 (m, 4H), 1.85 (d, J = 11.9 Hz, 2H)1H-NMR (500 MHz, CHLOROFORM-D) δ 8.14 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.26-7.17 (m, 3H), 7.11 (s, 1H), 4,91 (br s, 1H), 4.59 (d, J = 12.2 Hz, 2H), 3.88 (s, 3H), 3.66 (s, 3H), 3.07-2.94 (m, 4H), 1.85 (d, J = 11.9 Hz) , 2H)
LC/MS: 392.2 (M+H)LC/MS: 392.2 (M+H)
실시예 85: 5-클로로-6-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴 (5-chloro-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile)의 제조Example 85: 5-Chloro-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nico Preparation of tinonitrile (5-chloro-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile)
Figure PCTKR2023007091-appb-img-000141
Figure PCTKR2023007091-appb-img-000141
제조예 1의 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (50 mg, 0.193 mmol)과 5,6-다이클로로니코티노나이트릴 (66.7 mg, 0.386 mmol)을 이용하여 실시예 75와 유사한 방법으로 표제 화합물 (55 mg)을 얻었다.1-Methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (50 mg, 0.193 mmol) and 5,6-dichloronic acid of Preparation Example 1 The title compound (55 mg) was obtained in a similar manner to Example 75 using tinonitrile (66.7 mg, 0.386 mmol).
1H-NMR (500 MHz, DMSO-D6) δ 8.63 (s, 1H), 8.30 (s, 1H), 7.75 (d, J = 2.7 Hz, 1H), 7.43 (d, J = 4.6 Hz, 1H), 7.30 (t, J = 4.0 Hz, 2H), 4.81 (br s, 1H), 4.29 (d, J = 12.5 Hz, 2H), 3.53 (s, 3H), 3.22 (t, J = 12.7 Hz, 2H), 2.84-2.77 (m, 2H), 1.82 (d, J = 11.6 Hz, 2H)1H-NMR (500 MHz, DMSO-D6) δ 8.63 (s, 1H), 8.30 (s, 1H), 7.75 (d, J = 2.7 Hz, 1H), 7.43 (d, J = 4.6 Hz, 1H), 7.30 (t, J = 4.0 Hz, 2H), 4.81 (br s, 1H), 4.29 (d, J = 12.5 Hz, 2H), 3.53 (s, 3H), 3.22 (t, J = 12.7 Hz, 2H) , 2.84-2.77 (m, 2H), 1.82 (d, J = 11.6 Hz, 2H)
LC/MS: 396.1 (M+H)LC/MS: 396.1 (M+H)
실시예 86: 5-브로모-6-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴 (5-bromo-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile)의 제조Example 86: 5-Bromo-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl) Preparation of nicotinonitrile (5-bromo-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile)
Figure PCTKR2023007091-appb-img-000142
Figure PCTKR2023007091-appb-img-000142
제조예 1의 1-메틸-4-(피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온 (200 mg, 0.771 mmol)과 5-브로모-6-클로로니코티노나이트릴 (335 mg, 1.543 mmol)을 이용하여 실시예 75와 유사한 방법으로 표제 화합물 (312 mg)을 얻었다.1-methyl-4-(piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione (200 mg, 0.771 mmol) and 5-bromo-6- of Preparation Example 1 The title compound (312 mg) was obtained in a similar manner to Example 75 using chloronicotinonitrile (335 mg, 1.543 mmol).
