WO2023229375A1 - Composé hétérocyclique en tant qu'inhibiteur de diacylglycérol kinase et son utilisation - Google Patents

Composé hétérocyclique en tant qu'inhibiteur de diacylglycérol kinase et son utilisation Download PDF

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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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English (en)
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/fr

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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

La présente invention concerne un composé hétérocyclique représenté par la formule chimique 1, présentant une activité inhibitrice de la diacylglycérol kinase, une composition pharmaceutique le comprenant en tant que principe actif, et son utilisation.
PCT/KR2023/007091 2022-05-25 2023-05-24 Composé hétérocyclique en tant qu'inhibiteur de diacylglycérol kinase et son utilisation WO2023229375A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017058805A1 (fr) * 2015-09-28 2017-04-06 Araxes Pharma Llc Inhibiteurs de protéines kras portant la mutation g12c
WO2017101862A1 (fr) * 2015-12-18 2017-06-22 华东理工大学 Dérivé de 5,8-dihydroptéridine -6,7-dicétone en tant qu'inhibiteur de l'egfr et utilisation associée
WO2018192532A1 (fr) * 2017-04-19 2018-10-25 华东理工大学 Composé hétérocyclique utilisé en tant qu'inhibiteur de btk et son application
WO2021248095A1 (fr) * 2020-06-05 2021-12-09 Sparcbio Llc Composés hétérocycliques et leurs procédés d'utilisation
WO2022072783A1 (fr) * 2020-10-02 2022-04-07 Incyte Corporation Composés diones bicycliques en tant qu'inhibiteurs de kras
KR20220052975A (ko) * 2019-08-28 2022-04-28 브리스톨-마이어스 스큅 컴퍼니 T 세포 활성화제로서 유용한 치환된 피리도피리미디노닐 화합물

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017058805A1 (fr) * 2015-09-28 2017-04-06 Araxes Pharma Llc Inhibiteurs de protéines kras portant la mutation g12c
WO2017101862A1 (fr) * 2015-12-18 2017-06-22 华东理工大学 Dérivé de 5,8-dihydroptéridine -6,7-dicétone en tant qu'inhibiteur de l'egfr et utilisation associée
WO2018192532A1 (fr) * 2017-04-19 2018-10-25 华东理工大学 Composé hétérocyclique utilisé en tant qu'inhibiteur de btk et son application
KR20220052975A (ko) * 2019-08-28 2022-04-28 브리스톨-마이어스 스큅 컴퍼니 T 세포 활성화제로서 유용한 치환된 피리도피리미디노닐 화합물
WO2021248095A1 (fr) * 2020-06-05 2021-12-09 Sparcbio Llc Composés hétérocycliques et leurs procédés d'utilisation
WO2022072783A1 (fr) * 2020-10-02 2022-04-07 Incyte Corporation Composés diones bicycliques en tant qu'inhibiteurs de kras

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