1H-NMR (400 MHz, DMSO-D6) d 8.47 (d, J = 2.7 Hz, 1H), 8.33 (d, J = 2.3 Hz, 1H), 7.72 (t, J = 5.0 Hz, 1H), 7.39 (q, J = 3.2 Hz, 1H), 7.26-7.24 (m, 2H), 4.78 (br s, 1H), 4.36 (d, J = 13.3 Hz, 2H), 3.48 (s, 3H), 3.24 (d, J = 12.3 Hz, 2H), 2.71 (td, J = 12.0, 8.4 Hz, 2H), 1.78 (d, J = 9.6 Hz, 2H)1H-NMR (400 MHz, DMSO-D6) d 8.47 (d, J = 2.7 Hz, 1H), 8.33 (d, J = 2.3 Hz, 1H), 7.72 (t, J = 5.0 Hz, 1H), 7.39 ( q, J = 3.2 Hz, 1H), 7.26-7.24 (m, 2H), 4.78 (br s, 1H), 4.36 (d, J = 13.3 Hz, 2H), 3.48 (s, 3H), 3.24 (d, J = 12.3 Hz, 2H), 2.71 (td, J = 12.0, 8.4 Hz, 2H), 1.78 (d, J = 9.6 Hz, 2H)
LC/MS:440.1 (M+H)LC/MS:440.1 (M+H)
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 PCTKR2023007091-appb-img-000143
Figure PCTKR2023007091-appb-img-000143
Figure PCTKR2023007091-appb-img-000144
Figure PCTKR2023007091-appb-img-000144

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 PCTKR2023007091-appb-img-000145
    Figure PCTKR2023007091-appb-img-000145
    상기 화학식 1에서,In Formula 1,
    R1은 수소, 할로, 시아노(-CN), 알킬 또는 알킬카르보닐을 나타내고;R 1 represents hydrogen, halo, cyano(-CN), alkyl or alkylcarbonyl;
    R2는 수소, 할로, 시아노, 아미노, 알킬, 알키닐, 알킬카르보닐, 알킬카르보닐아미노, 알콕시 또는 사이클로알킬을 나타내며;R 2 represents hydrogen, halo, cyano, amino, alkyl, alkynyl, alkylcarbonyl, alkylcarbonylamino, alkoxy or cycloalkyl;
    R3는 수소 또는 알킬을 나타내고;R 3 represents hydrogen or alkyl;
    R4는 알킬을 나타내며;R 4 represents alkyl;
    R5는 아릴, 아르알킬, 아릴카르보닐, 불포화 헤테로사이클릴 또는 불포화 헤테로사이클릴-알킬을 나타내고;R 5 represents aryl, aralkyl, arylcarbonyl, unsaturated heterocyclyl or unsaturated heterocyclyl-alkyl;
    상기 아릴 및 헤테로사이클릴은 할로, 시아노, 아미노, 카르복시(-COOH), 알킬, 알케닐, 알키닐, 알콕시, 하이드록시알킬, 할로알킬, 시아노알킬, 할로알콕시, 알콕시알킬, 알킬카르보닐, 비치환되거나 알킬카르보닐로 치환된 알킬아미노알킬, 다이알킬아미노알킬, 알킬아미노설포닐, 알킬카르보닐아미노, 사이클로알킬카르보닐아미노, 비치환되거나 사이클로알킬-알킬로 치환된 아미노설포닐, 아르알킬, 비치환되거나 알킬 또는 할로로 치환된 포화 헤테로사이클릴-알킬, 및 불포화 헤테로사이클릴로 이루어지는 그룹에서 선택되는 하나 이상의 치환기로 임의로 치환될 수 있으며;The aryl and heterocyclyl are halo, cyano, amino, carboxy (-COOH), alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, haloalkyl, cyanoalkyl, haloalkoxy, alkoxyalkyl, alkylcarbonyl , unsubstituted or substituted with alkylcarbonyl, alkylaminoalkyl, dialkylaminoalkyl, alkylaminosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino, aminosulfonyl unsubstituted or substituted with cycloalkyl-alkyl, are may be optionally substituted with one or more substituents selected from the group consisting of alkyl, saturated heterocyclyl-alkyl unsubstituted or substituted with alkyl or halo, and unsaturated heterocyclyl;
    상기 헤테로사이클릴은 질소(N), 산소(O) 및 황(S) 원자로부터 선택되는 하나 이상의 헤테로원자를 가질 수 있다.The heterocyclyl may have one or more heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S) atoms.
  2. 제1항에 있어서,According to paragraph 1,
    R1은 수소, 할로, 시아노, C1-C7 알킬 또는 C1-C7 알킬카르보닐을 나타내고;R 1 represents hydrogen, halo, cyano, C 1 -C 7 alkyl or C 1 -C 7 alkylcarbonyl;
    R2는 수소, 할로, 시아노, 아미노, C1-C7 알킬, C2-C7 알키닐, C1-C7 알킬카르보닐, C1-C7 알킬카르보닐아미노, C1-C7 알콕시 또는 C3-C10 사이클로알킬를 나타내며;R 2 is hydrogen, halo, cyano, amino, C 1 -C 7 alkyl, C 2 -C 7 alkynyl, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkylcarbonylamino, C 1 -C 7 represents alkoxy or C 3 -C 10 cycloalkyl;
    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 C6-C10 아릴, C6-C10 아릴-C1-C7 알킬, C6-C10 아릴카르보닐, N, O 및 S로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 12원의 불포화 헤테로사이클릴, 또는 N, O 및 S로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 12원의 불포화 헤테로사이클릴-C1-C7 알킬을 나타내고;R 5 is 5 having 1 to 3 heteroatoms selected from C 6 -C 10 aryl, C 6 -C 10 aryl-C 1 -C 7 alkyl, C 6 -C 10 arylcarbonyl, N, O and S represents a to 12 membered unsaturated heterocyclyl, or a 5 to 12 membered unsaturated heterocyclyl-C 1 -C 7 alkyl having 1 to 3 heteroatoms selected from N, O and S;
    상기 아릴 및 헤테로사이클릴은 비치환되거나The aryl and heterocyclyl are unsubstituted or
    할로, 시아노, 아미노, 카르복시(-COOH), C1-C7 알킬, C2-C7 알케닐, C2-C7 알키닐, C1-C7 알콕시, 하이드록시-C1-C7 알킬, 할로-C1-C7 알킬, 시아노-C1-C7 알킬, 할로-C1-C7 알콕시, C1-C7 알콕시-C1-C7 알킬, C1-C7 알킬카르보닐, 비치환되거나 C1-C7 알킬카르보닐로 치환된 C1-C7 알킬아미노-C1-C7 알킬, 다이(C1-C7 알킬)아미노-C1-C7 알킬, C1-C7 알킬아미노설포닐, C1-C7 알킬카르보닐아미노, C3-C10 사이클로알킬카르보닐아미노, 비치환되거나 C3-C10 사이클로알킬-C1-C7 알킬로 치환된 아미노설포닐, C6-C10 아릴-C1-C7 알킬, 비치환되거나 C1-C7 알킬 또는 할로로 치환된 N, O 및 S로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 12원의 포화 헤테로사이클릴-C1-C7 알킬, 및 N, O 및 S로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 12원의 불포화 헤테로사이클릴로 이루어지는 그룹에서 선택되는 1 내지 4개의 치환기로 치환되는 것을 특징으로 하는 화합물, 또는 이의 약제학적으로 허용되는 염 또는 입체이성질체.Halo, cyano, amino, carboxy (-COOH), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, hydroxy-C 1 -C 7 alkyl, halo-C 1 -C 7 alkyl, cyano-C 1 -C 7 alkyl, halo-C 1 -C 7 alkoxy, C 1 -C 7 alkoxy-C 1 -C 7 alkyl, C 1 -C 7 Alkylcarbonyl, C 1 -C 7 alkylamino-C 1 -C 7 alkyl, unsubstituted or substituted with C 1 -C 7 alkylcarbonyl, di(C 1 -C 7 alkyl ) amino -C 1 -C 7 alkyl , C 1 -C 7 alkylaminosulfonyl, C 1 -C 7 alkylcarbonylamino, C 3 -C 10 cycloalkylcarbonylamino, unsubstituted or C 3 -C 10 cycloalkyl-C 1 -C 7 alkyl. substituted aminosulfonyl, C 6 -C 10 aryl-C 1 -C 7 alkyl, unsubstituted or substituted with C 1 -C 7 alkyl or halo, having 1 to 3 heteroatoms selected from N, O and S 1 to 12 membered saturated heterocyclyl-C 1 -C 7 alkyl selected from the group consisting of 5 to 12 membered unsaturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S. A compound characterized by being substituted with four substituents, 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)벤질)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    1-(1-(3-클로로벤질)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(3-chlorobenzyl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
    1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carbonitrile;
    1-(1-(5-((다이메틸아미노)메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-da ion;
    1-메틸-4-(1-(5-((4-메틸피페라진-1-일)메틸)피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(5-((4-methylpiperazin-1-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline -2,3-dione;
    6-클로로-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-chloro-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    6-클로로-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤질)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-chloro-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    2-(4-(6-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- carbonitrile;
    6-클로로-1-(1-(5-(하이드록시메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;6-chloro-1-(1-(5-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3- Dion;
    6-클로로-1-(1-(5-((다이메틸아미노)메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;6-Chloro-1-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2 ,3-dione;
    1-메틸-4-(1-(5-(트라이플루오로메틸)피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    2-(4-(7-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(7-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- carbonitrile;
    6-클로로-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    6-클로로-4-(1-(5-((다이메틸아미노)메틸)피리미딘-2-일)피페리딘-4-일)-1-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;6-Chloro-4-(1-(5-((dimethylamino)methyl)pyrimidin-2-yl)piperidin-4-yl)-1-methyl-1,4-dihydroquinoxaline-2 ,3-dione;
    6-클로로-4-(1-(3-클로로벤질)피페리딘-4-일)-1-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;6-chloro-4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydroquinoxaline-2,3-dione;
    6-클로로-1-메틸-4-(1-(4-(트라이플루오로메톡시)벤질)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    2-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 -carbonitrile;
    6-플루오로-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-fluoro-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    6-플루오로-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤질)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-fluoro-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    2-(4-(6-메톡시-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 -carbonitrile;
    6-메톡시-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤조일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-methoxy-4-methyl-1-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    6-메톡시-4-메틸-1-(1-(4-(트라이플루오로메톡시)벤질)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-methoxy-4-methyl-1-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    N-메틸-2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-설폰아마이드;N-methyl-2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- sulfonamide;
    1-메틸-4-(1-(5-메틸피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    1-(1-(5-클로로피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
    1-(1-(5-메톡시피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
    1-(1-(5-(하이드록시메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
    2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르복시산;2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5-carboxylic acid;
    1-(1-(5-아세틸피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-acetylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
    1-메틸-4-(1-(피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    1-(1-(5-에틸피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
    2-(4-(6-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 -carbonitrile;
    2-(4-(7-브로모-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(7-bromo-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 -carbonitrile;
    1-(1-(5-시아노피리미딘-2-일)피페리딘-4-일)-4-메틸-2,3-다이옥소-1,2,3,4-테트라하이드로퀴녹살린-6-카르보나이트릴;1-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline- 6-carbonitrile;
    4-(1-(5-시아노피리미딘-2-일)피페리딘-4-일)-1-메틸-2,3-다이옥소-1,2,3,4-테트라하이드로퀴녹살린-6-카르보나이트릴;4-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline- 6-carbonitrile;
    2-(4-(6-아세틸-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-acetyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- carbonitrile;
    2-(4-(7-아세틸-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(7-acetyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- carbonitrile;
    1-(1-(5-(아제티딘-1-일메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(azetidin-1-ylmethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3- Dion;
    1-(1-(5-((3,3-다이플루오로아제티딘-1-일)메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-((3,3-difluoroazetidin-1-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4- Dihydroquinoxaline-2,3-dione;
    N-메틸-N-((2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-일)메틸)아세트아마이드;N-methyl-N-((2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri midin-5-yl)methyl)acetamide;
    1-(1-(5-(메톡시메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(methoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
    1-(1-(5-(에톡시메틸)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(ethoxymethyl)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
    2-(2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-일)아세토나이트릴;2-(2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidin-5-yl ) Acetonitrile;
    N-(사이클로프로필메틸)-2-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-설폰아마이드;N-(cyclopropylmethyl)-2-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri Mydine-5-sulfonamide;
    1-(1-(4-메톡시피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
    1-메틸-4-(1-(5-프로필피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    1-(1-(5-브로모피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
    1-메틸-4-(1-(5-비닐피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(5-vinylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    1-메틸-4-(1-(5-(2-메틸프로프-1-엔-1-일)피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;1-methyl-4-(1-(5-(2-methylprop-1-en-1-yl)pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoc saline-2,3-dione;
    1-(1-(5-아이소부틸피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-isobutylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
    1-(1-(5-((7-옥사-2-아자스피로[3.5]노난-2-일)메틸)피리미딘-2-일)피페리딘-4-일)-6-클로로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-((7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)pyrimidin-2-yl)piperidin-4-yl)-6-chloro-4 -methyl-1,4-dihydroquinoxaline-2,3-dione;
    1-(1-(5-(다이플루오로메톡시)피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
    1-(1-(5-(다이플루오로메톡시)피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2, 3-dione;
    1-(1-(5-에티닐피리미딘-2-일)피페리딘-4-일)-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-ethynylpyrimidin-2-yl)piperidin-4-yl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
    2-(4-(6-에티닐-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-ethynyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 -carbonitrile;
    1-(1-(5-브로모피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione ;
    1-(1-(5-클로로피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
    5-플루오로-6-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴;5-fluoro-6-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl ) Nicotinonitrile;
    6-플루오로-4-메틸-1-(1-(5-프로필피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-fluoro-4-methyl-1-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2,3-dione;
    6-플루오로-4-메틸-1-(1-(티에노[3,2-d]피리미딘-2-일)피페리딘-4-일)-1,4-다이하이드로퀴녹살린-2,3-다이온;6-Fluoro-4-methyl-1-(1-(thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)-1,4-dihydroquinoxaline-2 ,3-dione;
    4-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)벤조나이트릴;4-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)benzonitrile;
    1-(1-(벤조[d]티아졸-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(benzo[d]thiazol-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione ;
    1-(1-(벤조[d]옥사졸-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(benzo[d]oxazol-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione ;
    1-(1-(5-(1,1-다이플루오로에틸)피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(1,1-difluoroethyl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoc saline-2,3-dione;
    1-(1-(5-아미노피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-aminopyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-dione;
    N-(2-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-일)아세트아마이드;N-(2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri midin-5-yl)acetamide;
    N-(2-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-일)사이클로프로판카르보사마이드;N-(2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyri midin-5-yl)cyclopropanecarbosamide;
    5-플루오로-6-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴;5-fluoro-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile ;
    1-(1-(5-(3,6-다이하이드로-2H-피란-4-일)피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1 ,4-dihydroquinoxaline-2,3-dione;
    1-(1-(5-(2,5-다이하이드로퓨란-3-일)피리미딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(2,5-dihydrofuran-3-yl)pyrimidin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl-1,4- Dihydroquinoxaline-2,3-dione;
    5-플루오로-6-(4-(6-메톡시-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴;5-fluoro-6-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl ) Nicotinonitrile;
    2-(4-(6-사이클로프로필-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-cyclopropyl-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5 -carbonitrile;
    2-(4-(6-아미노-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)피리미딘-5-카르보나이트릴;2-(4-(6-amino-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)pyrimidine-5- carbonitrile;
    3,5-다이플루오로-4-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)벤조나이트릴;3,5-difluoro-4-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)benzo nitrile;
    3,5-다이플루오로-4-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)벤조나이트릴;3,5-difluoro-4-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine- 1-1)benzonitrile;
    3,5-다이플루오로-4-(4-(6-메톡시-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)벤조나이트릴;3,5-difluoro-4-(4-(6-methoxy-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidine- 1-1)benzonitrile;
    N-(1-(1-(5-시아노피리미딘-2-일)피페리딘-4-일)-4-메틸-2,3-다이옥소-1,2,3,4-테트라하이드로퀴녹살린-6-일)아세트아마이드;N-(1-(1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)-4-methyl-2,3-dioxo-1,2,3,4-tetrahydro quinoxalin-6-yl)acetamide;
    1-(1-(5-(2,5-다이하이드로퓨란-3-일)-3-플루오로피리딘-2-일)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(5-(2,5-dihydrofuran-3-yl)-3-fluoropyridin-2-yl)piperidin-4-yl)-6-fluoro-4-methyl- 1,4-dihydroquinoxaline-2,3-dione;
    1-(1-(벤조[d]티아졸-2-일메틸)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-(benzo[d]thiazol-2-ylmethyl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-dihydroquinoxaline-2,3-da ion;
    2-(4-(6-플루오로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)벤조[d]티아졸-6-카르보나이트릴;2-(4-(6-fluoro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)benzo[d] Thiazole-6-carbonitrile;
    1-(1-((3-벤질-1,2,4-옥사다이아졸-5-일)메틸)피페리딘-4-일)-6-플루오로-4-메틸-1,4-다이하이드로퀴녹살린-2,3-다이온;1-(1-((3-benzyl-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)-6-fluoro-4-methyl-1,4-di Hydroquinoxaline-2,3-dione;
    4-(4-(6-클로로-4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)-3,5-다이플루오로벤조나이트릴;4-(4-(6-chloro-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)-3,5- difluorobenzonitrile;
    5-메톡시-6-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴;5-methoxy-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile ;
    5-클로로-6-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴; 및5-chloro-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile; and
    5-브로모-6-(4-(4-메틸-2,3-다이옥소-3,4-다이하이드로퀴녹살린-1(2H)-일)피페리딘-1-일)니코티노나이트릴.5-Bromo-6-(4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)nicotinonitrile .
  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 a 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.
PCT/KR2023/007091 2022-05-25 2023-05-24 Heterocyclic compound as diacylglycerol kinase inhibitor and use thereof WO2023229375A1 (en)

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WO2021248095A1 (en) * 2020-06-05 2021-12-09 Sparcbio Llc Heterocyclic compounds and methods of use thereof
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KR20220052975A (en) * 2019-08-28 2022-04-28 브리스톨-마이어스 스큅 컴퍼니 Substituted pyridopyrimidinonyl compounds useful as T cell activators

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WO2017058805A1 (en) * 2015-09-28 2017-04-06 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
WO2017101862A1 (en) * 2015-12-18 2017-06-22 华东理工大学 5,8-dihydropteridine-6,7-diketone derivative as egfr inhibitor and use thereof
WO2018192532A1 (en) * 2017-04-19 2018-10-25 华东理工大学 Heterocyclic compound as btk inhibitor and application thereof
KR20220052975A (en) * 2019-08-28 2022-04-28 브리스톨-마이어스 스큅 컴퍼니 Substituted pyridopyrimidinonyl compounds useful as T cell activators
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